Document NEYXj5a0zbMBZ2BmgKVZYYn9E

NIOSH HAZARD REVIEW Health Effects of Occupational Exposure to Respirable Crystalline Silica DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention National Institute for Occupational Safety and Health April 2002 Ordering Information To receive documents or more information about occupational safety and health topics, contact the National Institute for Occupational Safety and Health (NIOSH) at NIOSH--Publications Dissemination 4676 Columbia Parkway Cincinnati, OH 45226-1998 Telephone: 1-800-35-NIOSH (1-800-356-4674) Fax: 1-513-533-8573 E-mail: pubstaft@cdc.gov or visit the NIOSH Web site at www.cdc.gov/niosh This document is in the public domain and may befreely copied or reprinted. Disclaimer: Mention of any company or product does not constitute endorsement by NIOSH. DHHS (NIOSH) Publication No. 2002-129 ii Foreword ilicosis is the disease most associated with crystalline silica exposure; it is incurable but Spreventable. This debilitating and often fatal lung disease persists worldwide despite long-standing knowledge of its cause and methods for controlling it. This Hazard Review, Health Effects ofOccupational Exposure to Respirable Crystalline Silica, de scribes published studies and literature on the health effects of occupational exposure to respirable crystalline silica among workers in the United States and many other countries. The review indi cates a significant risk of chronic silicosis for workers exposed to respirable crystalline silica over a working lifetime at the current Occupational Safety and Health Administration (OSHA) permissi ble exposure limit (PEL), the Mine Safety and Health Administration (MSHA) PEL, or the Na tional Institute for Occupational Safety and Health (NIOSH) recommended exposure limit (REL). In addition to the risk of silicosis, epidemiologic studies indicate that workers exposed to respirable crystalline silica have an increased risk of developing lung cancer, pulmonary tuberculosis, and air ways diseases. The latest scientific information also indicates possible associations of occupational exposure to silica dust with various other adverse health effects. Until improved sampling and analytical methods are developed for respirable crystalline silica, NIOSH will continue to recommend an exposure limit of 0.05 mg/m3 as a time-weighted average (TWA) for up to a 10-hr workday during a 40-hr workweek. NIOSH also recommends substituting less hazardous materials for crystalline silica when feasible, using appropriate respiratory protec tion when source controls cannot keep exposures below the REL, and making medical examina tions available to exposed workers. Kathleen M. Rest, Ph.D., M.P.A. Acting Director, National Institute for Occupational Safety and Health Centers for Disease Control and Prevention in Abstract ccupational exposures to respirable crystalline silica are associated with the development of Osilicosis, lung cancer, pulmonary tuberculosis, and airways diseases. These exposures may also be related to the development of autoimmune disorders, chronic renal disease, and other adverse health effects. Recent epidemiologic studies demonstrate that workers have a significant risk of developing chronic silicosis when they are exposed to respirable crystalline silica over a working lifetime at the current Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL), the Mine Safety and Health Administration (MSHA) PEL, or the National Institute for Occupational Safety and Health (NIOSH) recommended exposure limit (REL). This NIOSH Hazard Review (1) examines the health risks and diseases associated with occupa tional exposures to respirable crystalline silica, (2) discusses important findings of recent epide miologic studies, (3) provides the reader with sources of more comprehensive information about health effects and experimental studies, (4) describes current sampling and analytical methods and their limitations for assessing occupational exposures to respirable crystalline silica, and (5) sug gests many areas for further research. Current sampling and analytical methods used to evaluate occupational exposure to respirable crys talline silica do not meet the accuracy criterion needed to quantify exposures at concentrations be low the NIOSH REL of 0.05 mg/m3 as a time-weighted average (TWA) for up to a 10-hr workday during a 40-hr workweek. Until improved sampling and analytical methods are developed for respi rable crystalline silica, NIOSH will continue to recommend an exposure limit of 0.05 mg/m3 to re duce the risk of developing silicosis, lung cancer, and other adverse health effects. NIOSH also recommends minimizing the risk of illness that remains for workers exposed at the REL by substi tuting less hazardous materials for crystalline silica when feasible, by using appropriate respiratory protection when source controls cannot keep exposures below the NIOSH REL, and by making medical examinations available to exposed workers. iv Executive Summary ccupational exposures to respirable al. 1998]. Over a 40- or 45-year working life Ocrystalline silica occur in a variety of time, workers have a significant chance (at industries and occupations because of itsleast 1 in 100) of developing radiographic extremely common natural occurrence and the wide uses of materials and products that contain it. At least 1.7 million U.S. workers are potentially exposed to respirable crystal line silica [NIOSH 1991], and many are exposed to concentrations that exceed limits defined by current regulations and standards. silicosis when exposed to respirable crystal line silica at the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL), the Mine Safety and Health Administration (MSHA) PEL, or the Na tional Institute for Occupational Safety and Health (NIOSH) recommended exposure limit (REL).* Silicosis, usually a nodular pulmonary fibrosis, is the disease most associated with exposure to respirable crystalline silica. Although the re ported mortality associated with silicosis has declined over the past several decades, many silicosis-associated deaths still occur (nearly 300 deaths were reported each year during the Silicosis may be complicated by severe myco bacterial or fungal infections. About half of these are caused by Mycobacterium tuberculo sis and result in TB. Epidemiologic studies have firmly established that silicosis is a risk factor for developing TB. period 1992-1995) [NIOSH 1996a; Althouse 1998]. In addition, the number of silicosisassociated deaths among persons aged 15 to 44 has not declined substantially [CDC 1998a,b]. An unknown number of workers also continue to die from silica-related diseases such as pul monary tuberculosis (TB), lung cancer, and scleroderma. The number of cases of silicosis and silica-related diseases in the United States today is unknown. The carcinogenicity of crystalline silica in hu mans has been strongly debated in the scien tific community. In 1996, the International Agency for Research on Cancer (IARC) re viewed the published experimental and epide miologic studies of cancer in animals and workers exposed to respirable crystalline sil ica and concluded that there was "sufficient evidence in humans for the carcinogenicity of inhaled crystalline silica in the form of quartz Symptoms of acute silicosis, another form of silicosis, may develop shortly after exposure to high concentrations of respirable crystalline silica. Epidemiologic studies focus on chronic silicosis, which develops years after exposure to relatively low concentrations of respirable crystalline silica. Epidemiologic studies have found that chronic silicosis may develop or or cristobalite from occupational sources" [IARC 1997]. In the same year, directors of the American Thoracic Society (ATS) adopted an official statement that described the adverse health effects of exposure to crystalline silica, including lung cancer [ATS 1997]. The ATS found that "the available data support the con clusion that silicosis produces increased risk progress even after occupational exposure has ceased [Hessel et al. 1988; Hnizdo and Sluis-Cremer 1993; Hnizdo and Murray 1998; Ng et al. 1987; Kreiss and Zhen 1996; Miller et *See appendix for the OSHA and MSHA PELs. The NIOSH REL is 0.05 mg/m3 as a time-weighted aver age (TWA) for up to a 10-hr workday during a 40-hr workweek. v for bronchogenic carcinoma." However, the ATS noted that less information was available for lung cancer risks among silicotics who had never smoked and for silica-exposed work ers who did not have silicosis. They also stated that it was "less clear" whether silica exposure was associated with lung cancer in the absence of silicosis. NIOSH has reviewed the studies considered by IARC and ATS, and NIOSH concurs with the conclusions of IARC [1997] and the ATS [1997]. These conclusions agree with NIOSH testimony to OSHA, in which NIOSH recommended that crystalline silica be considered a potential occupational carcinogen [54 Fed. Reg.* 2521 (1989)]. Further research is needed to determine the exposure-response relationship between lung cancer in nonsmok ers and occupational silica dust exposure and to determine why lung cancer risks appear to be higher in workers with silicosis. The cellu lar mechanisms for development of lung can cer after crystalline silica exposure have been explored in many experimental studies and are not yet fully understood. Statistically significant excesses of mortality from stomach or gastric cancer have been reported in various occupational groups ex posed to crystalline silica. However, no con clusion about an association has been reached because most studies did not adjust for the ef fects of confounding factors or assess an exposure-response relationship for crystalline silica. The same problem exists for the infre quent reports of statistically significant num bers of excess deaths or cases of other nonlung cancers in silica-exposed workers. Occupational exposure to respirable crystalline silica is associated with chronic obstructive pul monary disease, including bronchitis and em physema. The results of some epidemiologic studies suggest that these diseases may be less *Federal Register. See Fed. Reg. in references. frequent or absent in nonsmokers. Exposure to respirable crystalline silica is not associated with asthma. Significant increases in mortality from nonmalignant respiratory disease (a broad category that can include silicosis and other pneumoconioses, chronic bronchitis, emphysema, asthma, and other related respiratory conditions) have been reported for silica-exposed workers [Checkoway et al. 1997, 1993; Chen et al. 1992; Cherry et al. 1998; Brown et al. 1986; Costello and Graham 1988; Costello et al. 1995; Costello 1983; Steenland and Brown 1995b; Steenland and Beaumont 1986; Thomas and Stewart 1987; Thomas 1990] and silicotics [Goldsmith et al. 1995; Brown et al. 1997; Rosenman et al. 1995]. Many case reports have been published about autoimmune diseases or autoimmune-related diseases in workers exposed to crystalline sil ica or workers with silicosis. In addition, sev eral recent epidemiologic studies reported statistically significant numbers of excess cases or deaths from known autoimmune dis eases or immunologic disorders (scleroderma, systemic lupus erythematosus, rheumatoid ar thritis, sarcoidosis), chronic renal disease, and subclinical renal changes. The pathogenesis of autoimmune and renal diseases in silicaexposed workers is not clear. Various other health effects (such as hepatic or hepatosplenic silicosis, extrapulmonary depo sition of silica particles, liver granulomas, hepatic porphyria, cutaneous silica granulo mas, pulmonary alveolar proteinosis, podoconiosis, and dental abrasion) have been reported in studies of silica-exposed workers, but these effects have not been studied in depth with epidemiologic methods. This Hazard Review also provides an abbrevi ated review of experimental research studies conducted to identify the molecular mecha nisms responsible for the development of Vi viii Abbreviations ACGIH AMG ATS BAL BMG BMI C CA cc CDC CEN CFR CI cm COC COPD Cu CV CV CWP DE DLCO DNA EPA F FEV1 FVC American Conference of Governmental Industrial Hygienists alpha-1-microglobulin American Thoracic Society bronchoalveolar lavage beta-1-microglobulin body mass index degree(s) Celsius chromosomal aberration(s) cubic centimeter Centers for Disease Control and Prevention European Standardization Committee Code of Federal Regulations confidence interval centimeter(s) census occupation code chronic obstructive pulmonary disease copper coefficient of variation pooled coefficient of variation coal workers' pneumoconiosis diatomaceous earth diffusing capacity of the lung for carbon monoxide deoxyribonucleic acid U.S. Environmental Protection Agency degree(s) Fahrenheit forced expiratory volume in 1 second forced vital capacity Xi g HIV HLA hprt hr HSE HVLV IARC ICD-9 Ig IGLV ILO IR ISO K KBr kv L LOD m mA MDHS mg mg/m3 yr min ml mm mppcf MSHA NAG gram(s) human immunodeficiency virus human leukocyte antigen hypoxanthine-guanine phosphoribosyl transferase hour(s) Health and Safety Executive (United Kingdom) high-velocity/low-volume International Agency for Research on Cancer International Classification of Diseases, 9th edition immunoglobulin immunoglobulin lambda-variable chain International Labour Organization infrared absorption International Organization for Standardization electron ionization energy potassium bromide kilovolt(s) liter(s) limit of detection meter(s) milliamp(s) Methods for the Determination of Hazardous Substances (Health and Safety Executive, United Kingdom) milligram(s) milligrams per cubic meter times years minute(s) milliliter(s) millimeter(s) million particles per cubic foot Mine Safety and Health Administration beta-N-acetyl-D-glucosaminidase Xii NIOSH NIST NMRD NOES NOHSM NOMS NTM OR OSHA P PAP PAT PDGF PEL PMR ppm PVC RDS REL RF RFLP ROS RSD RSD SCE SCG SIC SiO2 SIR SMR National Institute for Occupational Safety and Health National Institute of Standards and Technology nonmalignant respiratory disease National Occupational Exposure Survey National Occupational Health Survey of Mining U.S. National Occupational Mortality Surveillance nontuberculous mycobacteria odds ratio Occupational Safety and Health Administration probability pulmonary alveolar proteinosis proficiency analytical testing platelet-derived growth factor permissible exposure limit proportionate mortality ratio parts per million polyvinyl chloride respirable dust standard recommended exposure limit radio frequency restriction fragment length polymorphism reactive oxygen species relative standard deviation pooled relative standard deviation sister chromatid exchange single cell gel/comet standard industrial classification silicon dioxide standardized incidence ratio standardized mortality ratio Xiii SRR TGF TB THF TWA U.K. U.S. VC WASP WHO wk XRD yr Pg pm % standardized rate ratio transforming growth factor pulmonary tuberculosis tetrahydrofuran time-weighted average United Kingdom United States vital capacity Workplace Analysis Scheme for Proficiency World Health Organization week(s) X-ray diffraction year(s) microgram(s) micrometer(s) percent XiV Glossary Aerodynamic diameter: The diameter of a sphere with a density of 1 g/cm3 and with the same ve locity (due to gravity) as the particle ofinterest [EPA1996]. Particles of a given aerodynamic diam eter move within the air spaces of the respiratory system identically, regardless of density or shape [NIOSH 1995a]. Chronic obstructive pulmonary disease (COPD): Includes airways diseases such as asthma, chronic bronchitis, and emphysema and is characterized by airways dysfunction [Becklake 1992]. Clearance: The translocation and removal of deposited particles from the respiratory tract. Concentration: The amount of a substance (e.g., dust particles) contained per unit volume of air. Confidence interval (CI), confidence limits: A range of values (determined by the degree of pre sumed random variability in the data) within which the value of a parameter (e.g., a mean or relative risk) is believed to lie with the specified level of confidence. The boundaries of a confidence inter val are the confidence limits [Last 1988]. These include the lower confidence limit and the upper confidence limit. Crystalline silica (orfree silica): Silicon dioxide (SiO2). "Crystalline" refers to the orientation of SiO2 molecules in a fixed pattern as opposed to a nonperiodic, random molecular arrangement de fined as amorphous. The three most common crystalline forms of silica encountered in the work place environment are quartz, tridymite, and cristobalite [NIOSH 1974]. ILO category: The determination of profusion of small opacities observed by reading chest radio graphs according to classification of pneumoconioses guidelines developed by the International Labour Organization (ILO). The latest classification guidelines were published by the International Labour Office in 1980 [ILO 1980]. Incidence: The frequency with which new cases of a disease occur in a given time period. Incidence rate: The rate at which new events occur in a population. The number of new events (e.g., new cases of a disease diagnosed or reported during a defined period) is divided by the num ber of persons in the population in which the cases occurred [Last 1988]. Inhalable dust: The particulate mass fraction of dust in the work environment that can be inhaled and deposited anywhere in the respiratory tract. Nontuberculous mycobacteria: Mycobacteria species other than the Mycobacterium tuberculosis complex (e.g., Mycobacterium avium complex). xv Prevalence: The number of disease cases in a specific population at aparticular time [Last 1988]. Prevalence rate (ratio): The total number of all individuals with an attribute or disease at a given time or during a given period divided by the population at risk of having the attribute or disease at this point in time or midway through the period [Last 1988]. Proportionate mortality ratio (PMR): Ratio of the proportion of deaths from a specific cause in an exposed population compared with the corresponding ratio in the nonexposed population. For ex ample, the proportion of deaths from disease X in the exposed population could be compared with the proportion of deaths from disease X in the nonexposed population [NIOSH 2000]. Quartz: Crystalline silicon dioxide (SiO2) not chemically combined with other substances and hav ing a distinctive physical structure. Respirable crystalline silica: That portion of airborne crystalline silica that is capable of entering the gas-exchange regions of the lungs if inhaled; by convention, a particle-size-selective fraction of the total airborne dust; includes particles with aerodynamic diameters less than approximately 10 pm and has a 50% deposition efficiency for particles with an aerodynamic diameter of approxi mately 4 pm. Sarcoidosis: A rare multisystem granulomatous disease characterized by alterations in the immune system [Fanburg 1992]. Scleroderma (progressive systemic sclerosis): A rare multisystem disorder characterized by in flammatory, vascular, and fibrotic changes usually involving the skin, blood vessels, joints, and skeletal muscle [Archer and Gordon 1996]. Standardized mortality ratio: The ratio ofthe number of deaths observed in the study population to the number of deaths expected if the study population had the same rate structure as the standard population [Last 1988]. Standardized rate ratio: A rate ratio in which the numerator and denominator rates have been stan dardized to the same (standard) population distribution [Last 1988]. XVi Acknowledgments his Hazard Review was developed by the staffofthe National Institute for Occupational Safety Tand Health (NIOSH). Paul A. Schulte, Director, Education and Information Division (EID), had overall responsibility for the document. Faye L. Rice (EID) was the principal author. The analytical methods section was prepared by Rosa Key-Schwartz, Ph.D.; David Bartley, Ph.D; Paul Baron, Ph.D; and Paul Schlecht. Michael Gressel and Alan Echt contributed material on control technology. The following NIOSH staff provided critical review and comments on this document and previous versions: Martin Abell; Heinz W. Ahlers, J.D.; Rochelle Althouse; Harlan Amandus, Ph.D.; Michael Attfield, Ph.D.; Nancy Bollinger, Ph.D.; Lorraine Cameron, Ph.D.; Robert Castellan, M.D.; Joseph Cocalis; Joseph Costello; Clayton Doak; Jerome Flesch; Bryan Hardin, Ph.D.; Kent Hatfield, Ph.D.; Frank Hearl; Paul Hewett, Ph.D.; Eva Hnizdo, Ph.D. (formerly of the National Centre for Occupational Health, South Africa); Michael Jacobsen, Ph.D. (visiting scientist); Kathleen Kreiss, M.D.; Kenneth Linch; Charles Lorberau; Tong-man Ong, Ph.D.; John Parker, M.D.; Larry Reed; Karl Sieber, Ph.D.; Rosemary Sokas, M.D.; Leslie Stayner, Ph.D.; Kyle Steenland, Ph.D.; Patricia Sullivan, Sc.D.; Marie Haring Sweeney, Ph.D.; Gregory Wagner, M.D.; William Wallace, Ph.D.; Joann Wess; Ralph Zumwalde. Editorial review and camera-copy production were provided by Vanessa L. Becks, Susan E. Feldmann, Joyce D. Godfrey, Anne C. Hamilton, Susan R. Kaelin, Laura A. Stroup, Kristina M. Wasmund, and Jane B. Weber. Dale Camper and Ronald Schuler performed literature searches, and the EID Library staff collected literature used in the development of the document. NIOSH also appreciates the comments of the following external reviewers: William Beckett, M.D., M.P.H. University of Rochester School of Medicine P.O. Box EHSC 575 Elmwood Avenue Rochester, NY 14642 Harvey Checkoway, Ph.D. Department of Environmental Health University of Washington Box 357234 Seattle, WA 98195-7234 Jeffrey Gift, Ph.D. Senior Health Scientist U.S. Environmental Protection Agency NCEA-RTP Maildrop 52 Research Triangle Park, NC 27711 David Goldsmith, Ph.D. Department of Environmental and Occupational Health George Washington University 2300 K Street, N.W., Suite 201 Washington, DC 20037 Gerald S. Davis, M.D. University of Vermont College of Medicine Pulmonary Unit Given C317 Burlington, VT 05405 Eva Hnizdo, Ph.D. Epidemiology and Surveillance Section National Centre for Occupational Health P.O. Box 4788 Johannesburg 2000, South Africa xvii Janet Hughes, Ph.D. Department of Biostatistics and Epidemiology Tulane School of Public Health and Tropical Medicine 1430 Tulane Avenue New Orleans, LA 70112 Carol Jones, Ph.D. Senior Health Specialist Mine Safety and Health Administration 4015 Wilson Boulevard, Room 622 Arlington, VA 22203 William Kojola American Federation of Labor and Congress of Industrial Organizations Department ofOccupational Safety and Health 815 Sixteenth Street, N.W. Washington, DC 20006 Loretta Schuman, Ph.D. Directorate of Health Standards Program Occupational Safety and Health Administration 200 Constitution Avenue, N.W., Room N3718 Washington, DC 20210 James Sharpe Director of Safety and Health Services National Stone Association 1415 Elliot Place, N.W. Washington, DC 20007-2599 David M. Tucker Manager, Industrial Hygiene Norfolk Southern Corporation Environmental Protection 110 Franklin Road, S.E. Box 13 Roanoke, VA 24042-0013 Allen G. Macneski Manager, Environmental Safety and Health Bechtel National, Inc. 151 Lafayette Drive Oak Ridge, TN 37830 John A. Ulizio Vice President U.S. Silica Company P.O. Box 187 Berkeley Springs, WV 25411 Michelle Schaper, Ph.D. Toxicologist Directorate of Technical Support Mine Safety and Health Administration 4015 Wilson Boulevard, Room 622 Arlington, VA 22203 James L. Weeks, Sc.D. George Washington University Medical Center Division of Occupational and Environmental Medicine 2300 K Street, N.W., Suite 201 Washington, DC 20037 References and information were submitted by William G.B. Graham, M.D., University of Ver mont, College of Medicine. The author especially thanks David Goldsmith, Ph.D., for his major contribution and efforts on a previous draft. xviii 1 Introduction 1.1 Definition of Crystalline Silica Silica refers to the chemical compound silicon dioxide (SiO2), which occurs in a crystalline or noncrystalline (amorphous) form. Crystalline silica may be found in more than one form (polymorphism). The polymorphic forms of crystalline silica are alpha quartz, beta quartz, tridymite, cristobalite, keatite, coesite, stishovite, and moganite [Ampian and Virta 1992; Heaney 1994; Guthrie and Heaney 1995]. Each polymorph is unique in its spacing, lattice struc ture, and angular relationship of the atoms. In nature, the alpha (or low) form of quartz is the most common [Virta 1993]. This form is so abundant that the term quartz is often used in place of the general term crystalline silica [BOM 1992; Virta 1993]. Quartz is a common component of soil and rocks; consequently, workers are potentially exposed to quartz dust in many occupations and industries (see Section 2.3). Cristobalite and tridymite are found in rocks and soil and are produced in some industrial operations when alpha quartz or amorphous silica is heated (such as foundry pro cesses, calcining of diatomaceous earth, brick and ceramics manufacturing, and silicon car bide production) [NIOSH 1974; Weill et al. 1994; Virta 1993; Altieri et al. 1984]. Burning of agricultural waste or products such as rice hulls may also cause amorphous silica to become cristobalite (a crystalline form) [Rabovsky 1995; IARC 1997]. The other polymorphs (i.e., keatite, coesite, stishovite, and moganite) are rarely or never observed in nature [Ampian and Virta 1992]. 1.2 Current Health Issues Occupational exposure to respirable crystal line silica is a serious but preventable health hazard. Since 1968, reported mortality associ ated with silicosis has declined; however, 200 to 300 such deaths were reported each year during the period 1992-1995 [NIOSH 1996a; Althouse 1998]. Furthermore, the number of silicosis-related deaths among persons aged 15 to 44 did not decline substantially during 1968-1994, accounting for 207 of the 14,824 silicosis-related deaths during this period [CDC 1998a,b]. In addition, an un known number of unreported or undiagnosed worker deaths occur each year from silicosis and other silica-related diseases such as pul monary tuberculosis (TB), lung cancer, and scleroderma. The number of current cases of silicosis and silica-related disease in the United States is also unknown. Prevention and elimination of silicosis and silica-related disease in the United States are priorities of the National Institute for Occu pational Safety and Health (NIOSH), the Oc cupational Safety and Health Administra tion (OSHA), the Mine Safety and Health Administration (MSHA), and the American Lung Association [DOL 1996]. International health agencies have also expressed concern about the continuing occurrence of silicosis and silica-related diseases. The International Agency for Research on Cancer (IARC) re cently reviewed the results of post-1986 epidemiologic studies of lung cancer and occu pational exposure to crystalline silica. They concluded that there is "sufficient evidence in 1 1 INTRODUCTION humans for the carcinogenicity of inhaled crystalline silica in the form of quartz or cristobalite from occupational sources" (i.e., IARC category "Group 1" carcinogen) [IARC 1997]. In 1991, the International Labour Office published a document describing methods for preventing and controlling occupational lung diseases, including silicosis [ILO 1991]. And in 1993, the Office of Occupational Health of the World Health Organization (WHO) called for increased medical surveillance of mineraldust-exposed workers to prevent pneumo conioses such as silicosis and asbestosis [WHO 1993]. Epidemiologic studies published after the IARC review [IARC 1997] provide addi tional evidence for an exposure-response rela tionship ofrespirable crystalline silica with lung cancer mortality or morbidity (see Section 3.4.2.1). Several recent epidemiologic studies indicate that current occupational standards are not suf ficiently protective to prevent the occurrence of chronic silicosis. Epidemiologic studies of workers in the United States [Kreiss and Zhen 1996; Steenland and Brown 1995a; Rosenman et al. 1996; Hughes et al. 1998], Canada [Muir et al. 1989a,b; Muir 1991], Hong Kong [Ng and Chan 1994], and South Africa [Hnizdo and Sluis-Cremer 1993] have reported significant risks of silicosis over a working lifetime at concentrations of quartz or respirable dust con taining quartz that are below the current NIOSH recommended exposure limit (REL) [NIOSH 1974], OSHA permissible exposure limit (PEL) [29 CFR*1910.1000], and the MSHA PEL [30 CFR 56, 57, 70, 71] (see Ap pendix and Table 12 in Chapter 3). TB is an infectious disease that poses a threat to the health of silica-exposed workers and the public. A survey ofU.S. mortality data for *Code ofFederal Regulations. See CFR in references. 1979 to 1991 reported that TB comortality was at least several times higher in decedents with silicosis than in decedents with asbestosis, with coal workers' pneumoconiosis (CWP), or without silicosis, asbestosis, or CWP [Althouse et al. 1995]. The U.S. Centers for Disease Control and Prevention (CDC), WHO, and the American Thoracic Society (ATS) have recently published information about risk fac tors for TB, including occupational exposure to respirable crystalline silica [CDC 1995; WHO 1996; ATS 1997]. The U.S. Environ mental Protection Agency (EPA) suggested "further investigation" of the health effects of ambient crystalline silica exposures in poten tially sensitive subgroups, including infants and persons with a respiratory infection or dis ease such as TB or pneumonia [EPA 1996]. Recent epidemiologic studies of occupational exposure to crystalline silica dust have also re ported increased incidence of--or mortality from--extrapulmonary diseases such as sclero derma, rheumatoid arthritis, other autoimmune disorders, and renal disease [ATS 1997]. Experimental research has shown that crystal line silica is not an inert dust. The toxicity of crystalline silica particles is related to reactive sites on the surfaces of silica particles. Further discussion of in vitro studies of the biologic activity and factors that modify toxicity are found in Section 3.2.1 and Section 4. 1.3 History of NIOSH Activity In 1974, NIOSH reviewed the available health effects data on occupational exposure to respi rable crystalline silica and determined that the principal adverse health effect was silicosis [NIOSH 1974]. At that time, NIOSH recom mended that occupational exposure to respira ble crystalline silica dust be controlled so that workers would not be exposed to the airborne particulate at a time-weighted average (TWA) 2 Respirable Crystalline Silica 1 INTRODUCTION concentration greater than 50 micrograms per cubic meter of air (50 pg/m3--or 0.05 mg/m3), determined during a full-shift sample for up to a 10-hr workday during a 40-hr workweek. A later NIOSH report (Review of the Literature on Crystalline Silica) concluded that addi tional toxicologic and epidemiologic studies were needed to determine (1) the relationship between respirable crystalline silica dose and the risk of developing silicosis and lung cancer and (2) the adverse effects of crystalline silica on the kidney [NIOSH 1983a]. Since then, ad ditional studies reported an increased inci dence of malignant tumors in the lungs of rats exposed to either inhalation or intratracheal administration of various forms and prepara tions of respirable crystalline silica [Holland et al. 1986; Dagle et al. 1986; Groth et al. 1986; Muhle et al. 1989; Spiethoff et al. 1992]. On the basis of the evidence from the animal studies published by 1986, IARC con cluded that "sufficient evidence" existed for the carcinogenicity ofrespirable crystalline sil ica in experimental animals but only "limited evidence" existed for carcinogenicity in hu mans [IARC 1987]. During the 1988 OSHA rulemaking activity on air contaminants, NIOSH recommended an exposure limit of 0.05 mg/m3 "as respirable free silica for all crystalline forms of silica" to protect workers from silicosis and cancer [54 Fed. Reg.* 2521 (1989)]. In addition, NIOSH testimony re ferred to the IARC [1987] review and recom mended that OSHA label crystalline silica a potential occupational carcinogen [54 Fed. Reg. 2521 (1989)]. 1.4 Purpose and Scope The numerous health effects of occupational exposure to respirable crystalline silica are re viewed in the chapters of several recent books [Graham 1998; Davis 1996; Green and Vallyathan 1996; McDonald 1996; Seaton 1995; Morgan and Reger 1995; Elmes 1994; Gold smith 1994a,b; Weill et al. 1994; Wagner 1994]. This NIOSH Hazard Review summarizes the health effects of occupational exposure to respi rable crystalline silica reported in literature pub lished through March 1999. The review empha sizes recent important epidemiologic studies of occupational exposure to respirable crystalline silica with regard to (1) the quantitative risk of chronic silicosis, (2) lung cancer, (3) autoim mune disease, (4) chronic renal disease, and (5) chronic obstructive pulmonary disease. In addition, the review describes limitations of the current sampling and analytical methods for quantifying occupational exposures to silica. Respirable Crystalline Silica *Federal Register. See Fed. Reg. in references. 3 2 Properties, Production, and Potential for Exposure 2.1 Chemical and Physical Properties In the crystalline state, one silicon atom and four oxygen atoms are arranged in an ordered, repetitive array of three-dimensional tetrahe drons. The silicon atom is the center of the tet rahedron. Each of the four corners consists of a shared oxygen atom. Exposure to changes in temperature and pres sure, either natural or synthetic, may cause the crystalline structure to change [Iler 1979; Klein and Hurlbut 1993; Navrotsky 1994; Hemley et al. 1994; IARC 1997]. An example of a naturally occurring pressure change is the transformation of alpha quartz to coesite in a rock subjected to the impact of a large meteor ite [Iler 1979; Klein and Hurlbut 1993; IARC 1997]. Alpha quartz and beta quartz are the re spective designations given to the low- and high-temperature crystal structures. Quartz changes from the alpha to the beta form at 573 C (1,063 F) [Ampian and Virta 1992; NIOSH 1983a; Virta 1993; Guthrie and Heaney 1995]. The solubility of quartz in water at room tem perature ranges from 6 to 11 micrograms per cubic centimeter (pg/cm3) (6 to 11 parts per million [ppm]) as SiO2 [Coyle 1982; Iler 1979]. Quartz is slightly soluble in body fluids, where it forms silicic acid and is excreted by the urinary system [IARC 1987]. The amount of silica dissolved depends on various factors, including particle size, shape, and structure; solution temperature; viscosity; pH; the pro portion of dust to liquid; and the presence of trace minerals [King and McGeorge 1938; King 1937; Iler 1979; Wiecek 1988; IARC 1997; Guthrie 1997]. However, the dissolution of quartz does not contribute substantially to its clearance or to changes in its biological ac tivity [IARC 1997; Heppleston 1984; Vigliani and Pernis 1958]. 2.2 Number of Workers Potentially Exposed NIOSH [1991] estimates that at least 1.7 mil lion U.S. workers are potentially exposed to respirable crystalline silica. This estimate is based on information from the National Occu pational Exposure Survey (NOES) [NIOSH 1983b] and the County Business Patterns 1986 [Bureau of the Census 1986]. Table 1 lists the nonmining industries (excluding agriculture) and mining industries with the largest numbers of workers potentially exposed to respirable crystalline silica. In addition, an undetermined portion ofthe 3.7 million U.S. agricultural work ers [Bureau ofthe Census 1997] may be exposed to dust containing a significant percentage of re spirable crystalline silica [Linch et al. 1998]. 2.3 Dust-Generating Activities, Uses, and Potential Exposures Crystalline silica (quartz) is a component of nearly every mineral deposit [Greskevitch et al. 1992]. Thus most crystalline silica exposures are to mixed dust with variable silica content that must be measured by dust collection and 4 Respirable Crystalline Silica Table 1. Nonmining and mining industries with the largest numbers of U.S. workers potentially exposed to respirable crystalline silica, 1986 SIC* Industry Estimated number of workers potentially exposed (1986) % total workers exposed (NOES) Nonmining industries: 174 Masonry, stonework, tile setting, and plastering 734 Services to dwellings and other buildings 327 Concrete, gypsum, and plaster products 176 Roofing and sheet metal work 356 General industrial machinery and equipment 807 Medical and dental laboratories 493 Combination of gas and electric and other utilities 179 Miscellaneous special trade contractors 753 Automotive repair shops 326 Pottery and related products 131,986 65,812 63,456 51,153 44,991 37,063 35,074 32,615 30,826 29,772 32.7 10.3 33.3 25.3 16.2 30.0 21.2 7.8 7.1 81.7 Mining industries: 13 Oil and gas extraction 12 Bituminous coal and lignite mining 14 Mining and quarrying of nonmetallic minerals, except fuels 10 Metal mining 408,175 174,131 100,546 39,856 100* 100 100 100 Source: NIOSH [1991]. Standard industrial classification. ^Estimated number of workers potentially exposed to the hazards of flint, quartz, sand, or silica powder; based on data from the County Business Patterns 1986 [Bureau ofthe Census 1986] and the National Occupational Exposure Survey (NOES) [NIOSH 1983b]. For SICs in which the estimates differed for individual hazards, the highest percentage was used for that SIC. ^Exposure is assumed to be 100% in the mining industries. Respirable Crystalline Silica 5 2 PROPERTIES, PRODUCTION, AND POTENTIAL FOR EXPOSURE analysis [Wagner 1995; Donaldson and Borm 1998]. Workers in a large variety ofindustries and oc cupations may be exposed to crystalline silica because of its widespread natural occurrence and the wide uses of the materials and pro ducts containing it. OSHA compliance officers found respirable quartz in 6,779 personal sam ples (8-hr TWA) taken in 255 industries that were targeted for inspection (excluding mining and agriculture). In 48% ofthe industries, aver age overall exposure exceeded the PEL for re spirable quartz [Freeman and Grossman 1995]. Linch et al. [1998] applied an algorithm to OSHA compliance data from the period 1979-1995 and County Business Patterns 1993 data [Bureau of the Census 1993] to estimate the percentage ofworkers by industry (exclud ing mining and agriculture) exposed to defined concentrations of respirable crystalline silica (e.g., >0.05 mg/m3) in 1993. Area samples and samples involving complaints to OSHA were excluded from the analysis. Although data lim itations could have resulted in underestimating or overestimating the number of workers ex posed, the authors found 5 three-digit stan dardized industrial classification (SIC) codes in which an estimated number ofworkers were exposed to concentrations at least 10 times the NIOSH REL: SIC No. workers 174 Masonry and plastering................. 13,800 (1.8%) 162 Heavy construction....................... 6,300 (1.3%) 172 Painting and paper hanging........... 3,000 (1.9%) 332 Iron and steel foundries................. 800 (0.3%) 347 Metal services................................ 400 (0.2%) Additional three-digit SICs had a number of workers with crystalline silica exposures that were two or five times higher than the NIOSH REL [Linch et al. 1998]. Table 2 lists the main industries around the world in which silica exposure has been re ported. Virtually any process that involves movement of earth or disturbance of silicacontaining products such as masonry and con crete may expose a worker to silica (see Table 3 for uses of industrial silica sand and gravel). Table 4 presents, from selected States, the most frequently recorded occupations of U.S. residents aged 15 or above whose death certifi cates list silicosis as an underlying or contri butory cause of death [NIOSH 1996a]. In addi tion, Table 5 lists published case reports ofsilicosis in workers from other industries and occupations. 2.4 Sampling and Analytical Methods Historically, several methods have been used to measure worker exposure to airborne crys talline silica (quartz, cristobalite, or tridymite). These methods differ primarily in the analyti cal technique employed, although they all rely on a collection procedure that uses a cyclone for size-selective sampling. Airborne samples are collected using a cyclone to remove nonrespirable particles and an appropriate fil ter medium (e.g., polyvinyl chloride) to retain the respirable dust fraction. Preparation of the sample for crystalline silica determination dif fers depending on the type of analytical tech nique used. One of three analytical techniques is typically used for the quantitative determina tion of crystalline silica: X-ray diffraction (XRD) spectrometry, infrared absorption (IR) spectrometry, or colorimetric spectrophoto metry. XRD and IR are the most common tech niques used for crystalline silica analyses. The quantitative limit of detection for these meth ods ranges from 5 to 10 pg per sample; but the accuracy is poor, particularly at the low filter loadings (<30 pg per sample) that are typically collected when workplace concentrations of airborne crystalline silica are near the NIOSH REL of 50 pg/m3 (or 0.05 mg/m3). 6 Respirable Crystalline Silica Table 2. Main industries and activities around the world in which silica exposure has been reported Industry or activity Agriculture Mining and related milling operations Quarrying and related milling operations Construction Glass, including fiberglass Cement Abrasives Ceramics, including bricks, tiles, sanitary ware, porcelain, pottery, refractories, vitreous enamels Iron and steel mills Operations and tasks Source materials Plowing, harvesting, using machinery, burning agricultural waste, processing agricultural products Soil Most occupations (underground, surface, mill) and mines (metal and nonmetal, coal), rock drilling, dredging Ores, associated rock Crushing stone, sand and gravel processing, stone monument cutting and abrasive blasting, slate work (e.g., pencil manufacturing), diatomite calcination Sandstone, granite, flint, sand, gravel, slate, diatomaceous earth Abrasive blasting of structures and buildings, highway and tunnel construction, excavation and earth moving and digging, masonry, concrete work, demolition, dry sweeping and brushing, pressurized air blowing, jack hammering, laying railroad track, removing rust or paint, sanding and scaling, replacement of asphalt roofing, and hauling, pouring, mixing, or dumping silica-containing materials Sand, concrete, rock, soil, mortar, plaster, shingles Raw material processing, refractory installation and repair Sand, crushed quartz, refractory materials Raw material processing Clay, sand, limestone, diatomaceous earth Silicon carbide production, abrasive products fabrication Sand, tripoli, sandstone Mixing, molding, glaze or enamel spraying, finishing, sculpting, firing Clay, shale, flint, sand, quartzite, diatomaceous earth Refractory preparation and furnace repair Refractory material (Continued) Sources: IARC [1987; 1997], NIOSH [1979a; 1983a,b; 1996b], DOL, NIOSH [1997], Fulekar and Alam Khan [1995], Jain et al. [1977], Corn [1980], Webster [1982], Froines et al. [1986], Davis [1996], Weill et al. [1994], Lucas and Salisbury [1992], Pike [1992], McCunney et al. [1987], Fairfax [1998]. Respirable Crystalline Silica 7 Table 2 (Continued). Main industries and activities around the world in which silica exposure has been reported Industry or activity Operations and tasks Source materials Silicon and ferro-silicon foundries (ferrous and nonferrous) Metal products, including structural metal, machinery, transportation equipment Shipbuilding and repair Rubber and plastics Paint Soaps and cosmetics Roofing asphalt felt Agricultural chemicals Jewelry Arts, crafts, sculpture Dental material Boiler scaling Automobile repair Raw materials handling, casting, molding and shaking out, abrasive blasting, fettling, furnace installation and repair Abrasive blasting Sand, refractory material Sand Abrasive blasting Raw materials handling Raw materials handling, site preparation Manufacturing or occupational use of abrasive soaps and scouring powders Filling and granule application Raw material crushing, handling, bagging; or dumping products or raw materials Cutting, grinding, polishing, buffing, etching, engraving, casting, chipping, sharpening, sculpting Pottery firing, ceramics, clay mixing, kiln repairs, abrasive blasting, sand blasting, engraving, cutting, grinding, polishing, buffing, etching, engraving, casting, chipping, sharpening, sculpting Sand blasting, polishing Coal-fired boilers Abrasive blasting, sanding, removing paint and rust Sand Fillers (tripoli, diatomaceous earth) Fillers (tripoli, diatomaceous earth, silica flour) Silica flour Sand and aggregate, diatomaceous earth Phosphate ores and rock Semiprecious gems or stones, abrasives, glass Clays, glazes, bricks, stones, rocks, minerals, sand, silica flour Sand, abrasives Ash and concretions Sand, metals, priming putty 8 Respirable Crystalline Silica Table 3. Industrial silica sand and gravel sold or used by U.S. producers in 1994, by major end use General use End use Sand: Glass-making Foundry work Metallurgical work Abrasive work Fillers Ceramics Filtration Petroleum manufacturing Recreation Gravel Containers, flat (plate and window), specialty, fiberglass (unground or ground) Molding and core, molding and core facing (ground), refractory Silicon carbide, flux for metal smelting Blasting, scouring cleansers (ground), sawing and sanding, chemicals (ground and unground) Rubber, paints, putty, whole grain fillers/building products Pottery, brick, tile Water (municipal, county, local), swimming pool, others Hydraulic fracturing, well packing, and cementing Golf course, baseball, volleyball, play sands, beaches, traction (engine), roofing granules and fillers, other (ground silica or whole grain) Silicon, ferrosilicon, filtration, nonmetallurgical flux, other Sources: IARC [1997]; BOM [1994] Respirable Crystalline Silica 9 Table 4. Most frequently recorded occupations of U.S. residents aged 15 or above whose death certificates list silicosis as an underlying or contributory cause of death--selected States, 1991-1992* COC+ Occupation Number % 616 Mining machine operator 39 16.0 889 Laborer, except construction 29 11.9 019 Manager or administrator, not elsewhere classified 11 4.5 633 Supervisor or precision production occupations 11 4.5 453 Janitor, cleaner 8 3.3 719 Molding, casting machine operator 8 3.3 243 Supervisor or proprietor of sales occupations 6 2.5 844 Operating engineer 6 2.5 637 Machinist 5 2.1 787 Hand molding, casting, and forming occupations 5 2.1 -- All other occupations 109 44.9 -- Occupation not reported 6 2.5 TOTAL Source: NIOSH [1996a]. *Data for 1985-1990 are reported in Table 4-11 of NIOSH [1994d]. *COC: 1980 census occupation code. * Column does not add to 100.0 because of rounding. 243 100.1* 10 Respirable Crystalline Silica Table 5. Other occupations* reporting cases of silicosis in workers Industry or occupation Reference Agriculture industry or forestry worker Brewery worker Confectioner Fennerty et al. [1983]; Dynnik et al. [1981]; Beaumont et al. [1995] Nemery et al. [1993] Canessa et al. [1990] Crystal cutter Suskovic et al. [1990] Drycleaning worker Seitz et al. [1982] Filter candle production worker Vigliani and Mottura [1948] Grave digger and well digger al-Kassimi et al. [1991] Kaolin worker Rodriguez et al. [1985] Metal polisher Malik et al. [1985] Pit digger de Barros Hatem and Cavalcanti [1990] Souvenir casting worker Carel et al. [1994] Woodworker Thoreux et al. [1990] * Includes only occupations not listed in Tables 2 or 4. Respirable Crystalline Silica 11 2 PROPERTIES, PRODUCTION, AND POTENTIAL FOR EXPOSURE 2.4.1 Sampling Methods Current sampling methods for crystalline silica involve the use of a cyclone attached to a filter cassette to collect the respirable fraction of the airborne particulate. To minimize measure ment bias and variability, these samplers should conform to the criteria of the Interna tional Organization for Standardization (ISO), the European Standardization Committee (CEN), and the American Conference of Gov ernmental Industrial Hygienists (ACGIH) for collecting particles ofthe appropriate size [ISO 1991; CEN 1992; ACGIH 2001]. Also, the cy clone should exhibit sufficient conductivity to minimize the electrostatic effects on particle collection. Cyclones typically used for crys talline silica measurements include the DorrOliver 10-mm nylon cyclone and the HigginsDewell conductive cyclone. These cyclones have been evaluated for their compliance with the ISO/CEN/ACGIH respirable aerosol sam pling convention. Flow rates of 1.7 L/min for the Dorr-Oliver cyclone and 2.2 L/min for the Higgins-Dewell cyclone provide minimum bias for a wide range of particle size distribu tions that are likely to occur in the workplace [Bartley et al. 1994]. The Dorr-Oliver 10-mm cyclone is required by MSHA, and the HigginsDewell cyclone is used in the United Kingdom. Recently, the GK2.69 cyclone [Kenny and Gussman 1997] has become available with a sampling rate equal to 4.2 L/min. The GK2.69 cyclone is expected to be at least as adequate as the nylon cyclone for conforming to the ISO/ CEN/ACGIH respirable aerosol sampling con vention; and it may be preferable for silica sampling since it is conductive, has welldefined dimensional characteristics, and can be used at higher flow rates for better mass sen sitivity. Because each type of cyclone exhibits specific particle collection characteristics, the use of a single cyclone type for each applica tion would be advisable until evidence be comes available indicating that bias among cyclone types will not increase laboratoryto-laboratory variability. Cyclones and filter cassettes should be leak tested to avoid gross failure in the field. The cyclones may be tested using a simple pressure- (or vacuum-) holding test. The filter cassette should also be checked for leakage while attached to the cyclone. Two approaches to testing the cassettes have been used. A mi cromanometer has been used to measure the pressure drop across a single type of cassette and compare it with the average pressure drop across well-sealed cassettes [Van den Heever 1994]. An alternative approach uses a particle counter to measure the penetration of submicro meter ambient aerosol through the cassette, with the percentage of penetration serving as an indicator of leakage [Baron 2001]. Mea surement of cassette leakage by several labora tories indicates that significant leakage can occur in certain situations. Cassettes should be assembled using a press, and they should be routinely checked for leakage. 2.4.2 Analytical Methods 2.4.2.1 XRD Spectrometry XRD methods used for crystalline silica de termination include NIOSH Method 7500 [NIOSH 1998], OSHA Method ID-142 [OSHA 1996], MSHA Method P-2 [MSHA 1999], and the Health and Safety Executive (HSE) Method for the Determination of Haz ardous Substances (MDHS) 51/2 [HSE 1988]. Details of these methods are presented in Table 6. XRD is capable of distinguishing the three prevalent polymorphs ofcrystalline silica (quartz, cristobalite, and tridymite) and can si multaneously analyze for each polymorph while correcting for interferences that may be present on the sample [Madsen et al. 1995]. Al though most samples collected in industrial workplaces are relatively free of mineral inter ferences, an XRD scan of some samples should be performed to ensure the absence of interfer ences through confirmation of the correct peak ratios for the three largest peaks. 12 Respirable Crystalline Silica Table 6. XRD* sampling and analytical methods for crystalline silica Item NIOSH Method 7500 OSHA Method ID-142 MSHA M ethod P-2 MDHS 51/2 Silica polymorph Sampler Filter Volume Filter preparation Redeposition Drift correction Quartz, cristobalite, tridymite 10-mm nylon cyclone, 1.7 L/min; Higgins-Dewell cyclone, 2.2 L/min 37-mm, 5-pm PVC membrane 400-1,000 L; total dust < 2 mg RF plasma asher, muffle furnace, or filter dissolution in THF On 0.45-pm silver membrane filter Silver internal standard X-ray source Calibration Proficiency testing Range (pg quartz) Cu K,,; 40 kV, 35 mA Suspensions of SiO2 in 2-propanol (deposited on silver membrane filter) PAT 20-2000 LOD (pg quartz) Precision 5 (estimated) RSD =0.08 50-200 pg Quartz, cristobalite Quartz, cristobalite Quartz 10-mm nylon Dorr-Oliver cyclone, 1.7 L/min 10-mm nylon Dorr-Oliver cyclone, 1.7 L/min Higgins-Dewell cyclone, 1.9 L/min 37-mm, 5-pm PVC membrane 408-816 L; total dust < 3 mg Dissolve filter in THF 37-mm, 5-pm PVC membrane 400-1,000 L; total dust < 3 mg RF plasma asher 25-mm, 5-pm PVC membrane >456 L; total dust < 2 mg None On 0.45-pm silver membrane filter On 0.45-pm silver membrane filter None Silver internal standard Silver internal standard External standard (e.g., aluminum plate) Cu K,,; 40 kV, 40 mA Cu K,,; 55 kV, 40 mA Cu K,,; 45 kV, 45 mA Suspensions of SiO2 in 2-propanol (deposited on silver membrane filter) Suspensions of SiO2 in 2-propanol (deposited on silver membrane filter) Sampling from a generated atmosphere of standard quartz dust PAT PAT WASP 50-160 (validation range) 20-500 50-2000 10 5 3 CV = 0.106 @ 50-160 pg CV = 10 % @ 20-500 pg CV = 5 % @ 50 pg *Abbreviations: Cu = copper, CV = coefficient of variation (equivalent to RSD); c V = pooled coefficient of variation; K,, = electron ionization energy; kV = kilovolt(s); LOD = limit of detection; mA = milliampere(s); MDHS = Methods for the Determination of Hazardous Substances (Health and Safety Executive, United Kingdom); MSHA = Mine Safety and Health Administration; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration; PAT = proficiency analytical testing; PVC = polyvinyl chloride; RF = radio frequency; RSD = relative standard deviation; rsd = pooled relative standard deviation (equivalent to C V ); THF = tetrahydrofuran; WASP = Workplace Analysis Scheme for Proficiency; XRD = X-ray diffraction. Respirable Crystalline Silica 13 2 PROPERTIES, PRODUCTION, AND POTENTIAL FOR EXPOSURE 2.4.2.2 IR Spectrometry IR methods used for crystalline silica deter mination include NIOSH Methods 7602 and 7603 [NIOSH 1994a,c], MSHA Method P-7 [MSHA 1994], and MDHS 37 and 38 [HSE 1987, 1984]. Details of these methods are pre sented in Table 7. Although IR is less specific than XRD (IR methods cannot readily distin guish crystalline silica polymorphs), the tech nique is less expensive and can be optimized for measuring quartz in well-defined sample matrices [Madsen et al. 1995; Smith 1997; Hurst et al. 1997]. Samples that contain other silicates (such as kaolinite) and amorphous sil ica can present interferences in the analyses. Also, a potential for bias exists when correct ing for matrix absorption effects, with an in creasing risk of bias at lower quartz concen trations. 2.4.2.3 Colorimetric Spectrophotometry The NIOSH colorimetric method for crystal line silica (NIOSH Method 7601) [NIOSH 1994b] is significantly less precise than IR or XRD methods. The colorimetric analytical method exhibits a nonlinear dependence on the mass of crystalline silica present [Eller et al. 1999a]. The linear range of the method is lim ited, and the blank values for samples can be high (20 p,g silica or higher) [Talvitie 1951, 1964; Talvitie and Hyslop 1958]. High intra laboratory variability of the method (up to twice that of IR or XRD) has been noted in studies conducted in the Proficiency Analyti cal Testing Program (PAT) [Shulman et al. 1992]. The colorimetric method cannot distin guish between silica and silicates, since it is based on the measurement of silicon. 2.4.2.4 Factors Affecting the Sensitivity and Accuracy of Analytical Techniques Samples prepared for XRD analyses are mea sured directly (MDHS 51/2) or are redeposited onto 25-mm silver membrane filters (NIOSH Method 7500 and OSHA Method ID-142). IR samples can be measured directly (MDHS 37), redeposited on an acrylic copolymer mem brane filter (NIOSH Method 7603 and MSHA Method P-7 ), or incorporated into a potassium bromide (KBr) pellet (NIOSH Method 7602 and MDHS 38). Techniques used for redepos iting the sample (both IR and XRD) are diffi cult to perform at low sample loadings and require the laboratory analyst to demonstrate good intralaboratory reproducibility. How ever, these techniques can be optimized by preparing multiple working standards from multiple suspensions of calibration standards and by ensuring that the sample is redeposited evenly as a thin layer on the filter. No statisti cally significant difference has been observed between ashing the filter (muffle furnace and low-temperature asher) and dissolving the fil ter by tetrahydrofuran before redepositing the sample [Eller et al. 1999a]. The instrument response of all three analytical techniques is influenced by the size of the par ticles in the sample. With XRD, the diffraction intensity (as measured by peak height) can vary considerably with particle size, with smaller particles showing lower intensities [Bhaskar et al. 1994]. The sensitivity of IR analyses decreases with increasing particle size. The colorimetric method requires the use of a precisely timed heating step with phospho ric acid to digest amorphous silica and silicates during sample preparation, causing a possible loss of some small crystalline silica particles [Eller et al. 1999a]. Since particle size affects the sensitivity of all three analytical tech niques, the particle size distribution ofthe cal ibration standard should closely match the size of the particles retained on the collected sample. For all analytical techniques, strict adherence to standardized procedures is necessary to pro duce accurate results. Specifically, appropriate 14 Respirable Crystalline Silica Item Matrix Sampler Table 7. IR* sampling and analytical methods for crystalline silica NIOSH Method 7602 NIOSH Method 7603 MSHA P-7 MDHS 37 Coal mine dust Coal mine dust MDHS 38 10-mm nylon cyclone, 1.7 L/min; Higgins-Dewell cyclone, 2.2 L/min 10-mm nylon cyclone, 1.7 L/min; Higgins-Dewell cyclone, 2.2 L/min 10-mm nylon Dorr-Oliver cyclone, 2.0 L/min Higgins-Dewell cyclone, 1.9 L/min HigginsDewell cyclone, 1.9 L/min Filter Volume Filter preparation Analytical samp le preparation Standard Calibration Proficiency testing Range (pg quartz) LOD (pg quartz) 37-mm filter; 5-pm PVC or MCE membrane 37-mm filter; 5-pm PVC membrane 37-mm filter; 5-pm PVC membrane, preweighed 37-mm filter; 5-pm PVC membrane 37-mm filter; 5-pm PVC membrane 400-800 L; total dust <2 mg 300-1,000 L; total dust <2 mg Not stated >456 L; total dust <1 mg >456 L; total dust <0.7mg RF plasma asher or muffle furnace RF plasma asher or muffle furnace RF plasma asher None Muffle furnace Mix residue with KBr, press 13-mm pellet Redeposit on 0.45-pm acrylic copolymer filter Redeposit on 0.45-pm acrylic copolymer filter None Mix residue with KBr, press 13-mm pellet Polystyrene film Polystyrene film Polystyrene film Polystyrene film Polystyrene film Quartz diluted in KBr Standard suspension of quartz in 2-propanol Standard suspension of quartz in 2-propanol Sampling from a generated atmosphere of standard quartz dust Sampling from a generated atmosphere of standard quartz dust PAT PAT PAT WASP WASP 10-160 30-250 25-250 10-1,000 5-700 5 (estimated) 10 (estimated) 10 Varies with particle size Varies with particle size See footnote at end of table. Respirable Crystalline Silica (Continued) 15 Table 7 (Continued). IR* sampling and analytical methods for crystalline silica Item NIOSH Method 7602 NIOSH Method 7603 MSHA P-7 MDHS 37 MDHS 38 Precision RSD <0.15 @ 30pig RSD = 0.098 @ 100-500pg CV = 5-10 % @100-500 pg CV = 5 % @ 50 pg CV = 5 % @ 50 pg *Abbreviations: CV = coefficient ofvariation (equivalent to RSD, relative standard deviation); IR = infrared absorption; KBr = potassium bromide; MCE = methyl cellulose ester; MDHS = Methods for the Determination of Hazardous Substances (Health and Safety Executive, United Kingdom); MSHA = Mine Safety and Health Administration; NIOSH = National Institute for Occupational Safety and Health; LOD = limit of detection; PAT = proficiency analytical testing; PVC = polyvinyl chloride; RF = radio frequency, RSD = pooled relative standard deviation (equivalent to CV,pooled coefficient of variation); WASP = Workplace Analysis Scheme for Proficiency. 16 Respirable Crystalline Silica 2 PROPERTIES, PRODUCTION, AND POTENTIAL FOR EXPOSURE calibration of the technique has been shown to be critical in the accurate measurement of crys talline silica [Eller et al. 1999b]. Also, it is es sential that only standard reference materials from the National Institute of Standards and Technology (NIST) (for which particle size and phase purity has been established) be used to prepare calibration curves for quartz (1878a) and cristobalite (1879a) [Eller et al. 1999a]. No standard reference material for tridymite is available, since this silica polymorph rarely exists in the workplace. However, a wellcharacterized sample oftridymite of the appro priate particle size is available from the U.S. Geological Survey and can be used as a refer ence standard. Direct-on-filter techniques are used by the United Kingdom, the European Union, and Australia [Madsen et al. 1995]. These tech niques require less time and labor than others and are amenable to both XRD and IR analyses [Lorberau et al. 1990]. However, direct-on-fil ter techniques are affected by the manner in which the particles are deposited on the filter sample (particle deposition may be nonuni form). Thus care must be taken when choosing the area of the filter to measure so that results can be compared with other methods. Sample overloading is possible for a sample collected over a full work shift. 2.4.3 Feasibility of Measuring Crystalline Silica at Various Concentrations The efficacy of sampling and analytical meth ods for measuring concentrations ofhazardous materials may be established using the NIOSH* *Tridymite reference material may be obtained from Dr. Stephen A. Wilson, U.S. Geological Survey, Box 25046, MS 973, Denver, CO 80225 (telephone: 303-236-2454; FAX: 303-236-3200; e-mail: swilson @usgs.gov; Web site: http://minerals.cr.usgs.gov/ geochem). accuracy criterion [NIOSH 1995b], which re quires better than 25% accuracy at concen trations ofexpected method application. Accu racy, as a percentage of true concentration val ues, is defined in terms of an interval expected to contain 95% of (future) measurements. To account for uncertainty in method evaluations, the upper 95% confidence limit on the accu racy is measured and used in the criterion. Generally, the accuracy of a method is mea sured over a range of concentrations brack eting the OSHA PEL. Use of a range of mea surements means that accuracy is assured-- both at concentrations below the PEL (for pos sible use in action level determinations) and, more significantly, at the PEL (where method results must be legally defensible). NIOSH has evaluated both the XRD silica method (NIOSH Method P&CAM 259, the forerunner to NIOSH Method 7500) [NIOSH 1979b] and an IR silica method (MSHA Method P-7, equivalent to NIOSH Method 7603) in a collaborative test among several laboratories [NIOSH, BOM 1983]. One result of the test was that the accuracy of the methods was estimated by evaluating the intralaboratory variability at various filter loadings. The con centrations to which these filter loadings corre spond depend on the flow rate of the pre sampler used. Experimental conditions and re sults relevant to the derivation of these esti mates are summarized in Tables 8 and 9. The results of the collaborative tests indicate that both the XRD and IR methods tested meet the NIOSH accuracy criterion [NIOSH 1995b] over the range of filter loadings measured. Currently, OSHA uses the 10-mm nylon cy clone at a sampling rate of 1.7 L/min for sam pling crystalline silica. The concentrations relevant to the collaborative test conditions are listed in Tables 10 and 11 and assume an 8-hr sampling period. As indicated in Tables 10 and 11, the traditional nylon cyclone meets the Respirable Crystalline Silica 17 Table 8. Intralaboratory results for evaluation of XRD silica method Filter loading Item 69.4 ig 98.4 ig 204 ig Degrees of freedom RSD for sampling and analytical methods (%) * T 12 8.8 11 12 6.3 8.1 Source: NIOSH, BOM [1983]. RSD = relative standard deviation. RSD for sampling and analytical methods represents the RSD in mass estimates, accounting for intersampler and analytical variability. ^Implications for XRD: Pooled filter levels and pump error (assumed to be <5%) indicate that the overall imprecision is as follows: Total RSD for sampling and analytical methods is 9.3%. Therefore, the upper 95% confidence limit on the accuracy (35 degrees offreedom) is 21%. Table 9. Intralaboratory results for evaluation of IR silica method Filter loading Item 67.2 ig 99.7 ig 161 ig Degrees of freedom RSD for sampling and analytical methods (%) * T 10 5.8 12 7.8 11 7.4 Source: NIOSH, BOM [1983]. RSD = relative standard deviation. RSD for sampling and analytical methods represents the RSD in mass estimates, accounting for intersampler and analytical variability. ^Implications for IR: Pooled filter levels and pump error (assumed to be <5%) indicate that the overall imprecision is as follows: Total RSD for sampling and analytical methods is 7.1%. Therefore, the upper 95% confidence limit on the accuracy (33 degrees of freedom) is 17%. 18 Respirable Crystalline Silica Table 10. XRD method evaluation: concentration ranges bracketing applicable exposure limits for which the NIOSH accuracy criterion is met* (Mg/m3) Filter loading Cyclone and sampling rate 69.4 Mg 98.4 Mg 204 Mg Applicable exposure limit Nylon cyclone, 1.7 L/min 85 121 251 100 GK2.69 cyclone, 4.2 L/min 34 49 102 50 *Eight-hour sampled masses are combined with results of NIOSH, BOM [1983]. Table 11. IR method: concentration ranges bracketing applicable exposure limits for which the NIOSH accuracy criterion is met* (M g/m3) Filter loading Cyclone and sampling rate Nylon cyclone, 1.7 L/min 6.72 Mg 83 99.7 Mg 123 161 Mg 198 Applicable exposure limit 100 GK2.69 cyclone, 4.2 L/min 34 50 80 50 *Eight-hour sampled masses are combined with results of NIOSH, BOM [1983]. Respirable Crystalline Silica 19 2 PROPERTIES, PRODUCTION, AND POTENTIAL FOR EXPOSURE accuracy criterion over a range of concentra tions bracketing 100 ^g/m3. Since the GK2.69 cyclone is expected to con form to the ISO/CEN/ACGIH respirable aero sol sampling convention, the NIOSH intralab oratory collaborative tests can be used to estab lish confidence limits on its accuracy. The results of the collaborative tests indicate that the GK2.69 cyclone meets the accuracy crite rion over a range of concentrations bracketing 50 0-g/m3, as illustrated in Tables 10 and 11. 20 Respirable Crystalline Silica 3 Human Health Effects 3.1 Epidemiologic Considerations in Occupational Respiratory Disease Studies 3.1.1 Study Designs Epidemiology is the study of patterns of dis ease occurrence in human populations and the factors that influence those patterns [Lilienfeld and Stolley 1994]. Epidemiology is the pri mary science used to study silica-related dis eases in workers. Most epidemiologic studies of silica-exposed workers discussed in this re view are cross-sectional studies (i.e., preva lence studies) or retrospective (i.e., historical) cohort studies. Cross-sectional studies meas ure symptom or disease occurrence in a se lected population at one point in time. An ex ample of a cross-sectional study design would be the spirometric testing of lung function in a group of granite shed workers during an annual health survey and comparison with respira tory function in nongranite workers. Cross sectional studies have two disadvantages: Usually only the "survivor" population is examined. Retired, former, or de ceased workers are not included, possi bly resulting in an underestimate of the disease prevalence. It may be impossible to determine whether exposure preceded the disease if both are measured at the same time. Many epidemiologic studies of silica-related diseases are retrospective cohort morbidity or mortality studies. In this approach, the ill nesses, deaths, and exposures (surrogate or re constructed) of an entire cohort (e.g., all work ers ever employed in one foundry) are followed forward from a time in the past to a Photograph by Kenneth Linch, NIOSH Construction workers drilling holes in concrete pavement during highway repair. Respirable Crystalline Silica 21 3 HUMAN HEALTH EFFECTS designated time in the future, and the number and causes of deaths that occur in that interval are assessed. Exposures for the followup pe riod may be reconstructed from historical in formation or a surrogate measure such as dura tion of employment. The mortality of the cohort is then compared with the mortality of a standard population. For example, Steenland and Brown [1995b] used a retrospective study design to examine the mortality of a cohort of white male underground gold miners em ployed for at least 1 year between 1940 and 1965. The miners were followed from their first date ofmining employment to their date of death or until the end of 1990, whichever came first. Their mortality was then compared with that of the U.S. population or the county where the mine was located. A disadvantage of silico sis mortality studies that use death certificate data is that silicosis cases could be under ascertained even when contributing causes of death are included, as suggested by a study of silicosis mortality surveillance in the United States [Bang et al. 1995]. 3.1.2 Sources of Bias Three main (but not mutually exclusive) types of bias may affect the results of epidemiologic studies of silica-exposed workers--selection bias, information bias, and confounding [Checkoway 1995]: Selection bias originates from the method of choosing study subjects. This type of bias is a common criticism of lung cancer studies of compensated silicotics because silicotic workers who sought compensation for their disease may differ from all silicotics in symp toms, radiographic changes, social and psychological factors, and industry [Weill and McDonald 1996; McDonald 1995]. However, Goldsmith [1998] re viewed this question and concluded that lung cancer risk estimates were not 22 higher in compensated silicotics when compared with those of silicotics ascer tained from other clinical sources (i.e., hospital or registry data). Information bias involves misclassification of study subjects by disease or ex posure status [Checkoway et al. 1989]. An example of disease (silicosis) misclassification occurred in a study of North Carolina dusty trades workers [Amandus et al. 1991; Rice et al. 1986]: a re-evaluation ofthe chest X-rays found that 104 of the 370 cases categorized as silicosis were actually International Labour Organization (ILO) category 0 (nonsilicotic) [Amandus et al. 1992]. Sources of exposure assessment errors include instrument error, incorrect im putation of exposure when data are missing, and data extrapolation errors [Checkoway 1995]. Misclassification of exposure may occur in retrospective co hort studies of silicosis when quantita tive dust exposure measurements are mathematically converted from particle counts to gravimetric respirable silica equivalents. Confounding variables are factors that are related to exposure and are also inde pendent risk factors for the disease under study [Checkoway 1995]. Most studies of silica-related diseases controlled for confounding factors such as age and race by study design or data analysis. Con founding from cigarette smoking is an important concern in studies oflung can cer, bronchitis, asthma, emphysema, chronic obstructive pulmonary disease (COPD), and lung function. Confound ing of an exposure-disease relationship by cigarette smoking is less likely when an internal comparison group is used-- e.g., when both groups are from the same plant [Siemiatycki et al. 1988]. Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS (Some studies in this review used exter nal comparison populations.) Most of the lung cancer studies among under ground miners did not control for the ef fects of other carcinogens that may have been present, such as arsenic, radon progeny, and diesel exhaust (see Sec tion 3.4.1). The effects ofbias discussed here can be mini mized by applying epidemiologic methods. Description of appropriate methodology is available in epidemiology textbooks. 3.2 Silicosis 3.2.1 Definition Silicosis most commonly occurs as a diffuse nodular pulmonary fibrosis. This lung disease (which is sometimes asymptomatic [NIOSH 1996b]) is caused by the inhalation and deposi tion of respirable crystalline silica particles (i.e., particles <10 pm in diameter) [Ziskind et al. 1976; IARC 1987]. According to a report from the U.S. Surgeon General [DHHS 1985], cigarette smoking has "no significant causal role" in the etiology of silicosis. Probably the most important factor in the development of silicosis is the "dose" of respirable silicacontaining dust in the workplace setting--that is, the product of the concentration of dust con taining respirable silica in workplace air and the percentage of respirable silica in the total dust. Other important factors are (1) the particle size, (2) the crystalline or noncrystalline nature of the silica, (3) the duration ofthe dust exposure, and (4) the varying time period from first expo sure to diagnosis (from several months to more than 30 years) [Banks 1996; Kreiss and Zhen 1996; Hnizdo and Sluis-Cremer 1993; Hnizdo et al. 1993; Steenland and Brown 1995a; ATS 1997]. Experimental evidence supporting the in fluence of these factors has recently been re viewed [Mossman and Churg 1998; Heppleston 1994]. Many in vitro studies have been conducted to investigate the surface charac teristics of crystalline silica particles and their influence on fibrogenic activity [Bolsaitis and Wallace 1996; Fubini 1997, 1998; Castranovaet al. 1996; Donaldson and Borm 1998; Erdogdu and Hasirci 1998]. These researchers found that a number of features may be related to silica cytotoxicity. Further research is needed to asso ciate the surface characteristics with occupa tional exposure situations and health effects [Donaldson and Borm 1998]. Such exposure sit uations may include work processes that produce freshly fractured silica surfaces [Bolsaitis and Wallace 1996; Vallyathan et al. 1995] or that in volve quartz contaminated with trace elements such as iron [Castranova et al. 1997]. A worker may develop one ofthree types of sil icosis, depending on the airborne concentra tion of respirable crystalline silica: (1) chronic silicosis, which usually occurs after 10 or more years of exposure at relatively low concentra tions; (2) accelerated silicosis, which develops 5 to 10 years after the first exposure; or (3) acute silicosis, which develops after exposure to high concentrations of respirable crystalline silica and results in symptoms within a period ranging from a few weeks to 5 years after the initial exposure [NIOSH 1996b; Parker and Wagner 1998; Ziskind et al. 1976; Peters 1986]. The symptoms of accelerated silicosis are similar to those of chronic silicosis, but clinical and radiographic progression is rapid. Also, fibrosis may be irregular and more dif fuse [Banks 1996; Seaton 1995; Silicosis and Silicate Disease Committee 1988] or not ap parent on the chest radiograph [Abraham and Weisenfeld 1997]. Acute silicosis is typically associated with a history of high exposures from tasks that produce small particles of airborne dust with a high silica content, such as sandblasting, rock drilling, or quartz milling [Davis 1996]. The pathologic charac teristics of acute silicosis (sometimes referred to as silicoproteinosis) resemble those of alve olar proteinosis [Wagner 1994; Davis 1996]. Respirable Crystalline Silica 23 3 HUMAN HEALTH EFFECTS Pulmonary fibrosis may not be present in acute silicosis [NIOSH 1996b]. Epidemiologic studies of gold miners in South Africa, granite quarry workers in Hong Kong, metal miners in Colorado, and coal miners in Scotland have shown that chronic silicosis may develop or progress even after occupational exposure to silica has been discontinued [Hessel et al. 1988; Hnizdo and Sluis-Cremer 1993; Hnizdo and Murray 1998; Ng et al. 1987; Kreiss and Zhen 1996; Miller et al. 1998]. Therefore, removing a worker from ex posure after diagnosis does not guarantee that silicosis or silica-related disease will stop pro gressing or that an impaired worker's condi tion will stabilize [Parker and Wagner 1998; Weber and Banks 1994; Wagner 1994]. 3.2.2 Epidemiologic Exposure-Response Models of Silicosis This section reviews published epidemiologic studies that provide evidence of an exposureresponse relationship for crystalline silica and silicosis using cumulative exposure data. Exposure-response models based on cumula tive exposure data can predict silicosis risk for a particular silica dust exposure over a period of time. Epidemiologic studies that provided evidence of an exposure-response relationship for silica and silicosis on the basis of other kinds of exposure data (e.g., duration of expo sure) have been reviewed elsewhere [EPA 1996; Davis 1996; Hughes 1995; Rice and Stayner 1995; Seaton 1995; Steenland and Brown 1995a; Goldsmith 1994a; WHO 1986]. Table 12 summarizes the published studies that predict the incidence or prevalence of radio graphic silicosis based on models of cumula tive exposure to respirable crystalline silica. Table 13 presents details about the cohorts, quartz content of the dust, followup periods, and limitations of each study. All of the studies predicted the occurrence of at least one case of radiographic silicosis per 100 workers at cumulative exposures approximately equal to the OSHA and MSHA PELs and the NIOSH REL over a 40- or 45-year working lifetime (see appendix for the PELs and REL). Three studies predicted prevalences of 47% to 95% at the OSHA PEL. Each study followed a cohort ofminers for at least three decades from first employment in the industry [Kreiss and Zhen 1996; Hnizdo and Sluis-Cremer 1993; Steenland and Brown 1995a]. Studies of foundry workers [Rosenman et al. 1996], hardrock miners [Muir et al. 1989a,b; Muir 1991], and workers in the diatomaceous earth industry [Hughes et al. 1998] followed work ers for less than 30 years (mean) and predicted prevalences of 1% to 3%. The studies pre sented in Table 12 predicted that approxi mately 1 to 7 silicosis cases per 100 workers would occur at respirable quartz concentra tions of0.025 mg/m3--halfthe NIOSH REL of 0.05 mg/m3--with the contingencies and ex ceptions noted in Table 12. However, that con centration cannot be measured accurately at this time for the reasons given in Section 2.4. Table 12 does not include a cohort study of 1,416 coal miners exposed to coal dust with quartz concentrations ranging from 0.4% to 29.4% of respirable dust [Miller et al. 1998]. This study predicted pneumoconiosis risks for 47 men with a "profusion of median small opacities" of ILO category >2/1 (i.e., 2/1+), a higher category of radiographic abnormality than reported in the studies listed in Tables 12 and 13. Logistic regression models predicted that the risk of small opacities of 2/1+ at the time of followup examination would be about 5% for miners exposed to a mean respirable quartz concentration of 0.1 mg/m3 and about 2% for miners exposed to a mean respirable quartz concentration of 0.05 mg/m3 for about 15 years [Miller et al. 1998]. The predicted risks increased with cumulative exposure to re spirable quartz dust. 24 Respirable Crystalline Silica Table 12. Predicted incidence or prevalence o f silicosis follow ing exposure to selected concentrations o f respirable quartz dust-- based on modeling o f cumulative exposure over a 45-year w orking lifetim e Si o ue T<Ot> rH ^ Al ^ M <*> ^ o c TO g<t> o^ OD O +H S0> cs 'O k-- CG Oh a <UD SQnJ PSH3 3V5 *S&o* 3 cs .^5 3 u* +H Cl <*> O Tf nI NO Tf oo co On CN NO oI ON o NO 00 NO NO O IN '--i Tf- <*> ahh sCL 4*> H N' MpH 'p+HH fl ^ S 3 5c3 TO +SH U TO 3cr p-A5-v3 w^wo IT) O DT O O oo oo 1-H oo o Tf NT) ON O i-< o o o oo - On On O -C cn o o o _ O Tf 60u CD W) 3TO so cn 3 CD Cd 53 u 00 TO T3O 5 '3 t/5 TO SO cd On On cd 3 cd r-1 C/3 u o SOSO cd "H N3 TsOo ^o O TO 3 W3) ^kN CD *-< p3 O ffi X ON B ON 0 3 TsOo si TO 0 Of) 1 *3 cd SO cd o ON o CN Wso) o u 6so0 o X Tf On co 2ZL ^ SO o pg Og 'HSO cd cd s-h 60 60 X (INN c/3 s -H ^ ,, S-< r---- 1 O NO k ON 3 Or~N.\ tkto-H> . so "o o so CcoD O ON ON CQ .3 TCOd INO SO 00 cd a Respirable Crystalline Silica 25 (Continued) Table 13. Sum m ary of epidemiologic studies o f silicosis w ith cum ulative dust exposure data and silicosis ris k estimates C/3 O00 vo"o- a s+5c-0 sso u cu 3|3 3 d 33 is C/3 a S acd *3 cad ^ 00c0d\ 1OS *1 -1 d *d i--i wa> 35C/3 'd53 a3: daa>> oo -<mC cd V a> 1-H > 35 3c3d a>C/3 d ^^5 OS <3\ ' >>% cd <n s a> 2a> om >A * s'"/ 4_r cd _cd *3 c5d3 O5333 cd S Ucd in OS Oi--si 3a3> 33 a> > cd 'd ^cd r33 q_, 1 J "cd 3a> -433 1 >v O cd lO a ffi c/3 c/3 *25 'O a>C/3 a d 33 3a3 C/3 g33 srst Xa> a>C/3 ?d *u> c3d*3 *a53>3 dS o a o s- 50 .'S2 Cd o 50 s 5530 T3 _a>> td 3Uds ao See footnotes at end o f table. aJah>o 'da> - -oC o U 2 C/3 4) c0 ^ cd O', 7 0sGo0\ at . 7 O 'd _C/3 Cfl d C/3 +a-do 55 'd53 cd s Oi--h', i--i 3tOoOn3 Ou cd < 26 Respirable Crystalline Silica Table 13 (Continued). Sum m ary o f epidemiologic studies o f silicosis w ith cum ulative dust exposure data and silicosis ris k estimates e+5B- Uo 9 -5 -M Oi W -<Mu CoS cs C 44 CO T< _(>D td "3 a o a> 1 o rjj o 3 oa cd m 3 c a5 w OO AC/3l ">'dkn'o in cOCd3 C/3 P _a J3 <*D o 4c3d 4O3 a cd OOton o <K C(D/3 3 ' (D1 3 cd TdJ> T-H 3 o-C Uo <N (D 43 43 ^ O2h 3g 6O0 ^S MP3 4c3d cd '*-* n P a> _ r-H Z s 3^ 0> M 1--.1 C/3,, OSh Respirable Crystalline Silica C/3 See footnotes at end o f table. (Continued) 27 && c/3 i in 28 Respirable Crystalline Silica Table 13 (Continued). Sum m ary o f epidemiologic studies o f silicosis w ith cum ulative dust exposure data and silicosis ris k estimates See footnotes at end o f table. (Continued) Table 13 (Continued). Sum m ary o f epidemiologic studies o f silicosis w ith cum ulative dust exposure data and silicosis ris k estimates Ca>0 *P pp o fto> o> TP p p Of) P cp O -ap> CP X> o> > cp ow PP 00 ft ft ^P P4 K0.*1 -J5--0I S S cp Ca>p <x> P o U g M -5 ^ Srp >v p CP a> cp 1--1 ^ p o r-*g-* 5P-1 50 2 > ~aTP CP Cp Of) 50 a> a >-> s s-*-* p h IXa 3 .3 5C0P <U 50 UP 5N - **1 O ^3 CP ^ 4) w -M CP 03 fl g ft ^ W 50 ft t o Of) p rpa> P B S P P rP op - p CP p .2 CP - 50 2550 fo^<yt p bN p >CP 0 S TP a CP P CP M a I PO a> s CD CP~Cp O') v ) 5--i -+--' *2 Al r^-J >hV P^3 ci OJ >v --1 ^S CP qS_i X TP ^o Of) <9 P P O m 50 \P4) cp P -xP TP O P Pp ~P -< Cp oa 2~M -f2t P-5P o p- 2--So ft os ft p ft ^r-H ft ft cp P3 0f0t Oh tp 3 CP CP -t-> CP >> fto o Of) rP <0N0 -t-1 C0 P o ^ (A) Al ft TP rPa> ft 2 <X> O -P oa o o o rP U *1 TP P CP ^ 'P -P O cp >TP 0 P rP TP P cp P Oft C0* ><C9 fti TJ C 0> sW .S50 p TJ T3 S P ^ O -M i--ft -Cfpt tC ft' 00 2S? 2 CPrt oSP ^^ O ' . _LP P S -B cp ,, P2 u 0> cp i--i ft ^ P s.ms p )&a--SI ,i3h 'p or-H >^3r s > s f-H C0 Respirable Crystalline Silica See footnotes at end o f table. (Continued) 29 30 Respirable Crystalline Silica Table 13 (Continued). Sum m ary o f epidemiologic studies o f silicosis w ith cum ulative dust exposure data and silicosis ris k estimates See footnotes at end o f table. (Continued) (Continued) Table 13 (Continued). Sum m ary o f epidemiologic studies o f silicosis w ith cum ulative dust exposure data and silicosis ris k estimates (D CD a C/3 Pd CD O 'Eh >^ TJ >> f+-i o o ^CD a ^ O ? a o P4 3 CD > g ocv C0 _C0rs C0. _J CD<--l P4 r C0 50 }h CD CD CD CD Se ^ s oaf+-i o }h CD sso au CD 'B 50 o aS <D P CD u r<mojXD .CpSo3rL1 Taao3J CD CD c3 a -S ~ g sOh X 21 C S CD C/3 ^ C-M -4-> _Cj PH a g 22 S3 ^ Ctf g. IO X p gP-i e$oH* X (D w *C/3 CD 60 a-is 2 o o c - 5o0 .*23 50 s 50 o a >1-H P-i 55 p w a C PCD O u O Z See footnotes at end o f table. SO o\ , Respirable Crystalline Silica 31 Table 13 (Continued). Sum m ary o f epidemiologic studies o f silicosis w ith cum ulative dust exposure data and silicosis ris k estimates cd +5esB- .a s 'tsD s t> s uo <o+-( '+o-< mo\ CD > a) r^jr-H >-< t/l <Z) Oh -Nt-J cd C/3i' C/3 s s.3 5B O CS O <U 5B ss CO T< _<>D td "3 a o & <u pfi W -M CS cs C a> 2 cd ^ \0 ---- 1 0s- cd CO OC/3 o C/3 3oOC/3 P - o -C Uo s S a 2 55 CQ n-l ft C/3 OC/3 ' C/3 C/3 C/3 ' C/3 cr. 32 Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS A currently unpublished study of 600 retired Vermont granite workers found nodular opaci ties consistent with silicosis (degrees of profu sion not reported in abstract) in 4.7% of 360 ra diographs read by three readers [Graham et al. 1998]. The average duration of employment for these workers was 31 years, and the aver age time from first exposure to radiographic examination was 39 years. Most workers in the cohort were first employed after 1940, when average quartz dust concentrations were below the current OSHA PEL [Graham et al. 1991; Ashe and Bergstrom 1964]. Although the variability in prevalence estimates (i.e., 1% to 90%) cannot be solely attributed to differences in followup periods, chronic silico sis is a progressive disease, and its development after a long latency period and after workers leave employment must be accounted for in epidemiologic studies. A study of autopsied gold miners in South Africa also supports the need for examining workers after a long la tency period and after they leave employment [Hnizdo et al. 1993]. Radiologic findings for profusion of rounded opacities (ILO category >1/1) were compared with pathological find ings for silicosis in 326 miners with an average of 2.7 years between the radiologic and patho logic examinations. Silicosis was not diag nosed radiographically for at least 61% of the miners with slight to marked silicosis at au topsy. The probability of a false negative read ing increased with years ofmining and average concentration of respirable dust [Hnizdo et al. 1993]. Experimental studies of rats also re ported a lack of complete agreement between histopathologic indicators of silica dust expo sure and radiographic readings [Drew and Kutzman 1984a,b]. In addition, improved exposure assessment methods and data analyses that account for variations and deficiencies in exposure data would improve the risk estimates for silicaexposed workers [Agius et al. 1992; Checkoway 1995]. Although epidemiologic studies that used cumulative exposure estimates represent the best available source of information for characterizing the dose-response relationship in occupational cohorts, peak exposures may predict silicosis risk better than cumulative ex posures [Checkoway and Rice 1992]. How ever, data on peak exposures are rarely avail able, and data supporting this hypothesis are limited. 3.3 TB and Other Infections 3.3.1 Definition As silicosis progresses, it may be complicated by severe mycobacterial or fungal infections [NIOSH 1996b; Ziskind et al. 1976; Parkes 1982; Parker 1994]. The most common of these infections, TB, occurs when the macro phages are overwhelmed by silica dust and are unable to kill the infectious organism Myco bacterium tuberculosis [Parker 1994; Ng and Chan 1991; NIOSH 1992a,b; Allison and Hart 1968]. About half of the mycobacterial infec tions that occur in workers with exposure to sil ica are caused by M. tuberculosis, and the other halfare caused by the nontuberculous mycobac teria (NTM) Mycobacterium kansasii and My cobacterium avium-intracellulare [Owens et al. 1988; NIOSH 1996b]. Infections in workers with silicosis may also be caused by Nocardia asteroides and Cryptococcus [Ziskind et al. 1976; NIOSH 1996b; Parker 1994; Parker and Wagner 1998]. ATS [1997] recommends that the diagnostic investigation of a patient with silicosis and possible TB include consideration of NTM disease. The ATS also recommends that tuberculin tests be administered to persons with silicosis and to those without silicosis who have at least 25 years of occupational exposure to crystalline silica [ATS 1997]. 3.3.2 Epidemiologic Studies Recent surveillance data indicate that TB rates in the United States are 5 to 10 times higher Respirable Crystalline Silica 33 3 HUMAN HEALTH EFFECTS among racial and ethnic minorities (after ad justment for the effects of age, sex, and country of birth) [Cantwell et al. 1998]. Cantwell et al. [1998] reported that the relative risk of TB in creased as socioeconomic status (measured by six indicators) decreased, after adjustment for the effects of age (relative risks ranged from 2.6 to 5.6 in the lowest versus highest quartiles). The number of TB cases among foreign-born persons in the United States increased by 56% during the period 1986 to 1997 [CDC 1998c]. The association between TB and silicosis has been firmly established by the results of epidemiologic studies conducted during this century [Balmes 1990]. This association was supported by a survey of TB deaths among silicotics in the United States for the period 1979 to 1991 [Althouse et al. 1995] and by the results of four recent epidemiologic studies [Goldsmith et al. 1995; Cowie 1994; Sherson and Lander 1990; Kleinschmidt and Church yard 1997]. Black South African gold miners [Cowie 1994] and Danish foundry workers [Sherson and Lander 1990] with chronic sili cosis had threefold and tenfold incidences of TB, respectively, compared with nonsilicotic, non-silica-exposed workers of similar age and race. Goldsmith et al. [1995] compared the mortality of 590 California silicosis claimants with that of U.S. males and found that the TB mortality of the claimants was 50 times that of all U.S. males (standardized mortality ratio [SMR]=56.35; 45 deaths observed, 0.8 expected; 95% confidence interval [CI]=41.10-75.40). A retrospective study of TB among 4,976 miners from the Freegold mines in South Africa re ported that the incidence rate ratio for miners with silicosis (ILO category >1/1) was 1.54 (95% CI=1.00-2.37) compared with miners without silicosis (after adjusting for the ef fects of age, followup period, cumulative service, and occupation) [Kleinschmidt and Churchyard 1997]. The incidence of TB for the oldest age group was 21 times that of the youngest group (incidence rate ratio=21.17; 95% CI=8.60-52.11); and for workers in oc cupations with high dust exposure (such as drilling), the incidence was twice that of sur face and maintenance workers (adjusted inci dence rate ratio=2.25; 95% CI=1.49-3.38) [Kleinschmidt and Churchyard 1997]. Some evidence indicates that workers who do not have silicosis but who have had long ex posures to silica dust may be at increased risk of developing TB. Two epidemiologic stud ies reported that, compared with the general population, a threefold incidence ofTB cases occurred among 5,424 nonsilicotic, silicaexposed Danish foundry workers employed 25 or more years [Sherson and Lander 1990], and nearly a tenfold incidence occurred among 335 nonsilicotic, black South African gold miners with a median underground employ ment of 26 years [Cowie 1994]. Westerholm et al. [1986] found 13 cases among 428 silicotic Swedish iron and steel workers and 1 case in a comparison group of 476 Swedish iron and steel workers with nor mal chest radiographs (level of statistical sig nificance not reported). Both groups had been exposed to silica for at least 5 years. A study of TB incidence in 2,255 white South African gold miners included 1,296 miners who had an autopsy [Hnizdo and Murray 1998, 1999]. The smoking-adjusted relative risk for TB in miners without silicotic nodules on au topsy examination (n=577) increased slightly with quartiles of cumulative dust exposure (relative risk=1.38 [95% CI=0.33-5.62] for the highest quartile of cumulative exposure). For miners without radiologically diagnosed sili cosis (n=1,934), the smoking-adjusted relative risk increased to 4.01 (95% CI=2.04-7.88) in the highest quartile of cumulative dust expo sure [Hnizdo and Murray 1998, 1999]. The au thors defined radiologic silicosis as ILO cate gory > 1/1. TB was diagnosed, on the average, 7.6 years after the end of dust exposure and 34 Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS 6.8 years after the onset of radiological silico sis--a result that supports the need for medical surveillance of workers after the end of expo sure to silica dust [Hnizdo and Murray 1998]. Miners who developed TB before completing 10 years ofunderground employment were ex cluded because they were not allowed to con tinue working underground after diagnosis. Corbett et al. [1999] conducted a recent casecontrol study of TB and pulmonary disease caused by NTM in South African gold miners. These researchers found that radiographic sili cosis, focal radiological scarring, and human immunodeficiency virus (HIV) infection were significant risk factors for NTM disease and for TB. Past medical history of TB treatment (odds ratio [OR]=15.1; 95% CI=7.64-29.93) and current employment in a "dusty job" at the mines (OR=2.5; 95% CI=1.46-4.44) were sig nificant risk factors for NTM. ORs for NTM and TB increased with years of employment (range of ORs was 1.0 to 9.4 for NTM and 1.0 to 4.1 for TB). The study included 206 NTM patients and 381 TB patients of known HIV status admitted to a South African hospital. Also included were 180 controls who were HIV-tested surgical or trauma patients admit ted to the same hospital during the same pe riod. Two recent studies about silica exposure and TB used U.S. occupational mortality data to conduct a proportionate mortality study ofper sons with TB by occupation for 1979 through 1990 [CDC 1995; Chen et al. 1997]. Although the study design did not control for confound ing, it identified six occupational groups with potential exposure to silica dust that had age-adjusted proportionate mortality ratios (PMRs) for TB that were statistically signifi cant (lower bound of the 95% CI>100) or greater than 200. Table 14 shows significant PMRs by race for construction occupations, mining machine operators, grinding and pol ishing machine operators, furnace and kiln operators, laborers, and mixing and blending machine operators [CDC 1995]. Chen et al. [1997] conducted a case-control study (8,740 cases; 83,338 controls) with U.S. National Occupational Mortality Surveillance (NOMS) data for 1983-1992. The study con trolled for confounding from age, sex, race, so cioeconomic status, potential exposure to ac tive TB, and the presence of silicosis and other pneumoconioses. The potential for silica expo sure was based on data from NOES [NIOSH 1988] and the National Occupational Health Survey of Mining (NOHSM) [NIOSH 1996c]. This potential was categorized as "high," "in termediate," or "low or no." The study found that decedents with high potential for exposure to silica and no documentation of silicosis on the death certificate had a 30% greater odds of mortality from respiratory TB than decedents with no potential exposure to silica after ad justment by logistic regression for the possi ble confounders mentioned earlier (OR=1.3; 95% CI=1.14-1.48). The results also suggest an exposure-response relationship between silica exposure (in the absence of silicosis) and death from respiratory tuberculosis [Chen et al. 1997]. 3.4 Cancer 3.4.1 Background The possible carcinogenicity of crystalline sil ica dust became a subject of considerable and intense debate in the scientific community in the 1980s, especially after (1) publication of new information presented at a 1984 sympo sium in North Carolina [Goldsmith et al. 1986], (2) epidemiologic studies by Westerholm [1980] and Finkelstein et al. [1982], and (3) a literature review by Goldsmith et al. [1982] (see McDonald [1989, 1995] and Gra ham [1998]). Many epidemiologic studies of cancer mortality and morbidity in silicaexposed occupational groups were published Respirable Crystalline Silica 35 36 ft ft T3 O fffttt -S S ^c fftl *o o00 ft s^ ft t I o'xf nI o ffttI-- 00 00 n<N I I'xf fot fffottt ft NO O 00 O os" 5g--i c*NI wa ^^ o V fftt no o in 'ft ft d ft ft rrj ft to ffl ft- ON ft- ftff3tt ft ^"x ft ON ft NO a^ U nI o<NI n00 on o On <N f,<ootu ffnttI-- foftt! ffOfftttt hifOnt V o NrronfO-It tn- N<NO fot _ft 2 Of) vo ft i 'ft Table 14. Selected age-adjusted PMRs*'+fo r pulm onary TB by usual occupation, sex, and race in 28 States, 1979-1990 Source: Adapted from CDC [1995]. This data file includes death records from 28 States (Alaska, California, Colorado, Georgia, Idaho, Indiana, Kansas, Kentucky, Maine, Missouri, Nebraska, Nevada, N ew Hampshire, N ew Jersey, N ew Mexico, N ew Y ork, N orth Carolina, Ohio, Oklahoma, Pennsylvania, Rhode Island, South Carolina, Tennessee, Utah, Vermont, Washington, West Virginia, and Wisconsin). *Abbreviations: PMRs = proportionate m ortality ratios; TB = tuberculosis; C I = confidence interval. S election criteria: (1) at least fo u r TB deaths in race- and sex-specific group and (2) either a PM R >200 or a PM R w ith a 95% C I excluding 100. nI iofrot-I" On 00 J? _ft fots '-f3t 'fftt Oft fftt f0t0 ft g O 0t-0 I00 <nN Nt-O NOnO <NI tn- 0ft0 -fot ft O .9 S5! CftN" 00 rf 0rn0-I oo o ft" r-I 'ft d5 o o. ft CO ^x ft fftt Uft NvoO ft i>. H O x--> Respirable Crys nftI" t- 0nft0I" 00 <N NO I ON CN On I nr- ft os=i ft .ft X fffuttt -mfg9t Oft Silica 3 HUMAN HEALTH EFFECTS later, but the issue remained unresolved. In October 1996, an IARC expert working group reviewed the published experimental and epidemiologic studies of cancer in animals and workers exposed to respirable crystalline sil ica. The working group concluded that there is "sufficient evidence in humans for the carcino genicity ofinhaled crystalline silica in the form of quartz or cristobalite from occupational sources" [IARC 1997]. In June 1996, the direc tors of the ATS adopted an official statement of their Committee of the Scientific Assembly on Environmental and Occupational Health. This statement, prepared at the request of the American Lung Association Occupational Health Expert Advisory Group [ATS 1997], described the adverse health effects of expo sure to crystalline silica, including lung cancer. The ATS found the following: The available data support the conclu sion that silicosis produces increased risk for bronchogenic carcinoma. However, less information is available for lung cancer risk among silicotics who never smoked and workers who were exposed to silica but did not have silicosis. Whether silica exposure is associated with lung cancer in the absence of silico sis is less clear. NIOSH concurs with the conclusions of the IARC working group and the ATS. These con clusions agree with NIOSH testimony to OSHA, in which NIOSH recommended that crystalline silica be considered a potentional occupational carcinogen [54 Fed. Reg. 2521 (1989)]. This section, like the IARC review, focuses on lung cancer and discusses the epidemiologic studies that were the least likely to have results affected by confounding and selection biases. In "mixed" environments such as ceramics, pottery, or brick manufacturing, where expo sure may be to two or more polymorphs of crystalline silica, epidemiologic studies have usually not identified specific exposures to quartz or cristobalite. Therefore, excess lung cancers that occurred in these environments cannot be associated with exposure to a given polymorph but only with exposure to respira ble crystalline silica. The epidemiologic stud ies of cancer have mainly investigated work ers exposed to respirable crystalline silica in (1) ore mining, (2) quarrying and granite works, (3) ceramics, pottery, glass, refractory brick, and diatomaceous earth industries, or (4) foundries. The other major study group was workers with silicosis, usually identified from national or local registries. Studies of workers and silicotics that were not discussed in this document because they failed to meet the "least confounded" criterion have been criti cized for the following reasons [Checkoway 1995; McDonald 1995, 1996; Morgan and Reger 1995; Weill and McDonald 1996; Sea ton 1995; Weill etal. 1994; Agiusetal. 1992]: Inadequate, incomplete, or invalid expo sure assessment Potential selection and confounding bi ases in the cohort studies of compen sated silicotics Inadequate control of confounding from cigarette smoking and from concurrent workplace exposures (e.g., potential ex posure to radon progeny, arsenic, or die sel exhaust in ore mines and potential exposure to polycyclic aromatic hydro carbons in foundries) Inability to distinguish differences in fibrogenic and carcinogenic potencies of the various silica polymorphs Lack of evidence of an exposureresponse relationship Respirable Crystalline Silica 37 3 HUMAN HEALTH EFFECTS 3.4.2 Epidemiologic Studies of Lung Cancer Following a comprehensive review ofthe large body of published epidemiologic studies, IARC [1997] found that the following studies provide the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer: 1. U.S. gold miners [Steenland and Brown 1995b] 2. Danish stone industry workers [Guenel etal. 1989] 3. U.S. granite shed and quarry workers [Costello and Graham 1988] 4. U.S. crushed stone industry workers [Costello et al. 1995] 5. U.S. diatomaceous earth industry workers [Checkoway et al. 1993, 1996] 6. Chinese refractory brick workers [Dong et al. 1995] 7. Italian refractory brick workers [Merlo et al. 1991; Puntoni et al. 1988] 8. U.K. pottery workers [McDonald et al. 1995,1997; Cherry et al. 1995,1997; Bur gess et al. 1997] 9. Chinese pottery workers [McLaughlin et al. 1992] 10. Cohorts ofregistered silicotics from North Carolina [Amandus et al. 1991,1992] and Finland [Kurppa et al. 1986; Partanen et al. 1994] Although a few of these studies did not find a statistically significant association between occupational exposure to crystalline silica and lung cancer (Table 15), most of the studies did. Study results are often not uniform when a large number of epidemiologic studies are re viewed and a variety of populations and work environments are studied [IARC 1997]. In ad dition, IARC noted that the carcinogenicity of quartz or cristobalite "may be dependent on in herent characteristics ofthe crystalline silica or on external factors affecting its biological ac tivity or distribution ofits polymorphs" [IARC 1997]. Some of the least confounded studies reported that lung cancer risk tended to increase with -- cumulative exposure to respirable silica [i.e., Checkoway et al. 1993, 1996], -- duration of exposure [i.e., Merlo et al. 1991; Partanen et al. 1994; Costello and Graham 1988; Costello et al. 1995; Dong et al. 1995], -- peak intensity of exposure [Burgess et al. 1997; Cherry et al. 1997; McDonald et al. 1997], -- the presence of radiographically de fined silicosis [Amandus et al. 1992; Dong et al.1995], and -- length of followup time from date of sil icosis diagnosis [Partanen et al. 1994] (see Table 15). These observed associations, including the exposure-response associations, are unlikely to be explained by confounding or other biases. Thus overall, the epidemiologic studies sup port increased lung cancer risks from occupa tional exposure to inhaled crystalline silica (i.e., quartz and cristobalite) [IARC 1997]. 3.4.2.1 Updated or New Studies Since the IARC Review Two studies discussed in this section have re cently been updated: Checkoway et al. [1997, 1999] updated their previous mortality studies 38 Respirable Crystalline Silica e m ,2 Respirable Crystalline Silica Table 15. IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer 'O +iU--+ i o o s- os n' m* f-rj' irnn om\ oI i/SI i ni c4 o' 0t^>I\i ltmo->HI o 39 See footnotes at end o f table. (Continued) e m ,2 'O U +i--+ i o - s O 00 vq sao i--i On Cl Cl cC O- 00 t> vq i-h ci 40 Respirable Crystalline Silica Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer See footnotes at end o f table. (Continued) C 6JD ,2 +-+ O 5^ 2 Oa o!m Respirable Crystalline Silica Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer se-5M0 s uo 'O fst 3pft CZ5 C0 ft s .3 3 C/3 <D <D Vh | 5 S> U f-H CO ^ t-h | iJ ^ 0> pg 3 O n00 5n0 0500 41 See footnotes at end o f table. (Continued) (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer ft O s o U . ft d M ^ 0) O CZ3 a ^ M 7^ tfl s2 2^Q c4 < fff4Ottt> Q ft m g ft ro Q Oft 77 fOt oo o a> U o i--i f5fPt-1t iIOO-->nnn U^ on c N i ia a C^5 R c *2 CQ o Z zo U foftt foaft>t oo ZZ nI c4l ft I ci as oo ftI ft O 7 vq DO o- 8 6SucJ31 ^f+at* (* %5ca Z 73 o' o ft ft o *N & o\ ft o - OX) O <f0s-H> f0a^-H> ,f-a7tj ApA (Z3 ad ccd/3 o S f2d21 p "4<ha"Jo -ua C/3 2ya2 d ?' aa <o "4""' ft C/3 a "t OX) fot 'SaS; ft ^ ft ft +uf-i fct 00 si! o ^a ft 22 .3 Uo Os ^a oft 4> 6fAtl f3^t *3 ^ o 0> oC0/>3 ft 1C0/>3 >>C/3 'gft. fISt .a .2 h ea Sf s . C/3 . _4> C/3 -ft 0> o T8h '3 eg .232 2Al l| o^ Z ft fot -a a as d 9 ft ft ft>v co ja o-13- g7 o Os O <o O C/3 7 C/3 a ^ Sg fot- -oa "^ S ?o r 2a 2S s s^ O 73 ^ 7 ij >S S fDt ^td ^^ oo 3--1 G\ D ^, Oo CO -a Oo C/3 C/3 Oh o C/3 sS C/3 . .<D C/3 ft l| o ew C0/>3 4> o ^^ --(DI if--tn dO l|| u ^23 42 Respirable Crystalline Silica See footnotes at end o f table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer P e +iu--+ i u O o O OO', c4i O-x'f, oc4 See footnotes at end o f table. 33 33 _oo s'cfl o - o e OX) s *50 +s- CZ5 o >,, - fi - O+- o XfaJi O SN O 23 'aO>w> OV^OO) a* .g co *ofe: 1*O 'O g o S a> fqn ,o mh 'SJ T3 ts e &: r_o o 2 S ,2 ^ ~ o g g, TJ .1? 00 ss gs2 d a a o fcfi a ao On O', 3v: C/3 CO 60 hIJ g t> Q Respirable Crystalline Silica 43 e m ,2 o s- V! & Os 'O cn XtX> XiXn U rc-ii oo 1-H c41-H 44 Respirable Crystalline Silica Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer t> OO <N 00 I I l-H oo in i-H See footnotes at end o f table. (Continued) e 6JD ,2 ^ Respirable Crystalline Silica Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer - o e OX) o*50 ^ fi C+'3f-l ufooi - o+- T5 +uh+ s >> - = ou XfdJi 00 c4i oo SO SO r? <N m* m* (NI tm>I i>I i-h && s 'S-oS'S-gS'S'gS Tt 3 *C * < CQ * ^7* o ^ft? ot>` j--i Eh vi i--i Ch Vi '--i AA A 45 See footnotes at end o f table. (Continued) *c3 (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer c m ,2 'O rn Os i--< vo in o\ o\ 1-H O t> ^ u+i--+ i cIi mI" TIf H ^ Ifl ,sIf 'sI f rIo roI O rC On Cl I O n o' oo` ci 4 4 4 J, 'O O Cl O' Cl Cl o 3- 50 os ?H t> rn O* c4 rc* Cl 1-H Cl rc* Cl rc* C On rc oo oo cc* ci rc* rc* i-H O in' d oo rc O n d- o\ rc rc in orco mi--i io--i m ccii ci o f3ot O-D pA 3 C'fl o- ^ 3 3 +CZ5 00 of+-( a oo C/3 -OO3 0>c/5 da as cd T3 a> 3(D * . 3d ? d3 ig^ ft ZZj ft d Of) I of+-( 3C0 O o C/3 C/5 X 1 4O> US & _CZ3 o> -3 O0> r3 a_3 C/3 d O .3 ft 46 3 Respirable Crystalline Silica See footnotes at end o f table. Table 15 (C ontinued). IA R C *-review ed epidem iologic studies having the least confounded investigations o f an association between occupational exposure to crystalline silica and lung cancer s s s o u s OX) O Oi 3 S 2 S Sg cbc S`og = a ^ a 3 o Oft pi Xft o> 3 4> to o> 3 r3 r630 ofcppot ^Z<>31j> o3> v: 3 'p 0r2 s^ 1 3 S o> rn U 7p0\ OJ - S as OJ - s ou s? s Z s ft foItI O 2 ,-b IoP B 3 O3 'oft 2ft fiti f3t o pCA03-Z5D o- " 3I aOfl ft *540) ^ -3 534 3 +3- 3 3 Respirable Crystalline Silica c5 % 1 0 as CD U a53 up 44 S9 . s? o S 3 aOS ^S 0V, fofttn .oftn 47 47 aa C/3 C/3 C/3 C/3 33 p0> p4> oS >3 >3 47 3 HUMAN HEALTH EFFECTS of diatomaceous earth workers [Checkoway et al. 1993, 1996] by including deaths after 1987 and through 1994, and by analyzing lung cancer risk among workers with radiographic silicosis. Lung cancer mortality risk was highest in the highest category of cumulative exposure to respirable crystalline silica (rate ratio with no exposure lag period=2.11; 95% CI=1.07-4.1; rate ratio for 15-year exposure lag period=1.05; 95% CI=0.99-1.11). The rate ratios were adjusted for the effects of age, cal endar year, duration of followup, and ethnicity. Among workers with radiological silicosis (ILO category >1/0 or large opacity; n=81), the lung cancer SMR was 1.57 (95% CI= 0.43-4.03) [Checkoway et al. 1999]. For work ers without silicosis (ILO category <1/0), the SMR was 1.19 (95% CI=0.87-1.57). The SMRs were adjusted for age and calendar year and were based on the expected number of deaths for white U.S. males. For the nonsilicotic workers, a statistically significant, positive dose-response relationship (P=0.02) was ob served between SMRs for lung cancer and cat egory of cumulative respirable silica exposure. The SMRs ranged from 1.05 in the lowest ex posure category (<0.5 mg/m3- year, 13 deaths, 95% CI=0.56-1.79) to 2.40 in the highest ex posure category (>5.0 mg/m3 - year; 12 deaths, 95% CI=1.24-4.20). For the 81 workers with radiographic silicosis, an SMR >1.0 was ob served only in the highest exposure category (i.e., >5.0 mg/m3 - year) (4 deaths observed; SMR=2.94; 95% CI=0.80-7.53). These results suggest that silicosis may not be a necessary condition for silica-related lung cancer. How ever, radiographic surveillance of this cohort did not extend beyond the dates of employ ment termination, and autopsies were not rou tinely conducted [Checkoway et al. 1999]. Cherry et al. [1998] finalized the preliminary results of a nested case-control study of 52 lung cancer deaths in 5,115 pottery workers (see Burgess et al. [1997], Cherry et al. [1997], and McDonald et al. [1997] in Table 15). After adjustment for smoking and inclusion of a 20-, 10-, or 0-year lag period, mean respirable silica concentration (i.e., estimated daily 8-hr TWA airborne concentrations in gg/m3) was associ ated with lung cancer (P<0.008 for each lag period): Lag 20 yr 10 yr 0 yr OR 95% CI 1.60 1.11-2.31 1.66 1.14-2.41 1.67 1.13-2.47 However, exposure duration and cumulative silica dust exposure were not significantly as sociated with lung cancer mortality, regardless of lag time [Cherry et al. 1998]. The presence of small, parenchymal radiographic opacities (ILO category >1/0) was not related to lung cancer mortality before adjustment for smok ing (P=0.78) or after adjustment for smoking and mean silica concentration (P=0.68). The authors concluded "that crystalline silica may well be a human carcinogen" [Cherry et al. 1998]. Other studies published since the IARC review also investigated exposure-response associa tions for lung cancer and exposure to crystal line silica. Rafnsson and Gunnarsdottir [1997] reported that the incidence of lung cancer cases among 1,346 diatomaceous earth workers in Iceland was not statistically significant for workers who had 9 years before start of followup and who were employed > 5 years (standardized incidence ratio [SIR] based on 3 cases observed=2.70; 95% CI=0.56-7.90) or employed <5 years (SIR based on 2 cases observed=1.19; 95% CI=0.14-4.30). de Klerk and Musk [1998] conducted a cohort study of 2,297 surface and underground gold miners in western Australia who participated in surveys of respiratory symptoms, smoking habits, and lung function in 1961, 1974, and 1975. Eighty-nine percent of the cohort was 48 Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS traced to the end of 1993 for trachea, bronchus, and lung cancer mortality and incidence of compensated silicosis (i.e., compensation awarded by the Pneumoconiosis Medical Board). A nested case-control analysis of the 138 lung cancer deaths found that lung cancer mortality was related to log total cumulative silica dust exposure after adjustment for smoking (cigarette, pipe, or cigar) and for the presence of bronchitis at survey (relative rate=1.31; 95% CI=1.01-1.70). However, the effect of cumulative silica dust exposure on lung cancer mortality was not significant after adjustment for smoking, bronchitis, and com pensation for silicosis (relative rate=1.20; 95% CI=0.92-1.56). Other silica exposure variables (i.e., duration of underground or surface employment and intensity of under ground or surface exposure) were not signifi cantly related to lung cancer mortality (P>0.15) after adjustment for smoking and bronchitis. Cigarette smoking (relative rate=32.5; 95% CI=4.4-241.2 for >25 cigarettes smoked per day), incidence of a compensation award for silicosis after lung cancer diagnosis (relative rate=1.59; 95% CI=1.10-2.28), and presence of bronchitis at survey (relative rate=1.60; 95% CI=1.09-2.33) were significantly related to lung cancer mortality [de Klerk and Musk 1998]. The results ofthis study do not support a relationship between lung cancer and silica ex posure in the absence of silicosis (i.e., a com pensation award for silicosis after lung cancer diagnosis). However, controlling for silicosis compensation and bronchitis may have masked a silica effect because both are markers of silica exposure. Hnizdo et al. [1997] conducted a nested case-control study of lung cancer deaths in a cohort of 2,260 white South African under ground gold miners. (A lung cancer mortality cohort study had been conducted earlier [Hnizdo and Sluis-Cremer 1991]). The mineral content ofthe rock in the gold mines was mostly quartz (70%-90%), silicates (10%-30%), pyrite (1%-4%), and heavy minerals with grains of gold and uranium-bearing minerals (2%-4%). Seventy-eight miners who died from lung cancer (69 ofthe 78 had a necropsy) during 1970-1986 were matched by year of birth with 386 control subjects from the same cohort [Hnizdo et al. 1997]. Conditional logis tic regression models were used to analyze the relationship of lung cancer mortality with ciga rette smoking (pack-years), cumulative "dust" exposure (mg/m3 year), years ofunderground mining, incidence of radiographic silicosis (ILO category >1/1 diagnosed up to 3 years be fore death of a matched case), and uranium production or uranium grade of the ore in the gold mine. Radon progeny measurements in the gold mines were not available. Lung cancer mortality was associated with cig arette smoking, cumulative dust exposure (lag time was 20 years from death), duration of un derground mining (lag time was 20 years from death), and silicosis. The best-fitting model predicted relative risks of 2.45 (95% CI= 1.2-5.2) for silicosis and the following relative risks for various pack-years of smoking: Pack-years <6.5 6.5-20 21-30 >30 95% CI -- 0.7-16.8 1.3-25.8 3.1-56.2 Relative risk 1 3.5 5.7 13.2 The authors stated that variables representing uranium mining were not significantly related to lung cancer mortality (modeling results for these variables were not presented) [Hnizdo et al. 1997]. The authors proposed three explana tions for their results: Miners with high dust exposure who de velop silicosis have increased lung can cer risk. Respirable Crystalline Silica 49 3 HUMAN HEALTH EFFECTS High silica dust exposure concentrations are important in the pathogenesis of lung cancer, and silicosis is coincidental. High silica dust exposure concentrations are a surrogate measure of exposure to radon progeny [Hnizdo et al. 1997]. 3.4.2.2 Lung Cancer Meta-Analyses Meta-analysis and other systematic literature review methods are useful tools for sum marizing exposure risk estimates from a large amount of information [Mulrow 1994]. Meta analyses or summary reviews of epidemiologic studies of silicotics with lung cancer have been conducted by investigators in the United States [Steenland and Stayner 1997; Smith et al. 1995] and Japan [Tsuda et al. 1997]. IARC is performing a pooled analysis of epidemiologic data from several cohorts to investigate lung cancer risks in nonsilicotic workers. Steenland and Stayner [1997] and IARC [1997] found that the majority of studies of silicotics reported statistically significant ex cess lung cancer risks across different coun tries, industries, and time periods while con trolling for the effects of cigarette smoking [Steenland and Stayner 1997; IARC 1997]. Exposure-response gradients were also ob served. The summary relative risk was 2.3 (95% CI=2.2-2.6) for 19 cohort and casecontrol studies of silicotics--excluding studies of miners and foundry workers because of potential exposure to other carcinogens, and omitting autopsy studies and proportionate mortality studies because of possible selection biases [Steenland and Stayner 1997]. Fifteen ofthe 19 studies directly or indirectly controlled for the effects of smoking. The summary rela tive risk of 16 cohort and case-control studies* *Cohort size ranged from 969 to 6,266 workers. of silica-exposed workers was 1.3 (95% CI= 1.2-1.4)--a moderate and statistically signifi cant relative risk estimate [Steenland and Stayner 1997]. Eight of the 16 studies con trolled for the effects of smoking, either di rectly or indirectly. Another meta-analysis of 23 lung cancer stud ies of silicotics (including 14 of the studies an alyzed by Steenland and Stayner [1997]) re ported a pooled risk estimate of 2.2 (95% CI= 2.1-2.4) [Smith et al. 1995]. The statistically significant pooled risk estimates from both meta-analyses strongly support an association between silicosis and lung cancer. The in creased risk of lung cancer for silicotics is also supported by the following [IARC 1997]: 1. The magnitude of the risk estimates (i.e., most studies reported risks greater than 2.0 for silicotics after adjusting for the effects of cigarette smoking--compared with ex posed nonsilicotics or the general popula tion) 2. The observation of exposure-response gra dients with various indicators of exposure 3. Consistent findings of excess risk in differ ent countries, industries, and time periods 4. Two studies that provided reasonable evi dence for an unconfounded association (i.e., Amandus et al. [1991, 1992, 1995] and Partanen et al. [1994], an update of Kurppa et al. [1986]) Tsuda et al. [1997] conducted a lung cancer meta-analysis of pneumoconiosis or silicosis studies (excluding asbestosis). Lung cancer risk estimates were pooled from 32 mortality studies published from 1980 to 1994. The esti mated rate ratios were similar to those reported by Steenland and Stayner [1997] and Smith et al. [1995]: 50 Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS Rate ratio All studies (321) . . . . . . 2.74 Cohort studies only (25 of 32)............ . . . 2.77 Case-control studies (5 of 32)............... . . . 2.84 95% CI 2.60-2.90 2.61-2.94 2.25-3.59 3.4.3 Other Cancers Mortality studies ofworkers have reported sta tistically significant excesses of deaths from stomach or gastric cancer in iron ore miners [St. Clair Renard 1984; Lawler et al. 1985; Mur et al. 1987], Canadian gold miners [Muller et al. 1983; Shannon et al. 1987; Miller et al. 1987; Kusiak et al. 1993b], lead and zinc min ers [Belli et al. 1989], brick production work ers [Katsnelson and Mokronosova 1979], foundry and other metal workers [Neuberger andKundi 1990], jewelry workers [Hayes etal. 1993; Dubrow and Gute 1987; Sparks and Wegman 1980], farmers (reviewed by Blair and Zahm [1991]), and farm workers [Stubbs et al. 1984] (reviewed by Zahm and Blair [1993]). A recent case-control study of 250 male hospital patients in Canada found a sta tistically significant excess ofpathologically confirmed stomach cancer among the 25 pa tients who reported a history of "substantial" occupational exposure to crystalline silica compared with 2,822 controls (OR=1.7; 95% CI=1.1-2.7 after adjusting for the effects of age, birthplace, education, and cigarette smok ing) [Parent et al. 1998]. However, in a review of epidemiologic studies of gastric cancer and dusty occupations, Cocco et al. [1996] noted that because most studies did not adjust for the effects of confounding factors or assess a dose-response relationship, evidence was in sufficient to conclude that silica is a gastric carcinogen. ^Two of the studies are proportionate mortality studies for which rate ratios were not reported. For workers who may have been exposed to crystalline silica, there have been infrequent reports of statistically significant excesses of deaths or cases of other cancers such as naso pharyngeal or pharyngeal cancer [Chen et al. 1992; Carta et al. 1991], salivary gland cancer [Zheng et al. 1996], liver cancer [Chen et al. 1992; Hua et al. 1992], bone cancer [Forastiere et al. 1989; Steenland and Beaumont 1986], pancreatic cancer [Kauppinen et al. 1995], skin cancer [Partanen et al. 1994; Rafnsson and Gunnarsdottir 1997], esophageal cancer [Pan et al. 1999; Xu et al. 1996; Belli et al. 1989], cancers of the digestive system [Decoufle and Wood 1979], intestinal or peritoneal cancer [Amandus et al. 1991; Goldsmith et al. 1995; Costello et al. 1995], lymphopoietic or hema topoietic cancers [Redmond et al. 1981; Silverstein et al. 1986; Steenland and Brown 1995b], brain cancer [Rafnsson and Gunnarsdottir 1997], and bladder cancer [Bravo et al. 1987]. Again, an association has not been established between these cancers and exposure to crystal line silica. 3.5 Other Nonmalignant Respiratory Diseases and Related Conditions 3.5.1 COPD 3.5.1.1 Definition COPD describes chronic airflow limitation that is usually irreversible [ATS 1987; Becklake 1992; Snider 1989]. COPD includes four interrelated disease processes: chronic bron chitis, emphysema, asthma [Barnhart 1994; Snider 1989], and peripheral airways disease [ATS 1987]. Cigarette smoking is a major cause of COPD, but community air pollution and occupational exposure to dust, particularly among smokers, also contribute to COPD [Becklake 1992]. Respirable Crystalline Silica 51 3 HUMAN HEALTH EFFECTS 3.5.1.2 Epidemiologic Studies Although thousands of studies have been pub lished about occupational exposure to nonorganic dusts and COPD, only 13 studies of4 co horts of silica-exposed workers met rigorous methodologic criteria for a review conducted by Oxman et al. [1993]. Three of the cohorts were coal miners and one was South African gold miners. According to Oxman et al. [1993], the studies provided evidence that exposure to gold mine dust is an important cause of COPD, particularly in smokers, and that the risk of COPD appeared to be greater for gold miners than for coal miners. 3.5.2 Asthma Crystalline silica has not been identified as an oc cupational asthma-inducing agent [Chan-Yeung 1994], and no published epidemiologic studies have specifically investigated whether asthma is related to crystalline silica dust exposure. 3.5.3 Chronic Bronchitis 3.5.3.1 Definition Chronic bronchitis is clinically defined as the occurrence of chronic or recurrent bronchial hypersecretion (i.e., a productive cough) on most days of the week for at least 3 months of 2 sequential years [ATS 1987, 1995; Barnhart 1994] . The excess mucus secretion should not be related to a disease such as TB [ATS 1987, 1995] . Chronic bronchitis has been associated with both airflow obstruction and abnormali ties in gas exchange [Barnhart 1994]. Although the terms "industrial bronchitis" and "occupa tional bronchitis" traditionally refer to chronic bronchitis that is associated with occupational exposure, bronchitic symptoms may also occur after occupational exposures that are acute or that last less than 2 years. An association be tween reduced ventilatory function and bron chitic symptoms has been reported in studies of workers exposed to coal dust, asbestos, or dust that contained crystalline silica [Barnhart 1994]. However, cigarette smoking is also as sociated with chronic bronchitis and must be considered when investigating the relationship between occupational exposures and bron chitic symptoms [Barnhart 1994; ATS 1997]. 3.5.3.2 Epidemiologic Studies Statistically significant (P<0.05) relationships independent of smoking were found between exposure* to gold mine dust and chronic bronchitis or chronic sputum production in cross-sectional studies of gold miners in South Africa [Wiles andFaure 1977; Cowie and Mabena 1991] and Australia [Holman et al. 1987]. However, no statistically signifi cant relationships independent of smoking were found between exposure and chronic bronchitis or bronchitic symptoms in cross sectional studies of molybdenum miners [Kreiss et al. 1989b], uranium miners [Samet et al. 1984], taconite miners [Clark et al. 1980], Indian agate grinders and chippers [Rastogi et al. 1991], and a populationbased study of South African gold miners [Sluis-Cremer et al. 1967] (Table 16). Wiles and Hnizdo [1991] studied the relation ship between mortality, airflow obstruction, and mucus hypersecretion in 2,065 South Afri can gold miners. They found that after stan dardization for airways obstruction, mucus hypersecretion was not related to mortality from COPD (54 deaths). However, mucus hypersecretion remained significantly related to mortality from ischemic heart disease and all causes of death, even after adjustment for years of cigarette smoking and particle-years of exposure to gold mine dust [Wiles and Hnizdo 1991]. ^Cumulative exposure, duration of exposure, or inten sity of exposure. 52 Respirable Crystalline Silica u ON f3Ot 0-D pCA3Z5 3 o^ Its On i O dLi Respirable Crystalline Silica Table 16. E pidem iologic studies o f b ro n ch itis in w o rke rs exposed to silica dust TsJ rf33 o00 oo o s >> 8^ O kS ft C3 0> CS 0> CS 00 roo a 53 See footnotes at end o f table. (Continued) T able 16 (C ontinued). E pidem iologic studies o f b ro n c h itis in w o rke rs exposed to silica dust S S o U 0D .S 50 !h .2.-2 2O S <1 ^ *43> S3 o 8 " o" B| C0 3 OO f1 C0 C0 0>(ShO '<-< 33 o o sS ft ri NO 'r) 3- ^3 r33 S OO -3 s .I ^ C0 Ox0f>t cj 3cr 3O 3) O rSd3 oo 3^ 33*34 ^34c3/>D 3 4-h 3 3 P > r 8 Q g O Qh T3 3 ^ 50 C0 C0>0 X O 3 _0> 50 C0 a^ Jp I fSfi 3O >< u s nI On T; ON nI Jm 3% 50 50 K '"go sw m* 1 a 3 W2) aOn cs ,0 CO 5 f3ot 0-D 3pA (Z3 3 T5 .Sf e" ft S =^ 1 - 2 5W +- ft 3 s3 XJ on q 1 rsD< <sSL> 3<_3 3 u112 1co 54 Respirable Crystalline Silica See footnotes at end o f table. (Continued) 0> T able 16 (C ontinued). E pidem iologic studies o f b ro n c h itis in w o rke rs exposed to silica dust <a 20 s oOn soo f3Ot 6-D 3pA CZ5 o o Ho oI O3f) CI\ oI O3f) oI oI *3 I f+o-( oa a C/3 (D t-H d^a3> oi-hI\ T3 S 1 to 'd 'f 2 a O s *d g A -tooodi Ip 6a. >0. fl H p d a U o Si w Of) <N a d * * d o^ s EE 0 A a.1ti rgdi 3a,, g s -a .d .o o ^ad> a d^ t> I--n Respirable Crystalline Silica See footnotes at end o f table. (Continued) 55 u ON r--i -v 3 56 Respirable Crystalline Silica Table 16 (C ontinued). E pidem iologic studies o f b ro n c h itis in w o rke rs exposed to silica dust See footnotes at end o f table. (Continued) u ON 620 -- Al fl Respirable Crystalline Silica Table 16 (C ontinued). E pidem iologic studies o f b ro n c h itis in w o rke rs exposed to silica dust 57 See footnotes at end o f table. (Continued) T able 16 (C ontinued). E pidem iologic studies o f b ro n c h itis in w o rke rs exposed to silica dust o 5B e s s o u P on +- .S d O o5B - 2 T P vn C/3 CD u ON P4> CXD n-j CD d Od JJSwd 23 03 rr-S 'oO&XD od d 'S tog 'S ^d dCoXCf/D3t -Sd2 ^53 os ao "X d cd i op d9 03 __ a S3 O CD CT Bo o _fi o V bo . ' dwoj ocVd XOh X-CD CD - ^dK ^oo' --<V _^g CD V 5 -5 _KS CdaD ^ CL) S % o3 OD 3'd doo 3 c/3 d <D!-H o3 2g .1 I C/3 CD CD 'B oC/3 p CD P O v: P P C/3 ft do 6D pA d C/5 C/3 I C>D P rbP C/5 d o3 O O c* 03 ft d o >> d C/3 P -4-* o IS 32 <a +- bid d od o- P o+p 0d3 C/5 CD C/5 58 C/3 3 C/3 (21 0d 1 C/3 C/3 C/3 O CD .a o sd -d p 060 ft L. CD P O r& p o1 S3 2 8.S ai B B Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS A mortality study of workers in "dusty trades" reported a statistically significant number of deaths from bronchitis when compared with mortality rates for other white males in the United States (P<0.05; 6 deaths observed; 0.8 deaths expected) [Amandus et al. 1991]. The discrepancies among the cross-sectional studies ofbronchitis in quartz-exposed popu lations may be attributable to the presence or absence of concurrent exposures among the cohorts that have been studied [Kreiss et al. 1989b]. Particle size is another factor that may have affected the results. The dust in one work environment may have had a higher proportion of particles that were not of respirable size compared with dust in an other work environment. Larger-sized dust particles may be responsible for large-airways diseases such as chronic bronchitis, whereas respirable dust particles are responsible for lung parenchymal diseases such as silicosis [Morgan 1978]. In addition to physical size, the shape and density of inorganic dust parti cles also influence where they are deposited in the airways and whether they can be cleared from the airways [Becklake 1985]. 3.5.4 Abnormalities in Pulmonary Function Tests 3.5.4.1 Definition Pulmonary function tests measure lung vol umes (e.g., vital capacity [VC]), air flow (e.g., expiratory volume in 1 second [FEV1]), blood gas exchange, and other aspects of lung func tion [Rosenstock 1994]. Spirometric pulmo nary function tests routinely performed are forced vital capacity (FVC), FEV1, and VC [Parkes 1982]. Lung function tests alone can not diagnose any particular disease [Parkes 1982]; however, they are an important part of Respirable particles have aerodynamic diameters less than approximately 10 p.m. the clinical evaluation ofworkers with occupa tional lung diseases. Nonoccupational factors (e.g., the subject's age, height, racial group, and smoking habit) as well as the quality and interpretation of the spirometric testing can in fluence pulmonary function test results [Parkes 1982; Rosenstock 1994; Crapo 1994]. In gen eral, an FEV1 loss of about 20 to 30 ml/year in nonsmokers or >60 ml/year in smokers [Crapo 1994] may suggest a decline greater than ex pected. Wagner [1994] suggests further clini cal evaluation of workers with a 15% decrease from the baseline percentage of predicted value for FEV1 or FVC (e.g., from 105% to 90% of the predicted FEV1). Loss of FEV1 has been associated with an in creased risk of death from various diseases, including COPD [Crapo 1994; Tockman and Comstock 1989; Anthonisen et al. 1986; Foxman et al. 1986]. Although pulmonary function tests can define and measure respira tory impairment, they are not a diagnostic tool for silicosis or a measure of silica exposure [Wagner 1997], because no single pattern of pulmonary function abnormality is associated with silica exposure or silicosis [Wagner 1997; Weill etal. 1994; ATS 1997]. 3.5.4.2 Epidemiologic Studies-- Quantitative Estimates of Dust-Related Loss of Lung Function Most epidemiologic studies of pulmonary function and occupational exposure to respira ble crystalline silica are cross-sectional studies that do not provide quantitative modeling of cumulative dust exposure. They report occupa tionally related annual declines in ventilatory function in workers with and without silicosis (i.e., gold and other hard-rock miners, iron ore miners, coal miners, talc miners, slate workers, and kaolin workers). Details of these studies are reported elsewhere [ATS 1997; Becklake Respirable Crystalline Silica 59 3 HUMAN HEALTH EFFECTS 1985, 1992; Eisen et al. 1995; NIOSH 1995a; EPA 1996; Graham et al. 1994]. Thirteen studies with quantitative dust expo sure data for four silica-exposed cohorts found statistically significant associations between loss of lung function (i.e., FEV1, FVC) and cumulative respirable dust exposure in coal miners and South African gold miners [Oxman et al. 1993]. The study of goldminers [Hnizdo 1992] estimated that a 50-year-old, white South African gold miner (nonsmoker) who was exposed to gold mine dust (contain ing 0.09 mg/m3 of crystalline silica) at an aver age respirable concentration of 0.3 mg/m3 for 24 years would lose 236 ml of FEV1 (95% CI= 134-337). This loss is equivalent to about half of the estimated loss of FEV1 in a typical U. S. male (nonminer) who smoked one pack of cigarettes per day for 30 years (i.e., 552 ml [95% CI=461-644]) [Dockery et al. 1988; Hnizdo 1992]. The combined effects of respi rable dust exposure and smoking on the loss of FEV1 were additive [Hnizdo 1992]. Epidemiologic studies of Vermont granite workers provided quantitative predictions of FEV1 loss based on cumulative past exposure to granite dust. As shown in Table 17, the pre dicted FEV1 loss for Vermont granite workers is 3 to 4 ml per mg/m3 year for cumulative exposure to granite dust and 2.9 ml per mg/m3 year for cumulative exposure to quartz dust. This estimate represents a loss of about 6.5 ml of FEV1 for a working lifetime (i.e., 45 years) of exposure to crystalline silica at the current NIOSH REL of 0.05 mg/m3. However, the findings of Theriault et al. [1974b] were based on measurements that may have been inaccurate. In 1979, Graham et al. [1981] administered pulmonary function test ing to about 73% (n=712) ofthe workers tested in 1974 and found small annual increases in FEV1. These researchers concluded that "tech nical deficiencies in the previous studies led to exaggerated and erroneous estimates of loss." The significance of predicted losses can be compared with the annual estimated FEV1 de cline for a nonminer who smokes one pack of cigarettes per day (10 ml/year) [Xu et al. 1992] or with the approximate annual FEV1 decrease in men over age 25 (25 to 30 ml/year) [Bur rows 1986]. A cross-sectional study of 389 male residents of a U.S. hardrock mining community also predicted FEV1 loss [Kreiss et al. 1989b]. Mul tiple regression analyses found a significant difference (P<0.05) in the mean FEV1 for non smokers with dust exposure (96% of predicted FEV1) compared with that of nonsmokers without occupational dust exposure (101% of predicted FEV1) [Kreiss et al. 1989b]. 3.5.5 Emphysema 3.5.5.1 Definition Emphysema is the abnormal enlargement of the air spaces distal to the terminal bronchiole with destructive changes in the alveolar walls [ATS 1987]. Obvious fibrosis is not present [ATS 1987, 1995; Barnhart 1994; Becklake 1992], although small emphysematous spaces are frequently seen radiographically around the edges of large silicotic masses [Weill et al. 1994]. The diagnosis of emphysema is defined by pathologic criteria, and more recently by the presence of avascular spaces on computed tomographic (CT) scans of the lung [Barnhart 1994; Hayhurst et al. 1984]. Clinical signs in clude hyperinflation on chest radiographs, in creased total lung capacity, reduced FEV1, re duced diffusing capacity for carbon monoxide (DLCO) [Barnhart 1994], and weight loss [Stulbarg and Zimmerman 1996]. Emphysema is caused mainly by destruction of the lung pa renchyma from excess proteolytic enzymes. One cause of excess proteolytic enzymes and the premature development of emphysema is the rare homozygous deficiency of the protein a1-antitrypsin [Laurell and Eriksson 1963; Stulbarg and Zimmerman 1996]. Excess 60 Respirable Crystalline Silica Table 17. Loss o f lung fu n c tio n (F E V J * associated w ith cum ulative exposure to respirable granite dust 'Forced expiratory volume in 1 second. fIn dropout group (i.e., subjects lost to follow up). No predicted loss in survivor group. *Per dust-year (i.e., granite shed dust exposure o f 0.52 mg/m3 fo r 40 hr/week for 1 yr). Included silicotics. 'Per quartz-year (i.e., quartz dust exposure o f 0.05 mg/m3 fo r 40 hr/week for 1 yr). fCtD 3 ft ft <D 3 O^ 3 3 rr) CD CD H ^ OO cfnt > ^ i ON 3 CD CD ss ft ftft O oo !--< a) i -e C/3 O ft 3 3-i cd 3 q_> 3 3 3 P cd CD B u M & S CD C/3 3 CD 3 ^3 /--' O3 3 > o ft& > .a o 3 O > f3t O Of) a o ft 3 C-" oo ft 3O O ft CD W5 f3t Of) CD 3V oo y ~ 2> 3 C/3 ft O ft ft' 3 .2 fCtDI *O 00 ft ft ft ft CD do 3 3 I--1 WO c 2 ft os CD < _ft 2 W5 3 3O 3 33 O3 ft O CD W5 3 s s g 3 S*h f > f-s ft a aO ,,ft 3 CD o o tj CD CD ft ft 3 3 CD CD CD P 3 ft CO a wX to2 X CD X CD >< ft ft -N s Js?> to ^ WD to too ft > Sh <*) ft tCfNt OftN II ft ft) o 5 spA ft) ft ft m rj fot fsot wo A (3/} fot f3t . cwo fot *ss 2 ft ft f^3t ts*o Sn C/5 o -uo3 ft CD ft nd Cc/D) ON 3 O ffi3 O 7 fto 73 CD Of) ft 3 n CD ft ft -S3 .2 a3'So 2 S3 ft S |O ft ft ft > p i tp 00 3 M 3 3 3 3 CD O o % 3 3 N* d w a -5 P 5N P +-> 33 <D CD to 55 ft 3 ^ CD cd ft _c/> ft On ZL f3t Respirable Crystalline Silica oft X f3t 32 Sh 3 oa ft %3 CD N co f3t 3 tft ^ ON O3 3 o a ft.2 p CD in ftO 3 3 3 cd 3 CO ^ c/)' y I CD m CN fCtD H CO ft o C-" 3 ft 3P 3 xo Sh Of) O 0s- U o Of) 3 O On W5 ft ft IN ON C/1 ^ ft . CD 3 E-- 61 3 HUMAN HEALTH EFFECTS proteolytic enzymes can also occur when there is excessive recruitment ofpolymorphonuclear leukocytes (e.g., from damage caused by ciga rette smoke) [Stulbarg and Zimmerman 1996]. Emphysema is classified microscopically by type based on the distribution of enlarged air spaces and destruction. The main types of em physema include centriacinar, focal, centrilobular, panacinar, distal acinar, and irregular (scar) [Barnhart 1994; Parkes 1994]. Focal and centrilobular emphysema are the types fre quently associated with environmental and oc cupational exposures. Focal emphysema is as sociated with exposure to coal dust, and centrilobular emphysema is commonly found in the upper lobes of the lungs of cigarette smokers and others exposed to chronic irritants [Barnhart 1994]. However, findings from a study of postmortem lung examinations showed that panacinar or centriacinar were the predominant types of emphysema found in the lungs of white South African gold miners [Hnizdo et al. 1991]. 3.5.5.2 Epidemiologic Studies Studies of emphysema in silica-exposed work ers (excluding coal miners) show conflicting results: it is not clear whether silica exposure is associated with emphysema in all exposed workers or mainly in silica-exposed workers who smoke. In these studies, researchers have investigated cohorts of South African gold miners, usually by combining historical data about occupational exposures and smoking with postmortem examination of the lungs. (Attending physicians in South Africa who know or suspect that their deceased patient was a miner are legally required to remove the cardiorespiratory organs and send them to the Medical Bureau for Occupational Diseases if permission is granted by the next-of-kin [Goldstein and Webster 1976]). Of the five studies presented in Table 18, one found that a significant relationship (P<0.05) independent of smoking and silicosis existed between gold mine dust exposure** and em physema [ et al. 1987]. Two studies found no relationship between emphysema and years of mining [Chatgidakis 1963; Cowie et al. 1993]. A study of emphysema type in 1,553 miners with autopsy examinations found that centriacinar emphysema was more common in smok ers, whereas panacinar emphysema was more common in nonsmokers; exposure to gold mine dust was related to both types. A miner who had worked 20 years in high-dust occupa tions was 3.5 times more likely (95% CI= 1.7-6.6) to have emphysema (i.e., an emphy sema score >30%) at autopsy than a miner who did not have a dusty occupation. However, the authors stated that this result was likely to "be true of smoking miners only because there were only four nonsmokers with an emphy sema score between 30% and 40%" [Hnizdo et al. 1991]. Later, a study of 242 miners who were lifelong nonsmokers found that the sever ity of emphysema at autopsy was not related to most recent lung function measurements or to years of gold mining, cumulative dust expo sure, or parenchymal silicosis after adjustment for age at death [Hnizdo et al. 1994]. All of the studies but two [Becklake et al. 1987; Hnizdo et al. 1994] found that the presence of emphysema was significantly associated with silicosis. 3.5.6 Nonmalignant Respiratory Disease (NMRD) Mortality Epidemiologic studies of silica-exposed work ers [Checkoway et al. 1993, 1997; Chen et al. 1992; Cherry et al. 1998; Brown et al. 1986; Costello and Graham 1988; Costello et al. 1995; The number of shifts worked in mining occupations with high dust exposure. 62 Respirable Crystalline Silica  o <hoi* gC55 wcua fS?i T3 fi Respirable Crystalline Silica Table 18. E pidem iologic studies o f em physem a in w o rke rs exposed to silica dust 63 See footnotes at end o f table. (Continued) Table 18 (C ontinued). E p id e m io lo g ic studies o f em physem a in w o rke rs exposed to silica dust go g , .Q3 S So U oao Sj W) Tp "Via SoO(--O5 Q^O-_.o-^OtcModhoTC!33phd) ?s O to 3^5 22 TP 5=^ aS oOta<o>u JoC>CB>f>Ll ^.1S^3h ^-Oa, o &0 . -a 2fl P I W) ^ & > 1 a a> cd b M % s cd heo*J 0> 0> O PO" "OWC) '5b ^ -S O H O TP <t> 6sJD 2to 5n -2.fi TP o s < a> u oITs) &to u3to VP? 08 to til "- 4to> a S0m> S<toU 3 U 3 ou ,c S ^ 2- o A OJD pA3 z^ <U ;QJ TP c3 ^ao> 2S3P a3oA&JD C3Z) Ito TSp 'R I soI *a3o 0I> K5*'* #atCo>l S o a> tp c2d Ta^p> cd TaP> !' 1' 1"sofi W) S^ ,2f B ft '^OS. uo Sga ^ -3 O 3 CZ) ^ T3cPd pp 3 CO/1 64 Respirable Crystalline Silica See footnotes at end o f table. (Continued) Table 18 (C ontinued). E p id e m io lo g ic studies o f em physem a in w o rke rs exposed to silica dust ON V3 2 2s in cn ft fftt o 0-D pAft CZ5 o0 oft Xa> 1 CZJ fftt 'fftt ft r. I-Td-) 5f>t OO ^M .3 f o -?c <oH a fs So ^ f ^og o -TS -4--'" J^sQ3 S?<SD -a fT-IORgrilt fl WSS"f II 5 Uf-Hv/ S 3 TfOt 3a> cn O rft ".Nft lQ--H\ ft On ffi -- fit fOOtN- 1ft ds> sB o-.8a Ift rj ft ^5 -Offtt gB 5: ft o4> Sfat *f32t ftO! Respirable Crystalline Silica See footnotes at end o f table. (Continued) 65 S S o U T able 18 (C ontinued). E p id e m io lo g ic studies o f em physem a in w o rke rs exposed to silica dust 0D .S 2</) U .2.-2 o S <1 k. <D trs3i "U oPa >- C/3 3 U SICi ON 3 C* </) ft 33 o o- O !m pA ^ o &D &.c s As 3 Z g a TJ ^ ft c/a C 55 cd 3 o . &D W) g CA3Z5 8 CD f&t 3 fOt 3 *? 3 ft s*s ^. 'S oN a E3 3 VI c3s +- s3o <u C* -a3 7*1 O CD 7 .3 O 7 >> o -ft ftV ^ 3 ft > OC/3 3 Mft -3 fot 'So3 3s 53 73 3 4_, O CD C/3 O rft 7N 0fftt\ c& S5 p:z f-n i--> .C3D 7O CD P 2Cf/Dt `33C S ^ - ' 3 ft Hi a3 7--i <D pS po S -S CD I'xCDj3- fr3tj pOc3 Oftn Al KS ft ^SS3 cwd) 'fat aS aS 7ft d x tf>t CD < 66 Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS Costello 1983; Steenland and Brown 1995b; Steenland and Beaumont 1986; Thomas and Stewart 1987; Thomas 1990] and silicotics [Goldsmith et al. 1995; Brown et al. 1997; Rosenman et al. 1995] found significant in creases in mortality from NMRD, a broad cate gory that can include silicosis and other pneumoconioses, chronic bronchitis, emphy sema, asthma, and other related respiratory conditions. The studies ofU.S. gold miners [Steenland and Brown 1995b], U.S. diatomaceous earth work ers [Checkoway et al. 1993, 1997], silicotic men in Sweden and Denmark [Brown et al. 1997] and parts of the United States [Rosen man et al. 1995], and U.S. pottery workers [Thomas and Stewart 1987] reported mortality ratios (SMRs or PMRs) for some categories of NMRD. However, the other studies either did not report SMRs for categories of NMRD or did not separate silicosis deaths from other cat egories of NMRD, thus limiting any conclu sion about the association of silica exposure with death from a specific COPD based on death certificate data. Some studies have reported exposure-response trends for NMRD and silica exposure. The study of diatomaceous earth workers found a statistically significant exposure-response trend for cumulative exposure to respirable crystalline silica and NMRD mortality after adjustment for the effects of age, calendar year, duration of followup, and ethnicity (rate ratio=5.35 in the highest exposure stratum [>5.0 mg/m3 year]; 95% CI=2.23-12.80; 15-year exposure lag) [Checkoway et al. 1997]. Other studies found exposure-response trends for NMRD mortality and duration of employment [Costello et al. 1995; Thomas and Stewart 1987], years since first exposure [Thomas and Stewart 1987], or qualitative cat egories of silica exposure (none, low, and high) [Thomas and Stewart 1987]. 3.6 Autoimmune and Chronic Renal Diseases In this century, many published case reports have described various autoimmune disorders in workers or patients who were occupation ally exposed to crystalline silica [Bramwell 1914; Erasmus 1957; Jones et al. 1976; Mehlhorn 1984; Mehlhorn et al. 1990a; de Bandt et al. 1991; Yanez Diaz et al. 1992; Pelmear et al. 1992; Caux et al. 1991; Cointrel et al. 1997; Yamamoto et al. 1994; Guseva 1991; Ebihara 1982; Agarwal et al. 1987; Koegeretal. 1991,1992, 1995; Anandanetal. 1995; Sanchez-Roman et al. 1993; Aoki et al. 1988; Fukata et al. 1983, 1987; Muramatsu et al. 1989; Masuda 1981; Tokumaru et al. 1990; Perez Perez et al. 1986; Bernardini and Iannaccone 1982; Siebels et al. 1995; Suratt et al. 1977; Meyniel et al. 1981; Hatron et al. 1982; Masson et al. 1997; Ozoran et al. 1997; Haustein 1998; Cledes et al. 1982; Mehlhorn and Gerlach 1990]. The most frequently re ported autoimmune diseases were sclero derma, systemic lupus erythematosus (lupus), rheumatoid arthritis, autoimmune hemolytic anemia [Muramatsu et al. 1989], and dermatomyositis or dermatopolymyositis [Robbins 1974; Koeger et al. 1991]. Case reports have also described health effects such as the fol lowing that may be related to the immunologic abnormalities in patients with silicosis: chronic renal disease [Saita and Zavaglia 1951; Bolton et al. 1981; Giles et al. 1978; Pouthier et al. 1991; Neyer et al. 1994; Dracon et al. 1990; Sherson and Jorgensen 1989; Rispal et al. 1991; Osorio et al. 1987; Bonnin et al. 1987; Arnalich et al. 1989; Wilke et al. 1996; Banks et al. 1983; Hauglustaine et al. 1980; Slavin et al. 1985], ataxic sensory neuropathy [Toku maru et al. 1990], chronic thyroiditis [Masuda 1981], hyperthyroidism (Graves' disease) [Koeger et al. 1996], monoclonal gammopathy [Fukata et al. 1983, 1987; Aoki et al. 1988], and poly arteritis nodosa [Arnalich et al. 1989]. Respirable Crystalline Silica 67 3 HUMAN HEALTH EFFECTS In addition to these case reports, 13 post-1985 epidemiologic studies reported statistically significant numbers of excess cases or deaths from known autoimmune diseases or immuno logic disorders (scleroderma, systemic lupus erythematosus, rheumatoid arthritis, and sarcoidosis), chronic renal disease, and subclinical renal changes (Table 19). Epi demiologic studies found statistically signifi cant associations between occupational expo sure to crystalline silica dust and several renal diseases or effects, including end-stage renal disease morbidity [Steenland et al. 1990], mor bidity from end-stage renal disease caused by glomerulonephritis [Calvert et al. 1997], chronic renal disease mortality [Steenland and Brown 1995b], Wegener's granulomatosis (systemic vasculitis often accompanied by glomerulonephritis) [Nuyts et al. 1995], and subclinical renal changes [Hotz et al. 1995; Boujemaa et al. 1994; Ng et al. 1992a, 1993]. The pathogenesis of glomerulonephritis and other renal effects in silica-exposed workers is not clear. Some case reports provide evidence of an immunologic injury by immune complex formation, and other reports point to a direct toxic effect of silica [Calvert et al. 1997; Calvert and Steenland 1997; Kallenberg 1995; Wilke et al. 1996; Wilke 1997]. The immuno logic aspects of renal disease are reviewed in Ambrus and Sridhar [1997]. The cellular mechanism that leads from silica exposure to autoimmune diseases is not known [Otsuki et al. 1998]. One theory is that when respirable silica particles are encapsulated by macrophages, fibrogenic proteins and growth factors are generated, and ultimately the im mune system is activated [Haustein and Anderegg 1998; Ziegler and Haustein 1992; Haustein et al. 1992]. Immune activation by re spirable crystalline silica may be linked to scleroderma, rheumatoid arthritis, polyarthritis, mixed connective tissue disease, systemic lupus erythematosus, Sjogren's syndrome, polymyositis, and fibrositis [Ziegler and Haustein 1992; Haustein et al. 1990; Otsuki et al. 1998]. A possible mechanism for develop ment of scleroderma is a direct local effect of nonrespirable quartz particles that have pene trated the skin of workers [Green and Vallyathan 1996], as observed in skin samples from deceased scleroderma patients [Mehlhorn et al. 1990b]. In addition to the studies summarized in Ta ble 19, there may be other epidemiologic data sets that have not been analyzed by methods that would detect a possible association be tween occupational exposure to crystalline sil ica and autoimmune diseases [Steenland and Goldsmith 1995]. Further clinical and immu nologic studies are needed to characterize the relationship between occupational exposure to crystalline silica and autoimmune diseases. 3.7 Other Health Effects Extrapulmonary deposits of silica have been reported. A review of the literature [Slavin et al. 1985] indicates that silica particles may be transported from the lungs and tracheobron chial lymph nodes to the spleen, liver, kidneys [Osorio et al. 1987], bone marrow, and extrathoracic lymph nodes as a result of (1) forma tion of silicotic lesions in pulmonary veins, (2) erosion of silicotic hilar nodules into pul monary veins, and (3) rupture of silicotic nod ules into the lymphatic system. Roperto et al. [1995] reported two cases of extrapulmonary silicosis in two water buffaloes that lived on a farm near a quartz quarry. Silicotic lesions were observed in the mesenteric lymph nodes, tonsils, and spleen. In humans with occupa tional exposure to silica, peritoneal silicosis has been misdiagnosed as pancreatic carci noma [Tschopp et al. 1992] or abdominal ma lignancy [Miranda et al. 1996]. Intravenous injections of silica into the tail veins of rats have resulted in large liver 68 Respirable Crystalline Silica T a b le 19. E p id e m io lo g ic studies o f im m u n o lo g ic , autoim m une, and ch ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers u ON s 5B s 5* "e o O-X pA Respirable Crystalline Silica 69 See footnotes at end o f table. (Continued) T a b le 19 (C o n tin u e d ). E p id e m io lo g ic studies o f im m u n o lo g ic, a u to im m u n e , and ch ro n ic re n a l disease (in c lu d in g subclinical renal changes) in silica-exposed w orkers fi 70 50 Uo U I0C\i os 50 Z*c 0o0I 'xf o' Respirable Crystalline Silica See footnotes at end o f table. (Continued) T a b le 19 (C o n tin u e d ). E p id e m io lo g ic studies o f im m u n o lo g ic, a u to im m u n e , and ch ro n ic re n a l disease (in c lu d in g subclinical renal changes) in silica-exposed w orkers TO ho m r3 s+5c0s o u o 4> o34> BL hJ Ca0 o> a> *a> C/3 ,--i 3 m * a o 3 C/3 0> 0\ O', o3En 4> JZ) OC0 gft 3 u Oi-h NT) no NrOi IT/ 1-H <N ft III ON Oi--ii Ooon -3n"T o oo o 350 3cO" ftot Oto-l sao O* z3 XJ f3ot - W> pA 3 C'fl CO on CO O3 a Oft o4> 3 1-H o to a 3a - o XJ >* XJ 3 C'fl 3 oa> a> ce0 o a<*> 0O 3 CQ 5o Respirable Crystalline Silica o I "1 ftOn no Oi-Hn no tN>T) 1111c4i <N On <N 00* NO 00 3" O-l 3" no m cn o o' O* o* o* o Vi *o %f CO M oo id 3" o' 1-H n NO ^ -- 3 o a> a> C/3 O3 O Off-Ht o s(DOC e^ ft o o 3 C/3 3 3 3 O O3 O ci . 4) ^ '3 4> a> t> >o it 2 50 4) 3 U 71 See footnotes at end o f table. (Continued) T a b le 19 (C o n tin u e d ). E p id e m io lo g ic studies o f im m u n o lo g ic , a u to im m u n e , and c h ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers 50 u u o\ICl coss 00 50 3^ Z* e 0> 72 Respirable Crystalline Silica O See footnotes at end o f table. (Continued) T a b le 19 (C o n tin u e d ). E p id e m io lo g ic studies o f im m u n o lo g ic , a u to im m u n e , and c h ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers 2 60 S_I ftc/3 ^ B cOdf) 50 +e- CD ft O fSt 1g-H n s t> c so u CD ft 6 S3 s^ ft aW) O CD s8 gs O OfHt . fadt. <on o U IQIf)\ ft>t oI* cn o s- s5o0 CO o o' V & fat> o CftDft X CD C/3 fl _cd 'Eh 'o CD Jh VO 3 S3 * C ft^ 4> pn f3ot 0-D 3pfi CZ5 " I aOX) ft 50 ft ft ^c ft f5ft3i dc3 sft d W o> e C/3 P-H 4> c3- ,-ft j^2 00 ft, Respirable Crystalline Silica O o' V & ft CD O CD Oh X CD C/3 fl _cd 'Eh 'o CD Jh cn t>* C\ 73 See footnotes at end o f table. (Continued) T a b le 19 (C ontinued). E p id e m io lo g ic studies o f im m u n o lo g ic, autoim m une, and c h ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers +s- CZ5 T3 fi O 74 S ts C* - o u S IQC\i aos fst o O-X) spft C/5 o a^ w ^S2O o\ O'. '--1 a> . r-H <tto> .(25i) 2; t/3 0^0 0^0 ^ Al Respirable Crystalline Silica See footnotes at end o f table. (Continued) ft M .`2 rSvi (Continued) T a b le 19 (C o n tin u e d ). E p id e m io lo g ic studies o f im m u n o lo g ic, a u to im m u n e , and ch ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers ft u xiI ICi 0\ o 3ft a 50 in ^3 *ft fi n ft 3 o 0-D pA C'3fl T3 3S3 O *QSJ ft 3 +CZ5 T3 S3 ft CO 3 3 ft ^ ft ft -3 C/3 _"3ft 3 Oh 3 O C/3 o ft i-H 3 W3 Oft Xft ft ft O -"3 C/3 C0 O ft P ^ 3 o f3t 03 ft 3 3 13 -3 M 3 C/3 C/3 a of01t 0(33 o ^ a> V 8 s _3 3 7f?t ft CQ C/3 n 3K*~> oo\\ Respirable Crystalline Silica O', o 7 c4 ri m* 3 -H ft 3 3a o '3 3 3ft '3O 3 35 3 3 4_, 3 3 3 'ft c/) 3ft 2 ^ p^> ^ CD H fOt 3 w M C/3 3 3 c3n fit 3ft fftt fth 00 fftt ft o 3 Of) 3 r-3 q_, 9 "s C/3 3 C/3 -'-I +2 3 O .2 3 3O ft ft ^ o rt33 t: j 3 ^3 C/3 35 a> C/3 O 3 O H ft ft ft ^ 3ft 3 f7t o o^ 3O3 ffUtt 3 >, .2 33 t s =3 ft fv 3 ft ft ftft ft 3 ft H -4-> f2t f5t ft ft ;>> C/3 SO * fftt 3o ft ft Q ft s S ft 2 O H O3 ^ ft ft ^ 3 fot ft -ft ft co 3ft 'ft 3 3 <s 3 75 See footnotes at end o f table. T a b le 19 (C ontinued). E p id e m io lo g ic studies o f im m u n o lo g ic, autoim m une, and c h ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers ft aa _C0 50 c oCo0 Uo C0 f3t ft 00 U ft CO On Q\ICi ^J. ^ 01 & & 3o - ft A0-D 3 3 Z C0 ft COO0 3o A0-D (Z33 O CO o\ s 3& "I aOX) ft f45^t0) ^f3t f<+3Zt-5 f53t4 c3Ou & 76 ^aO> O ,, po a> o ^ SO CO co vq 00* ft* OIl ^I t> 00 1-H Gt>\ fOtn CO 1 1O--n' fftt 0> 5 ^3 c0 3 m3 '3C3M/510 ^31) -fC3O3/t0 Respirable Crystalline Silica See footnotes at end o f table. (Continued) T a b le 19 (C o n tin u e d ). E p id e m io lo g ic studies o f im m u n o lo g ic , a u to im m u n e , and c h ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers 4> 3i-H OC/3 0> >o <D C/3 cf- U s c4i ci IQC\i o o - 3 50 Os ^3 3<U 3p*n a> ft 3o 3o 0-D C/3 O pA C3Z5 . *-h ^a> a> 3i-H COf/3t ao *43> 34a> 2o o 0fa-H>> CD o r3 C/3 oO ctf aC/3 o xal oo o *-ca333> a> oI o ci cc'3ccI- 00 o c4 <N Cl C/3 CD C/3 1h C/3 Respirable Crystalline Silica (D G\ Ctf 5? ZL 5? 77 T a b le 19 (C ontinued). E p id e m io lo g ic studies o f im m u n o lo g ic, autoim m une, and c h ro n ic re n a l disease (in clu d in g subclinical renal changes) in silica-exposed w orkers ft a cS X-i O ft 2Of) rft >>> O S3 ao o Oh X ft a ac 3 a3 o U W) H-t a ff~tt 3ao o 3o ^ fot ft ?d f3tcod fPtC OC/3 CS Oh X Of) fdt >* SSj > d ft 3 C/0 'S o ft afSt a as oO ft do Oh U SICi 0\ oftI ft ON & & do A3 0-0 dpA d Z ft, ft ft <N fotI ft ci ft! O d 2oo v 0 1 ffdtt U a ft do ftI - A00 3 _ ft" CZ5 'S Oo ft s ft I Q U CO C/3 C/3 ON Cl P! s t> W ft, ft, rc o r- Of) | faot offtt ft S3 S o ft Of) i>I fot t>1 s & "I aOX) ft T530 ^ft ^C ft ft 5C4 00 2ft) ft u0> ft d g ^ ft) ft dO oft s a & 3 fftt c/3 ft' 20OW>) Kj f5t3 2S 2H fot ft d fat a &^ ft * Al 0\ W OO cu3 f^mt >* ft Oft C/3 cO Oh ft 3d ft ,,da ^f^__ti a ft oo ft d >d ft 2s in CQ b> _d fot 3C/3 8 "T fat oQ <o d Of) fCt,,/y3 ->C-/3i C/3 O!--i <d Of) Z ft o Oh X C/3 w* fctO ft d Of) ft OP Of) ft od f!t- ao ooco oo U O d f&t bd 00 d fftt! O ^d a a Q o3 fotn O00 fdt ,'C ft ajs , g ft fftt ft. o!:, fo^t 3fdOt ;o9 *$ S3 ft Q% 'S !! ^" ^1 i!, fftt oonj ' ^ d2 'c5c3i 11 fat Coj_l on 1 ' dw ccS ft I s g 2. Jf, > f<t fxt; fOt *i ofot ^on 5 h ^d o 2 ^1 I Q c !: 9/ & &3 J o 3 ft -2 d i&2 8ft oso ft&! 78 Respirable Crystalline Silica 3 HUMAN HEALTH EFFECTS granulomas and hepatic silicosis [Kanta et al. 1986]. In workers exposed to crystalline silica, hepatic changes [Liu et al. 1991], hepatic or hepatosplenic silicosis [Clementsen et al. 1986; Oswald et al. 1995], and hepatocellular carcinoma [Clementsen et al. 1986] have been identified. Two studies reported a significantly higher proportion (P<0.05) of symptomatic hepatic porphyria (a chronic metabolic dis ease) in silica-exposed workers compared with control groups having no history of occupa tional silica exposure [Okrouhlilik and Hykes 1983; Zoubek andKordac 1986]. However, the effect of silica on porphyrin synthesis and me tabolism is not clear. In one study, alcohol con sumption (quantity not specified) may have been a confounder [Okrouhlilik and Hykes 1983]. Mowry et al. [1991] reported a case of a cuta neous silica granuloma in a 57-year-old stone mason. Silica granulomas are firm, nontender dermal or subcutaneous nodules that usually appear at least several years (mean=10 years) after the exposure to silica. They may appear as a result of occupational exposure or trauma [Kuchemann and Holm 1979; Murphy et al. 1997] and are usually treated by excision. The mechanism that causes the silica crystals in the tissue to form a granuloma is unknown. Cor pulmonale (enlargement of the right ven tricle of the heart because of structural or functional abnormalities ofthe lungs) may oc cur as a complication of silicosis [Green and Vallyathan 1996] and other pneumoconioses [Kusiak et al. 1993a]. This condition is usually preceded by pulmonary arterial hypertension. An epidemiologic case-control study of 732 white South African autopsied gold miners re ported a statistically significant association (P<0.05) of cor pulmonale with "extensive" and "slight" silicosis [Murray et al. 1993]. Pulmonary alveolar proteinosis is a rare respi ratory disease identified by an accumulation of phospholipid material in the alveoli [McCunney and Godefroi 1989]. Cases of this disease were identified in a U.S. cement truck driver [McCunney and Godefroi 1989], a U.S. sandblaster [Abraham and McEuen 1986], and a French ceramics worker [Roeslin et al. 1980]. Each worker had been potentially exposed to crystalline silica. Skin absorption of crystalline and amorphous silica particles from soil, and subsequent obstructive lymphopathies related to the fibrogenic effects of the particles may be re lated to the development of nonfilarial tropical elephantiasis (podoconiosis) in the lower legs ofresidents of East Africa and certain volcanic areas [Frommel et al. 1993; Fyfe and Price 1985; Price and Henderson 1981]. Silica dust exposure may be associated with abrasion-related deterioration of dental health. Petersen and Henmar [1988] reported a 100% prevalence of dental abrasion in a group of 33 Danish granite workers. The authors recom mended that dust concentrations be reduced, that workers wear face guards, and that dental abrasion from occupational dust exposure be considered an occupational disease. Respirable Crystalline Silica 79 4 Experimental Studies This section provides an abbreviated review of various experimental research studies. The reader is encouraged to consult the cited mate rials for complete information. 4.1 Biomarkers A biomarker can indicate (1) the occurrence of exposure, (2) the effects of exposure, (3) the presence of early or frank disease, or (4) the susceptibility to disease or early effects of ex posure [Committee on Biological Markers of the National Research Council 1987; Schulte 1995]. Useful biomarkers require (1) a defini tive, validated link with the exposure or the risk of disease and (2) evidence of a doseresponse relationship between the marker and the exposure [Schulte 1995]. The relationship between respirable silica dust exposure and sil icosis is well established. However, the complex chain of cellular responses that leads to fibrosis and silicosis has not been fully dis covered. The usefulness of biomarkers as a screening tool for silicosis risk will be realized when biomarkers in the chain of complex cel lular responses are validated for their relation ship to disease. In addition, the studies of blood, serum, sputum, bronchoalveolar lavage samples, and gene patterns of silicaexposed workers or silicotics (Table 20) are in conclusive for the following reasons: 1. The numbers of subjects are small, and few studies of similar markers exist for com parison. 2. The studies lack control for factors other than silica exposure that could change im munoglobulin concentrations. 3. The studies lack information about control groups, diagnostic criteria for silicosis, and baseline levels of markers. 4. Study results are inconsistent. Further research on biomarkers in silicaexposed workers is needed to do the following: 1. Quantify the exact amount of soluble prod ucts in bronchoalveolar lavage in individ ual patients to provide more information about the mechanisms of fibrogenesis [Sweeney and Brain 1996] 2. Determine whether silicosis or silica-related lung cancers are associated with a specific gene or gene pattern 3. Determine whether a relationship exists between changes in immunoglobulin con centrations and silica exposure 4. Determine whether a dose-response rela tionship exists between changes in certain cellular components (lymphocytes and Clara cell protein) and silica exposure Detailed reviews of the immunologic response to silica and other mineral dusts are available elsewhere (i.e., Heppleston [1994]; Haslam [1994]; Weill et al. [1994]; Davis [1991,1996]; Kane [1996]; Driscoll [1996]; Sweeney and Brain [1996]; Hook and Viviano [1996]; Gu and Ong [1996]; Iyer and Holian [1996]; Weissman et al. [1996]; Mossman and Churg [1998]). 80 Respirable Crystalline Silica Table 20. M o le c u la r epidem iology studies o f biom arkers fo r carcinogenesis or silicosis izi <t> S S Uo IZ) <d%t> C* cs s y *o3d so IZ) U0> d IZ) O p<uOt> s d z * u -C ow TC3 WCD IZ) T3 (+d/}'Oc T3 dc3 C/3 O VO VO 00 00 ci a> gH Ov -td>0 m4> ^^ m Respirable Crystalline Silica (D , 0) p, 1--1 O tzT oo rd o inCZ3 O<N w cn ad rvt 81 See footnotes at end o f table. (Continued) Table 20 (Continued). M olecular epidemiology studies o f biom arkers fo r carcinogenesis or silicosis tu PPJ g o -.OC2 .a2 33 Sh <2 . .a ^ .a pT3 " ^ '5 CD '--1 Ph O OJ s S aS &o C/3 ' 1 CD SP O >> PJ M C>D 0c/3 I> 00 O Sh P oON P? 8 oU S| I 13PC/3h cO tr. ^ a P P a--I P> 00 p co 00 o -t On sp p* w ^ CD > P CD >N ^ P 5h P H-H - rH rP O C/3 PJ CO clT 'P p _P pOf) p 1*3 p& oO o PCD P 1*5 00 op PI & oP< p oCO P ^p p} +H pp rP r PJ P "3C/3rP p} p rP -CD p^p PI P- .60 kP CO ffl m o OPh Ph QQ Ph Ph psi PCD p C0D0 Ph o Q Ph o O ' Ph wp o oH'So o P^ <+* wO p so PJ rP ^ ^'s O O -- $O-Hf) 1O-Hf) CQ 0H-J p rP rP 1pA A o p} p 1A p h O z pp< 00 * u -oC 'O C p WCD I*> p 'O 'O +H (Z) 'O C & rCPD P 3? H P p cp oO Of) 5h P Pi p} a _> P a a--I & On 81 CP/3^ CP/3 P P OP CD P5> CD O P w CD PPJ P co 00 P P PJ Sh P^ w p<2 P P r_) w -rCPd/3 pP p) ^p Mo "53 Pcj Sh CD P On Ph P< P< pH _0 g <N ^ On Ph p^Pj 1^o1-H4n ^p3) PP p -PrH PP P P-H 82 Respirable Crystalline Silica See footnotes at end o f table. (Continued) (Continued) Table 20 (C ontinued). M o le c u la r epidem iology studies o f biom arkers fo r carcinogenesis o r silicosis d ddJ d d0J> d dJ s s s<t> dJ d 60 a^ so OO Ch d do3 u d '5 t/5 .2 a <u t/5 r5od--( doSd d t0/>5 5--i 0) c/3 >> IZ> 3 dtZ5 ud CO ud pA d IZ> O5--( ood On O dJ d d CO A d Z O On W) d 'd C/3 idwOO dt1OnJ> d oo> do CO 5a-->i 5o--( d U o o ^ 3 H. '3 o 'd o o doo 1 # O 2? S ^ .a o .2? o a oo co dJ d d O&o s d d O O O ddJ CO O co O d- O(H See footnotes at end o f table. <i> 'd ON d QS u ^ 55 Respirable Crystalline Silica M (oSo d> ^d ^ O O ^ on 83 d (Continued) Table 20 (C ontinued). M o le c u la r epidem iology studies o f b io m a rke rs fo r carcinogenesis o r silicosis 8I g a dCD <St> so u ! -S o no ft d o5h o <+ 'ohCD CD CO d .g- rrs C/3 CD ft 2 fot g a d < ft no s o Cdo/3 >> o P 03 fC*CtDD- O ^C>PD ^2 Mw S fdctd CfaDt oC/3 ofot '3 On d uG CD o CbD/) dd , fCCOt/D3 ft 'dbn fddt r- fmt g d VS d ft p & oO .CD ft ft dd Mu 2G _dW) oin o ^ V a. -CaD >> ft+Coot-D* r--fdCgtDi o a a2ofdt dft dodJd <OD Odo) ft ^ofWt) oi"H sO fOt >lH> .22 dO fdCtD nDo OP^ft nO t- cd ICfDt Ioo ff>cdtt> focdtdd f fCd0t3D M0fxCDt-2cSofdto f2uoftt o fdCdtD d fo*tr.)s fCctdD a V cdd &C/3 ft ^d ft G V a^ CCDT* " 01 f<t! ffi f&t a^> d ftCdtD & fStO s& CfQt t CD i CD co/} fOOat Offfttth 3ft U Jr2>h cd rcgd cd fCtD bCd'n 2 od -tCCaoDD f.2dt ft ft 3 O ft C/3 ft CD CD ft ft ft bdCC5--//33f() .ffSdtti fot d CdCbDDf) o d _o ffddtt dbO fsto > ft fPt d CbDO OOJD Gc3 JI ae - Cl w_8o o 33 C(HD ^CD GO >n pAA ffdddctt3 fC*oftoDt Ap- fdot ft P C/3 P A z I* a3 8 fddt bf) %^ Px 2CD fCtD ! gis cy d a ft >j O BOS* Gi--< gO dft tfo;t C$--D< ft On fddt oo CN ft fftt ddd < o 2 |1h a -O ffl--tt1 fSoth -oopcfCCtG fOJlD fOt ft Ccs pp a p C/3 ft *COdbd-OOi dfCtD CD HM ft cd c5d-i Obf) fdt no o sobd ft _do ddoPft O ocbdof) fCtD Idd O ft $uH' CD A *a SO fdt ffcfbtdtOt u fC1C5O^ht/D-31 S-H (--3 OC"Nf| _o fctd n od fCfOtDt fcdtd fC>tD> 1o5ofh3t offCaDtt ft o dbf) co ft< O CD 3 fftt w^3 fffttl 1O S ffCtt/3 pP d !bo--oi ft dSh ft fdt pMp f-dat ffOtt oO3h fftt fdt .S a o^ ft d fPt d0f3t *--d> ft P 84 Respirable Crystalline Silica See footnotes at end o f table. Table 20 (C ontinued). M o le c u la r epidem iology studies o f b io m a rke rs fo r carcinogenesis o r silicosis -s Respirable Crystalline Silica 85 See footnotes at end o f table. (Continued) Table 20 (C ontinued). M o le c u la r epidem iology studies o f biom arkers fo r carcinogenesis o r silicosis co C - co 86 Respirable Crystalline Silica See footnotes at end o f table. (Continued) (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers fo r carcinogenesis or silicosis s<t> o o CZ) >> *0 o d2 do "od ' Pa> 2 co a df o0^a 0o s d oo d P-> ph _do S d n=l d di u o>d tO o dJ doop< O d 5o0&-->( > Ph ci O d tO Sd ffl x5n s--r" cs=o| j^O: d 0> dJ y--V dJ rmopH o> d dJ O o>CO CO do CO 'd Ph nd 0) rd _dd5 d *3 rr- .3. rPEs On -h O O ^ X tn C/5 O O c/3 0) tO on0s- Ph OO NO I d O d oN0s- co d CO do d oNT) > rd d0J> 3 P .a 5d* ad) d 0)d di co O PO o O 0> O CO d Q o Id d 'co do WU d)n d-7--J( di CD (/} co PH oCO O ^ do o ;Pd . P< dJ > CD ^ P \0 d 0s- P< PI O V B 'N OV Mco oC/3 d d di d d P P Or U[/) di ^cu M d to dJ d N 0s- 0) So oCO ffi a SrH- dj' CO dJ d <Ut> d pA d CO PH d O P< <t>U CO CO A s d Z co O PI PI Pi Pi CO O m O /w' P ^ O'--1 POhN*POPP-I NT) PI di co See footnotes at end o f table. -d Respirable Crystalline Silica 87 .n o> o ao <fsti> so u K'''* ' a 60 0> g o I^ .a(aZ) .1 S u >do 0 CD CD 5> Table 20 (C ontinued). M o le c u la r epidem iology studies o f biom arkers fo r carcinogenesis o r silicosis dJ dcd cd a od W I cd aOf) , OOJD dJ oO o>~> ^o o o ~ rd cd o vmH. oHo HO ^ ,, >? o` O (5 a? i - dtH CD C/D W) pAd dJ d cd A s 2A _CD t/5 z 0C&0l ooa -oowc C cd WCD d -n C Cd u ucAo d cd cddn cd cd cd d cd a 88 <s Respirable Crystalline Silica 4 EXPERIMENTAL STUDIES 4.2 Cytotoxicity Respirable crystalline silica is known to cause silicosis; however, the molecular mechanism responsible for the cellular injury that precedes the lung disease is unknown. Extensive in vitro and in vivo research has been conducted to evaluate the effects of crystalline silica on mammalian cells. Several mechanisms have been proposed to explain the cause ofthe cellu lar damage [Lapp and Castranova 1993]: 1. Direct cytotoxicity of crystalline silica 2. Stimulation of the alveolar macrophages by silica and subsequent release of cytotoxic enzymes or oxidants 3. Stimulation of the alveolar macrophages to release inflammatory factors (e.g., inter leukin-8, leukotriene B4, platelet-activating factor, tumor necrosis factor, plateletderived growth factor) that recruit poly morphonuclear leukocytes, which in turn may release cytotoxins 4. Stimulation of the alveolar macrophages to release factors that initiate fibroblast pro duction and collagen synthesis (e.g., interleukin-1, tumor necrosis factor, platelet-derived growth factor, fibronectin, and alveolar macrophage-derived growth factor) 4.3 Genotoxicity and Related Effects Some studies have demonstrated the ability of quartz to induce micronuclei in mammalian cells in culture [Hesterberg et al. 1986; Nagalakshmi et al. 1995; Oshimura et al. 1984] (Table 21). However, other in vitro studies did not observe chromosomal aberration [Nagalakshmi et al. 1995; Oshimura et al. 1984], hprt (hypoxanthine-guanine phosphoribosyl transferase) gene mutation [Driscoll et al. 1997], or aneuploid or tetraploid cells [Price-Jones et al. 1980; Oshimura et al. 1984; Hesterberg et al. 1986]. An in vivo treatment of rats with quartz induced mutation in rat alveo lar epithelial cells (Table 21) [Driscoll 1995; 1997]. Pairon et al. [1990] tested tridymite (i.e., Tridymite 118) and quartz (i.e., Min-U-Sil 5) particles for genotoxic effects. Tridymite in duced a significant number of sister chromatid exchanges (SCEs) in co-cultures ofhuman lym phocytes and monocytes (P<0.05 compared with control cells) at doses of 5 and 50 pg/cm2 (87.9% of the tridymite particles had a diame ter <1 pm). However, the number of SCEs in purified human lymphocytes that were treated with the same doses of tridymite particles did not differ significantly from control cells [Pairon et al. 1990]. Results of the same exper iments with quartz did not yield a clear conclu sion about the ability of quartz to induce a sig nificant number of SCEs (Table 21) [Pairon et al. 1990]. In vitro cellular transformation systems model the in vivo process of carcinogenesis [Gao et al. 1997; Gu and Ong 1996]. The abil ity of quartz to induce dose-dependent mor phological transformation of cells in vitro has been demonstrated in experiments with Syrian hamster embryo cells [Hesterberg and Barrett 1984] and mouse embryo BALB/c-3T3 cells [Saffiotti and Ahmed 1995]. Gu and Ong [1996] also reported a significant increase in the frequency of transformed foci of mouse embryo BALB/c-3T3 cells after treatment with Min-U-Sil-5 quartz. These studies indicate that crystalline silica can morphologically trans form mammalian cells. However, further stud ies are needed to determine whether the trans forming activity of silica is related to its carcinogenic potential. Respirable Crystalline Silica 89 Table 21. Summary of the genotoxic effects of quartz in mammalian cells In vitro studies In vivo studies Genotoxic effect Number of positive studies/number of studies available Reference Number of positive studies/number of studies available Reference Sister chromatid exchange 1 */3 Price-Jones et al. [1980] Pairon et al. [1990] (2 experiments) 1*/1 Sobti and Bhardwaj [1991] Chromosomal aberrations 0/3 Nagalakshmi et al. [1995] 1*/1 Sobti and Bhardwaj (2 experiments) [1991] Oshimura et al. [1984] Micronuclei 3/4 Oshimura et al. [1984] 0/1 Hesterberg et al. [1986] Nagalakshmi et al. [1995] (2 experiments)'1' Vanchugova et al. [1985] Aneuploidy or tetraploidy 0/3 Price-Jones et al. [1980]; Oshimura et al. [1984]; Hesterberg et al. [1986] 0/0 hprt mutation* 0/1 Driscoll et al. [1997] 2/2 Driscoll et al. [1995, 1997] Source: IARC [1997]. 'One questionably positive study available. tOne experiment by Nagalakshmi et al. [1995] showed an increase in the frequency of micronucleated cells at all concentrations tested, but the increase was statistically significant (P<0.05) only at the two highest concentrations tested. thprt = hypoxanthine-guanine phosphoribosyl transferase. Mutagenic response associated with inflammation. 90 Respirable Crystalline Silica 4 EXPERIMENTAL STUDIES Researchers at the National Cancer Institute have examined the ability of quartz, cristobalite, and tridymite particles to cause deoxyri bonucleic acid (DNA) damage (i.e., strand breakage) [Saffiotti et al. 1993; Shi et al. 1994; Daniel et al. 1993; Daniel 1993, 1995]. Al though the results of those studies demon strated the ability of crystalline silica to cause damage to isolated DNA in acellular systems, reviewers at IARC [1997] recently stated that the relevance of these assays to assess quartz-related genetic effects in vivo was "questionable" because (1) the nonphysiological experimental conditions did not apply to intracellular silica exposure and (2) very high doses of silica were used in the DNA breakage assays [IARC 1997]. Several studies conducted since the IARC re view found that crystalline silica induced DNA damage (i.e., DNA migration). Zhong et al. [1997] found that by using the alkaline single cell gel/comet (SCG) assay, crystalline silica (Min-U-Sil 5) induced DNA damage in cul tured Chinese hamster lung fibroblasts (V79 cells) and human embryonic lung fibroblasts (Hel 299 cells) [Zhong et al. 1997]. Amor phous silica (Spherisorb), but not carbon black, was also found to induce DNA damage in these mammalian cells. However, the DNAdamaging activity of amorphous silica was not as high as the damaging activity of crystalline silica [Zhong et al. 1997]. Liu et al. [1996, 1998] challenged Chinese hamster lung fibroblasts with dusts pretreated with a phospholipid surfactant to simulate the condi tion of particles immediately after deposition on the pulmonary alveolar surface. Results of the experiments showed that untreated Min-U-Sil 5, Min-U-Sil 10, and noncrystalline silica induced micronucleus formation in a dose-dependent manner, but surfactant pre treatment suppressed that activity [Liu et al. 1996]. A subsequent experiment found that surfactant pretreatment suppressed quartzinduced DNA damage in lavaged rat pulmonary macrophages, but DNA-damaging activity was restored with time as the phospholipid surfactant was removed by intracellular diges tion [Liu et al. 1998]. Shi et al. [1998] recently reviewed published literature on (1) the generation of reactive oxygen species (ROS) directly from silica and from silica-stimulated cells, (2) the role of ROS in silica-induced DNA damage and silica-induced cell proliferation, and (3) other silica-mediated reactions. A proposed mecha nism for silica-induced generation ofROS spe cies and carcinogenesis is described by Shi et al. [1998]. Experimental research is continuing to determine whether crystalline silica parti cles have a direct genotoxic effect that could cause lung tumor formation in humans. 4.4 Carcinogenicity Experimental evidence of the carcinogenicity of quartz particles is based on the results of long-term inhalation and intratracheal instilla tion studies of rats, which are summarized in Tables 22 and 23 [Saffiotti et al. 1996]. Sev eral issues are apparent from the results of the rat studies [Holland 1995]: 1. The appearance of tumors (usually adeno carcinomas or epidermoid carcinomas) is a late phenomenon. 2. Lung fibrosis is usually present in the rats with tumors. 3. No adequate dose-response data exist be cause multiple-dose experiments have not been conducted in the rat except for the in halation study by Spiethoff et al. [1992]. 4. Comparability of the intratracheal instilla tion and inhalation studies is difficult be cause of notable differences in methods and materials. Respirable Crystalline Silica 91 Table 22. Summary of data on lung tumors induced in rats by crystalline silica Sample and exposure conditions Rat strain Sex Incidence of lung * tumors Treated rats Controls Reference Comments Quartz (Min-U-Sil 5): Intratracheal instillation of 7 mg/wk for 10 wk SpragueDawley __ t Inhalation (no se only) of 12 5 mg/m3 for up to 2 yr Fischer 344 F 6/36 20/60 0/58 0/54 Holland et al. [1983] Treated rats had 1 adenoma and 5 carcinomas. Holland et al. [1986] Treated rats had 6 adenomas, 11 adenocarcinomas, and 3 epidermoid carcinomas. Inhalation of 51.6 mg/m3 for various durations; sacrificed at 24 months Fischer 344 F M 10/53 1/47 0/47 0/42 Dagle et al. [1986] Treated female rats had 10 epidermoid carcinomas. Treated male rats had 1 epidermoid carcinoma. Intratracheal instilla tion of 20 mg in left lung; sacrificed at 12, 18, or 22 months, or found dead Fischer 344 Novaculite (i.e., micro crystalline quartz): Intratracheal instilla tion of 20 mg in left lung; sacrificed at 12, 18, or 22 months, or found dead Fischer 344 Raw shale dust: Inhalation (nose only) of 152 51 mg/m3 (average quartz content: 8%-12%) Fischer 344 M M F 30/67 21/72 17/59 1/75 Groth et al. [1986] Treated rats had 30 adenocarcinomas. Controls had 1 adenocarcinoma. 1/75 Groth et al. [1986] Treated rats had 20 adenocarcinomas and 1 epidermoid carcinoma. Controls had 1 adeno carcinoma. 0/54 1/15* Holland et al. [1986] Treated rats had 2 adenomas, 8 adenocarcinomas, and 7 epidermoid carcinomas. Controls had 1 adenoma. See footnotes at end of table. 92 (Continued) Respirable Crystalline Silica Table 22 (Continued). Summary of data on lung tumors induced in rats by crystalline silica Sample and exposure conditions Rat strain Sex Incidence of lung tumors* Treated rats Co ntro ls Reference Comments Spent shale dust: Inhalation (nose only) of 176 75 mg/m3 (average quartz content: 8%-12%) Fischer 344 F Quartz (DQ12): Inhalation of 1 mg/m3 for 24 months Fischer 344 F Fischer 344 M 11/59 0/54 1/15' Holland et al. [1986] Treated rats had 2 adenomas, 8 adenocarcinomas, and 1 epidermoid carcinoma. Controls had 1 adenoma. 12/50 6/50 3/100 (male and female) -- Muhle et al. [1989] Treated female rats had 2 keratinizing cystic squamous cell tumors, 2 adenomas, and 8 adenocarcinomas. Treated male rats had 2 keratinizing cystic squamous cell tumors, 2 adenocarcinomas, 1 adenosquamous carcin oma, and 1 squamous cell carcinoma. Controls had 2 adenomas and 1 adenocarcinoma. Inhalation (nose only) of 6 mg/m3 for 29 days followed by lifetime observation Wistar F 62/82 0/85 Spie thoff et al. [1992] Treated rats had 8 adenomas, 17 bronchioloalveolar carcinomas, and 37 squamous cell carcinomas. Inhalation (nose only) of 30 mg/m3 for 29 days followed by lifetime observation Wistar F 69/82 0/85 Source: Adapted from Saffiotti et al. [1996]. 'Number of lung tumors per number of rats observed. 'Not reported. 'Investigators used two control groups. Spie thoff et al. [1992] Treated rats had 13 adenomas, 26 bronchioloalveolar carcinomas, and 30 squamous cell carcinomas. Respirable Crystalline Silica 93 Table 23. Lung tumors induced in Fischer 344 rats by a single intratracheal instillation of quartz Treatment * sample and dose Sex Observation time Incidence of lung tumors Number* % Total number of lung tumors* Histological types Untreated: No dose No dose Quartz (Min-U-Sil 5): 12-mg dose M Died after 17 months F Died after 17 months 0/32 1/20 M Sacrificed at 11 months 3/18 Sacrificed at 17 months 6/19 Died after 17 months 12/14 5 17 32 86 12-mg dose F Sacrificed at 11 months 8/19 Sacrificed at 17 months 10/17 Died after 17 months 8/9 42 59 89 0 1 1 adenoma 37 6 adenomas, 25 adenocarcinomas, 1 undifferen tiated carcinoma, 2 mixed carcinomas, and 3 epi dermoid carcinomas 59 2 adenomas, 46 adenocarcinomas, 3 undifferen tiated carcinomas, 5 mixed carcinomas, and 3 epi dermoid carcinomas 20-mg dose F Died after 17 months 6/8 75 Quartz (hydrogen fluoride-etched Min-U-Sil 5): 12-mg dose 12-mg dose M Sacrificed at 11 months Sacrificed at 17 months Died after 17 months 2/18 7/19 7/9 F Sacrificed at 11 months 7/18 Sacrificed at 17 months 13/16 Died after 17 months 8/8 Sources: Saffiotti et al. [1993; 1996]. *As mg quartz suspended in 0.3 ml saline. dumber ofrats with lung tumors per number of rats observed. *At all observation times. 11 37 78 39 81 100 13 1 adenoma, 10 adeno carcinomas, 1 mixed carcinoma, and 1 epi dermoid carcinoma 20 5 adenomas, 14 adenocarcinomas, and 1 mixed carcinoma 45 1 adenoma, 36 adenocarcinomas, 3 mixed carcinomas, and 5 epi dermoid carcinomas 94 Respirable Crystalline Silica 4 EXPERIMENTAL STUDIES Although new long-term carcinogenesis studies in animals may provide information about dose-response relationships and inhi bition of quartz toxicity or reactivity in vivo, in vitro studies are needed to develop effec tive cellular and molecular models of carcinogenesis [Holland 1995; Saffiotti et al. 1996]. Respirable Crystalline Silica 95 5 Conclusions The following conclusions about the health effects caused by exposure to respirable crystalline silica are derived from studies in humans and animals published since the 1974 criteria document [NIOSH 1974]. These studies support the risk of silicosis, lung cancer, and several other debilitating and fatal diseases from occupational exposure to crystalline silica. The onset of silicosis and lung cancer is thought to be related to the biological activity and the lack of solubility of crystalline silica particles in body fluids and tissues. 5.1 Lung Cancer In 1988 testimony to the U.S. Department of Labor, NIOSH recommended that respirable crystalline silica be considered a potential occupational carcinogen [54 Fed. Reg. 2521 (1989)]. Since then, additional studies have supported a lung cancer risk from exposure to crystalline silica: Lung cancer is associated with occupa tional exposures to crystalline silica [ATS 1997], specifically quartz and cristobalite [IARC 1997]. An exposure-response relationship has been reported in studies of miners, diatomaceous earth workers, granite work ers, pottery workers, refractory brick workers, and other workers (see Section 3.4.2). Meta-analyses of the epidemiologic studies of silica exposure and lung can cer reported a moderate summary rela tive risk of 1.3 for silica-exposed workers [Steenland and Stayner 1997] and higher summary relative risks of 2.2 to 2.8 for silicotic workers [Steenland and Stayner 1997; Tsuda et al. 1997; Smith et al. 1995]. Some of the studies of silica-exposed workers controlled for the effects of smoking and others did not. The available data also support the conclusion that silicosis produces an in creased risk for bronchogenic carci noma, but the data are "less clear" as to whether silica exposure is associated with lung cancer in the absence of silicosis [ATS 1997]. 5.2 Noncarcinogenic Health Effects In 1974, NIOSH established an REL for respirable crystalline silica of 0.05 mg/m3 as a 10-hr TWA to prevent the risk of silicosis from occupational exposure [NIOSH 1974]. Since then, additional studies have indicated that a risk for silicosis exists at the NIOSH REL. Three recent epidemiologic studies have shown that the estimated risk of silicosis for a 45-year working lifetime is 47% to 90% for cumulative silica exposures at concentra tions equal to the current OSHA and MSHA PELs, and approximately 10% to 30% at concentrations equal to the NIOSH REL (see appendix) [Kreiss and Zhen 1996; Steenland and Brown 1995a; Hnizdo and Sluis-Cremer 1993]. The results from these studies support the need for continued medical and epide miologic surveillance of workers after they leave employment and for revision of OSHA and MSHA standards for respirable crystalline silica. 96 Respirable Crystalline Silica 5 CONCLUSIONS Additional studies have reported the risk for several other debilitating and fatal diseases: Several epidemiologic studies have re ported statistically significant numbers of excess deaths or cases of immuno logic disorders and autoimmune dis eases in silica-exposed workers. These diseases and disorders include sclero derma [Steenland and Brown 1995b; Cowie 1987], rheumatoid arthritis [Sluis-Cremer et al. 1986; Klockars et al. 1987; Rosenman and Zhu 1995], sys temic lupus erythematosus [Steenland and Brown 1995b], and sarcoidosis [Rafnsson et al. 1998]. Recent epidemiologic studies have re ported statistically significant associa tions of occupational exposure to crys talline silica with renal diseases and subclinical renal changes [Steenland et al. 1990, 1992; Steenland and Brown 1995b; Calvert et al. 1997; Nuyts et al. 1995; Hotz et al. 1995; Boujemaa et al. 1994; Ng etal. 1993]. Crystalline silica may affect the immune system, leading to mycobacterial infec tions (tuberculous and nontuberculous) or fungal infections [ATS 1997; NIOSH 1992a,b, 1996b; Ziskind et al. 1976; Parkes 1982; Parker 1994], especially in workers with silicosis [Corbett et al. 1999; Kleinschmidt and Churchyard 1997; Althouse et al. 1995; Goldsmith et al. 1995; Hnizdo and Murray 1998; ATS 1997]. Occupational exposure to respirable cry stalline silica is associated with bron chitis, COPD, and emphysema (see Sec tion 3.5). Some epidemiologic studies suggest that these health effects may be less frequent or absent in nonsmokers. 5.3 Exposures, Monitoring, and Controls Published studies on workers exposed to crystalline silica indicate that exposures still occur at concentrations exceeding the OSHA and MSHA PELs and the NIOSH REL. Engineering control methods used to control silica exposures in some industrial environ ments may not be feasible for reducing airborne exposures in other workplaces where their implementation is hindered by the type of work being performed. In addition, sampling and analytical techniques used to measure airborne crystalline silica exposures are limited in their ability to accurately quantify exposures below the NIOSH REL. The following issues must be resolved to prevent silicosis and other debilitating and fatal diseases: Many occupational exposures to crystal line silica still exceed applicable Federal standards. Of the 255 industries targeted for OSHA inspection between 1980 and 1992, 48% had overall average expo sures for respirable quartz that exceeded the PEL [Freeman and Grossman 1995]. Analysis of OSHA compliance data for five ofthe three-digit SICs (masonry and plastering, heavy construction, painting and paper hanging, iron and steel found ries, and metal services) for the period 1979-1995 indicated that an estimated number ofworkers were exposed to con centrations of respirable crystalline sil ica that were at least 10 times the NIOSH REL of 0.05 mg/m3 (10-hr TWA) [Linch et al. 1998] (see Section 2.3). Workers are exposed to crystalline silica in a variety ofindustries and occupations in which engineering controls may not be feasible for reducing exposures and may necessitate the use of other worker protection measures such as substitution Respirable Crystalline Silica 97 5 CONCLUSIONS (use of a less hazardous material) or res pirator use. Current sampling and analytical meth ods used to evaluate occupational expo sure to crystalline silica do not meet the appropriate accuracy criterion needed to quantify exposures at concentrations be low the NIOSH REL of 0.05 mg/m3 (see Section 2.4). However, the recent intro duction of a new sampler that can operate at a higher flow rate and the ongoing im provements in the analysis of crystalline silica should soon make it possible to measure crystalline silica exposure accu rately when it is below 0.05 mg/m3. Until these improved sampling and analytical methods are developed for respirable crystalline silica, NIOSH will continue to recommend an exposure limit of 0.05 mg/m3 to reduce the risk of developing silicosis, lung cancer, and other adverse health effects. NIOSH also recommends minimizing the risk of illness that remains for workers exposed at the REL by substituting less hazardous materials for crystalline silica when feasible, by using appropriate respiratory protection when source controls cannot keep exposures below the NIOSH REL, and by making medical examinations available to exposed workers. 98 Respirable Crystalline Silica 6 Research Needs 6.1 Health-Related Research The relationship of occupational crystalline silica exposure with silicosis and other silicarelated diseases is well documented in the lit erature. However, the mechanisms and particle characteristics that cause silicosis and other silica-related diseases have not been precisely defined. Prevention of silicosis, lung cancer, and other silica-related diseases can be facili tated by the following: Development of methods for earlier de tection or more definitive noninvasive evaluation of silica-related pulmonary disease, such as methods to improve the sensitivity of radiography for detecting silicosis (these methods were reviewed by Wilt et al. [1998] and Talini et al. [1995]) Further in vitro and in vivo studies of mechanisms for development of -- silicotic nodules [Craighead 1996] -- autoimmune diseases -- DNA damage by silica particles [Saffiotti et al. 1994] Further in vitro and in vivo studies ofthe toxicity and pathogenicity of -- alpha quartz compared with its poly morphs [Craighead 1996] Respirable Crystalline Silica -- crystalline silica compared with crystalline glass, amorphous sili cone, and silicates [Craighead 1996] -- crystalline silica compared with sub stitute materials for abrasive blasting and other tasks that use crystalline silica -- dust mixtures that contain crystalline silica [Craighead 1996; Donaldson and Borm 1998; Dufresne et al. 1998] -- quartz contaminated with trace ele ments [Castranova et al. 1997] The association of surface properties of silica particles with specific work pro cesses and health effects Cellular, molecular, and animal models of silica carcinogenesis to explore whether silica dust is an initiator or a promoter of lung cancer [Craighead 1996] and to evaluate a dose-response relationship Animal models of individual suscepti bility and the development of fibrosis [Craighead 1996], including the translo cation of silica particles from the lungs [Adamson and Prieditis 1998] Animal models of the adverse effects of crystalline silica on the kidneys and liver 99 6 RESEARCH NEEDS Routes and kinetics of lymphatic trans port and deposition of silica particles [Craighead 1996] Further epidemiologic studies and surveillance of silica-exposed workers are needed to do the following: Determine the exposure-response rela tionship between occupational silica dust exposure and lung cancer in non smokers Determine why lung cancer risks appear to be higher in silicotic workers (e.g., de termine the histologic type and anatomic location of lung cancers in workers with and without silicosis [Ducatman et al. 1997]) Evaluate exposure-response relation ships between occupational silica dust exposure and (1) TB [ATS 1997] and (2) changes in cellular components (lymphocytes, Clara cell protein) or im munoglobulin concentrations Determine the relationship between oc cupational exposure to silica dust and --TB in silica-exposed workers without diagnosed silicosis -- clinically significant changes in the lung function of nonsmokers -- emphysema in nonsmokers -- gastric cancer and other nonpulmonary cancers Gather uniform national and interna tional prevalence and incidence data about silicosis cases to identify indus tries, occupations, and work areas where preventive measures could be imple mented [CSTE 1996; Wagner 1997] Gather prevalence, incidence, and mor tality data about silica-related diseases such as cancer, scleroderma and other autoimmune diseases, nonmalignant re nal disease, and other adverse health ef fects to assess morbidity and mortality risk factors and to identify areas where preventive measures could be imple mented Determine whether silicosis or silicarelated lung cancers are related to a spe cific gene, gene pattern, or other individ ual susceptibility factors Improve the methods for estimating his torical exposures for retrospective co hort studies Improve the assessment of potential confounding and synergistic effects of smoking in silica-exposed workers [Checkoway 1995] Improve the assessment of potential confounding and synergistic effects of other carcinogens present in the work environment of silica-exposed workers [Dufresne et al. 1998] Determine whether adverse health ef fects are associated with occupational exposure to materials that could be sub stitutes for crystalline silica [NIOSH 1992a] 6.2 Research Related to Exposure Measurement Reducing the OSHA and MSHA PELs for crystalline silica to concentrations below the NIOSH REL (0.05 mg/m3 for up to a 10-hr workday during a 40-hr workweek) would re quire new methods that can accurately mea sure low airborne concentrations at the NIOSH accuracy criterion. (Limitations of 100 Respirable Crystalline Silica 6 RESEARCH NEEDS current NIOSH methods for measuring worker exposure to airborne crystalline silica are dis cussed in Chapter 2). Such new methods will depend on the following types of research and development: Reevaluation of the 10-mm nylon cy clone, the GK2.69 cyclone, or other pro posed devices at exposure concentra tions below 0.05 mg/m3 Ascertainment of the sampling effi ciency of proposed samplers versus par ticle aerodynamic diameter Side-by-side comparison of proposed samplers under field conditions Development of samplers that can oper ate at higher flow rates than those cur rently available Development of working standards that use different types of filter media (e.g., PVC) to reduce errors in calibration Further improvement of the system used to produce replicate crystalline silica samples for the PAT Program* to --improve the reproducibility of inter laboratory results for silica analysis, -- eliminate problems with sample over loading, and -- determine how to account for bias be tween results from different analyti cal methods *This system has undergone improvements from its orig inal form to reduce the intersample variability. Cur rently, intersample CV is on the order of 0.08 to 0.12. Only cursory testing of these improvements has been carried out, and further improvements may be neces sary. Further research to validate the feasibil ity of "on-filter" analysis under field conditions (preliminary investigation of particle transition between the cyclone and the sample collection cassette indi cates that it is possible to improve the uniformity of particles deposited on the filter to permit an accurate on-filter anal ysis) Collaborative testing of any improved or new sampling and analytical methods to demonstrate equivalence 6.3 Research Related to the Control of Exposure Protecting workers from crystalline silica ex posures can be accomplished through a num ber of means. Respiratory protection and ad ministrative controls are important means of protecting workers, but they should not be used as the primary method of preventing worker exposure. Other exposure control methods (in cluding process modifications to eliminate hazards, substitution, and engineering con trols) should be the primary focus of any safety and health program in preventing occupational exposures. For some industries, research is needed to develop cost-effective controls; whereas in other industries, work is needed to increase the availability and use of control measures and to explore barriers that prevent the introduction of control technology. Spe cific types ofresearch are needed in the follow ing industries: Construction. The construction industry presents a major challenge for protecting workers. In this industry, crystalline sil ica is present in many of the building materials and construction substrates (i.e., rock and soil). Silica sand is a ma jor component of concrete and mortar and is used in the production of brick Respirable Crystalline Silica 101 6 RESEARCH NEEDS and concrete masonry units. In addition to the ubiquitous presence of silica in construction, this industry also faces a challenge from the ever-changing nature of the worksite. These changes create two problems in the control of silica ex posures. First, permanent control mea sures are not feasible for many worksites because of the short duration of the task (e.g., concrete cutting or coring opera tions). Second, the manner in which the work is performed at a worksite can cre ate a silica exposure for workers at adja cent worksites. Control methods such as wet cutting of bricks and concrete ma sonry units and use of high-velocity/ low-volume (HVLV) ventilation sys tems during cutting and grinding of con crete have been effective in reducing ex posures to silica at some worksites. However, the following research is needed to improve these techniques and the feasibility of their use: -- The use ofwater is not a feasible con trol method for reducing exposures on many interior jobs or in cold tem peratures. Research is needed to find methods for increasing (1) the appli cability of water to more operations and (2) the use of water in applica tions where it is considered feasible. -- The use of HVLV ventilation in volves problems such as insufficient hood capture velocity, obstruction of the work area by the control, and poor dust collector performance. Re search is needed to improve the per formance of HVLV systems and the feasibility of their use in other opera tions. -- Alternative materials and work methods can be used to reduce crys talline silica exposures. For example, 102 concrete forms can be used to impart smoother surface finishes and reduce the need for additional grinding or rework. Additional research is needed to investigate alternative methods for blowing and sweeping on construc tion sites (e.g., the use of vacuums instead of compressed-air lances to remove debris from cracks in road construction). Foundries. Foundries use large volumes of sand in the molds and the cores to pro duce castings. In general, foundries that cast higher-temperature metals (steel, gray iron, and stainless steel) have the potential for creating higher silica expo sures than foundries that cast lowertemperature metals (aluminum, brass, and bronze). The molding sand used in most foundries contains a small percent age of water and other binders. High temperatures dry the sand, making it more likely to become airborne. Various types of controls are being used in foundries, but additional research is needed: -- Alternative processes such as the lost foam casting process have been used for some metal castings, but they re quire additional investigation to de termine whether they can effectively reduce exposures by minimizing the amount of casting cleaning and sand handling required to produce highquality castings. -- Industrial ventilation is widely used to capture and contain silica-contain ing aerosols. However, its effective ness is only as good as its design, in stallation, and maintenance. Research is needed on methods for effectively communicating the need for routine Respirable Crystalline Silica and proper maintenance of ventila tion systems. -- Automated processes in foundries need to be explored so that workers can be removed from operations that generate high silica exposures. -- The use of HVLV ventilation sys tems during casting cleaning needs to be evaluated. -- Alternative methods should be in vestigated for blowing and sweeping in foundries. Vacuums may be feasi ble as an alternative to compressedair lances and dry sweeping. Abrasive blasting operations. Abrasive blasting operations have been docu mented to generate some of the highest crystalline silica exposures. Other blast ing materials such as steel shot, steel grit, and boiler slag have been used as substitutes for silica sand. However, ad ditional research is needed to determine the safety of substitute blasting materi als. In addition, replacing silica sand with a substitute blasting material will not eliminate silica exposures when blasting on silica substrates such as con crete or granite. Many of these opera tions may be modifiable to reduce the amount of blasting required. Additional research is needed on alternative blast ing methods such as high-pressure water jetting, slurry blasting, and vacuum blasting. All of these may reduce 6 RESEARCH NEEDS exposures associated with silica-con taining substrates. Surface and other mining. Technology exists in the surface mining industry to control exposure to crystalline silica. However, silicosis persists because con trols are often not implemented or prop erly maintained [NIOSH 1996b]. Effec tive methods are needed for informing drillers and drill owners about the need for continued maintenance and proper use of dust controls on drills. Mine workers at other than surface sites have silica exposures that have not been well characterized. For example, little or no information is available about dust con trol measures for hard-rock tunneling operations. Research is needed to deter mine which control measures provide the best protection and are feasible to implement. Paints, coatings, glass, cosmetics, plas tics, and cleaning products. Crystalline silica is used in a diverse number of pro ducts, including paints, coatings, glass, cosmetics, plastics, and cleaning prod ucts. However, the hazards associated with silica exposure are often not recog nized in these industries. Research is needed to develop methods for commu nicating hazards and controls to workers and employers. The need is for innova tive technologies that can be transferred across industries. Additional research is needed to investigate the feasibility of using HVLV ventilation systems and water to reduce exposures in these in dustries. 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Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occu pational Safety and Health, Division of Surveillance, Hazard Evaluations and Field Studies, Industrial Hy giene Section, Industrywide Studies Branch. 126 Respirable Crystalline Silica Appendix Occupational Exposure Limits Table A-1. U.S. guidelines and limits for occupational exposure to crystalline silica Reference Substance Guideline or limit (mg/m3) NIOSH [1974] OSHA [29 CFR 1910.1000-Table Z-3] MSHA [30 CFR 56, 57, 70, 71] ACGIH [2001] Crystalline silica:* quartz, cristobalite, and tridymite as respirable dust Respirable crystalline silica, quartz Respirable crystalline silica, cristobalite Respirable crystalline silica, tridymite Respirable quartz in underground and surface metal and nonmetal mines Respirable crystalline silica present in concentrations >5% in surface and underground coal mines Respirable crystalline silica, quartz Respirable crystalline silica, cristobalite Respirable crystalline silica, tridymite RELf = 0.05 (for up to a 10-hr workday during a 40-hr workweek) PEL = 10 ^ % quartz + 2 (8-hr TWA) PEL = half of the value calculated from the formula for quartz PEL = half of the value calculated from the formula for quartz PEL = 10 ^ % quartz + 2 (8-hr TWA) RDSf = 10 ^ % quartz (8-hr TWA) TLV = 0.05 (8-hr TWA) TLV = 0.05 (8-hr TWa) TLV = 0.05 (8-hr TWa) Adapted from Heart [1996]. * Identified by NIOSH as a potential occupational carcinogen [54 Fed Reg. 2521 (1989)]. 1 Abbreviations: REL = recommended exposure limit; PEL = permissible exposure limit; RDS = respirable dust standard; TLV = threshold limit value; TWA = time-weighted average. Respirable Crystalline Silica 127 Table 1. Nonmining and mining industries with the largest numbers of U.S. workers potentially exposed to respirable crystalline silica, 1986 SIC* Industry Estimated number of workers potentially exposed (1986)t % total workers exposed (NOES) Nonmining industries: 174 Masonry, stonework, tile setting, and plastering 734 Services to dwellings and other buildings 327 Concrete, gypsum, and plaster products 176 Roofing and sheet metal work 356 General industrial machinery and equipment 807 Medical and dental laboratories 493 Combination of gas and electric and other utilities 179 Miscellaneous special trade contractors 753 Automotive repair shops 326 Pottery and related products 131,986 65,812 63,456 51,153 44,991 37,063 35,074 32,615 30,826 29,772 32.7 10.3 33.3 25.3 16.2 30.0 21.2 7.8 7.1 81.7 Mining industries: 13 Oil and gas extraction 12 Bituminous coal and lignite mining 14 Mining and quarrying of nonmetallic minerals, except fuels 10 Metal mining 408,175 174,131 100,546 39,856 100* 100 100 100 Source: NIOSH [1991]. Standard industrial classification. ^Estimated number of workers potentially exposed to the hazards of flint, quartz, sand, or silica powder; based on data from the County Business Patterns 1986 [Bureau of the Census 1986] and the National Occupational Exposure Survey (NOES) [NIOSH 1983b]. For SICs in which the estimates differed for individual hazards, the highest percentage was used for that SIC. ^Exposure is assumed to be 100% in the mining industries. Table 2. Main industries and activities around the world in which silica exposure has been reported Industry or activity Agriculture Mining and related milling operations Quarrying and related milling operations Construction Glass, including fiberglass Cement Abrasives Ceramics, including bricks, tiles, sanitary ware, porcelain, pottery, refractories, vitreous enamels Iron and steel mills Operations and tasks Source materials Plowing, harvesting, using machinery, burning agricultural waste, processing agricultural products Soil Most occupations (underground, surface, mill) and mines (metal and nonmetal, coal), rock drilling, dredging Ores, associated rock Crushing stone, sand and gravel processing, stone monument cutting and abrasive blasting, slate work (e.g., pencil manufacturing), diatomite calcination Sandstone, granite, flint, sand, gravel, slate, diatomaceous earth Abrasive blasting of structures and buildings, highway and tunnel construction, excavation and earth moving and digging, masonry, concrete work, demolition, dry sweeping and brushing, pressurized air blowing, jack hammering, laying railroad track, removing rust or paint, sanding and scaling, replacement of asphalt roofing, and hauling, pouring, mixing, or dumping silica-containing materials Sand, concrete, rock, soil, mortar, plaster, shingles Raw material processing, refractory installation and repair Sand, crushed quartz, refractory materials Raw material processing Clay, sand, limestone, diatomaceous earth Silicon carbide production, abrasive products fabrication Sand, tripoli, sandstone Mixing, molding, glaze or enamel spraying, finishing, sculpting, firing Clay, shale, flint, sand, quartzite, diatomaceous earth Refractory preparation and furnace repair Refractory material (Continued) Sources: IARC [1987; 1997], NIOSH [1979a; 1983a,b; 1996b], DOL, NIOSH [1997], Fulekar and Alam Khan [1995], Jain et al. [1977], Corn [1980], Webster [1982], Froines et al. [1986], Davis [1996], Weill et al. [1994], Lucas and Salisbury [1992], Pike [1992], McCunney et al. [1987], Fairfax [1998]. Table 2 (Continued). Main industries and activities around the world in which silica exposure has been reported Industry or activity Operations and tasks Source materials Silicon and ferro-silicon foundries (ferrous and nonferrous) Metal products, including structural metal, machinery, transportation equipment Shipbuilding and repair Rubber and plastics Paint Soaps and cosmetics Roofing asphalt felt Agricultural chemicals Jewelry Arts, crafts, sculpture Dental material Boiler scaling Automobile repair Raw materials handling, casting, molding and shaking out, abrasive blasting, fettling, furnace installation and repair Abrasive blasting Sand, refractory material Sand Abrasive blasting Raw materials handling Raw materials handling, site preparation Manufacturing or occupational use of abrasive soaps and scouring powders Filling and granule application Raw material crushing, handling, bagging; or dumping products or raw materials Cutting, grinding, polishing, buffing, etching, engraving, casting, chipping, sharpening, sculpting Pottery firing, ceramics, clay mixing, kiln repairs, abrasive blasting, sand blasting, engraving, cutting, grinding, polishing, buffing, etching, engraving, casting, chipping, sharpening, sculpting Sand blasting, polishing Coal-fired boilers Abrasive blasting, sanding, removing paint and rust Sand Fillers (tripoli, diatomaceous earth) Fillers (tripoli, diatomaceous earth, silica flour) Silica flour Sand and aggregate, diatomaceous earth Phosphate ores and rock Semiprecious gems or stones, abrasives, glass Clays, glazes, bricks, stones, rocks, minerals, sand, silica flour Sand, abrasives Ash and concretions Sand, metals, priming putty Table 3. Industrial silica sand and gravel sold or used by U.S. producers in 1994, by major end use General use End use Sand: Glass-making Foundry work Metallurgical work Abrasive work Fillers Ceramics Filtration Petroleum manufacturing Recreation Gravel Containers, flat (plate and window), specialty, fiberglass (unground or ground) Molding and core, molding and core facing (ground), refractory Silicon carbide, flux for metal smelting Blasting, scouring cleansers (ground), sawing and sanding, chemicals (ground and unground) Rubber, paints, putty, whole grain fillers/building products Pottery, brick, tile Water (municipal, county, local), swimming pool, others Hydraulic fracturing, well packing, and cementing Golf course, baseball, volleyball, play sands, beaches, traction (engine), roofing granules and fillers, other (ground silica or whole grain) Silicon, ferrosilicon, filtration, nonmetallurgical flux, other Sources: IARC [1997]; BOM [1994] Table 4. Most frequently recorded occupations of U.S. residents aged 15 or above whose death certificates list silicosis as an underlying or contributory cause of death--selected States, 1991-1992* COC* Occupation Number % 616 Mining machine operator 39 16.0 889 Laborer, except construction 29 11.9 019 Manager or administrator, not elsewhere classified 11 4.5 633 Supervisor or precision production occupations 11 4.5 453 Janitor, cleaner 8 3.3 719 Molding, casting machine operator 8 3.3 243 Supervisor or proprietor of sales occupations 6 2.5 844 Operating engineer 6 2.5 637 Machinist 5 2.1 787 Hand molding, casting, and forming occupations 5 2.1 -- All other occupations 109 44.9 -- Occupation not reported 6 2.5 TOTAL Source: NIOSH [1996a]. *Data for 1985-1990 are reported in Table 4-11 of NIOSH [1994d]. *COC: 1980 census occupation code. * Column does not add to 100.0 because of rounding. 243 100.1* Table 5. Other occupations* reporting cases of silicosis in workers Industry or occupation Reference Agriculture industry or forestry worker Brewery worker Confectioner Fennerty et al. [1983]; Dynnik et al. [1981]; Beaumont et al. [1995] Nemery et al. [1993] Canessa et al. [1990] Crystal cutter Suskovic et al. [1990] Drycleaning worker Seitz et al. [1982] Filter candle production worker Vigliani and Mottura [1948] Grave digger and well digger al-Kassimi et al. [1991] Kaolin worker Rodriguez et al. [1985] Metal polisher Malik et al. [1985] Pit digger de Barros Hatem and Cavalcanti [1990] Souvenir casting worker Carel et al. [1994] Woodworker Thoreux et al. [1990] Includes only occupations not listed in Tables 2 or 4 Table 6. XRD* sampling and analytical methods for crystalline silica Item Silica polymorph Sampler Filter Volume Filter preparation Redeposition Drift correction NIOSH Method 7500 Quartz, cristobalite, tridymite 10-mm nylon cyclone, 1.7 L/min; Higgins-Dewell cyclone, 2.2 L/min 37-mm, 5-pm PVC membrane 400-1,000 L; total dust < 2 mg RF plasma asher, muffle furnace, or filter dissolution in THF On 0.45-pm silver membrane filter Silver internal standard X-ray source Calibration Proficiency testing Range (pg quartz) Cu K" 40 kV, 35 mA Suspensions of SiO2 in 2-propanol (deposited on silver membrane filter) PAT 20-2000 LOD (pg quartz) Precision 5 (estimated) RSD = 0.08 50-200 pg OSHA Method ID-142 Quartz, cristobalite MSHA Method P-2 Quartz, cristobalite MDHS 51/2 Quartz 10-mm nylon Dorr-Oliver cyclone, 1.7 L/min 10-mm nylon Dorr-Oliver cyclone, 1.7 L/min Higgins-Dewell cyclone, 1.9 L/min 37-mm, 5-pm PVC membrane 408-816 L; total dust < 3 mg Dissolve filter in THF 37-mm, 5-pm PVC membrane 400-1,000 L; total dust < 3 mg RF plasma asher 25-mm, 5-pm PVC membrane $456 L; total dust < 2 mg None On 0.45-pm silver membrane filter On 0.45-pm silver None membrane filter Silver internal standard Silver internal standard External standard (e.g., aluminum plate) Cu K" 40 kV, 40 mA Cu K" 55 kV, 40 mA Cu K" 45 kV, 45 mA Suspensions of SiO2 in 2-propanol (deposited on silver membrane filter) Suspensions of SiO2 in 2-propanol (deposited on silver membrane filter) Sampling from a generated atmosphere of standard quartz dust PAT PAT WASP 50-160 (validation range) 20-500 50-2000 10 5 3 CV = 0.106 @ 50-160 pg CV = 10 % @ 20-500 pg CV = 5 % @ 50 pg *Abbreviations: Cu = copper; CV = coefficient of variation (equivalent to RSD); CV = pooled coefficient of variation; K" = electron ionization energy; kV = kilovolt(s); LOD = limit of detection; mA = milliampere(s); MDHS = Methods for the Determination of Hazardous Substances (Health and Safety Executive, United Kingdom); MSHA = Mine Safety and Health Administration; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration; PAT = proficiency analytical testing; PVC = polyvinyl chloride; RF = radio frequency; RSD = relative standard deviation; rsd = pooled relative standard deviation (equivalent to CV); THF = tetrahydrofuran; WASP = Workplace Analysis Scheme for Proficiency; XRD = X-ray diffraction. Item Matrix Sampler Table 7. IR* sampling and analytical methods for crystalline silica NIOSH Method 7602 NIOSH Method 7603 MSHA P-7 MDHS 37 Coal mine dust Coal mine dust MDHS 38 10-mm nylon cyclone, 1.7 L/min; Higgins-Dewell cyclone, 2.2 L/min 10-mm nylon cyclone, 1.7 L/min; Higgins-Dewell cyclone, 2.2 L/min 10-mm nylon Dorr-Oliver cyclone, 2.0 L/min Higgins-Dewell cyclone, 1.9 L/min HigginsDewell cyclone, 1.9 L/min Filter Volume Filter preparation Analytical sample preparation Standard Calibration Proficiency testing Range (pg quartz) LOD (pg quartz) 37-mm filter; 5-pm PVC or MCE membrane 37-mm filter; 5-pm PVC membrane 37-mm filter; 5-pm PVC membrane, preweighed 400-800 L; total dust <2 mg 300-1,000 L; Not stated total dust <2 mg RF plasma asher or muffle furnace RF plasma asher or muffle furnace RF plasma asher Mix residue with KBr, press 13-mm pellet Redeposit on 0.45-pm acrylic copolymer filter Redeposit on 0.45-pm acrylic copolymer filter Polystyrene film Polystyrene film Polystyrene film Quartz diluted in KBr Standard suspension of quartz in 2-propanol Standard suspension of quartz in 2-propanol PAT PAT PAT 37-mm filter; 5-pm PVC membrane 37-mm filter; 5-pm PVC membrane $456 L; total dust <1 mg None $456 L; total dust <0.7mg Muffle furnace None Mix residue with KBr, press 13-mm pellet Polystyrene film Polystyrene film Sampling from a generated atmosphere of standard quartz dust Sampling from a generated atmosphere of standard quartz dust WASP WASP 10-160 30-250 25-250 10-1,000 5-700 5 (estimated) 10 (estimated) 10 Varies with particle size Varies with particle size See footnote at end of table. (Continued) Table 7 (Continued). IR* sampling and analytical methods for crystalline silica Item NIOSH Method 7602 NIOSH Method 7603 MSHA P-7 MDHS 37 MDHS 38 Precision RSD <0.15 @ 30pg RSD = 0.098 @ 100-500pg CV = 5-10 % @ 100-500 pg CV = 5 % @ 50 pg CV = 5 % @ 50 pg *Abbreviations: CV = coefficient of variation (equivalent to RSD, relative standard deviation); IR = infrared absorption; KBr = potassium bromide; MCE = methyl cellulose ester; MDHS = Methods for the Determination of Hazardous Substances (Health and Safety Executive, United Kingdom); MSHA = Mine Safety and Health Administration; NIOSH = National Institute for Occupational Safety and Health; LOD = limit of detection; PAT = proficiency analytical testing; PVC = polyvinyl chloride; RF = radio frequency; RSD = pooled relative standard deviation (equivalent to CV, pooled coefficient of variation); WASP = Workplace Analysis Scheme for Proficiency. Table 8. Intralaboratory results for evaluation of XRD silica method Filter loading Item 69.4 pg 98.4 pg 204 pg Degrees of freedom 12 11 12 RSD for sampling and analytical methods (%) 8.8 6.3 8.1 Source: NIOSH, BOM [1983]. RSD = relative standard deviation. RSD for sampling and analytical methods represents the RSD in mass estimates, accounting for intersampler and analytical variability. ^Implications for XRD: Pooled filter levels and pump error (assumed to be <5%) indicate that the overall imprecision is as follows: Total RSD for sampling and analytical methods is 9.3%. Therefore, the upper 95% confidence limit on the accuracy (35 degrees of freedom) is 21%. Table 9. Intralaboratory results for evaluation of IR silica method Filter loading Item Degrees of freedom 67.2 pg 10 99.7pg 12 161 pg 11 RSD for sampling and analytical methods (%) 5.8 7.8 7.4 Source: NIOSH, BOM [1983]. RSD = relative standard deviation. RSD for sampling and analytical methods represents the RSD in mass estimates, accounting for intersampler and analytical variability. ^Implications for IR: Pooled filter levels and pump error (assumed to be <5%) indicate that the overall imprecision is as follows: Total RSD for sampling and analytical methods is 7.1%. Therefore, the upper 95% confidence limit on the accuracy (33 degrees of freedom) is 17%. Table 10. XRD method evaluation: concentration ranges bracketing applicable exposure limits for which the NIOSH accuracy criterion is met* (pg/m3) Filter loading Cyclone and sampling rate Nylon cyclone, 1.7 L/min 69.4 pg 85 98.4 pg 121 204 Pg 251 Applicable exposure limit 100 GK2.69 cyclone, 4.2 L/min 34 49 102 50 *Eight-hour sampled masses are combined with results of NIOSH, BOM [1983]. Table 11. IR method: concentration ranges bracketing applicable exposure limits for which the NIOSH accuracy criterion is met* (pg/m3) Filter loading Cyclone and sampling rate Nylon cyclone, 1.7 L/min 6.72 pg 83 99.7 pg 123 161 pg 198 Applicable exposure limit 100 GK2.69 cyclone, 4.2 L/min 34 50 80 50 *Eight-hour sampled masses are combined with results of NIOSH, BOM [1983]. Table 12. Predicted incidence or prevalence of silicosis following exposure to selected concentrations of respirable quartz dust--based on modeling of cumulative exposure over a 45-year working lifetime Study and cohort Selected mean concentration of respirable quartz dust (mg/m3) Mean time since first quartz exposure (yr) Maximum time since first quartz exposure (yr) Predicted incidence or prevalence of silicosis, ILO category $ 1/1 (cases/100 workers) Hnizdo and Sluis-Cremer [1993], 2,235 South African gold miners Hughes et al. [1998], 2,342 U.S. workers in a diatomaceous earth mining and processing facility Kreiss and Zhen [1996], 100 U.S. hardrock miners and 34 community controls Muir et al. [1989a,b] and Muir [1991], 2,109 Canadian gold and uranium miners Ng and Chan [1994], 338 Hong Kong granite workers Rosenman et al. [1996], 1,072 U.S. gray iron foundry workers Steenland and Brown [1995a], 3,330 U.S. gold miners 0.05 0.10 0.05 0.10 0.05 0.10 0.05 0.045*"` 0.05 0.10 0.05 0.09 36` -- 11.5 -- 41.6` 33.5** 18 __ ttt 28 -- 37 -- 50` -- 46 -- 66` 68** 38` --ttt >30 -- 73 -- 13t 70* 1.5-4*" 4-17*" 30*,tt 90*,tt 0.09-0.62 6 2*** 3*** 10"" 47"" `Silicotic miners. Estimate reported in Rice and Stayner [1995]. ^Approximate. Primarily cristobalite dust. Cumulative risk of small opacities $ILO category 1/0 and/or large opacities. For 1,452 workers with an average crystalline silica exposure #0.50 mg/m3; 1,138 (78%) of these workers were hired in 1950 or later. "Primarily cristobalite dust. Cumulative risk of small opacities $ILO category 1/0 and/or large opacities. For 357 workers with an average crystalline silica exposure >0.50 mg/m3; 319 (89%) of these workers were hired before 1950. nBased on cumulative silica exposure model with 10 yr of post-employment followup. **Nonsilicotic miners. No post-employment followup and no retired miners included. The range includes five estimates (one for each reader). Estimate reported in Rice and Stayner [1995]. ```Based on a 50-year-old worker with cumulative silica exposure of 2 mg/m3-yr. tnNot reported. Mean duration of employment was 17 yr for all workers and 27.5 yr for workers in the highest category of cumulative silica exposure. ***ILO category $ 1/0. Based on a 40-yr working lifetime and controlling for pack-years of cigarette smoking, race, and silica exposure other than in the foundry under study. Steenland [1998]. ````Includes 141 cases documented on death certificate only. Estimated risk not adjusted for age or calendar time [Steenland 1997]. Table 13. Summary of epidemiologic studies of silicosis with cumulative dust exposure data and silicosis risk estimates Reference, country, and study design Cohort Definition of silicosis, mean duration of employment, and mean yr since first quartz exposure Silica (quartz) content of respirable dust Measure of association Comments Hnizdo and SluisCremer [1993], South Africa, cohort study 2,235 white underground gold miners who were aged 45 to 54 at time of medical examination in 1968-1971, started working after 1938, worked $ 10 yr, and were followed until 1991. ILO* category $ 1/1and rounded opacities (313 cases); 23.5 yr for total cohort and 26.9 yr for cases; 36 yr for cases. 30% after heat and acid treatment [Beadle and Bradley 1970]. Cumulative risk Authors speculated that these silicosis risk estimates were higher than estimates for Canadian miners reported by Muir et al. [1989a,b] and Muir [1991] because (1) dust exposure may have been under estimated, (2) South African gold mine dust may be more fibrogenic than Canadian mine dust, (3) average proportion of quartz may be >30%, (4) there may have been differences in age at end of radiological follow up, and (5) exposures for Canadian miners (Hnizdo's [1995] response to Hughes and Weill [1995]) may have been overestimated. See footnotes at end of table. (Continued) Table 13 (Continued). Summary of epidemiologic studies of silicosis with cumulative dust exposure data and silicosis risk estimates Reference, country, and study design Cohort Definition of silicosis, mean duration of employment, and mean yr since first quartz exposure Silica (quartz) content of respirable dust Measure of association Comments Hughes et al. [1998], United States, retro spective cohort study 2,342 white male workers employed at least 1 yr between 1942 and 1987 in one diatomaceous mining and processing facility. Exposure-response analy ses included the 1,809 men with a radiograph taken more than 1 month after hire. Small opacities $ILO profusion category 1/0 and/or large opacities (81 cases); 5.54 yrf; 11.5 yr. Natural diatomite, 3%; calcined diatomite, 20%; flux-calcined diatomite, 60% (see comments). Cumulative risk 82 workers had radiographs taken after retirement--development of opacities was not recorded for other workers after they left employ ment. Quantitative air-monitoring data were available after 1948; respirable dust concentrations be fore 1948 were estimated [Seixas et al. 1997]. Cumulative risk estimates for radiographic opacities were lower for workers who were hired after 1950 and who had lower average exposures to crystalline silica dust (mainly cristobalite). Estimated percentages of respirable crystalline silica reported by Checkoway et al. [1997] in mortality study of same cohort: 10% for calcined diatomaceous earth, and 20% for flux-calcined diatomaceous earth. See footnotes at end of table. (Continued) Table 13 (Continued). Summary of epidemiologic studies of silicosis with cumulative dust exposure data and silicosis risk estimates Reference, country, and study design Cohort Kreiss and Zhen [1996], 134 male residents of a United States, hardrock* mining town community-based who were aged $40: 100 random sample survey silica-exposed hardrock miners (included 32 sili cosis cases) and 34 com- munity controls without occupational dust expo sure. Definition of silicosis, mean duration of employment, and mean yr since first quartz exposure ILO category $ 1/0; 27.6 yr for silicotics and 22.9 yr for nonsilicotic miners; 41.6 yr for silicotics and 33.5 yr for nonsilicotics. Silica (quartz) content of respirable dust 12.3% Measure of association Prevalence Comments Possible overestimation of silicosis risk because of underestimation of pre-1974 dust and silica exposures. Exposures were also estimated for mines where there were no expo sure data (17.1% of the person-yr of followup). Risk estimates were presented for models of cumulative silica dust exposure or cumulative dust exposure--the models of cumu lative silica dust exposure gave higher estimates. Silicosis (i.e., $ category 1/1) risk estimates from models of cumulative dust expo sure were similar to estimates for South African gold miners [Hnizdo and Sluis-Cremer 1993] and U.S. gold miners [Steenland and Brown 1995a]. See footnotes at end of table. (Continued) Table 13 (Continued). Summary of epidemiologic studies of silicosis with cumulative dust exposure data and silicosis risk estimates Reference, country, and study design Cohort Definition of silicosis, mean duration of employment, and mean yr since first quartz exposure Silica (quartz) content of respirable dust Measure of association Comments Muir et al. [1989a,b], Verma et al. [1989], Muir [1991]; Canada; retrospective cohort study 2,109 current Ontario gold and uranium miners who started and worked $ 5 yr between 1940 and 1959 and were followed to 1982 or to the end of their dust exposure, whichever came first. ILO category $ 1/1 and small, rounded opacities (32 cases); approximately 20 yr; approximately 25 yr (based on interpre tation of data in table and graph of Muir et al. [1989b]). 6.0% for gold mine dust; 8.4% for uranium mine dust. Cumulative risk Retired and former workers not included, which may have under estimated silicosis risk. Disagree ment about silicosis classification among the five readers of the chest X-rays may have "complicated the analysis" [Muir et al. 1989b]. See footnotes at end of table. (Continued) Table 13 (Continued). Summary of epidemiologic studies of silicosis with cumulative dust exposure data and silicosis risk estimates Reference, country, and study design Cohort Definition of silicosis, mean duration of employment, and mean yr since first quartz exposure Silica (quartz) content of respirable dust Measure of association Comments Ng and Chan [1994], Hong Kong, cross sectional study 338 current and previous granite workers employed $ 1 yr between 1967 and 1985. ILO category $1/1 (rounded or irregular opacities); 17.4 yr; not reported. 27% Prevalence Cumulative risks not calculated. Exposure data for 1976-1981 in one quarry and for 1971-1975 and 1976-1981 in another quarry were not available and were assumed to be the same concentrations measured in 1982 for the period 1976-1981 and in 1971 for the period 1971-1985 [Ng et al. 1987]. Possible under estimate of silicosis risk because decedents were not included. See footnotes at end of table. (Continued) Table 13 (Continued). Summary of epidemiologic studies of silicosis with cumulative dust exposure data and silicosis risk estimates Reference, country, and study design Cohort Definition of silicosis, mean duration of employment, and mean yr since first quartz exposure Silica (quartz) content of respirable dust Measure of association Comments Rosenman et al. [1996], United States, cross sectional study 549 current, 497 retired, and 26 current salaried workers that were former production workers in a gray iron foundry that pro duced automotive engine blocks (total workers=1,072). ILO category $ 1/0 and rounded opacities (28 cases); 19.2 yr; 28.3 yr. Not reported. Prevalence Prevalence of silicosis cases increased with (1) years of employment, (2) cigarette smoking, (3) mean silica exposure, and (4) cumulative silica exposure. Exposure estimates were derived from conversions of "early silica exposure data" collected by impingers. Underascertainment of sili cosis cases is likely because there was no systematic radiologic fol lowup of retired workers. Results showed that African-American workers had two times the risk of radiographic silicosis compared with white workers but a similar duration of employment; however, African-American workers had greater mean exposure to silica dust. When exposure to silica was controlled for in the analysis, the prevalence of radiographic silicosis was similar for African-American workers and white workers. See footnotes at end of table. (Continued) Table 13 (Continued). Summary of epidemiologic studies of silicosis with cumulative dust exposure data and silicosis risk estimates Reference, country, and study design Cohort Definition of silicosis, mean duration of employment, and mean yr since first quartz exposure Silica (quartz) content of respirable dust Measure of association Comments Steenland and Brown [1995a], United States, cohort study 3,330 white male under ground gold miners em ployed $ 1 yr between 1940 and 1965 and followed through 1990. Mortality5 and ILO category $ 1/1 (1976 radiographic survey) or "small opacities" or "large opacities" (1960 radiographic survey) (170 cases); 9 yr; 37 yr. 13% [Zumwalde et al. 1981] Cumulative risk Silicosis risk estimates could have been affected by (1) combining silicosis deaths with silicosis cases detected by cross-sectional radio graphic surveys, (2) difference in quartz content of dust in early years, (3) lack of dust measure-ments before 1937. `International Labour Organization. fMedian [Checkoway et al. 1997]. ^Molybdenum, lead, zinc, and gold mining. Underlying or contributing cause of death was silicosis, silico-tuberculosis, respiratory tuberculosis, or pneumoconiosis. Table 14. Selected age-adjusted PMRs*^ for pulmonary TB by usual occupation, sex, and race in 28 States, 1979-1990 Male decedents Female decedents Occupation of decedent and 1980 census code White Black Number PMR 95% CI Number PMR 95% CI White Black Number PMR 95% CI Number PMR 95% CI Construction occupations (553-599, 865, and 869) 169 134' 114-156 105 128' 104-155 0 0 Brick and stone mason (553 and 563-564) 12 213' 110-371 11 159 80-285 0 ---- 0-- -- Carpenter (554, 567, and 569) 50 147' 109-194 9 97 44-184 0 ---- 0-- -- Roofer (595) 6 290' 106-630 1 53 1-293 0 ---- 0-- -- Construction laborer (869) 34 175' 121-244 61 156' 120-201 0 ---- 0-- -- Mining machine operator (616) 54 276' 207-360 4 128 35-328 0 ---- 0-- -- Grinding, abrading, buffing, or polishing machine operator (709) 7 265' 107-547 1 94 2-523 0 0 Mixing or blending machine operator (756) 1 58 2-326 5 376' 122-878 0 ---- 0-- -- Furnace, kiln, or oven operator, except food (766) 1 27 1-153 5 206' 67-481 0 1 15,000 372-82,842 Laborer, except construction (889) 85 159' 127-196 92 111 89-136 12 162 84-283 8 147 64-291 Source: Adapted from CDC [1995]. This data file includes death records from 28 States (Alaska, California, Colorado, Georgia, Idaho, Indiana, Kansas, Kentucky, Maine, Missouri, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, Rhode Island, South Carolina, Tennessee, Utah, Vermont, Washington, West Virginia, and Wisconsin). *Abbreviations: PMRs = proportionate mortality ratios; TB = tuberculosis; CI = confidence interval. Selection criteria: (1) at least four TB deaths in race- and sex-specific group and (2) either a PMR >200 or a PMR with a 95% CI excluding 100. See footnotes at end of table. (Continued) Table 15. IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Amandus et al. [1991], United States Mortality study of 714 male, North Carolina dusty trades workers diagnosed with silicosis between 1940 and 1983 and compared with the 1940-1983 lung cancer mortality rates for U.S. males. Whites Nonwhites White silicotics: Diagnosed while employed Employed in jobs with silica exposure only Past or current smokers Silicotics, never smoked Number of lung cancer deaths or cases 33 1 28 26 18 5 Risk measureT 2.6 0.7 2.5 2.3 3.4 1.7 Smoking information available and CI* analyzed Comments 1.8-3.6 Not reported 1.7-3.7 1.5-3.4 2.0-5.3 0.5-3.9 Yes The age- and smokingadjusted rate ratio for white silicotics with lung cancer was 3.9 (95% CI= 2.4-6.4) compared with a referent group of metal miners. "Exposure to respirable silica dust" was defined as working in a dusty trade and having radio-graphic silicosis. No quantitative exposure data were available. Amandus et al. [1992], United States Mortality study of subgroup of 306 white males from Amandus et al. [1991] cohort of silicotics diagnosed and traced from 1940 through 1983. 143 of the subgroup were reclassified as silicotics, and 96 were reclassified as having a normal radiograph. 10 deaths from lung cancer occurred in the reclassified group. Silicotics Nonsilicotics** Smokers: Silicotics Nonsilicotics** 8 2.5 1.1-4.9 Yes "Exposure to respirable silica dust" was defined as 2 1.0 0.1-3.5 working in a dusty trade and having radiographic silicosis. 5 3.4 1.1-7.9 1 1.3 0.03-7.1 No quantitative exposure data were available. Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer See footnotes at end of table. (Continued) Reference Study design, cohort, and country and followup Subgroup Burgess et al. [1997], Cherry et al. [1997], McDonald et al. [1997], United Kingdom Nested case-control study of lung cancer deaths within Cherry et al. [1995], including duration and intensity of exposure, smoking, and radiological changes. Cases were employed as pottery workers for $ 10 yr. Each death was matched with 3 or 4 controls on date of birth and date of first expo sure. Cumulative exposure to respirable crystalline silica dust $4,000 :g/m3-yr Duration of employment $20 yr Mean intensity of silica dust exposure $200 :g/m3 Maximum silica dust exposure $400 :g/m3 Number of lung cancer deaths or cases 52 Risk measure* 0.60ft 0.48tt 1.68tt 2.07tt CI* 0.26-1.41** 0.21-1.09** 0.93-3.03** 1.04-4.14** Smoking information available and analyzed Comments Yes ORs were adjusted for smoking and radio-graphic changes. This was the only epi demiologic study of peak exposure effects and lung cancer. Results support significant lung cancer risk for high-intensity silica exposures. Silica dust exposures $400 :g/m3 occurred in firing and post-firing operations. Exposures to cristobalite were possible. See footnotes at end of table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Number of lung cancer deaths or cases Risk measure* Smoking information available and CI* analyzed Comments Checkoway et al. [1993; 1996], United States Mortality study of 2,570 male workers at diatomaceous earth plants employed $ 1 yr and worked $ 1 day between 1942 and 1987. Cohort mortality traced for that period. Checkoway et al. [1996] reanalyzed 2,266 work-ers (a subset of the orig-inal cohort). Mortality traced from 1942 through 1987. Cherry et al. [1995], United Kingdom Mortality study of 5,115 pottery workers, ex cluding exposure to asbestos, foundry, and other dusts; with mortality followup to June 30, 1992. -- 59 1.43 1.09-1.84 Limited to Estimated relative risks for comparisons of lung cancer (not shown) smoking were adjusted for age, prevalence. calendar year, dura-tion of followup, and ethnicity. The risks in-creased significantly (P<0.05 for trend) with duration of employment and 52 1.41 1.05-1.85 cumulative exposure to crystalline silica [Checkoway et al. 1993]. Checkoway et al. [1996] also adjusted for asbestos exposure. 68 1.28 1.04-1.57** No Lung cancer rates in pot tery workers were com pared with local mor-tality rates. See footnotes at end of table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Costello and Graham [1988], United States Mortality study of 5,414 white male workers in Vermont granite sheds and quarries employed between 1950 and 1982 with at least one radiologic examination in the worker surveillance program. Quarry workers Shed workers: Started before 1940, latency period $40 yr, tenure $30 yr Started after 1940, latency period $25 yr, tenure $ 10 yr Number of lung cancer deaths or cases 20 98 47 17 Risk measureT 0.82 1.27 1.81 1.73 Smoking information available and CI* analyzed Comments Not reported Not reported 1.33-2.41*** 1.01-2.77 No Dust exposure data were not included, limiting conclusions about exposure-response. Cohort overlaps with cohort of Davis et al. [1983]. CIs reported by IARC [1997]. Costello et al. [1995], United States Mortality study of 3,246 male workers employed $ 1 yr between 1940 and 1980 at 20 U.S. crushed stone (i.e., granite, limestone, traprock, or sand- stone) operations. Whites Nonwhites Workers in granite facilities with $20-yr latency period and $10-yr tenure Workers in limestone facilities Workers in traprock facilities 40 11 7 23 3 1.2 0.9-1.6 No 1.9 0.9-3.3 3.5 1.4-7.3 1.5 1.0-2.3 0.6 0.1-1.8 See footnotes at end of table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Dong et al. [1995], China Mortality study of lung cancer in 6,266 male silicotic and nonsilicotic refractory brick workers employed before 1962 and followed for mor- tality from 1963 to 1985. 11,470 nonsilicotic male steel workers used as controls. Silicotics Silicotics in Chinese radiological category: I II III Nonsilicotics Number of lung cancer deaths or cases 35 21 10 4 30 Risk measureT 2.1tn 2.0 2.3 2.6 1.1 Smoking information available and CI* analyzed Comments Not reported*** Not reported*** Not reported* Not reported* Not reported*** Yes Twofold excess lung cancer mortality occurred in both smokers and nonsmokers. Exposureresponse trends were found for years since first employment and lung cancer mortality, and for severity of silicosis and lung cancer mortality. Guenel et al. [1989], Denmark Cohort study of 2,175 Danish stone workers who met the following criteria: were alive on Jan. 1, 1943, or were born later, and were aged <65 when first identified in one of 6 data sources. The cohort included 2,071 cancer cases identified in the Danish cancer registry between 1943 and 1984. Lung cancer cases 44 2.00w 1.49-2.69 Yes Adjusted for regional differences in smoking. Lung cancer mortality highest among Copen hagen sandstone cutters hired before 1940 prior to ventilation improve-ments. See footnotes at end of table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Number of lung cancer deaths or cases McDonald et al. [1995], United Kingdom Preliminary report of proportionate mortality study of 7,020 pottery workers born between 1916 and 1945 with mortality followup to June 30, 1992. Prelim-inary nested case-control study of 75 lung cancer cases and 75 controls. Lung cancer deaths in pottery workers not exposed to asbestos Smokers and nonsmokers with $ 10 yr of silica exposure Smokers with $ 10 yr of silica exposure McLaughlin et al. [1992], China Nested case-control study of 62 pottery fac-tory workers employed between 1972 and 1974 who died from lung cancer before 1990; 238 controls matched by decade of birth and factory. Cumulative respirable silica dust exposure (pg/m3-yr): None Low (0.1-8.69) Medium (8.70-26.2) High ($26.3) 112 75 47 11 17 27 7 Risk measure* 1.22 1.4ft 2.8tt 1.0 1.8 1.5 2.1 Smoking information available and cr analyzed Comments 1.04-1.43** 0.7-2.7** 1.1-7.5** -- 1.04-2.87 0.99-2.18 0.80-4.12 No Preliminary results (final results in Cherry et al. [1995]). Lung cancer rates in pottery workers were compared with local mor-tality rates. Yes ORs were adjusted for age and smoking. Test for exposure-response trend was not statistically significant (f>0.05) for cumulative exposure to dust or respirable silica. High OR (7.4; CI and number of deaths not reported) for lung cancer in workers who smoked >20 cigarettes per day. CIs reported in IARC monograph [1997]. See footnotes at end of table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Merlo et al. [1991], Italy 1,022 male refractory brick workers employed at least 6 months between 1954 and 1977. Retrospective cohort study of mortality through 1986. All brick workers Brick workers: #19 yr since 1st exposure and employed #19 yr >19 yr since 1st exposure and employed # 19 yr >19 yr since 1st exposure and employed >19 yr Number of lung cancer deaths or cases 28 Risk measureT 1.51 7 1.05 8 1.75 13 2.01 CI* 1.00-2.18 0.42-2.16 Smoking information available and analyzed Comments Yes Smoking habits of cohort comparable with the national population (includes the men in Puntoni et al. [1988]). 0.75-3.46 1.07-3.44 See footnotes at end of table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Number of lung cancer deaths or cases Risk measure! Smoking information available and CI* analyzed Comments Partanen et al. [1994], Finland Cohort study of 811 male silicotics, compen-sated and not compen-sated, who were diag-nosed between 1936 and 1977 in Finland. Cancer incidence for 1953-1991 was obtained from the Finnish Cancer Registry. Length of followup from date of silicosis diagnosis: <2 yr 2-9 yr >10 yr Histology of lung cancers: Adenocarcinoma Squamous-cell Small-cell Other/unknown Industry: Mining/quarrying (excluding granite) Granite Glass/ceramic Grinding/sharpening Casting/founding Construction Excavation/foundation 1 32 168 5 34 9 53 38 13 10 3 22 2 9 0.4W 2.7 3.3 2.0 3.2 2.1 3.0 3.7 2.9 3.3 3.0 1.8 10 5.8 0.01-2.3 1.9-3.9 2.5-4.1 0.6-4.6 2.3-4.5 0.9-3.9 2.2-3.9 2.6-5.0 1.6-5.0 1.6-6.1 .6-8.7 1.1-2.6 1.3-37 2.7-11.1 Yes Update of Kurppa et al. [1986]. No evidence of confounding by tobacco smoking. See footnotes at end of table. (Continued) Table 15 (Continued). IARC*-reviewed epidemiologic studies having the least confounded investigations of an association between occupational exposure to crystalline silica and lung cancer Reference Study design, cohort, and country and followup Subgroup Number of lung cancer deaths or cases Risk measure* Smoking information available and CI* analyzed Comments Steenland and Brown [1995b], United States Cohort study of 3,328 white male gold miners employed underground $ 1 yr between 1940 and 1965 and followed for mortality from 1977 to 1990. Mortality rates of U.S. males used for comparison. 115 1.13 0.94-1.36 Yes High historical expo-sures. No exposure-response trend by cumu-lative dust exposure. Low radon and arsenic exposures. Source: IARC [1997]. `Abbreviations: CI=confidence interval; IARC=International Agency for Research on Cancer; PMR=proportional mortality ratio; OR=odds ratio; SIR=standardized incidence ratio; SMR=standardized mortality ratio; SRR=standardized rate ratio fSMR unless otherwise noted. *95% CI unless otherwise noted. Workers who had no known exposure to other occupational carcinogens such as asbestos manufacturing, insulation work, olivine mining, talc, and foundry work. ``Nonsilicotics are subjects with normal radiographs. ftOR. **90% CI. P <0.05. ```P <0.01. tttValues in this study are SRRs. ***Values in this study are SIRs. PMR. Table 16. Epidemiologic studies of bronchitis in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Bronchitis cases in subgroup* Risk measure (OR1) 95% CI Adjusted for smoking Comments Clark et al. Cross-sectional study 80 dust-exposed smokers with [1980], United of bronchitic symp- cough all day Yes Note that subgroups represent 24% __t _ bronchitic symptoms_not cases. States toms in 249 white 33 controls were employees of a male taconite miners; 52 dust-exposed nonsmokers with school; however, occupations of mean age was 49 with cough all day 1% -- _ the other controls were not re- $ 20 yr of exposure to ported. Occupational dust expo- taconite dust. 24 nondust-exposed nonsmokers sures to the control group may Control group of with cough all day 1% _ _ have contributed to the similar or 86 men with no his- higher prevalences of bronchitic tory of exposure to 32 nondust-exposed smokers with symptoms in that group. taconite mine dust. cough all day 16% __ 80 dust-exposed smokers with phlegm all day 18% __ 24 nondust-exposed nonsmokers with phlegm all day 1% __ 32 nondust-exposed smokers with phlegm all day 37% See footnotes at end of table. (Continued) Table 16 (Continued). Epidemiologic studies of bronchitis in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Bronchitis cases in subgroup* Risk measure (OR1) 95% CI Adjusted for smoking Comments Cowie and Mabena [1991], South Africa Cross-sectional study of 1,197 black, male underground gold miners aged 28-76 with 25.1 yr since first exposure (mean). 857 miners had chronic silicosis. Miners with chronic sputum pro duction and "high" dust exposure Miners with 24 pack-yr of smok ing exposure and chronic sputum production 1.8s 1.19-2.69 Yes 62% of miners who smoked and 45% of miners who never smoked had "chronic bronchitic symptom complex." 3.7 2.62-5.23** "High" and "low" dust exposure categories were based on quali tative assessments of underground mine dust exposure and occupa tion. Authors stated that bronchitic symptoms may also have been re lated to underground mining expo sures other than respirable quartz dust. See footnotes at end of table. (Continued) Table 16 (Continued). Epidemiologic studies of bronchitis in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Holman et al. [1987], Australia Cross-sectional study of 1,363 male, current gold miners (51% were underground miners) aged 20 to >60. 53% of the cohort worked underground 1-19 yr. Total cohort Miners with chronic bronchitis: 1-9 yr of underground gold mining 10-19 yr of underground gold mining $ 20 yr of underground gold mining Bronchitis cases in subgroup* 14%n -- Risk measure (OR1) -- 1.8 95% CI -- 1.0-3.3 Adjusted for smoking Comments Yes ORs were based on comparison with nonminers and were adjusted for effects of smoking and age. -- 2.5 1.2-5.2 -- 5.1 2.4-10.9 Kreiss et al. [1989b], United States Community-based cross-sectional study of 389 male residents of Leadville, CO. 281 (72.2%) of the sample had worked at the local molybdenum mine. Mean yr of exposure: 9.3. Mean age of cohort: 44. Underground miners with >10 yr of employment: With chronic cough With chronic phlegm -- 0.84 0.93 0.37-1.90 0.42-2.06 Yes ORs were based on comparison with residents having no history of occupational dust exposure. Nearly half (49%) of personal samples for quartz exposures among the miners exceeded the NIOSH REL of 0.05 mg/m3 (total number of samples was not reported). See footnotes at end of table. (Continued) Table 16 (Continued). Epidemiologic studies of bronchitis in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Ng et al. [1992b], Singapore Cross-sectional study of 85 granite quarry workers with "high" dust exposure and 154 quarry workers with "low" dust exposure (see comments); mean age was 42. Mean duration of employment was 13.7 yr. Comparison group of 148 male postal workers with no exposure to granite dust; mean age was 40. Quarry workers with "high" dust exposure: All (85) Nonsmokers (34) Ex-smokers (5) Current smokers (46) Bronchitis cases in subgroup* Risk measure (OR1) 95% CI Adjusted for smoking Comments Yes No quantitative exposure concen- 9 __ _ 2 __ _ -- --_ 7 __ _ trations for dust or silica were reported: granite quarry rock drillers and rock crushers were assumed to have "high" silica exposure; and administrative workers, truck drivers, vehicle maintenance workers, and loader operators were assumed to have "low" silica expo- sure. Results were adjusted for effects of age. See footnotes at end of table. (Continued) Table 16 (Continued). Epidemiologic studies of bronchitis in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Bronchitis cases in subgroup* Risk measure (OR1) 95% CI Adjusted for smoking Comments Rastogi et al. [1991], India Cross-sectional study of 240 male and 102 female agate grinders and chippers, and 116 male and 33 female controls with nondusty occupations. The mean duration of exposure was 10 yr for males and 8.9 yr for females. Chronic bronchitis: Male: Agate workers Controls Female: Agate workers Controls Acute bronchitis: Male: Agate workers Controls Female: Agate workers Controls 3.75/100 4.58/100 0 9.1/100 9.1/100 5.17/100 9.8/100 0 -- -- -- -- -- -- P<0.05 -- -- -- -- -- -- -- -- -- Yes Association between dust exposure and chronic bronchitis may not have been detected because the control group included workers who may have occupational exposure to respirable silica dust (e.g., rickshaw-pullers and sweepers). High prevalence of tuberculosis in agate workers and controls may have masked an association for bronchitis. Samet et al. Cross-sectional study Miners with chronic cough: Yes Chronic cough and chronic phlegm [1984], United of 192 male, current 10-19 yr of mining 14.1/100*** -- -- were not associated with duration States underground urani- $ 20 yr of mining 22.7/100*** -- -- of silica exposure in multiple um miners aged <40, logistic regression analysis (results 40-59, and $60. Miners with chronic phlegm: were not reported). 145 miners (76%) 10-19 yr of mining 31.9/100*** -- -- mined $ 10 yr under $ 20 yr of mining 36.6/100*** -- -- ground. See footnotes at end of table. (Continued) Table 16 (Continued). Epidemiologic studies of bronchitis in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Bronchitis cases in subgroup* Risk measure (OR1) 95% CI Adjusted for smoking Comments Sluis-Cremer Community-based, Residents w/chronic bronchitis: Yes "Dust-exposed" was defined as et al. [1967], cross-sectional study Dust-exposed: self-reported occupational expo- South Africa of chronic bronchitis in 827 male residents Smokers Nonsmokers 199/394 (51%) 22/168 (13%) -- -- -- -- sure in a "scheduled dusty area" of a mine. who were aged >35 Nondust-exposed: and who lived in Smokers 45/161 (28%) -- -- A significant difference existed be- Carletonville, a Nonsmokers and ex-smokers 7/104 (7%) -- -- tween the prevalence of chronic South African town bronchitis in dust-exposed smok- with four gold mines. ers and nondust-exposed smokers (P<0.01). No significant difference existed between dust-exposed and nondust-exposed nonsmokers or ex-smokers. Wiles and Cross-sectional study 138 miners in highest cumulative Yes Prevalence of chronic bronchitis Faure [1977], of chronic bronchitis dust exposure group: increased with increasing mean South Africa in 2,209 underground gold miners Nonsmokers Ex-smokers 2/14 (14%) 4/31 (13%) -- -- -- -- dust concentration (P<0.001) and with cumulative dust exposure in (race not reported) aged 45-54 with Smokers 47/93 (51%) -- -- nonsmokers (P<0.05), ex-smokers (P<0.05), and smokers (P<0.001). $ 10 yr of employ ment. 653 were ex- miners for $ 1 yr. `Number of cases unless otherwise indicated. Abbreviations: CI=confidence interval; NIOSH=National Institute for Occupational Safety and Health; OR=odds ratio; REL=recommended exposure limit. *Dash indicates not reported. Compared with miners having "low" dust exposure. "Compared with miners having 0 pack-yr. nEstimated prevalence. MRisk measure was not reported, but P<0.01 compared with controls. Risk measure was not reported, but F>0.05 compared with controls. ```Standardized to the overall distribution of cigarette smoking. Table 17. Loss of lung function (FEVj)* associated with cumulative exposure to respirable granite dust Loss of FEV1 Reference and Study design, country cohort, and followup Subgroup Observed (estimated ml/yr) Predicted (ml per mg/m3-year) Adjusted for smoking Comments Eisen et al. [1995], United States Longitudinal study of 618 white male granite workers hired after 1940, aged 25-65; employed 14.7 yr (mean), and followed 1970-1974 for annual pulmonary function testing [Eisen et al. 1983]. Quartz content of dust was 11% [Hosey et al. 1957]. Nonsmokers Smokers Nonsilicotic nonsmokers 34-72 53-69 -- Yes Significant dose-response -- (P<0.05) was observed in the 43 "dropout" group but not in the "survivor" group or the total cohort [Eisen et al. 1983]. After 1940, granite dust concentra tions in Vermont granite sheds were <10 million particles per cubic foot (mppcf), or a respir able silica concentration of about 0.075 mg/m3 [Davis et al. 1983]. Predicted loss based on results of linear regression models. Theriault et al. [1974b], United States Cross-sectional study of 792 male, current granite shed workers aged 25-65. Quartz content of dust was 9% [Theriault 1974a]. Granite dust exposure Quartz dust exposure 1.6*, 1.5** `Forced expiratory volume in 1 second. fIn dropout group (i.e., subjects lost to followup). No predicted loss in survivor group. *Per dust-year (i.e., granite shed dust exposure of 0.52 mg/m3 for 40 hr/week for 1 yr). included silicotics. ``Per quartz-year (i.e., quartz dust exposure of 0.05 mg/m3 for 40 hr/week for 1 yr). 3 Yes Predicted loss based on results 2.9 of multiple regression analysis. Exposure-response relationship found between cumulative dust exposure and cumulative quartz exposure and loss of FEVL. Table 18. Epidemiologic studies of emphysema in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Number of emphysema deaths or cases in subgroup Becklake et al. [1987], South Africa Chatgidakis [1963], South Africa Unmatched case- control study of 44 autopsied white gold miners with emphysema > grade 2.0 (i.e., moderate or marked emphysema) and 42 controls without emphysema. Miners and controls were aged 51-70 at death (1980-1981). Miners who smoked 20 cigarettes/day before 1960 Miners aged 70 at death Miners who worked 20 yr in occupations with "high" dust exposure Prevalence study of 800 consecutive autopsies of white gold miners conducted between January 1957 and October 1962. Miners with silicosis and emphysema __t -- _ 297 Risk measure 30.3* 26.8* 12.7* 44.58 95% CI* 7.0-141.0 2.0-327.0 3.0-52.0 Adjusted for smoking Comments The presence of emphysema at autopsy was not Yes associated with the presence of silicosis. No Deaths during 1980-1981 may not be typical of deaths in the total cohort of South African gold miners. No Degree of emphysema was _** No not related to years of service. Pulmonary diffuse emphysema increased significantly with incidence and degree of silicosis and with age. See footnotes at end of table. (Continued) Table 18 (Continued). Epidemiologic studies of emphysema in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Cowie et al. [1993], South Africa Random sample of 70 black underground gold miners selected for computed tomography lung examination from 1,197 partici pants in a cross sectional study conducted in 1984-1985. Miners by emphysema grade: Grade 0 (no evidence) Grade 1 (<25% of lung affected) Grade 2 (25%-50% of lung affected) Number of emphysema deaths or cases in subgroup 22 38 10 Risk measure 95% CI* Adjusted for smoking Comments Yes Presence and grade of emphysema were associ ated with silicosis (P<0.002; P=0.006 ) and smoking (P<0.02; _P=0.01) but were not associated with years of underground mining. Low agreement (i.e., 37/70) between computed tomographic and radio logic assessments of silicotic nodule profusion categories. See footnotes at end of table. (Continued) Table 18 (Continued). Epidemiologic studies of emphysema in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Number of emphysema deaths or cases in subgroup Risk measure 95% CI* Adjusted for smoking Comments Hnizdo et al. [1991], South Africa Retrospective co hort study of the relationship of emphysema with lung function changes in 1,553 white gold miners aged $40 with autopsy examin ation between 1974 and 1987 and panacinar, centriacinar, or a mixed type of emphysema. Miners who worked 20 yr in occupations with "high" dust exposure up to age 45 Yes (in some Logistic regression model analyses) showed significant associ ation between 3.5* 1.7-6.6 centriacinar emphysema and silicosis (P<0.001), emphysema and years of employment in a high- dust occupation for miners who smoked, age and emphysema, and average number of cigarettes smoked/day and emphysema. Possible misclassification of emphysema type. Table 18 (Continued). Epidemiologic studies of emphysema in workers exposed to silica dust Reference and country Study design, cohort, and followup Subgroup Number of emphysema deaths or cases in subgroup Risk measure 95% CI* Adjusted for smoking Comments Hnizdo et al. [1994], South Africa Retrospective cohort study of rela tionship of emphy sema with lung function in 242 white gold miners who were life-long nonsmokers, were aged $45 at death, and had an autopsy examination during 1974-1990. Nonsmoking miners with moderate emphysema 4 `Abbreviations: CI=confidence interval; OR=odds ratio. fDash indicates not reported. *OR for emphysema $ grade 2 at autopsy. Chi-square value (comparing silicotic miners with emphysema to silicotic miners without emphysema). "P<0.00001. Yes For nonsmokers, degree of -- (all study emphysema at autopsy was subjects were not associated (i.e., F>0.05 nonsmokers) in multiple regression model) with years of gold mining, cumulative dust exposure, parenchymal silicosis, or lung function impairment after adjusting for age at death. See footnotes at end of table. (Continued) Table 19. Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Boujemaa et al. [1994], Belgium Cross-sectional case-control study of 116 silicotic, male underground miners with no history of diabetes, nephrolithiasis, or hypertension and 61 agematched controls from the general population. Urine samples were tested for albumin, retinol-binding protein, and NAG. Serum samples were tested for creatinine and $2-microglobulin. Subgroup Silicotics Number of deaths or cases Risk in subgroup measure* 116 t 95% cr comments Miners were examined an average of 23 yr after cessation of exposure. Mean duration of exposure was 14.9 yr. Duration of exposure and severity of silicosis were not associated with the measures of renal dysfunction. Silicotic miners had significantly higher urinary concentrations of albumin (P=0.017), retinol-binding protein (P=0.0045), and NAG (,P=0.0001). Results were similar to those found by Hotz et al. [1995]. See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Subgroup Number of deaths or cases Risk in subgroup measure* 95% cr Comments Bovenzi et al. [1995], Italy Case-control study of 527 patients admitted to all hospitals in Trento province 1976-1991 and discharged with diagnosis of musculoskeletal disorder or connective tissue disease. Each scleroderma case was matched by age and gender to two controls who were without the disease under study and were from the same database. Patients discharged with diagnosis of systemic sclerosis (according to specific diagnostic criteria): Women Men 16 5 0* 5.20s -- 0.48-74.1 See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and Study design, cohort, and country followup Subgroup Number of deaths or cases in subgroup Risk measure* 95% cr Comments Bums et al. [1996], United States Population-based casecontrol study of 274 women with confirmed systemic sclerosis diagnosed in Michigan between 1985 and 1991 and 1,184 female controls matched by race, age, and geographic region. Women with selfreported exposure to the following: Abrasive grinding or sandblasting Sculpting or pottery making Working in a dental laboratory Working with or near silica dust, sand, or other silica products Calvert et al. [1997], United States Cohort morbidity study of 2,412 white, male underground gold miners employed $ 1 yr between 1940 and 1965 and alive on January 1, 1977. Miners with cases of treated end-stage renal disease Nonsystemicn Systemic Unknown 3 20 3 12 11 6 4 1 0.34 0.10-1.10 1.53 0.89-2.65 1.52 0.44-5.26 Adjusted for age, race, and date of birth. Systemic sclerosis was not associated with self-reported exposures to silica dust or silicone (including breast implants). Same study design was applied to Ohio women with systemic sclerosis, and results were published later in a letter [Lacey et al. 1997]. 1.50 0.76-2.93 1.37** 4.22** 0.80** 1.54** 0.68-2.46 1.54-9.19 0.22-2.06 0.04-8.57 First epidemiologic study to examine incidence of end-stage renal disease in an occupational cohort. Subcohort of gold miners studied by Steenland and Brown [1995b]. Mean respirable silica dust exposure of this subcohort was 0.05 mg/m3. See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Subgroup Number of deaths or cases Risk in subgroup measure* 95% CI* Comments Cowie [1987], South Africa Cohort study of incidence of Miners with scleroderma in black gold scleroderma that met miners seen by the medical diagnostic criteria service from July 1981 to June 1986. 10 81.8** Hotz et al. Cross-sectional case-control [1995], Belgium study of prevalence of subclinical renal effects in 86 quarry workers employed 11 to 20 months with no clinical, spirometric, or radiographic signs of silicosis. Controls were manual workers [Bernard et al. 1994] matched by smoking status, body mass index, and age. -- 86 -- Urine samples were tested for albumin, transferrin, creatinine, $2-microglobulin, retinol-binding protein, silicon, and NAG. Serum samples were tested for creatinine and $2microglobulin. Same cohort studied by Bernard et al. [1994]. Quarry workers had significantly higher urinary concentrations of albumin (P<0.0004), transferrin (P<0.03), retinol-binding protein (P<0.001), NAG (,P<0.001), and silicon (P<0.0001). Controls may have been exposed to silica dust--occupational history of controls was not reported. Narrow range of employment duration may have limited the assessment of effects. See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Subgroup Number of deaths or cases Risk in subgroup measure* 95% cr Comments Klockars et al. Cohort morbidity study of Granite workers: Mean quartz concentrations [1987], Finland 1,026 granite workers hired Awarded disability measured in the granite quarries, between 1940 and 1971 with followup until the end of pensions for rheumatoid arthritis processing yards, and crushing 17 5.08*** 3.31-7.79 plants in 1970-1972 ranged from 1981 for (1) incidence of 0.02 to 4.9 mg/m3. disability pension awards for Receiving pensions rheumatoid arthritis during for rheumatoid 1969-1981, (2) prevalence of rheumatoid arthritis on arthritis at end of study period 10 -- 1.6 recipients expected (P<0.001) December 31, 1981, and (3) prevalence of subjects Receiving free receiving free medication medication for for rheumatoid arthritis at rheumatoid arthritis the end of 1981. Referent at end of study group was composed of period 19m -- -- 7.5 recipients expected (P<0.001) Finnish males. See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Subgroup Number of deaths or cases Risk in subgroup measure* 95% cr Comments Ng et al. [1993], Singapore Cross-sectional study of subclinical renal effects in 67 granite quarry workers with no history of glomerulonephritis, urinary calculi, renal disease, diabetes, hypertension, or regular ingestion of analgesics. Workers' urine samples were tested for indicators of glomerular and tubular functions (i.e., albumin, AMG, BMG, and NAG). Workers with low-dustexposure jobs and no radiographic evidence of silicosis Workers with highdust-exposure jobs and <10 yr of employment Workers with highdust-exposure jobs and $10 yr of employment 31 17 19 Workers in the high-exposure group with $ 10 yr of employment had significantly greater (P<0.05) urinary concentrations of AMG, BMG, and NAG compared with workers in the low-exposure group. Quantitative dust exposure data not available. Preliminary findings were reported in Ng et al. [1992a]. Further studies are needed to define the clinical significance of AMG, BMG, and NAG as indicators of renal dysfunction in silica-exposed workers. See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and Study design, cohort and country followup Subgroup Number of deaths or cases in subgroup Risk measure* 95% cr Comments Nuyts et al. Case-control study of [1995], Belgium occupational exposures of 16 patients diagnosed with Wegener's granulomatosis at six Belgian renal units between June 1991 and June 1993. Each patient was matched (by age, sex, and region of residence) with two controls randomly selected from lists of voters. Patients with Wegener's granulomatosis (renal involvement) and reported occupational exposure to silica Rafnsson et al. [1998], Iceland Population-based casecontrol study of residents in a district with a diatomaceous earth processing plant. Population included 8 sarcoidosis patients who were linked to a file of all past and present workers employed at the plant after it opened in 1967. 70 controls were randomly selected from the district population. Sarcoidosis patients with occupational exposure to diatomaceous earth and cristobalite at the community plant 5 6 Study had small sample size and was not designed specifically to examine exposure-response relationship of Wegener's 5.0 1.4-11.6 granulomatosis with occupational exposure to silica. Further study is needed. No matching of cases with controls. Mean values of personal samples of respirable cristobalite dust taken in 1978 and 1981 ranged from 0.002 to 13.2 2.0-140.9 0.6 mg/m3. Stratification by number of hr worked ($1,000 hr or <1,000 hr) indicated a dose-response trend. Further study of sarcoidosis and silica exposure is needed. See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Subgroup Number of deaths or cases Risk in subgroup measure* 95% CI* Comments Rosenman and Zhu [1995] Cohort morbidity study of men and women aged $ 20 and discharged from Michigan hospitals 1990-1991. Patients with silicosis and rheumatoid arthritis: Women Men Sluis-Cremer et al. [1985], South Africa Case-control study of silicosis in 79 white gold miners diagnosed with "definite" or "probable" progressive systemic sclerosis between 1955 and June 1984. Randomly selected control group of 79 miners in same patient index examined between May 1970 and April 1971; matched by age; without progressive systemic sclerosis. -- Sluis-Cremer et al. [1986], South Africa Case-control study of silicosis in 157 white gold miners diagnosed with "definite" or "probable" rheumatoid arthritis between 1967 and 1979. Each case was matched by age to a control subject without rheumatoid arthritis. Miners with "definite" rheumatoid arthritis Miners with "probable" rheumatoid arthritis 0 3 79 91 66 -- 3.2** 1.18 3.79*** 1.94*** No patients had silicosis and scleroderma. -- 1.1-9.4 0.26-5.38 Controlled for cumulative dust exposure. Although reported ORs suggested no association between silicosis and progressive systemic sclerosis, cases had higher cumulative dust exposure (P<0.001). 1.72-8.36 0.81-4.63 This study was not designed to examine the possibility of a direct association between silica dust exposure and progressive systemic sclerosis. Although the reported ORs suggested that gold miners with probable or definite rheumatoid arthritis were more likely to have silicosis as well, the study was not designed to examine the possibility of a direct association between silica exposure and rheumatoid arthritis. The results could not be explained by cumulative dust exposure or the intensity of exposure to gold mine dust. See footnotes at end of table. (Continued) Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Subgroup Number of deaths or cases Risk in subgroup measure* 95% cr Comments Steenland et al. [1990], United States Population-based casecontrol study of occupational exposures of 325 men listed in the Michigan kidney registry and diagnosed with endstage renal disease (excluding diabetic, congenital, and obstructive nephropathies) between 1976 and 1984. 325 controls matched by age, race, and area of residence. Men with end-stage renal disease who reported occupational exposure to silica 87 1.67 1.02-2.74 Possible overreporting of exposure by cases. Steenland et al. [1992], United States Proportionate mortality study of 991 granite cutters who died after 1960 compared with causes of death in U.S. population. Granite cutters: Arthritis deaths Chronic renal disease deaths (ICD-9 categories 582, 583, 585, 587)**** Study included all underlying and 17 2.01 1.17-3.21 contributing causes of mortality after 1960 and other significant conditions that were documented on the death certificate. 26 2.18 1.43-3.20 Table 19 (Continued). Epidemiologic studies of immunologic, autoimmune, and chronic renal disease (including subclinical renal changes) in silica-exposed workers Reference and country Study design, cohort, and followup Subgroup Number of deaths or cases in subgroup Risk measure* 95% ci* Comments Steenland and Brown [1995b], United States Mortality study of 3,328 white male gold miners employed underground $ 1 yr between 1940 and 1965 and followed for mortality from 1977 to 1990. Mortality rates of U.S. males used for comparison. Arthritis (ICD-9 categories 711-716, 720-721) (see comments) Other musculoskeletal disease as well as sclerosis, scleroderma, and lupus (ICD-9 categories 710, 717-719, 722-729, 731-739) (see comments) 17 10 2.19tm 1.27-3.50 Study included all underlying and contributing causes of mortality after 1960 and other significant conditions documented on the death certificate. Statistically significant exposureresponse trend (P<0.05) for chronic renal disease mortality and cumulative dust exposure. 2.14tttt 1.03-3.94 Nonmalignant skin diseases (ICD-9 categories 690-709) (see comments) 10 2.45tttt 1.17-4.51 Chronic renal disease in miners in highest cumulative dust expo sure category (i.e., $48,000 dust-days) 8 2.77mt 1.20-5.47**** 'Odds ratio unless otherwise indicated. Abbreviations: Dash indicates not reported, AMG=alpha-1-microglobulin; BMG=beta-2-microglobulin; CI=confidence interval; NAG=beta-n-acetyl-D-glucosaminidase; OR=odds ratio. *None exposed. For history of silica dust exposure. "Standardized incidence ratio (SIR). nThat is, caused by glomerulonephritis or interstitial nephritis. ^Incidence (cases) per million black gold miners. Incidence in general population of black men of similar age (33-57) was 3.4 cases per million (P<0.001). Disability cases. '"Rate ratio. tttReceiving arthritis medication through national insurance plan. ***OR is for presence of silicosis. PMR. ****ICD-9 is the International Classification ofDiseases, 9th Revision [WHO 1977]. ttttSMR. ****Reported in Steenland and Goldsmith [1995]. Table 20. Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Results Comments Bernard et al. [1994], Belgium Borm et al. [1986], Netherlands Belgium quarry workers who had worked <2 yr. Controls were manual workers without silica dust exposure, matched by smoking status, body mass index, and age. 86 quarry workers and 86 controls Male silicosis patients at a hospital in the Netherlands; exposed to silica for 10-38 yr. Controls were "healthy male, Caucasian blood donors" aged 50-65. 20 silicosis patients (15 coal miners, 4 ceram ics workers, 1 foundry worker); 48 controls Serum and sputum Clara cell protein (Clara cell 16) Decreased concentrations of serum and sputum Clara cell protein in quarry workers (P=0.04) compared with controls. Blood and plasma concentrations of hemoglobin, reduced and oxidized gluta thione, glutathione peroxidase, and super oxide dismutase Silicosis patients had sig nificantly higher concen trations of red blood cell glutathione (P<0.0001). Controls may have been exposed to silica dust. Short duration of exposure among quarry workers may have limited the analysis. Authors state that serum Clara cell 16 may be marker for toxic effects of silica particles on respiratory epithelium. Small number of subjects. Controls were not inter viewed for their occupa tional history, and def inition of "healthy" was not reported. Medication administered to patients may have been a confounder. See footnotes at end of table. (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Results Comments Brandt-Rauf et al. [1992], Finland Prospective study of com pensated pneumoconiosis patients; 91 blood samples were collected between 1983 and 1987. Cancer cases were identified in the Finnish Cancer Registry. 4 silicotics had worked as stone workers, 1 as a stone crusher, 2 as miners, and 3 as foundry workers. 3 silicotics with lung cancer were matched by age and smoking habits with 7 con trols without cancer. 46 patients: 36 with asbestosis and 10 with ILOt category $1/1 silicosis 9 serum oncogenerelated proteins or growth factors: growth factor PDGF-B (sis), TGF-Pj, ras, fes, myb, int-1, mos, src, myc 7/15 asbestosis patients had ras (p21) oncogene, but no oncogene-related proteins were found in the 10 silicosis patients. All silicosis patients had PDGF-B (sis) growth factor; only 42% of asbestosis patients had PDGF-B (sis). Prospective study found that 3 of the 10 silicosis patients developed cancer during the study period (1983-1987). 2 patients had bladder cancer and 1 had lung cancer. PDGF may be a possible marker for development of severe or progressive silicosis. Study results suggest different pathogeneses for silicosis and asbestosis. See footnotes at end of table. (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Results Comments Calhoun et al. [1986], United States Healthy, male, employed granite workers (non smokers) with no clinical or radiographic evidence of silicosis. Volunteer controls of similar age and smoking history with no history of occupational exposure to dust. All workers and con trols had BAL. 9 workers and 9 controls IgG, IgM, IgA, albumin, and total protein (all were measured in BAL fluid and serum) Galikova [1982], Slovakia Miners, drillers, and tunnelers, half with silicosis, aged 43-81, exposed 2-30 yr. Control group of healthy blood donors aged 42-82 with no history of exposure to inorganic dusts. 40 workers and 40 con trols Serum IgG, IgM,and IgA No significant differences in mean serum concen trations between workers and controls. Statistically significant differences (i.e., higher concentra tion) between IgG, IgA, IgM concentrations and lymphocyte counts in lavage fluid of workers compared with controls. Authors concluded that inhalation of granite dust might initiate and sustain an immune-inflammatory response. No difference in IgM concentration. Significantly elevated average concentration of IgG in workers compared with controls (P<0.001). Significantly elevated average concentration of IgA in workers compared with controls (P<0.05). No significant differences in IgG, IgM, or IgA be tween silicotic and nonsilicotic workers. Method of silicosis diag nosis not reported. See footnotes at end of table. (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Results Comments Gualde et al. [1977], France Caucasian silicosis patients (radiographic diagnosis) who had a silica-related occupation for 10-40 yr (38 gold, wolfram, and uran ium miners; 35 porcelain workers; 2 quarry workers). "Normal and healthy" Caucasian controls plus second control group of porcelain workers employed 20-40 yr but with no clinical or radiographic signs of silicosis. 75 patients, 160 controls in first group, and 46 in control group of porcelain workers Honda et al. [1993], Japan Japanese silicosis patients who had been sandblasters and who had radiographic evidence of silicosis. Controls were "healthy unrelated Japanese." 46 patients, 315 controls for HLA typing, and 94, 127, 100, or 128 controls for other analyses 27 HLA antigens (serum) HLA-DQ alleles, RFLP patterns, and IGLV gene extracted from peripheral gran ulocytes (medium not reported) Prevalence of B7 antigen was significantly less (P<0.05 before correction for multiple comparisons of tested antigens) than in healthy or silica-exposed controls. No other signif icant differences found between silicotics and controls. Small number of controls may have resulted in low statistical power to detect any differences after cor rection for multiple com parisons. Authors sug gested that presence of B7 antigen may be related to resistance to development of silicosis. (See also Sluis-Cremer and Maier [1984] later in table.) Some HLA-DQ alleles were more frequent in silicosis patients (P<0.05). RFLP pattern of C4A3-C4B5 allotype and IGLV more frequent in silicosis patients (P<0.05). Source and occupational history of control group not reported. Definition of "healthy" not reported. Potential confounders of exposure and immuno logical outcomes not re ported. Authors suggested that their findings indicate that a gene for silicosis may be near the HLA-B locus. Validation of these findings is needed. See footnotes at end of table. (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Results Comments HusgafvelPursiainen et al. [1997], Finland Karnik et al. [1990], India Finnish white males with lung cancer (see comments). Male slate pencil workers. Controls with no history of occupational exposure to dust or silica. 5 patients with silicosis and 16 patients with asbestosis Mutation of p53 gene and serum elevation of p53 protein (serum samples were not available for the silicosis patients) Two of the five silicosis patients had lung tumors with DNA mutations of the p53 gene. Subjects for study were drawn from cohort studied by Brandt-Rauf et al. [1992] (described earlier). The results of the serum tests do not support use of p53 assay by itself as a screening tool for lung cancer because only 36% of cancer cases tested pos itive for the mutant pro tein. The authors state that it may be a useful bio marker if combined with serum assays for altered oncoproteins as in the study by Brandt-Rauf [1992]. 130 silica-exposed workers: 80 with ILO category 1, 2, or 3 silicosis and 50 controls Serum IgG, IgM, and IgA Higher concentrations (P<0.05) of IgG, IgM, and IgA in silicotic workers compared with controls. Results may have been confounded by bacterial infections in some work ers. Authors stated that an increase in immuno globulin concentrations was not a marker for severity of silicosis. See footnotes at end of table. (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Koskinen et al. Finnish male silicosis pa [1983], Finland tients (ILO category $ 1/1) who had been exposed to silica dust $ 10 yr. Nonsilicotic controls matched by age (5 yr), duration of silica exposure ( 5 yr), and work environment. Addi tional control group of healthy Finnish blood donors. 27 patients; 27 nonsilicotic, silica-exposed controls; and 900 blood donor controls Serum HLA antigens Kreiss et al. [1989a], United States Silicotic residents from hardrock mining town in Colorado who had mined for 5-58 yr and were aged 30-59 when diagnosed with ILO category $ 1/0 silicosis. Published antigen preva lences of North American whites and international whites used for comparison. 49 silicotics, 1,029 North American controls, and 1,061-1,082 international controls HLA-A, HLA-B, HLA-DR, and HLADQ antigens (blood) Results Comments Higher prevalence of HLA-Aw19 in silicotics compared with nonsilicotic, silica-exposed controls (P=0.02). Higher prevalence of HLA-Aw19 in unexposed blood donor group than in silicaexposed controls (P=0.04). Authors state HLA-Aw19 may be marker for silicosis progression in Finnish population, but larger study groups are needed. Significantly higher prev alence of A29 and B44 in silicotics compared with two control groups (P<0.05 after correction for num ber of antigens tested). Population-based study design. A29 is a component of Aw19 (see Koskinen et al. [1983] above). See footnotes at end of table. (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Results Comments Pevnitskiy et al. [1978], Russia Male Russian patients aged 30-50 with "Stage I" sili cosis who had been em ployed >10 yr in occupa tions with exposure to quartz dust (i.e., casting shop cleaners, sandblasters, and molders). Controls were "clinically healthy" Russian male blood donors aged 30-50. 32 silicosis patients and 32 controls Sluis-Cremer and Maier [1984], South Africa White South African gold miners who had been ex posed to at least 20 "lowdust" years. Control group of Caucasian nonminers. 101 miners (45 silicotics of category $ 1/0 and 56 nonsilicotics) and 279 controls Sobti and Bhardwaj [1991], India Male sandstone-crushing workers. Control group of local university teachers and students. 50 workers and 25 controls 11 HLA antigens (6 on A locus and 5 on B locus) (serum) Prevalence of HLA-B8 and HLA-B13 in silicotics was twice the prev alence in the control group (P value not re ported). Occupational history of control group not reported. Definition of "healthy" not reported. Definition of "Stage I" silicosis not re ported. Small number of subjects and controls. 29 HLA antigens (medium not reported) Significantly fewer silicotics had B40 antigen compared with both silica-exposed and nonexposed comparison groups (P=0.02). Source of control group not reported. No signif icant difference was found in the prevalence of B7, which does not agree with the findings of Gualde et al. [1977] (discussed earlier). Blood: SCE and CA Higher proportion of SCE and CA in silica-exposed workers compared with controls (2.72% versus 1.28%; P<0.01). More SCEs (P<0.01) in smokers--both silicaexposed and nonexposed. Dust contained 50%-60% crystalline silica, 14%-16% aluminum oxide, and 4%-5% iron oxide. Pos sible effect of socioeco nomic differences between workers and control group not accounted for. No statistical test for correla tion between duration of exposure and levels of SCE and CA. Silica expo sure concentrations not reported. See footnotes at end of table. (Continued) Table 20 (Continued). Molecular epidemiology studies of biomarkers for carcinogenesis or silicosis Reference and country Study design and cohort* Number of subjects Biologic marker Results Comments Watanabe et al. Males aged 34-78, hospital[1987], Japan ized with ILO category $ 2 silicosis and employed as tunnel workers or metal miners for a mean duration of 23.8 yr. "Normal" male controls aged 46-72 with out silicosis. 82 patients and 25 controls Total blood lymphocyte count and lymphocyte subsets: OKT3+, OKT4+, OKT8+, OKIa-1+ Serum IgG, IgM, IgA, IgD, and IgE Silicosis patients with low lymphocyte counts (#1,500 pi) had signifi cantly increased IgG and IgA levels compared with controls (P<0.001). Decreased number of cir culating T-cells in pa tients. Source and occupational history of control group not reported. Definition of "normal" controls not reported. Potential confounders of exposure and immunological outcomes not reported. Need further study of rela tionship of silicosis with serum immunoglobulin levels and lymphocytes. Studies were cross-sectional unless otherwise indicated. Abbreviations: BAL = bronchoalveolar lavage; CA = chromosomal aberrations; HLA = human leukocyte antigen; Ig = immunoglobulin; IGLV = immunoglobulin lambda variable chain; ILO = International Labour Organization; PDGF = platelet-derived growth factor; RFLP = restriction fragment length polymorphism; SCE = sister chromatid exchange; TGF = transforming growth factor. Table 21. Summary of the genotoxic effects of quartz in mammalian cells In vitro studies In vivo studies Genotoxic effect Number of positive studies/number of studies available Reference Number of positive studies/number of studies available Reference Sister chromatid exchange Chromosomal aberrations 1*/3 Price-Jones et al. [1980] Pairon et al. [1990] (2 experiments) 0/3 Nagalakshmi et al. [1995] (2 experiments) Oshimura et al. [1984] 1*/1 1*/1 Sobti and Bhardwaj [1991] Sobti and Bhardwaj [1991] Micronuclei 3/4 Oshimura et al. [1984] Hesterberg et al. [1986] Nagalakshmi et al. [1995] (2 experiments)* 0/1 Vanchugova et al. [1985] Aneuploidy or tetraploidy 0/3 Price-Jones et al. [1980]; Oshimura et al. [1984]; Hesterberg et al. [1986] 0/0 hprt mutation* 0/1 Driscoll et al. [1997] 2/2 Driscoll et al. [1995, 1997] Source: IARC [1997]. *One questionably positive study available. *One experiment by Nagalakshmi et al. [1995] showed an increase in the frequency of micronucleated cells at all concentrations tested, but the increase was statistically significant (P<0.05) only at the two highest concentrations tested. *hprt = hypoxanthine-guanine phosphoribosyl transferase. Mutagenic response associated with inflammation. Table 22. Summary of data on lung tumors induced in rats by crystalline silica Sample and exposure conditions Rat strain Sex Incidence of lung tumors Treated rats Controls Reference Comments Quartz (Min-U-Sil 5): Intratracheal instillation of 7 mg/wk for 10 wk SpragueDawley __ t Inhalation (nose only) of 12 5 mg/m3 for up to 2 yr Fischer 344 F 6/36 20/60 Inhalation of 51.6 mg/m3 for various durations; sacrificed at 24 months Fischer 344 F M 10/53 1/47 Intratracheal instilla tion of 20 mg in left lung; sacrificed at 12, 18, or 22 months, or found dead Novaculite (i.e., micro crystalline quartz): Intratracheal instilla tion of 20 mg in left lung; sacrificed at 12, 18, or 22 months, or found dead Raw shale dust: Inhalation (nose only) of 152 51 mg/m3 (average quartz content: 8%-12%) Fischer 344 Fischer 344 Fischer 344 M M F 30/67 21/72 17/59 0/58 0/54 0/47 0/42 1/75 Holland et al. [1983] Treated rats had 1 adenoma and 5 carcinomas. Holland et al. [1986] Treated rats had 6 adenomas, 11 adenocarcinomas, and 3 epidermoid carcinomas. Dagle et al. [1986] Treated female rats had 10 epidermoid carcinomas. Treated male rats had 1 epidermoid carcinoma. Groth et al. [1986] Treated rats had 30 adenocarcinomas. Controls had 1 adenocarcinoma. 1/75 Groth et al. [1986] Treated rats had 20 adenocarcinomas and 1 epidermoid carcinoma. Controls had 1 adeno carcinoma. 0/54 1/15* Holland et al. [1986] Treated rats had 2 adenomas, 8 adenocarcinomas, and 7 epidermoid carcinomas. Controls had 1 adenoma. Table 22 (Continued). Summary of data on lung tumors induced in rats by crystalline silica Sample and exposure conditions Rat strain Sex Incidence of lung tumors Treated rats Controls Reference Comments Spent shale dust: Inhalation (nose only) of 176 75 mg/m3 (average quartz content: 8%-12%) Fischer 344 F Quartz (DQ12): Inhalation of 1 mg/m3 for 24 months Fischer 344 F Fischer 344 M 11/59 0/54 1/15* Holland et al. [1986] Treated rats had 2 adenomas, 8 adenocarcinomas, and 1 epidermoid carcinoma. Controls had 1 adenoma. 12/50 6/50 3/100 (male and female) -- Muhle et al. [1989] Treated female rats had 2 keratinizing cystic squamous cell tumors, 2 adenomas, and 8 adenocarcinomas. Treated male rats had 2 keratinizing cystic squamous cell tumors, 2 adenocarcinomas, 1 adenosquamous carcin oma, and 1 squamous cell carcinoma. Controls had 2 adenomas and 1 adenocarcinoma. Inhalation (nose only) of 6 mg/m3 for 29 days followed by lifetime observation Wistar F 62/82 0/85 Inhalation (nose only) of 30 mg/m3 for 29 days followed by lifetime observation Wistar F 69/82 0/85 Source: Adapted from Saffiotti et al. [1996]. *Number of lung tumors per number of rats observed. *Not reported. ^Investigators used two control groups. Spiethoff et al. [1992] Treated rats had 8 adenomas, 17 bronchioloalveolar carcinomas, and 37 squamous cell carcinomas. Spiethoff et al. [1992] Treated rats had 13 adenomas, 26 bronchioloalveolar carcinomas, and 30 squamous cell carcinomas. Table 23. Lung tumors induced in Fischer 344 rats by a single intratracheal instillation of quartz Treatment sample and dose Sex Observation time Incidence of lung tumors Number1 % Total number of lung tumors1 Histological types Untreated: No dose No dose Quartz (Min-U-Sil 5): 12-mg dose M Died after 17 months F Died after 17 months 0/32 1/20 M Sacrificed at 11 months 3/18 Sacrificed at 17 months 6/19 Died after 17 months 12/14 -- 5 17 32 86 12-mg dose F Sacrificed at 11 months 8/19 Sacrificed at 17 months 10/17 Died after 17 months 8/9 42 59 89 0-- 1 1 adenoma 37 6 adenomas, 25 adenocarcinomas, 1 undifferentiated carcinoma, 2 mixed carcinomas, and 3 epi dermoid carcinomas 59 2 adenomas, 46 adenocarcinomas, 3 undifferentiated carcinomas, 5 mixed carcinomas, and 3 epi dermoid carcinomas 20-mg dose F Died after 17 months 6/8 75 Quartz (hydrogen fluoride-etched Min-U-Sil 5): 12-mg dose 12-mg dose M Sacrificed at 11 months Sacrificed at 17 months Died after 17 months 2/18 7/19 7/9 F Sacrificed at 11 months 7/18 Sacrificed at 17 months 13/16 Died after 17 months 8/8 Sources: Saffiotti et al. [1993; 1996]. *As mg quartz suspended in 0.3 ml saline. fNumber of rats with lung tumors per number of rats observed. *At all observation times. 11 37 78 39 81 100 13 1 adenoma, 10 adeno carcinomas, 1 mixed carcinoma, and 1 epi dermoid carcinoma 20 5 adenomas, 14 adenocarcinomas, and 1 mixed carcinoma 45 1 adenoma, 36 adenocarcinomas, 3 mixed carcinomas, and 5 epi dermoid carcinomas