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Occupational Exposure to Respirable Crystalline Silica -- Review of

Health Effects Literature and Preliminary Quantitative Risk

Assessment

Occupational Safety and Health Administration

Docket OSHA-2010-0034
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Occupational Exposure to Respirable Crystalline Silica -- Review of Health Effects

Literature and Preliminary Quantitative Risk Assessment

TABLE OF CONTENTS

I. Health Effects Literature Review 7

I.A. Introduction 7

I.A.1. Background Information on Crystalline Silica and the Literature Review 7

I.A.2. Background and Terminology for Measuring Worked Exposures to Dust 8

I.A.3. Current Methods for Measuring Respirable Crystalline Silica 11

I.A.4. Methods Used for Collecting Dust Concentration Data for Epidemiologic

Evaluation 11

I.A.4.a. Dust sampling techniques 12

I.A.4.b. Estimation of the percentage of silica content 15

I.B. Silicosis 16

I.B.1. Clinical and Epidemiological Considerations in Assessing Workers at

Risk of Developing Silicosis 19

I.B.1.a. Clinical features of silicosis 19

I.B.1.b. Chest radiography and other imaging techniques to assess silicosis 22

I.B.1.c. Pulmonary function testing (PFT) 28

I.B.2. Review of Surveillance Data 31

I.B.2.a. Silicosis mortality 32

I.B.2.b. Silicosis morbidity 40

I.B.2.c. Underreporting of surveillance data 45

I.B.3. Progression of Silicosis and Its Associated Impairment 49

I.B.3.a. Factors influencing radiological progression of silicosis 50

I.B.3.b. Relationship of progression to pulmonary function impairment 60

I.B.4. Pulmonary Tuberculosis 68

I.B.5. Preliminary Conclusions: Silicosis and Disease Progression 71

I.C. Carcinogenic Effects of Silica (Cancer of the Lung and Other Sites) 75

I.C.1. Introduction 76
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I.C.2. Evaluation of Cohort Studies 96

I.C.2.a. Danish stone industry workers 96

I.C.2.b. U.S. granite shed and quarry workers 97

I.C.2.c. U.S. crushed stone industry workers 102

I.C.2.d. Finnish granite workers 102

I.C.2.e. Chinese refractory brick workers 104

I.C.2.f. Italian refractory brick workers 105

I.C.2.g. South African gold miners 106

I.C.2.h. Western Australia gold miners 113

I.C.2.i. U.S. gold miners 115

I.C.2.j. Chinese tin and tungsten miners 117

I.C.2.k. British Coal Miners 123

I.C.2.l. North American industrial sand workers 124

I.C.2.m. United Kingdom industrial sand workers 130

I.C.2.n. United Kingdom pottery workers 132

I.C.2.o. Chinese pottery workers 135

I.C.2.p. Dutch ceramic workers 136

I.C.2.q. German stone and ceramic workers 138

I.C.2.r. U.S. diatomaceous earth industry workers 139

I.C.2.s. Danish foundry workers 143

I.C.2.t. U.S. (Michigan) foundry workers 143

I.C.2.u. Chinese iron and steel workers 144

I.C.2.v. Swedish aluminum foundry workers 144

I.C.2.w. Norwegian silica carbide workers 145

I.C.2.x. Canadian silica carbide workers 147

I.C.2.y. Finnish road paving and asphalt workers 147

I.C.2.z. Canadian bricklayers and associated crafts 148

I.C.3. Pooled IARC Sponsored Multicenter Exposure-Response Analyses for

Lung Cancer 148

I.C.4. Multi-National Pooled Population and National Death Certificate Studies 151

I.C.4.a. U.S. national (27 states) case-control study 152

I.C.4.b. Finnish nationwide job exposure matrix (FINJEM) 153

I.C.4.c. European multi-center community-based case-control study 154

I.C.5. Studies of Lung Cancer Risk Among Silicotics 156

I.C.6. Preliminary Conclusions from the Lung Cancer Evidence 164

I.C.6.a. Overall and industry sector-specific findings 164

I.C.6.b. Smoking, silica exposure, and lung cancer 170

I.C.6.c. Silicosis and lung cancer risk 171

I.C.6.d. Relationship between silica polymorphs and lung cancer risks 172

I.C.7. Cancer of Other Sites 172
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I.C.7.a. Cancer of the larynx and nasopharyn 173

I.C.7.b. Gastric (stomach) cancer 174

I.C.7.c. Esophageal cancer 177

I.C.7.d. Other miscellaneous cancers 181

I.D. Other Nonmalignant Respiratory Disease 181

I.D.1. Emphysema 182

I.D.1.a. Summary and conclusion for emphysema 186

I.D.2. Chronic Bronchitis 187

I.D.2.a. Summary and conclusions for bronchitis 190

I.D.3. Pulmonary Function Impairment 192

I.D.3.a. Summary and Conclusion for Pulmonary Function Impairment 202

I.D.4. Nonmalignant Respiratory Disease Mortality 204

I.D.4.a. Summary and conclusions for NMRD mortality 206

I.D.5. Preliminary Conclusions for Other Nonmalignant Respiratory Disease 207

I.E. Renal and Autoimmune Effects 208

I.E.1. Renal Disease 211

I.E.2. Autoimmune Effects 223

I.E.3. Preliminary Conclusions for Renal and Autoimmune Effects 228

I.F. Physical Factors That May Influence Toxicity of Crystalline Silica 229

I.F.1. Mechanism of Action 230

I.F.1.a. Relationship between silicosis and lung cancer 238

I.F.2. Toxicity of Crystalline Polymorphs 239

I.F.3. Freshly Fractured vs. Aged Silica 242

I.F.3.a. In vitro studies 243

I.F.3.b. In vivo studies 244

I.F.3.c. Human studies 246

I.F.3.d. Discussion and conclusions 247

I.F.4. Metal Impurities/Clay Encapsulation 247

I.F.5. Preliminary Conclusions for Factors Affecting the Toxicity of Crystalline
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Silica 258

I.G. Overall Conclusions 261

II. Preliminary Quantitative Risk Assessment 266

II.A. Introduction 266

II.B. Lung Cancer Risk Estimates 269

II.B.1. Steenland et al. (2001a) Pooled Cohort Analysis 270

II.B.2. Rice et al. (2001) Analysis of Diatomaceous Earth Workers 277

II.B.3. Attfield and Costello (2004) Analysis of Granite Workers 281

II.B.4. Kuempel et al. (2001) Assessment Based on a Lung Dosimetry Model 282

II.B.5. Hughes et al. (2001) Analysis of Industrial Sand Workers 285

II.B.6. Miller and MacCalman (2009) Analysis of British Coal Workers 287

II.B.7. Summary of OSHA’s Estimates of Lung Cancer Mortality Risk 289

II.C. Silicosis and Non-Malignant Respiratory Disease Mortality Risk Estimates 292

II.C.1. Mannetje et al. (2002b) Pooled Analysis 292

II.C.2. Park et al. (2002) Study of Diatomaceous Earth Workers 295

II.D. Uncertainty in Lung Cancer and Silicosis Mortality Risk Estimates 299

II.D.1. Selection Bias 299

II.D.2. Confounding 300

II.D.3. Exposure Measurement Error 302

II.D.3.a. Lung cancer uncertainty analysis 303

 Monte Carol analysis of error in the assignment of individual

exposure values 303

 Monte Carlo analysis of error in estimating exposures to silica

from historical dust concentration data 305

 Monte Carlo analysis incorporating both types of measument error 306

 Sensitivity analyses of biased conversion factors 308
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II.D.3.b. Silicosis mortality 310

 Monte Carlo anayses incorporating two types of random

measument error 310

 Potential effects of random measurement errors on silicosis

mortality risk estimates 313

II.E. Quantitative Assessment of Renal Disease Mortality 314

II.F. Quantitative Assessment of Silicosis Morbidity Risk 316

II.F.1. Definition of Silicosis 321

II.F.2. Summary of Silicosis Morbidity Studies 322

II.F.2.a. Cross-sectional studies 322

II.F.2.b. Cumulative risk studies with little or no post-employment

follow up 328

II.F.2.c. Cumulative risk studies with post-employment follow up 331

II.F.3. Summary of Risk Estimates 340

II.G. Issues Related to Assessing Crystalline Silica-Related Risk 342

II.G.1. Choice of Cumulative Dose as the Dose Metric 342

II.G.2. Physical Factors That May Influence Toxicity of Crystalline Silica 344

II.H. Preliminary Conclusions 350

Appendix A: Life Tables Used for Assessments of Lung Cancer, Non-Malignant

Respiratory Diseases, and Renal Disease Mortality Rate 360

III. Response to Peer Review Comments 379

III.A. Peer Review of the Health Effects Literature Review 381

III.B. Peer Review of the Preliminary Quantitative Risk Assessment 389

References 399
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I. Health Effects Literature Review.

I.A. Introduction.

I.A.1. Background Information on Crystalline Silica and the Literature Review.

Silica is comprised of silicon and oxygen (SiO2) and is one of the most abundant

compounds on earth. It occurs in either a crystalline or non-crystalline (amorphous) form.

Crystalline silica, in which the silicon and oxygen atoms are arranged in a tetrahedron structure,

exists in several forms, or polymorphs. The most commonly encountered polymorph is quartz;

crystobalite and tridymite are two other naturally-occuring polymorphs of crystalline silica. The

importance of the crystalline feature is that it is highly stable, insoluble in water, and possesses

on its surface reactive oxygen species when fractured (Castranova et al., 1996). The presence of

these reactive species on the crystal surface is largely responsible for the toxicity of crystalline

silica particles when inhaled. OSHA currently enforces an occupational exposure limit for

respirable dust that contains quartz, as well as for respirable dust that contains crystobalite or

tridymite.

Quartz is a common component of rock and soils. Consequently, workers are exposed to

quartz-containing dust when performing operations that disturb or break up soils and rock, or

materials derived from them such as concrete and masonry. Crystobalite and tridymite are also

naturally occurring but to a much lesser degree than quartz. These polymorphs are formed from

quartz that has been subjected to high temperatures. Work operations that involve subjecting

quartz-containing materials to high temperatures may cause quartz to morph into crystobalite,

resulting in worker exposures to dusts containing crystobalite.

Health hazards associated with exposure to crystalline silica-containing dusts arise from

the inhalation of the respirable dust fraction, which is comprised of particles sufficiently small to

reach the deep lung. The respirable fraction is broadly defined as particles having a diameter of

10 μm or less (IARC, 1997). It is this portion of crystalline silica-containing dust that is of most

concern to OSHA and is the focus of this health effects section. The occupational diseases

associated with inhalation of respirable crystalline silica and discussed in detail in this section

include: silicosis and other non-malignant respiratory diseases; pulmonary tuberculosis; chronic

bronchitis with airflow limitation, and emphysema (both more commonly referred to as “chronic

obstructive pulmonary disease,” or COPD); and several extra-pulmonary diseases (renal and

immunologic) and cancer (lung and other). These occupational diseases, either alone or in

concert, are life-altering and debilitating disorders that annually affect thousands of workers

across the United States. Many of these diseases are also life-threatening. The preponderance of

evidence for the adverse health effects associated with inhalation of crystalline silica, as

described extensively in the scientific literature consists of studies of exposed workers.

However, many animal and in vitro studies have also been conducted in an effort to elucidate the

mechanisms by which crystalline silica increases the risks of adverse health effects.

The purpose of providing an extensive review of the scientific literature in this health

effects section is to present OSHA’s preliminary findings on the nature of the hazards presented
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by exposure to respirable crystalline silica, and to present an adequate basis for the quantitative

risk assessment section to follow. The health effects section is organized by type of disease with

silicosis addressed first, in Section B.

The next section, Section C, deals with the carcinogenic effects of inhalation of respirable

crystalline silica which have been investigated in numerous epidemiological studies, almost all

dealing with workplace exposures. The section mostly focuses on studies of lung cancer but also

includes discussion of suggestive evidence that exposure to silica may increase the risk of

esophageal cancer and possibly other cancers. In addition to the OSHA analysis, the

International Agency for Research on Cancer (IARC) has concluded that there is sufficient

evidence of lung carcinogenicity in humans exposed to crystalline silica (IARC, 1997).

Section D discusses and evaluates the scientific literature describing emphysema, chronic

bronchitis, pulmonary function impairment, and other non-malignant respiratory diseases. The

subsequent section, Section E, discusses non-respiratory diseases; in particular, renal disease and

auto-immune diseases associated with inhalation of respirable crystalline silica. Finally, Section

F evaluates the evidence on the physical characteristics of silica that may affect its toxicity.

Information on mechanisms of action of silica and results from in vivo and in vitro studies are

also reviewed and summarized in Section F.

OSHA has included in its review all published studies that the Agency deems relevant to

assessing the hazards associated with exposure to respirable crystalline silica. These studies

were identified from numerous scientific reviews that have been published previously such as the

IARC (1997) and NIOSH (2002) evaluations of scientific literature as well as from literature

searches and contact with experts and stakeholders. Not included in this review are studies

primarily of historical interest and numerous case studies describing silicosis and other silicarelated diseases. Some of the studies reviewed by OSHA contain sufficient quantitative

information on exposures and disease incidence or mortality rates that the Agency believes them

appropriate for use in its quantitative risk assessment (Section II).

The epidemiological studies reviewed here concern exposures of worker populations

dating back several decades, as early as in the 1930’s. Over this period of time, the assessment

of worker exposures, a crucial element in epidemiological study, evolved dramatically.

Consequently, epidemiological studies have had to rely on exposure information derived form a

wide array of different kinds of data, a factor that complicates interpretation of the studies. To

aid the evaluation of the epidemiological literature base, the remainder of this section presents

background information on the various methods that have been used to measure workplace dust

concentrations and to assess worker exposures to respirable crystalline silica.

I.A.2. Background and Terminology for Measuring Worker Exposures to Dust.

Exposure data for dusts can reflect measurements of total dust or respirable dust. The

term “respirable dust” generally refers to particles small enough to reach the alveolar spaces in

the lung (i.e., < 10 μm in aerodynamic diameter). Exposures to dusts are expressed either as a

particle concentration (i.e., millions of particles per cubic foot of air or mppcf) or a gravimetric
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concentration (i.e., unit mass of particles per unit volume of air, such as mg/m3). Particle

concentrations are determined by microscopically counting the number of respirable-sized

particles collected from an air sampling device that either deposited an air sample onto a slide

(i.e., a thermal precipitator) or into a liquid, after which an aliquot was deposited on a counting

slide (such as is done when using an impinger). Gravimetric concentration is determined from

the mass of respirable dust collected on a filter media by a particle-size-selective air sampling

device (i.e., a device designed to exclude non-respirable particles from the collection media).

It is important to state whether a measurement of dust concentration reflects exposure to

all airborne respirable dust or just to the respirable crystalline silica fraction. Following the

convention used in most of the studies reviewed here, exposure to “respirable dust” means

exposure to all airborne respirable particles (or the mass concentration of all respirable particles),

and exposure to “respirable crystalline silica” (or “respirable quartz”) means exposure only to

the crystalline silica (or quartz) fraction of airborne respirable dust (such as the mass

concentration of respirable dust times the percent quartz content of the dust).

When an air sample is taken over a period of time, the resulting measure of exposure

represents an average concentration to which a worker was exposed over the sampling period;

this is referred to as a “time-weighted average” (TWA) concentration. As used in this document,

a TWA exposure usually refers to an average concentration over a full work shift, such as for an

8-hour TWA concentration. When the sampling period approximates a full-shift exposure, the

resulting TWA measure is considered to be the most useful metric to characterize chronic disease

risk caused by exposure to crystalline silica and other pneumoconiosis-producing dusts.

Reliance on shorter-term airborne dust measurements (as was done with sampling technologies

that pre-dated current sampling methods) adds uncertainty to the characterization of full-shift

exposures and, consequently, exposure-related risks.

Epidemiologic investigations use data on past exposures of a cohort to an air contaminant

in an effort to quantitatively relate exposure to risk of disease. Cumulative exposure, which is

the product of average exposure and exposure duration (or the sum of such products over several

exposure periods), is the exposure metric that tends to best predict chronic disease risk. As the

discussion in the sections that follow demonstrates, cumulative exposure is the exposure metric

that has been consistently demonstrated to be associated with risk of silicosis, lung cancer, and

other non-malignant respiratory diseases. Investigators often use other measures or surrogates of

long-term exposure as well, such as average exposure or duration of employment in an industry

where exposure is known to occur. In the case of crystalline silica, most epidemiological studies

characterize cumulative exposure from particle count data (yielding particle-years of exposure)

or from gravimetric measures (yielding mg/m3-years of exposure). It may be the case that the

total surface area of the airborne particles is an even better predictor of risk, since it is the

surfaces of insoluble particles that interact with cells in the lung (see Section I.F). However,

because surface area measurements require sophisticated and expensive analytical

instrumentation that is not readily available to most employers, it is not practical for routine risk

management.
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A brief discussion of OSHA’s current and proposed permissible exposure limits (PELs)

for quartz serves to illustrate the concepts discussed above. OSHA’s current PELs for respirable

quartz are expressed both in terms of a particle count as well as a gravimetric concentration (both

are listed in OSHA’s general industry Air Contaminants standard, while only the particle count

formula applies to construction and shipyard employment). The PELs are formulas that impose

a limit on the 8-hour time-weighted average (TWA) concentration to respirable dust, with the

PEL varying depending on the percent quartz content of the respirable dust. In general industry,

the gravimetric formula PEL for quartz is:

PEL (mg/m3respirable dust) = 10 mg/m3/ % Quartz + 2.

So, for example, the PEL for a dust containing 18 percent quartz is 0.5 mg/m3as a limit

on the respirable dust concentration. As the quartz content of the dust increases, the limit on

respirable dust exposure decreases reaching a lower limit of 0.100 mg/m3for respirable dust

comprised of 100 percent quartz. For respirable dusts having a quartz content of from 5 to 100

percent, the formula PEL equates to a respirable quartz concentration of from 0.083 to 0.1

mg/m3. Therefore, for the purposes of this document, the gravimetric PEL formula is considered

to be approximately equivalent to a respirable quartz concentration of 0.100 mg/m3. For general

industry, the current PELs for two other polymorphs of crystalline silica, cristobalite and

tridymite, are half the value of the quartz formula PEL.

The formula PEL for the construction and shipyard industries, based on particle

concentration is:

PEL (mppcf respirable dust) = 250 mppcf / % Quartz + 5.

The relationship between these two formula PELs is discussed further below and in Section II,

Preliminary Quantitative Risk Assessment.

OSHA is proposing a PEL of 0.05 mg/m3for respirable crystalline silica, as an 8-hour

TWA, a value that is half that of the current general industry formula PEL for quartz and equal to

the current general industry formula PEL for dust cristobalite and tridymite. Thus, the proposed

PEL is expressed, not as a limit on respirable dust mass concentration that varies with the content

of crystalline silica, but as a limit on respirable crystalline silica mass concentration.

To illustrate further the concept of cumulative exposure, assuming that a worker is

exposed to respirable crystalline silica at the current PEL (i.e., about 0.100 mg/m3of respirable

silica) every workday for 45 years (i.e., from age 20-65), his or her cumulative exposure to

respirable crystalline silica would be 4.5 mg/m3-years (0.100 mg/m3 multiplied by 45 years). A

worker exposed to the proposed PEL for 45 years would have a cumulative exposure of 2.25

mg/m3-years. Many of the epidemiological studies evaluated in the sections that follow describe

the effects of cumulative exposures within the range of cumulative exposure permitted by the

current and proposed PELs.

I.A.3. Current Methods for Measuring Respirable Crystalline Silica.
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This section reviews the main methodologies that OSHA, MSHA, NIOSH and similar

organizations in other countries have relied upon to determine airborne concentration levels of

dust or particles and the analytical methods available to evaluate silica content.

The two basic approaches for measuring airborne concentrations are sample collection

with analysis and real-time, direct dynamic measurements. Either of these sample collection

approaches can be used for either personal or area sampling. Sampling collection methods

involve collecting particles onto a filter substrate or into a liquid medium for later analysis.

Devices used to collect air samples can include inertial devices such as impactors or cyclones,

which separate particles based on their size, or impingers, which pull air samples through liquid

medium to capture air contaminants. Analysis of collected samples can be performed through a

variety of methods, including, but not limited to: optical or electron microscopy for counting

particles; X-ray diffraction (XRD); and infrared spectrophotometry. Instruments that perform

direct measurements for personal sampling include optical particle counters that can provide

gravimetric and particle size distribution data on a real-time basis. (For a complete discussion of

sampling methods for dusts, see Ayer and Rice, 2000.)

The current OSHA convention for measuring airborne dust is to measure respirable mass

with a dust sampler using a cyclone designed to be worn by the worker in the breathing zone and

attached to an air pump placed on the worker’s belt. Dust-laden air is pulled through a cyclone

that removes the non-respirable dust (i.e., particles greater than 10 μm) and deposits respirable

dust on a filter that is subsequently weighed. The cyclone is generally operated for a full work

shift to yield a TWA measure of exposure to respirable dust mass, although shorter-term samples

may also be taken (for example to measure exposures during a specific work task). Although

there are other ways of characterizing particle size distribution, the cyclone is the device that is

most commonly used to collect personal samples because its size permits it to be worn near the

breathing zone, and it is relatively insensitive to orientation. By way of contrast, a horizontal

elutriator, an earlier technology for collecting area samples of respirable dust, must remain

horizontal and cannot be worn as a personal sampler.

In the next section, OSHA briefly describes historical methods for measuring airborne

concentrations not only to show how the current measurement convention evolved, but also to

illustrate the need for and the limitations of translating historical dust exposure measures to

equivalent respirable dust mass, which is the current conventional exposure metric.

I.A.4. Methods Used for Collecting Dust Concentration Data for Epidemiological

Evaluation.

This section outlines in more detail the methods used in gathering airborne concentration

data for the epidemiological studies reviewed in the health effects section (I) and the preliminary

quantitative risk assessment (Section II). The epidemiologic studies reviewed in this section

present airborne concentration data from a variety of different kinds of dust measurements,

which largely reflect changes in technology and industrial hygiene practices that have evolved
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since the 1930’s. In this section, OSHA summarizes dust measurement technologies that have

been used to generate the airborne concentration data relied on by the studies.

I.A.4.a. Dust sampling techniques.

Most of the retrospective cohort studies included in OSHA’s analysis span a timeframe of

40-65 years. Consequently, these studies often incorporate data collected using a number of

different measurement protocols. In 1947, measurements for silica taken with felted layers of

salicylic acid crystals were reported by Hatch in the industrial sand industry (Hatch et al., 1947).

These were fixed-location (area), short-term samples. Also, optical particle counting devices

(Konimeters) were designed to take short-term samples (also described as “snap samples”) that

could be collected near the worker’s breathing zone. These measurements were well-suited to

characterize the variability in aerosol concentrations, and Beadle used Konimeters in South

African gold mines to measure dust concentrations over a series of two-minute periods (Beadle

and Bradley, 1970). The use of snap samples was of limited value for determining exposures

over longer periods, because a prohibitive amount of work was required to examine each sample

by optical microscopy. However, as Morrow observed in 1964, dust sampling had mainly been

used up to that time to evaluate dust controls, and short-term snap or “grab” samplers were

useful for that purpose. These short-term approaches were suitable to depict variations in

dustiness, as well as average exposures over short periods of time.

Since chronic pneumoconiosis, including silicosis, was thought to be associated with

prolonged exposure to airborne dust over many years, devices that measured cumulative airborne

dust concentrations over longer periods were more suitable for hazard assessments. This was the

case, even though they did not provide useful information about the variability of short-term

peak concentrations. In the U.S., starting in the 1950’s, there was a gradual conversion from the

collection of silica dust by Greenburg-Smith impingers, and later, midget impingers for

respirable dust counting, to the collection of respirable samples on a filter membrane with a

cyclone pre-selector for gravimetric silica analysis (Ayer and Rice, 2000). Greenburg-Smith

impingers were area samplers that used dust counting techniques in the analysis. Dust-laden air

was drawn at high velocity through a nozzle in a glass flask, usually containing water and

impinged against a glass plate immersed in the water. Dust particles were counted and sized

with an optical microscope on a Wattman reticule. Midget impingers, introduced later, could be

used in explosive atmospheres because they were hand-cranked, and could be worn in the

person’s breathing zone. Sample times varied from 15 to 20 minutes with a midget impinger, to

2-4 hours with a Greenburg-Smith impinger (ACGIH, 1972).

At about the same time in Great Britain, there was a gradual transition from the standard

thermal precipitator, followed by the long-running thermal precipitator, to respirable gravimetric

measuring instruments, e.g., horizontal elutriator, in mines and in selected dusty industries (Ayer

and Rice, 2000). The thermal precipitator operated at very low velocities and drew dust-laden

air at rates ranging from 7 ml/minute to 1 liter/minute past a hot wire that caused the thermal

deposition of particles against a cooler collection surface. An inlet elutriator was commonly

used to remove the coarse particles from the air. Thermal precipitators are nearly 100 percent

efficient in obtaining most particles from 0.01-5 micrometers (microns). Because sample
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collection was limited in size, the thermal precipitator tended to be used as a fixed area sampler

for a half or full shift of work. Typically, dust counting was done with an optical microscope

using a Porton® microscope eyepiece reticule, (ACGIH 1972).

In South Africa, exposures of gold miners was extensively characterized using Konimeter

snap measurements taken at 10-minute intervals throughout the work shift, as well as thermal

precipitator measurements taken continuously during the shift (Page-Shipp and Harris, 1972).

These intensive sampling protocols to characterize exposures over the work shift combined with

an approach for estimating respirable dust mass concentration from the resulting particle count

data permitted the researchers to construct one of the early exposure-response analyses for

silicosis among South African miners (DuToit, 1991; Hnizdo and Sluis-Cremer, 1991; PageShipp, 1972). Investigators studying exposures of Canadian gold and other miners initially used

Konimeter dust measurements. Over time, this was replaced with gravimetrically analyzed

respirable mass sampling. In a few studies, mostly based in China and Finland, available

exposure data is primarily derived from total dust measurements requiring the use of appropriate

correction factors to estimate respirable dust exposures.

Investigators have devised several approaches to making optimum use of historical

airborne dust concentration measurements to estimate worker exposures. Generally, these

approaches have been empirical in nature, based on data collected by simultaneous, or nearly

simultaneous, sampling with two (or more) devices in the same environment. The comparative

data were then used to derive one (or more) conversion factor(s) or to create an algorithm so that

airborne dust concentrations could be expressed in a uniform manner. This has been done, for

example, by transforming particle count data measured by liquid impinger sampling to an

estimate of respirable particle mass concentration. Drinker and Hatch (1954) described several

complications in making this conversion and advised against making such a conversion in the

absence of knowing the particle size distribution. In any case, making this conversion was a

prominent feature in the development of the mass-based ACGIH TLV in 1968.

Table I-1 summarizes the selected U.S. and British studies that developed either studyspecific internal conversion factors or external conversion factors used to estimate gravimetric

measures of dust exposure from historic measurements (e.g., dust particle counts). Three

investigators evaluated and used pre-existing external conversion factors: Rice et al. (1984) in

her study of North Carolina dusty trades; Cherry et al. (1998) for the British pottery workers

study; and Sanderson et al. (2000) in their study of U.S. industrial sand workers. Investigators of

three other cohorts (diatomaceous earth workers, Vermont granite workers, and U.S. industrial

sand workers) developed internally derived estimates. There is reasonable correspondence in the

findings of U.S. investigators who have sought to derive empirical (data-based) relationships

between airborne dust particle count measurements and gravimetric respirable dust

measurements to estimate occupational exposures to silica. There is certainly variability

between the types of dust that were evaluated in these studies, which must be considered in

generalizing the findings. Most U.S. investigators developed conversion factors from concurrent

impinger-based measures of particle count and measures of respirable mass from cyclone

sampling. A variety of approaches were used, from calculated ratios of measurements taken

side-by-side with the sampling devices being compared in laboratory exposure chambers and in
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field settings, to modeling approaches that considered the influence of sampling location, type of

industry, and specific process within the industry.

Table I-1 Conversion Factors (CF)Used in Select U.S. Studies and Research Converting

Respirable Dust Counts Collected by Impingers in Millions of Particles Per Cubic Foot

(mppcf) to a Mass Respirable Dust Equivalent in Milligrams Per Cubic Meter (mg/m3)

Study Description/

Author

CF

Internal/

External

Conversion

to

Respirable

Dust

1 mppcf = _

μg/m3

Conversion

to

Respirable

Silica

1 mppcf

=_μg/m3

Comment

Lab Research/

Nelson et al. 1978 Internal 0.110.083

Greenburg-Smith

Impinger

Midget impinger

Vermont Granite/

Ayer et al. 1973 Internal 0.1 1 mppcf =0.01 mg/m3

Reported as 10 mppcf =

0.1 mg/m3

Vermont Granite/

Davis et al. 1983 Internal 0.075

1 mppcf =

0.0075

mg/m3

Reanalysis using paired

data from Sutton and

Ayer

North Carolina Dusty

Trades,.

Rice et al. 1984

External 0.09 Used mean of four

previous studies

Diatomaceous Earth

Seixas et al. 1997 Internal 0.09 – 0.18 Station-specific factors

U.S. Industrial Sand

Sanderson et al. 2000 External 0.1

U.S. Industrial Sand

Rando et al. 2001 Internal .275.206 - .364

Reported as 1 mppcf =

276 μg/m3

British Pottery

Cherry et al. 1998 External 0.09 Based on Rice’s papercited above
15

The industry-based studies of particle samples in the granite mining and processing

industry (Sutton and Reno, 1968; Ayer et al., 1968; and Rice et al., 1984), and the re-calculation

of these data (Davis et al., 1983), have all estimated conversions around 0.1 mg/m3respirable

dust as equivalent to 1 million particles per cubic foot (mppcf). In laboratory studies of small

diameter (0.9 μm) silica flour particles, Nelson et al. (1978) observed relationships between dust

count and mass concentration of 1 mppcf = 0.11 mg/m3for the Greenburg-Smith impinger, and

0.088 mg/m3for the midget impinger. In the diatomaceous earth industry study by Seixas et al.

(1997), estimated conversion factors ranged from 0.09 to 0.18 mg/m3per mppcf over seven

departments and operations. In the industrial sand industry, Rando et al. (2001) estimated a

mean conversion factor of 0.275 mg/m3per mppcf with a range of 0.206 – 0.364 mg/m3higher

than those reported by other investigators.

The approach used for the South African studies did not rely on a single conversion

factor; instead, their approach used the size distributions obtained from the particle counts to

estimate total respirable particle surface area based on previously determined relationships

between particle diameter, sampling efficiency, and particle surface area. From that, respirable

particle mass was estimated.

I.A.4.b. Estimation of the percentage of silica content.

Since the 1970s, crystalline silica content of airborne respirable dust has been determined

directly from the air sample used to measure exposure to respirable dust. However, historically

the estimation of the percentage of silica in dust was a separate process from air sampling used to

quantify employee exposure to airborne dust. XRD analysis was available in the 1940s and early

1950s for measuring crystalline silica content, but it required relatively large bulk or airborne

dust samples on the order of 1 gram.

In a study of South African gold mines prior to 1958, large electronic precipitators with a

sampling flow rate of 3,000 liters per minute were used to collect samples of crystalline silicacontaining dust for bulk analysis by XRD (Beadle and Bradley, 1970). During the 1950s, the

sensitivity of XRD improved markedly, allowing investigators to collect a 1-milligram sample

(1,000 times smaller) of total dust for crystalline silica analysis. A portable battery operated

pump with flow rates ranging from 2 to 10 liters per minute was developed and used by Beadle

and Bradley (1970) for sample collection in the mines.

For most of the cohort studies described in this section, crystalline silica content of

airborne respirable dust was estimated by XRD or infrared analysis of either airborne respirable

dust samples, total dust samples, or settled dust samples. In general, use of total dust or settled

dust samples tends to overstate the silica content of airborne respirable dust because crystalline

silica is harder than most other minerals, and thus, resists being fragmented into respirable-sized

particles. For example, Hatch et al. (1947) partially relied on XRD analysis of settled dust for

U.S. industrial sand worker studies conducted from 1947 to 1955. Rando et al. (2001) elected

not to use Hatch’s settled dust samples because of a concern that they would overestimate the

silica content of airborne respirable dust. Instead, he used more current data taken from personal

and area respirable dust samples. In more recent years (since approximately the early 1970s),
16

laboratory methods were devised to prepare and analyze airborne respirable dust samples directly

for crystalline silica content. Since then, these have been the laboratory methods of choice.

Some of the better historical characterizations of respirable dust silica content were

employed in the Vermont granite studies, U.S. diatomaceous earth studies, studies of British

pottery workers, and those of U.S. industrial sand workers. These four groups of studies relied

on modern sampling data that characterizes both respirable gravimetric dust and the percentage

of silica in the dust. The modern data was used to supplement and to serve as a reference point

for historic respirable dust and silica content measurements or estimates, thus, allowing these

investigators to create representative job exposure indexes.

I.B. Silicosis.

Silicosis refers to a spectrum of lung diseases attributable to the inhalation of respirable

particles of silicon dioxide, or silica, in crystalline form. Crystalline silica is a naturally

occurring mineral, the most common form being quartz. Less frequently encountered in industry

is cristobalite (Becklake, 1994; Balaan and Banks, 1992), which usually is produced by hot

processes. Respirable crystalline silica particles are those that are smaller than 10 μm in

diameter (Ziskind et al., 1976).

Unlike other conditions that can result from both occupational and non-occupational

sources of exposure, silicosis is, with rare exception, an occupational disease. Crystalline silica

exposure and silicosis have been associated with work in mining, quarrying, tunneling,

sandblasting, masonry, heavy construction, foundry work, glass making, stone grinding, ceramic

and pottery production, cement and concrete production, stone and cut stone and gemstone work,

and work with certain materials in dental laboratories (Linch et al., 1998; Becklake, 1994;

Balaan and Banks, 1992).

Silicosis most commonly occurs as a diffuse nodular pulmonary fibrosis (NIOSH, 1996).

Three types of silicosis have been described: an acute form following intense exposure to

respirable dust of high crystalline silica content for a relatively short period (i.e., a few months or

years); an accelerated form, resulting from about 5 to 15 years of heavy exposure to respirable

dusts of high crystalline silica content; and, most commonly, a chronic form that typically

follows less intense exposure of usually more than 20 years (Becklake, 1994; Balaan and Banks,

1992).

Acute silicosis (sometimes referred to as “silicoproteinosis”) is a fatal pulmonary

condition of rapid progression. Acute silicosis develops after exposure to very high

concentrations of respirable crystalline silica and results in symptoms in a few weeks to four or

five years after the initial exposure (Davis, 1996; NIOSH, 1992a, 1992b; Peters, 1986). Workers

who perform occupational tasks such as sandblasting, rock drilling, quartz milling, or any other

process resulting in high exposures to small particles of dust with a high quartz content are at

risk for developing acute silicosis. The distinguishing feature of acute silicosis is the presence of

a surfactant-like liquid in the alveoli, caused by filling of lung’s airspaces with fluid containing

debris from dismembered cells of the respiratory tract and lung (Becklake, 1994; Wagner, et al.,
17

1993). Acute silicosis usually progresses rapidly to acute respiratory failure, typically in less

than two years (Becklake, 1994; Balaan and Banks, 1992; Davis, 1996).

Less severe than acute silicosis, but often associated with unprotected dust exposure (i.e.,

from lack of respiratory protection), is accelerated silicosis. This disease can be seen today

among sandblasters, concrete cutters, mine and tunnel drillers and workers in other occupations

who work without sufficient respiratory protection and who are exposed to respirable quartz.

This disease has the same symptoms as acute silicosis, which include shortness of breath

(restrictive and/or obstructive defects) and production of bloody sputum. Unlike acute silicosis,

accelerated silicosis is marked by silicotic nodules that are detectable on chest radiographs.

Accelerated silicosis usually manifests over a period from 5 to 15 years (Becklake, 1994), but

can develop in as little as 2 to 5 years if exposure to crystalline silica is intense (Davis, 1996). It

is ultimately fatal, even if affected workers are removed from high silica exposures.

Chronic silicosis is the most frequently observed type of silicosis in the U.S. today. It

usually requires a minimum of 10 years of employment in jobs involving exposure to crystalline

silica in some of the dusty industries described above, albeit at lower concentrations of silica

than those associated with development of acute or accelerated silicosis. Affected workers may

have a dry chronic cough, sputum production, shortness of breath, and reduced pulmonary

function. These symptoms result from airway restriction and/or obstruction caused by the

development of fibrotic scarring in the alveolar sacs and the lower region of the lung. The

scarring can be detected by chest x-ray or computerized tomography when the lesions become

large enough to appear as visible opacities. The result is restriction of lung volumes and

decreased pulmonary compliance with concomitant reduced gas transfer (Balaan and Banks,

1992). A standardized system exists to classify the opacities seen on chest radiographs

(Merchant and Schwartz, 1998). The International Labor Organization (ILO) International

Classification of Radiographs of the Pneumoconioses. (the ILO 1980, and the 2000 revision), is

the currently accepted standard against which chest radiographs are evaluated in epidemiologic

studies, for medical surveillance, and for clinical evaluation (ILO, 1980). The ILO system

standardizes the description of chest x-rays with respect to the size, shape, and density of

opacities, which together indicate the severity and extent of lung involvement. The density of

opacities seen on chest x-ray films is described using a 12-step scale divided into four major

numeric categories, from 0 to 3, where 0 indicates the absence of visible opacities and categories

1 to 3 reflect increasing profusion of opacities and a concomitant increase in severity of disease.

A more detailed description of the ILO’s system for classifying pneumoconiosis and surveillance

criteria for identifying silicosis cases appears later in this section.

Various terms have appeared in the literature to describe the presence and severity of

chronic silicosis. The term “simple” silicosis has often been used to refer to the early stages of

chronic silicosis as evidenced by radiologic findings of diffuse, small, rounded opacities that

appear in low density in the upper zone of the lungs (Davis, 1996; Banks, 2005). In pulmonary

massive fibrosis (PMF), the radiologic findings are distinguishable from earlier stages of silicosis

by the appearance of larger (>1 cm) opacities. When the large opacities becomes extensive,

larger opacities can coalesce and result in a “snowstorm” appearance on chest x-ray film.

Though there is general agreement on the definitions and use of the terms “accelerated” and
18

“acute” silicosis in the literature, such is not the case with the term “chronic” silicosis. Early

stages of chronic silicosis can be referred to as either simple or nodular silicosis; later stages are

referred to as either pulmonary massive fibrosis (PMF), complicated, or advanced silicosis.

Though the terms “PMF” and “complicated silicosis” both refer to the later stages of chronic

silicosis, they are not always synonymous, as complications of advanced stages of chronic

silicosis can also include infection by mycobacteria or fungi, cor pulmonale, spontaneous

pneumothorax and broncholithiasis (Becklake, 1994). Based on these definitions, the term

“simple silicosis,” when used by researchers and reported in this document, will be considered

synonymous with chronic silicosis, absent PMF or other complications

The knowledge that silicosis is associated with certain dusty occupations has existed

since antiquity. Hippocrates reported that miners developed dyspnea (shortness of breath) with

exertion. In the sixteenth century, Agricola was instrumental in recognizing the relationship

between exposure to rock dust and the development of dyspnea (Agricola, 1556). In the United

States, the greatest death toll from silicosis occurred with the excavation of Hawk's Nest Tunnel,

critical to the construction of a hydroelectric plant in West Virginia during 1930 to 1931.

Approximately 5,000 workers bored through Gauley Mountain to create the tunnel; an estimated

2,500 worked inside. A subsequent study determined that silicosis claimed the lives of at least

764 workers at Hawk's Nest Tunnel (Cherniack, 1986).

Occupational cohorts exposed to silica have been studied extensively, resulting in several

hundred epidemiological studies investigating silicosis morbidity or mortality, as well as other

health effects. These studies have conclusively linked occupational exposure to crystalline

silica-containing dust with silicosis (Davis, 1996; Becklake, 1994; NIOSH, 1974, 2002; Balaan

and Banks, 1992; Banks, 2005; Wagner et al., 1993). Because the causal relationship between

exposure to crystalline silica and silicosis has long been accepted in the medical community, the

studies that contributed to understanding that causal link will not be discussed here.

Of greater interest to OSHA is the quantitative relationship between exposure to

crystalline silica and development of silicosis. A large number of cross-sectional and

retrospective studies have been conducted to evaluate this relationship. Some of these are crosssectional studies in which radiographs taken at a point in time were examined to ascertain cases

(Kreiss and Zhen, 1996; Love et al., 1999; Ng and Chan, 1994; Rosenman et al., 1996); these

radiographs may have been taken as part of a health survey conducted by the investigators or

represent the most recent chest x-ray available for study subjects. Other studies were designed to

examine radiographs over time in an effort to determine onset of disease. Some of these studies

examined primarily active, or current, workers (Hughes et al., 1998; Muir et al., 1989a, 1989b;

Park et al., 2002), while others included both active and retired workers (Chen et al., 2001;

Hnizdo and Sluis-Cremer, 1993; Miller et al., 1998; Buchanan et al., 2003; Steenland and

Brown, 1995b). In general, these studies, particularly those that included retirees, have found

radiological silicosis risk (most often defined as x-ray films classified ILO 1/0+ or 1/1+) among

workers exposed near the range of cumulative exposure permitted by current exposure limits.

These studies are not presented in detail here, but are discussed in section II, Preliminary

Quantitative Risk Assessment.
19

Occupational exposure to crystalline silica continues to be widespread today in a large

number of industry sectors and occupations. More detailed information on current occupational

exposures will be presented later in this section in the discussion on surveillance data.

The next part of this section reviews published studies and other information that

describes the tools and approaches used in both clinical evaluations and epidemiologic

investigations to assess the presence and severity of silicosis. These include the use of

radiography and other standardized imaging methods for detecting lung fibrosis as well as

pulmonary function studies.

I.B.1. Clinical and Epidemiological Considerations in Assessing Workers at Risk of

Developing Silicosis.

I.B.1.a. Clinical features of silicosis.

The clinical diagnosis of silicosis has three requisites (Balaan and Banks, 1992; Banks,

2005). The first is the recognition by the physician that silica exposure adequate to cause this

disease has occurred. The second is the presence of chest radiographic abnormalities consistent

with silicosis. The third is the absence of other illnesses that could resemble silicosis on chest

radiograph, e.g., pulmonary fungal infection or miliary tuberculosis. Biopsy is not necessary to

make a diagnosis and a diagnosis does not require that chest x-ray films be rated using the ILO

system (NIOSH, 2002). In addition, an assessment of pulmonary function, though not itself

necessary to confirm a diagnosis of silicosis, is important to evaluate whether the individual has

impaired lung function. Assessment of impairment is based on symptoms and measurements of

pulmonary function at rest, and while exercising, if indicated (Becklake, 1994).

As discussed in the introduction to this section, there are three types of silicosis: acute,

accelerated, and chronic. A worker may develop any of these types, depending on the airborne

levels of respirable silica in the work environment, the length of the exposure, and some physical

characteristics of the respirable silica itself (NIOSH, 2002; Banks, 2005). Another consideration

is whether or not the worker was provided with effective respiratory protection (Banks, 2005).

Acute silicosis is the most infrequent yet most devastating form of this disease (Abraham

and Weisenfeld, 1997; CDC, 1998; Becklake, 1994; Banks, 2005). Chest radiographs reveal few

silicotic nodules (NIOSH, 1996); the appearance is that of a diffuse perihilar alveolar filling

process with opacities that have been described as having the appearance of “ground glass.”

Workers with acute silicosis have been reported to present with an irritative, sometime

productive cough, weight loss, fatigue, and occasionally, pleuritic pain (Banks, 2005). The onset

of symptoms is usually one to three years after the initial exposure, but symptoms occurring less

than a year after beginning sandblasting have been reported (CDC, 1998). Serial lung function

tests show progressive restriction of lung volumes and impairment of diffusing capacity. This

form of silicosis has often been complicated by fulminating tuberculosis (Becklake, 1994). The

invariable downhill clinical course of acute silicosis includes rapid progression to acute
20

respiratory failure (Becklake, 1994), usually within several years of beginning exposure (Balaan

and Banks, 1992).

Accelerated silicosis is marked by irregular nodular lung fibrosis that is detectable on

chest radiographs (Abraham and Weisenfeld, 1997; Becklake, 1994). Unlike simple chronic

silicosis, the radiographic picture is of diffuse, small, irregular opacities, or reticulonodular

opacities (Davis, 1996). Pathologic features of accelerated silicosis include the appearance of

numerous nodules at various stages of development, sometimes with irregular interstitial fibrosis

(Becklake, 1994).

The symptoms of accelerated silicosis are similar to those of chronic silicosis, but clinical

and radiographic progression is disabling (Davis, 1996), rapid (NIOSH, 2002; Banks, 2005), and

often leads to progressive massive fibrosis (Banks, 2005), severe respiratory impairment (Banks,

2005) and respiratory failure (Becklake, 1994).

Chronic (also called “classic”) silicosis is the most common form of silicosis today, and

can be described by the degree of radiologic chest involvement (Balaan and Banks, 1992). The

hallmark of the chronic form is the silicotic islet or nodule, one of the few agent-specific lesions

in pathology (Balaan and Banks, 1992). The typical presentation of chronic silicosis on chest xray is with upper and midzone nodular opacities that are rounded in shape; however, the lesions

may be irregular and involve other zones of the lungs. Calcification of lymph nodes in a

peripheral, or “eggshell” pattern is classic in silicosis, though not all chest x-rays of persons with

silicosis will demonstate this (Davis, 1996; Becklake, 1994). This eggshell pattern may also be

seen in sarcoidosis (Balaan and Banks, 1992). However, in addition to the differences in the

clinical courses of the two diseases, described elsewhere (see Davis, 1996), silicosis is

distinguished from sarcoidosis by an extensive history of exposure to silica (Davis, 1996).

The mature lesion of chronic silicosis is characterized by a cell-free and largely dust-free

central area of concentrically arranged, whorled hyalinized collagen fibers, surrounded by an

area of concentrically arranged collagen fibers and a more peripheral zone of randomly oriented

fibers interspersed with dust-laden macrophages (Davis, 1996). Affected workers may have a

dry chronic cough, sputum production, shortness of breath, and reduced pulmonary function.

These symptoms result from restricted airways caused by the fibrotic scarring in the alveolar sacs

and the ends of the lung tissue. The scarring can be detected from chest x-rays when the lesions

become large enough to be visible opacities (Balaan and Banks, 1992).

The small rounded opacities seen in accelerated and chronic silicosis may “progress” and

develop into large fibrotic masses, resulting in progressive massive fibrosis (PMF). The

appearance of ILO category 2 or 3 background profusion of small opacities appears to be

consistent with the histopathhological view that massive fibrosis is formed by the

conglomeration of individual fibrotic nodules (Ng and Chan, 1991). These conglomerate lesions

appear against a background of smaller nodules (Davis, 1996) and may obliterate bronchi and

vessels and cause marked distortion of lung structure and function (Wagner et al., 1993). The

result is typically restriction of lung volumes, decreased pulmonary compliance, and reduced gas

transfer (Balaan and Banks, 1992). In cases involving PMF, (sometimes referred to as
21

complicated silicosis), death is commonly attributable to progressive respiratory insufficiency

(Balaan and Banks, 1992). Once established, the fibrotic process of chronic silicosis is thought

to be irreversible (Becklake, 1994). The primary risks to the worker with silicosis are

progression of disease with progressive decline of lung function. Development of mycobacterial

infection is also a concern. Both conditions can hasten the development of respiratory

impairment (Banks, 2005). In addition to infection by mycobacteria, other complications include

infection by fungi, cor pulmonale, spontaneous pneumothorax, broncholithiasis, and

tracheobronchial obstruction from polypoid granuloma developing in the vicinity of egg-shell

calcification in hilar nodes (Becklake, 1994).

There is no specific treatment for silicosis (Davis, 1996: Banks, 2005), though a number

of treatment modalities, including whole lung lavage (washing) and administration of

corticosteroids (medications that suppress inflammation, and can have serious side effects) have

been tried in individual patients (Banks, 2005).

In addition to the functional impairments described here, including increased ventilatory

impairment, shortness of breath, and inability to continue to perform activities of daily living,

research has shown that people with silicosis advanced beyond ILO category 1 have a higher

mortality rate than the general population (Infante-Rivard et al., 1991; Ng et al., 1992a;

Westerholm, 1980).

Westerholm (1980) found that the life expectancy of individuals identified through a

silicosis case registry in Sweden was lower than that of the general population. This registry

used the Johannesburg classification scheme, which, like the ILO system, uses increasing

gradations of severity of opacities. The authors did not attempt to re-classify older cases

according to newer criteria, or to align the silicosis categories in this study with those of the ILO.

Data are presented for two time periods, 1931 to 1948 and 1949 to 1969. In addition to severity

of silicosis, tuberculosis status was also considered. Reduction of life expectancy was increased

for higher stages of silicosis (category 2 and 3) and having tuberculosis. If data from just the

later reporting period (1949 to 1969) are considered, median reduction in life expectancy for

categories 2 and 3 was 6.5 years (95% CI = 3.5-8.5). Category 1 showed a shortening of median

survival time of 3.5 years, as compared to a sample drawn from the general population

(Westerholm, 1980).

Infante-Rivard et al. (1991) examined factors influencing survival of silicotic patients

who received workers’ compensation. Using multivariate analysis of clinical prognostic factors

with the Cox proportional hazards model, the authors concluded that among this population,

having complicated silicosis (large opacities), dyspnea, expectoration, abnormal breath sounds,

low vital capacity, and current smoking status were all risk factors for poorer survival (InfanteRivard et al., 1991).

Ng et al. (1992a) examined predictors of mortality in persons who had silicosis. The

mortality of a cohort of 1,487 male patients with silicosis in a population-based register followed

up from 1980 to 1986 was evaluated with reference to the mortality rates of the general male

population. A striking excess of deaths from all causes (368 observed, SMR = 3.00) was noted.
22

Seventy-four percent of the deaths were due to respiratory conditions and complications either

directly or indirectly related to silicosis. The risk of death was higher than expected in younger

patients less than 45 years of age. Patients with simple silicosis of ILO profusion category 1 did

not appear to be at increased risk of death relative to the general population. Higher degrees of

profusion and conglomerate disease were associated with increased mortality. Among patients

having the same degree of profusion, the presence of tuberculosis increased the mortality rate;

however, increased mortality was also observed in tuberculosis-free patients. There was no

evidence, however, that patients who smoked had higher mortality than silicosis patients who did

not. Age at diagnosis, degree of silicotic nodule profusion, and the occurrence of tuberculosis

were therefore strong predictors of increased mortality rate in patients with silicosis.

I.B.1.b. Chest radiography and other imaging techniques to assess silicosis.

Chest x-rays have been central to clinical evaluation and surveillance of dust-exposed

workers. Epidemiologic studies of occupational cohorts exposed to dust rely on chest

radiographs to investigate the development and progression of pneumoconiosis, including

silicosis.

For many decades, the chest radiograph has been the standard approach to assessing dust

diseases of the lung, being relatively simple, inexpensive, non-invasive, and safe (NIOSH,

2008a). Today, the chest radiograph, or chest x-ray, remains the primary means of determining

the presence and extent of pneumoconiosis, including silicosis. As such, it is an important tool

in epidemiologic investigations of silica-exposed workers, in surveillance, in clinical evaluations,

and in disability determinations (Wagner et al., 1993).

However, there is a major distinction between reading and classifying radiographs for

epidemiologic research and reading radiographs for clinical purposes (Wagner et al., 1993). In

epidemiologic investigations, the intent is to obtain reliable data for a large group of people, and

data collection is done using tightly controlled protocols, often by more than one investigator. In

clinical practice, it is the individual person under investigation who is the focus of interest.

Detailed medical information is usually elicited by physicians working singly, and making their

own decisions to medically evaluate the patient. The ultimate objective of a clinical evaluation is

to learn all that is necessary to diagnose and treat that particular individual.

Because of the susceptibility of silicosis patients to tuberculosis, miners and other silicaexposed workers were the subject of chest radiographic studies starting in the in the 1920s

(Merchant and Schwartz, 1998). As early as 1930, the need for a standardized approach to

classifying the opacities viewed on chest radiographs was recognized, and led to improvements

that over time developed into the International Labor Organization (ILO) International

Classification of Radiographs of the Pneumoconioses (Merchant and Schwartz, 1998). As noted

above, the ILO 1980, and the 2000 revision, is the currently accepted standard against which

chest radiographs are evaluated in epidemiologic studies, for medical surveillance, and for

clinical evaluation (ILO, 1980).

NIOSH describes the classification system as follows:
23

The Classification system includes the Guidelines and two sets of standard films.

The standard films represent different types and severity of abnormalities and are

used for comparison to subject films during the classification process. The

system is oriented towards describing the nature and extent of features associated

with the different pneumoconioses, including silicosis. It deals with parenchymal

abnormalities (small and large opacities), pleural changes, and other features

associated, or sometimes confused, with occupational lung disease.

In the present manifestation of the ILO system, readers are first asked to grade

film quality. They are then asked to categorize small opacities according to shape

and size. The size of small round opacities is characterized as p (up to 1.5 mm), q

(1.5-3 mm), or r (3-10 mm). Irregular small opacities are classified by width as s,

t, or u (same sizes as for small rounded opacities). Profusion (frequency) of small

opacities is classified on a 4-point major category scale (0 – 3), with each major

category divided into three [subcategories], giving a 12-point scale between 0/-

and 3/+. Large opacities are defined as any opacity greater than 1 cm that is

present in a film. Large opacities are classified as category A (for one or more

large opacities not exceeding a combined diameter of 5 cm), category B (large

opacities with combined diameter greater than 5 cm but not exceeding the

equivalent of the right upper zone), or category C (bigger than B). Pleural

abnormalities are also assessed with respect to location, width, extent, and degree

of calcification. Finally, other abnormal features of the chest radiograph can be

commented upon (ILO 2002). (NIOSH, 2008a).

Although the ILO system provided a standardized approach for classifying and

describing pneumoconioses seen on radiographs, there were, prior to the early 1970s, issues

surrounding the inconsistent application of the ILO system and its use by physicians not having

proper training. NIOSH responded by initiating the B Reader Certification Program to train and

certify licensed physicians in the use of the ILO Classification System. The B Reader Program

tests the ability of a reader to classify a sample set of radiographs and certifies only those who

achieve a certain level of proficiency. The B Reader Program is intended to ensure the accuracy

of ILO readings regarding the presence of pneumoconiosis. NIOSH’s B Reader Program began

in 1974, although it was not until 1978 that the certification exam was given widely (Merchant

and Schwartz, 1998; NIOSH 2008a). NIOSH plays a major role in administering the B reader

program and is continually updating the program to account for advances in medicine and

technology.

Assuming that the quality of chest radiographs is adequate, of great importance in

assessing the ability of chest radiography to detect silicosis are sensitivity, specificity, and

concordance (agreement between readers). Sensitivity refers to the frequency with which

radiographs detect silicosis in persons who have silicosis and specificity refers to the frequency

with which radiographs indicate absence of silicosis in persons without the disease. Studies that

evaluated the ability of chest radiography to detect silicosis (i.e., sensitivity) have used various

methodologies, but are essentially of two types: 1) those that compared radiological findings
24

with pathological evidence, and 2) those that compared findings of chest radiographs to those of

computed tomography (CT) scans, or other imaging techniques.

Because pathological findings are the most definitive for silicosis, findings on biopsy and

autopsy provide the best comparison for determining sensitivity and specificity of chest imaging.

Unfortunately, there is no non-invasive technique for detecting silicosis that can serve as a “gold

standard” against which other diagnostic approaches can be compared.

Hnizdo et al. (1993) evaluated the sensitivity, specificity and predictive value of

radiography by correlating radiological and pathological (autopsy) findings of silicosis. The

study used three readers and defined a profusion score of 1/1 as positive for silicosis. Sensitivity

was defined as the probability of a positive radiological reading (ILO category > 1/1) given that

silicotic nodules were found in the lungs at autopsy. Specificity was defined as the probability of

a negative radiological reading (ILO category < 1/1) given that no, or only an insignificant

number of silicotic nodules were found at autopsy. The average sensitivity values were low for

each of the three readers (0.39, 0.37, and 0.24), whereas the average specificity values were high

(0.99, 0.97, and 0.98). For all readers, the proportion of true positive readings (i.e., the

sensitivity) increased with the extent of silicosis found at autopsy. Two of the readers had

similar sensitivity and specificity values, while the third had a lower average sensitivity value,

but the same specificity value.

Thus, radiography was consistently found in this study to yield a high degree of

specificity (very few false positives), but low sensitivity (negative chest x-ray, with silicosis

actually present), suggesting that the use of radiography to assess presence and progression of

silicosis is a relatively crude tool and underestimates the true prevalence of silicosis in

populations exposed to crystalline silica.

To address the low sensitivity of chest x-rays for detecting silicosis, Hnizdo et al. (1993)

recommended that radiographs consistent with an ILO category of 0/1 or greater be considered

indicative of silicosis among workers exposed to a high concentration of silica-containing dust.

In like manner, to maintain high specificity, chest x-rays classified as category 1/0 or 1/1 should

be considered as a positive diagnosis of silicosis. This recommendation underscores the

importance of taking an accurate occupational history, including information on exposures to

crystalline silica, and obtaining any available exposure monitoring data to augment the history.

Other studies reported similar findings. Craighead and Vallyathan (1980) examined postmortem lung tissue from 15 Vermont granite workers, and found silica-associated lesions in all

workers, despite the failure of radiological studies to reveal evidence of pneumoconiosis.

Rosenman et al. (1997) also compared the ability (or sensitivity) of radiologic methods to detect

cases of silicosis. In a state-based surveillance system, 577 individuals were identified as having

silicosis by radiologic methods. An additional nineteen (3.3%) had biopsy evidence of silicosis

but normal radiographs.

As with most medical determinations, radiographic classifications are subject to accuracy

and precision considerations. Accuracy is defined as the ability of a measurement to reflect the
25

true degree of underlying abnormality. Precision reflects the extent to which a measurement is

consistent across repeated determinations. Both criteria are important – a measurement

technique should preferably be both accurate and precise.

Inter- and intra-reader variability in chest radiography has existed since chest

radiography was first used to identify and classify pneumoconiosis (Fletcher and Oldham, 1949).

Inter-reader variability occurs when different readers disagree on a classification. Intra-reader

variability occurs when a reader classifies a given radiograph differently on different occasions.

Inter-reader variation consists of two components: systematic differences and random

variability. Systematic variation between readers, in which one reader persistently reports more

or less abnormality than another, is related to bias. Bias can be reduced by blinding the readers

to any information concerning the radiographs being classified that can consciously or

unconsciously influence their classifications, for example knowledge of exposure. Reducing

bias, along with instituting concurrent quality control measures, increases the accuracy of the

measurement.

Both accuracy and precision in film classification is gained through the use of summary

measures based on independent and unbiased classifications of multiple different readers who

classify the films independently (that is without other readers being present and without

knowledge of other readers’ classifications). Summary classifications derived from the

independent classifications are more precise than any single individual classification. Valid

summarization methods include the use of median classifications or properly-designed consensus

measures.

In a study of a silica-exposed occupational cohort within a general population, three

NIOSH-certified B readers independently classified chest radiographs for 124 subjects without

personal identifiers and in random order (Kreiss and Zhen, 1996). Silicosis cases were defined

as those cases with a mean radiologic profusion of small opacities of > 1/0 using the 1980 ILO

classification. The authors used the Kappa statistic to evaluate the concordance (agreement)

between pairs of B readers, using a 1/0 profusion criterion for abnormality, with values of 0.70

(p < 0.0001) for the first and second readers, 0.66 (p < 0.0001) for the first and third readers, and

0.58 (p < 0.0001) for the second and third readers. (When the two measurements agree only at

the chance level, the value of kappa is zero; when the two measurements agree perfectly, the

value of kappa is one.) The Kappa statistics for abnormality using the 1/1 criterion were 0.80,

0.75, and 0.75, respectively.

Newer imaging technologies with both research and clinical applications include

computed tomography, and high resolution tomography. Computed tomography (CT) of the

chest represents an important advance that may substantially improve our ability to

noninvasively identify and quantify pleural and paranchymal (lung tissue) lesions, as in silicosis,

or may add other important information when it comes to diagnosis. High-resolution computed

tomography (HRCT) uses thinner image slices and a different reconstruction algorithm to

improve spatial resolution over CT.
26

Two older studies that compared CT and HRCT with chest x-rays for identifying silicosis

did not find CT or HRCT to be a more sensitive diagnostic tool than chest x-rays. However,

several more recent studies and reviews have suggested that HRCT may be superior to chest xray in the early detection of silicosis and the identification of progressive massive fibrosis

(PMF).

One of the older studies (Bégin et al., 1987a) also found that the CT scan did not identify

more cases of minimal paranchymal disease than did chest x-ray films. However, CT scan did

identify significantly more coalescence and/or large opacities in 33 percent of patients who were

thought to have simple silicosis based on chest x-ray.

In the second older study, Talini et al. (1995) studied 27 subjects with varying degrees of

silicosis who underwent chest x-ray and pulmonary function testing to compare the utility of

HRCT with chest x-ray in the diagnosis and assessment of the severity of silicosis. The authors

used the major ILO categories (i.e., 0, 1, 2, or 3) to categorize the chest x-ray films; the HRCT

images were graded according to a standardized system developed by the authors, based on the

profusion of parenchymal (lung tissue) opacities, and also with a visual scoring system based on

estimating the percentage of overall area that showed emphysematous or nodular changes.

Although the systems used to score both chest x-rays and HRCT images were based on four

categories of increasing severity of changes in the lung, it is unclear to what extent the categories

are actually comparable to the four ILO categories that describe profusion. According to the

authors, there are no standard ILO-type films for use in classifying the extent of pneumoconiosis

in the HRCT images. When comparing the agreement between two readers on the categories of

parenchymal opacities on chest x-rays and HRCT, the authors found that concordance

(agreement) between readers was better with HRCT than for chest x-rays (Cohen’s k statistic:

0.49 vs. 0.29 respectively). However, the concordance between the two different imaging

methods, chest x-ray and HRCT, was fairly low; only 10 of 27 subjects were classified as the

same profusion category for both chest x-ray and HRCT. Eight subjects were classified as

category 0 by chest x-ray, but only two of these eight were classified as category 0 by HRCT,

suggesting improved sensitivity. However, five additional subjects were classified in the

category 0 by HRCT, but category 1 or higher for chest x-ray. For category 1, a similar pattern

was observed. For the higher profusion categories (3 and 4), HRCT identified twice as many (4

vs. 2) subjects as did chest x-ray. Thus, there was no consistent pattern that would suggest

HRCT had higher sensitivity than chest radiography for detecting silicosis.

No relation was found between pulmonary function studies and profusion of parenchymal

opacities as assessed by chest x-ray, except for a reduction of maximal flow at 50 percent of

FVC in the highest profusion category. On the contrary, the profusion of opacities detected by

HRCT correlated reasonably well with indices of airway obstruction and diffusion capacity. In

particular, subjects classified in the highest profusion category by HRCT exhibited lower values

of FEV1, expiratory flows, and diffusion capacity than did subjects classified as category 0 or 1.

Multiple logistic regression analyses between pulmonary function studies and HRCT categories

showed that the relationship was not explained by smoking history or symptoms of chronic

bronchitis.
27

Talini et al. (1995) concluded that, in the absence of a gold standard for the diagnosis of

silicosis, (i.e., examination of lung tissue, obtained by necropsy or biopsy) it is difficult to

determine which technique more accurately detected early paranchymal involvement in silicosis.

The authors pointed to the greater concurrence among the readers when rating HRCT images

compared to chest x-ray films, despite the absence of ILO-type standard films for HRCT images.

In addition, the presence of a significant correlation between HRCT profusion categories and

pulmonary function decrements seemed to indicate that HRCT was a better predictor of disease

than chest x-ray. However, the data showed that HRCT was not a more sensitive tool for

identifying early stages of silicosis, but the authors believed it could be useful to identify those

silicotics more likely to have pulmonary impairment.

Sun et al. (2008) studied the value of HRCT as compared to x-ray in the diagnosis of

small opacities and complications of silicosis in 90 mine machinery manufacturing workers in

China. The authors also briefly reviewed previous studies. The authors believed that previous

research had indicated that HRCT is more sensitive than chest x-ray in detecting lung

parenchymal changes suggestive of silicosis and early confluence of small opacities in the lung,

but that HRCT was not currently accepted as a diagnostic tool for the detection of the disease. In

the present study, Sun et al. found that HRCT results led to the diagnosis of silicosis in subjects

who originally were not diagnosed with silicosis based on chest x-ray. In other subjects

previously diagnosed with silicosis by chest x-ray, use of HRCT revealed a higher degree of

profusion of small opacities. The numbers of small opacities in HRCT were significantly higher

than those seen in x-ray in all lung zones (p < 0.01). A statistically significant increase in the

detectability of bulla, emphysema, pleural, mediastinal, and hilar changes was also observed (p <

0.05). Sun et al. (2008) concluded that HRCT has potential diagnostic value for silicosis,

especially in the early stage.

Lopes et al. (2008) studied 44 non-smoking patients with silicosis and without a history

of tuberculosis in an effort to correlate HRCT parameters with respiratory function parameters

and to compare the HRCT findings with the chest x-ray findings. As in the Sun et al. (2008)

study above, HRCT identified more cases of silicosis than x-ray. There were four patients who

were classified as category 0 based on x-ray and as category 1 based on HRCT. For large

opacities, there was concordance between the two methods in 70.5 percent of the cases. HRCT

also identified PMF in 33 patients as compared to 23 patients by x-ray. Seventy-five percent of

the patients in this study had large opacities (HRCT findings) and there was a progressive

decrease in pulmonary function in parallel with increases in the extent of damage (HRCT

classification). This was not the case among patients with small opacities only. The authors

concluded that an HRCT finding of large opacities can be an important indicator of severity of

silicosis. The authors also concluded that HRCT is superior to x-ray in the diagnosis of silicosis,

both for the early detection of the initial phases of the disease and for the identification of PMF.

A review of recent studies of the use of HRCT for diagnosis and grading of silicosis and

other pneumoconioses was conducted by Blum et al. (2008). The authors noted that HRCT has

been acknowledged as the gold standard in the noninvasive diagnosis of pneumoconiosis,

providing essential visual information far beyond x-ray, predominately in the early stages of

disease. The authors reported that, in 2005, an international expert panel harmonized several
28

national HRCT classifications of occupational and environmental thoracic diseases and

published the harmonized system in book format combined with digital reference films.

Blum et al.’s. (2008) review also highlighted the following findings:

 PMF and emphysema indicies, as detected by HRCT, were significantly

correlated with measured lung function decrements;

 In an investigation of the role of expiratory HRCT in estimating the obstructive

impairment in patients with silicosis, the extent of emphysema and air trapping

correlated well with lung function impairment consistent with emphysema, while

other radiological patterns did not;

 Pleural disease was observed in previous CT studies of subjects with autopsyproved silicosis; and

 In the early detection of silicosis, branching centrilobular structures are a useful

HRCT feature besides nodules because they showed a statistically significant

correlation with restrictive lung function losses.

Blum et al. concluded that HRCT provides access to a higher diagnostic level in dust-induced

occupational lung diseases and that, in comparison to x-ray, several studies demonstrated a

superiority of HRCT in predicting clinical impairment due to occupational lung diseases.

I.B.1.c. Pulmonary function testing (PFT).

Although not essential for the diagnosis of silicosis, lung function tests are used to assess

the degree of impairment caused by exposure to crystalline silica. Standard practice guidelines

for administering and interpreting pulmonary function studies are available from the American

Thoracic Society (ATS) (Miller et al., 2005) and the American College of Occupational and

Environmental Medicine (ACOEM) (ACOEM, 2004) and are summarized here. The most

common pulmonary function test, spirometry, measures how quickly and how much air can be

expired from the lungs after a maximal inspiration. The individual blows into a device called a

spirometer. The most common measurements reported from a spirometry test are the forced vital

capacity (FVC), the forced expiratory volume in one second (FEV1), and the FEV1/FVC ratio.

Although some clinicians use the mean forced expiratory flow between 25 percent and 75

percent of the FVC (FEF25-75%) as an indicator of small airways disease, ATS recommends

caution in this practice due to the high variability of the measurement and its dependency on the

test subject’s level of expiratory effort.

More detailed measurement of lung function can be performed with other pulmonary

function tests. In some circumstances, measurement of absolute lung volumes is required for

specific diagnoses. There are three possible measurement techniques for determining absolute

lung volumes: 1) body plethsymography, 2) nitrogen washout, and 3) helium dilution. Although
29

there are several indices that are either measured or calculated for lung volume assessment, the

most important include the following:

 The functional residual capacity (FRC) is the volume of gas remaining in the lung

at end-expiration after tidal breathing;

 Residual volume (RV) is the volume of gas remaining in the lung after a maximal

expiration;

 Total lung capacity (TLC) refers to the volume of gas in the lungs after maximal

inspiration; and

 Vital capacity (VC) is the volume change between full inspiration and complete

expiration.

Lung diffusing (DL) capacity is another test that provides information about the ability of

the lungs to exchange gas across the lung (alveolus) and blood (capillary) interface. The

principle measurement, carbon monoxide uptake by the lung (DLco), reflects the gas exchange

properties of those regions of the lung that are ventilated. The subject inhales some gas

containing a very small quantity of carbon monoxide, holds his breath for 10 seconds, then

rapidly exhales. The single exhaled gas is analyzed to determine how much carbon monoxide

was absorbed during the breath. DLco may be elevated or reduced, depending on the underlying

disease. Individuals with interstitial lung diseases, such as silicosis, may have a reduced DLco,

depending on the severity of the disease.

Interpretation of pulmonary function results for individual patients is based on

comparisons to reference (predicted) values from populations of healthy, non-smoking

individuals having similar anthropometric (age, sex, height) and ethnic characteristics as the

patient. Reference values define the upper and lower limits of the normal range. For each lung

measurement index, values below the 5th percentile of the distribution of values for the reference

population have traditionally been considered to be below the normal range. However, as

discussed below, “normality” is an elusive concept when discussing pulmonary function because

of a high degree of individual variation (Becklake, 1994)

When lung function tests were first introduced in the 1940s and 1950s, emphasis was put

on the profile of functional impairment, leading to widespread use of the terms obstructive defect

and restrictive defect (Becklake, 1994). Spirometry is useful for determining whether lung

function impairment has an obstructive, restrictive, or mixed pattern, but spirometry alone cannot

diagnose specific diseases. Obstructive lung disease is characterized by decreased forced

expiratory volumes with respect to FVC (or FEV/FVC ratio), of hyperinflation, and/or of air

trapping reflected in increases in functional residual capacity (FRC) and residual volume (RV),

with or without gas exchange impairment. An obstructive impairment, airway narrowing during

exhalation, shows a disproportionate reduction in maximal flow rate compared to the total

volume exhaled. This is reflected by an FEV1/FVC ratio that falls below the 5th percentile.

Restrictive impairments do not allow the lungs to fully expand. A restrictive impairment would
30

be demonstrated by a normal FEV1/FVC ratio accompanied by a reduction in TLC below the 5th

percentile. A reduced VC alone would not be indicative of restrictive disease. Mixed ventilatory

impairment is defined by the presence of obstructive and restrictive patterns. A mixed

impairment is characterized by both the FEV1/FVC ratio and TLC below their relative 5th

percentile values. The terms obstructive and restrictive to describe respiratory disorders are

useful when disease is obviously present, but is less helpful when using lung function tests to

evaluate earlier stages of disease. Becklake (1994) suggested the following reasons for this.

First, a clear profile of restriction is seldom demonstrated in the early stages of pneumoconiosis,

whereas in the later stages, relatively cursory testing (e.g., measurement of FVC or TLC) may be

all that is required to characterize the impairment. Second, interpretation of results in an

individual is complicated by the need to define what is normal. As mentioned above, this is

usually done by the use of reference or predicted values for a population; however, published

prediction formulas vary considerably due primarily to differences in the characteristics of the

subjects examined to generate the various predicted values. Thus, no one set of prediction

equations is likely to be applicable to all laboratories, in all circumstances, and for all

populations (Becklake, 1994).

Traditionally, an individual's measured lung function has been compared with a

"predicted" value, i.e., the average expected for an asymptomatic non-smoker of the subject's

age, height, race/ethnicity, and sex. Many sources of predicted values have been derived from

studies of asymptomatic non-smoking populations, and some applications require the use of

specific sets of prediction equations. In the occupational setting, many healthy workers are

tested periodically, not because they have abnormal lung function, but to monitor their response

to potentially harmful occupational exposures. Because of their health, working populations

usually have higher levels of pulmonary function than clinic populations, and many workers

have lung function that is above average, i.e., greater than 100 percent of predicted. Such

individuals may lose their lung function at an excessive rate but still remain in the normal range

throughout their working lifetime and into retirement. Remaining in the normal range does not

indicate respiratory health, since their function may drop from the top to the bottom of the

normal range, but these individuals must lose large fractions of their lung function before they

will fall below the normal range. For these workers, the widespread practice of repeatedly

comparing serial test results with the traditional normal range may not detect serious pulmonary

function deterioration. For this reason, longitudinal evaluation that compares current measured

values with previously measured values, "using the subject as his/her own control," is needed

especially for this group (ACOEM, 2004). In addition, the inter-individual variation discussed

above (Becklake, 1994) makes it difficult to detect abnormality cross-sectionally.

Although the lung impairment associated with silicosis is more frequently reported as

restrictive in nature, it is not clear that this is always the case. Studies report finding both

restrictive and obstructive lung function decrements in workers exposed to silica. It is not clear

whether functional impairments differ at various stages of silicosis (e.g., reduction in capacity

(restrictive) that is associated with fibrosis earlier in the process, and an “obstructive” pattern

later) or is a “mixed” type of pulmonary impairment.
31

In addition to what is known about the clinical presentation of silicosis and what is

learned through epidemiologic investigations, surveillance systems for silicosis, though

incomplete, continue to provide information on the extent of silicosis present in the U.S. today.

Many individuals with silicosis were initially identified through hospital records or other health

care providers. Through some surveillance programs implemented at the state level, silicosis

cases are confirmed and information is collected on each case’s occupation and history of

employment to obtain industry specific data on silicosis prevalence. The next part of this section

reviews existing silicosis surveillance systems and the data those systems produce.

I.B.2. Review of Surveillance Data.

According to the National Institute for Occupational Safety and Health (NIOSH),

“Occupational respiratory disease surveillance is the ongoing, systematic collection, analysis,

and dissemination of health and hazard data to monitor the extent and severity of occupationallyrelated lung disease and related workplace exposures for use in public health education and in

disease prevention” (NIOSH, 2008b). Mortality and morbidity data for lung diseases that are

caused predominantly by work exposures are included in NIOSH’s Work-Related Lung Disease

Surveillance System. The surveillance information is used for establishing priorities, for

investigation and intervention, and for tracking progress toward elimination of preventable

disease (NIOSH, 1997).

This section presents a discussion of the surveillance systems that currently report

silicosis mortality and morbidity data, along with the data reported through those systems,

with a focus on the more recent data. A discussion of the literature on underreporting of

surveillance data specifically related to silicosis concludes this section.

In general, surveillance methods can be divided into four categories: passive, active,

sentinel, and special systems. In general, passive and active systems are based on conditions

that are reportable to health jurisdictions. Sentinel systems and special systems are usually

designed to obtain information that is not generally available to health departments.

Passive surveillance is the most common form of surveillance and relies on standardized

reporting forms or cards provided by or available through the state or local health departments.

These completed forms are returned to the health department when cases of disease or deaths are

detected. The term “passive” is used to convey the idea that health authorities take no action

while waiting for report forms to be submitted. Additionally, case reports received by the public

health authority may require further action to ensure completeness and proper case classification.

In contrast, active surveillance involves outreach by the public authority, such as regular

telephone calls or visits to laboratories, hospitals, and providers to stimulate reporting of specific

conditions or events and thus may capture more cases than passive surveillance systems.

Sentinel surveillance involves the collection of case data from only part of the total

population (from a sample of providers) to learn something about the larger population, such as

trends in diseases and mortality. Special systems are occasionally designed and implemented to
32

generate surveillance information that is not possible to acquire by any of the other systems

already mentioned.

Based on these definitions, the silicosis surveillance systems described here are all of the

passive type. Because passive surveillance systems depend upon health practitioners (1) being

aware that there is a reporting requirement for a particular condition or event, and (2) being

diligent in both recognizing and reporting cases, the actual prevalence of diseases may be higher

than is suggested by the surveillance data. There is no national surveillance program that

accurately and completely collects mortality data associated with silicosis for the entire U.S.

The most comprehensive and current source of surveillance data in the U.S. related to

occupational lung diseases, including silicosis, is NIOSH’s Work-Related Lung Disease

(WoRLD) Surveillance System; the WoRLD Surveillance Report is complied from the most

recent data from the WoRLD System. The seventh and most current edition was published in

2008 (NIOSH, 2008c). Updates to the (WoRLD) Surveillance System can be found online

(eWoRLD). Data contained in the eWoRLD surveillance system originate from various

publications reports, data files and tabulations provided by various sources including Department

of Labor (DOL), and the National Center for Health Statistics (NCHS).

The CDC also publishes the Morbidity and Mortality Weekly Report, which reports on

provisional data based on weekly reports to CDC by state health departments, and the CDC

Surveillance Summaries, which provide a means for CDC programs to disseminate surveillance

findings, permitting detailed interpretation of trends and patterns based on those findings (CDC,

2006a). NIOSH also published the Worker Health Chartbook (NIOSH, 2004), a compilation of

occupational injury and illness surveillance data from some of the same sources discussed here.

The following sections review statistics describing silicosis mortality and morbidity

indicators of silicosis.

I.B.2.a. Silicosis mortality.

Since 1968, NIOSH has obtained mortality data from the National Center for Health

Statistics (NCHS) for various respiratory conditions, including silicosis, coded according to the

International Classification of Diseases (ICD). Because each death record includes codes for up

to 20 conditions (underlying and contributing causes) listed on the death certificate, deaths

involving silicosis can be thought of as deaths “from silicosis” or “with silicosis” (i.e., though

not related to the immediate cause-of-death, silicosis was present at the time of death). Other

data on death certificates include age, race, sex, and state and county of residence at time of

death. In addition, usual industry and occupation codes are available for decedents from a

selected list of states, but only for 1985–1999 (NIOSH, 2004, 2008c).

National statistics on mortality associated with occupational lung diseases are compiled

in the National Occupational Respiratory Mortality System (NORMS, available on the Internet at

http://webappa.cdc.gov/ords/norms.html), a searchable database administered by the National
33

Institute for Occupational Safety and Health (NIOSH). The source of these data is death

certificates reported to state vital statistics offices, which are collected by the NCHS.

In a recent review of statistics specific to silicosis mortality, MMWR Report Silicosis

Mortality, Prevention, and Control — United States, 1968–2002 (CDC, 2005), NIOSH identified

silicosis deaths from 1968 to 2002, and included all deaths for which an ICD code for silicosis

was listed as either the underlying or contributing cause of death. Death rates (per million

persons aged >15 years) were age-adjusted to the 2000 U.S. standard population. Codes for

usual occupation or industry were available for each year 1985 -1999 for up to 26 states (CDC,

2005).

During 1968 to 2002, silicosis was recorded as an underlying or contributing cause of

death on 16,305 death certificates; of these, a total of 15,944 (98 percent) deaths occurred in

males (CDC, 2005). From 1968 to 2002, the number of silicosis deaths decreased from 1,157

(8.91 per million persons aged >15 years) to 148 (0.66 per million), corresponding to a 93-

percent decline in the overall mortality rate. The racial distribution of persons who died from

silicosis was approximately 88 percent (14,310 decedents) white, 12 percent (1,925) black, and

less than one percent (70) other. Since 1996, on average, almost 31 silicosis-related deaths per

year have been recorded among persons aged 15 to 64 years (NIOSH, 2008c). In its most recent

WoRLD Report (NIOSH, 2008c), NIOSH reported that the number of silicosis deaths in 2003,

2004, and 2005 were 179, 166, and 161, respectively, slightly higher than that reported in 2002.

The number of silicosis deaths identified each year has remained fairly constant since the late

1990’s. Figure I-1 depicts the change in the number of silicosis deaths identified since 1968.

Figure I-1. Number of silicosis deaths and age-adjusted mortality rate, U.S. residents age

15 years and older, 1968-2005

Source: NIOSH, 2008c
34

The findings reported by CDC (2005) and NIOSH (2008c) indicate a decline in silicosis

mortality during the time period 1968 to 2005. NIOSH cited two main factors that were likely

responsible for the declining trend in silicosis mortality. First, many of the deaths in the early

part of the study period occurred among persons whose main exposure to crystalline silica dust

probably occurred before introduction of national standards for silica dust exposure established

by OSHA and the Mine Safety and Health Administration (MSHA) (i.e., permissible exposure

limits (PELs). These regulatory limits, coupled with other recommendations, such as that by

NIOSH in 1974 (which issued a recommended exposure limit (REL) to respirable crystalline

silica of 0.05 mg/m3), have likely led to reduced silica dust exposure since the 1970s. NIOSH

also stated that ancillary preventive measures (e.g., use of respiratory protection, hazard

communication, and recordkeeping and reporting of occupational illnesses) where practiced,

might have contributed to a reduction of personal exposures to respirable crystalline silica. The

second major factor identified by NIOSH as contributing to a reduction in silicosis mortality

relates to declining employment in heavy industries (e.g., foundries) where silica exposure was

prevalent (CDC, 2005). Declining employment in industries with high exposure to silica would

reduce the number of people at risk for developing silicosis, as well as the rate of silicosis

mortality within the U.S. population. Although the factors described by NIOSH are reasonable

explanations for the steep reduction in silicosis-related mortality, it should be emphasized that

the surveillance data are insufficient for the analysis of the residual risk associated with current

occupational exposure limits for crystalline silica. Analyses designed to explore this question

must make use of appropriate exposure-response data, as is presented in OSHA’s Preliminary

Quantitative Risk Assessment (Section II).

NIOSH also identified the following limitations to the findings in the MMWR Report

(NIOSH, 2004). First, accuracy of the coding of usual industry and occupation on death

certificates was not verifiable because individual work histories are not listed on death

certificates. Second, codes for usual industry and occupation were available only for the period

1985 to 1999 for 26 states; thus, these data are not nationally representative. Twenty-four states

do not provide decedents' employment data to NCHS. Third, the state of residence at death is

not always the state in which decedents' exposures occurred. Fourth, no exposure information is

listed on death certificates. Therefore, no silica exposure-response relationship was evaluated.

Finally, physicians might have misclassified or underreported silicosis deaths. These limitations

apply to the use of death certificates as a source of mortality surveillance data in general, and do

not reflect any particular limitation of the use death certificates for silicosis mortality

specifically. While the 1970s saw a precipitous drop in the number of silicosis deaths as

recorded on death certificates, reductions occurring in the 1980s and later appear more modest.

(See Figure I-1.) To compare the percent reduction in the number of deaths over time, OSHA

queried the NORMS database (http://webappa.cdc.gov/ords/norms.html) for the total number of

decedents age 15 and older with any mention of silicosis coded on the death certificate (i.e.,

silicosis as underlying or contributing cause of death), for all races and both sexes. The total

number of relevant deaths per each 5-year interval during the years 1970–2004 was generated by

NORMS. OSHA then calculated the percent change from each 5-year interval to the next, for

comparison purposes. These data are presented in Table I-2, which shows that the largest

reduction (36 percent) occurred from the early 1970’s (1970-1974) to the later 1970’s (1975-
35

1979). The smallest reduction occurred from the 1985-1989 to the early 1990’s (13 percent).

From the last half of the 1990’s to the 2000-2004 interval, the reduction was 20 percent.

Table I-2. Total Number of Deaths with Silicosis Mentioned on Death

Certificate, (U.S. residents, age 15 and older, all races, both sexes) 1970-

2004.

Years Total number of

Silicosis Deaths

Percent Change

(Reduction)

1970-1974 4,263

1975-1979 2,711 36%

1980-1984 1,958 28%

1985-1989 1,601 22%

1990-1994 1,389 13%

1995-1999 1,018 27%

2000-2004 809 20%

*NORMS database (http://webappa.cdc.gov/ords/norms.html)

NIOSH has also reported silicosis mortality data by state (NIOSH, 2008c) for the years

1996-2005. Although larger numbers of silicosis deaths are concentrated in some states (e.g.,

Pennsylvania, the highest, with 228 over this period), at least one death with silicosis was

reported to have occurred in each of the fifty states, plus the District of Columbia. Table I-3

shows the number of silicosis deaths in each state for U.S. residents age 15 and over, for the

years 1996 to 2005.

Although the number of deaths from silicosis overall has declined since 1968, the number

of silicosis associated deaths reported among persons aged 15 to 44 had not declined

substantially prior to 1995 (CDC 1998). NIOSH reported results from an analysis of the age of

silicosis-related decedents for the years 1968 to 1994, noting that: “(A)mong young persons (i.e.,

aged 15-44 years), deaths from silicosis declined less [than overall].” Young silicosis decedents

resided in 38 states and the District of Columbia; the majority of the deaths (150 (72.5 percent)

of the “young” decedents) were aged 35 to 44 years; 40 (19.3 percent) were aged 25 to 34 years;

and 17 (8.2 percent) were aged 15 to 24 years. For the years 1968 to 2003, 234 of the silicosis

deaths were among persons aged 15 to 44 (NORMS). Of the 59 young silicosis decedents who

died between 1985 and 1994, a total of 25 (42.4 percent) died in a year for which their state of

residence provided decedents' employment information to NCHS. Construction and

manufacturing were coded most frequently as the usual industry (28.0 percent each); no deaths

were attributed to mining (CDC, 1998). It is plausible that the deaths of some of these young

workers were due to acute silicosis, but data is not available to distinguish between acute and

chronic silicosis cases.

One measure of the impact of silicosis-related mortality is the number of years of

potential life lost (YPLL), which is calculated both to life expectancy and to age 65. While

YPLL to life expectancy represents a loss of years from the overall life span, YPLL to age 65

may be considered a loss of years from a working life (NIOSH, 2003). Between 1996 and 2005,
36

Table I-3. Number of silicosis deaths by state, U.S. residents age 15 and FDMS Docket Manager/Agency Administrator

Trainingover, 1996-2005.
37

a total of 1,746 deaths resulted in a total of 20,235 YPLL, with an average of 11.6 YPLL to life

expectancy due to silicosis mortality among U.S. workers. For the same period, among 307

decedents who died before age 65, there were 3,045 YPPL to age 65, with an average of 9.9

YPPL to age 65 (NIOSH, 2007).

Another statistical measure of mortality reported in the WoRLD Report (NIOSH, 2008c)

is the proportionate mortality ratio (PMR). The PMR is defined as the observed number of

deaths due to the condition of interest within a specified industry/occupation, divided by an

expected number of deaths calculated as the total number of deaths in the specified industry or

occupation multiplied by the proportion of all deaths across all industries or occupations that

were caused by the condition of interest. Though the PMR does not reflect the risk of dying

from or with silicosis, it is useful in indicating the relative importance of silicosis compared to

other causes of death among workers in an industry sector (Lilienfeld and Lilienfeld, 1980). A

PMR greater than 1.0 indicates that there were more deaths associated with the condition in a

specified occupation or industry than would be expected under an assumption that the causespecific mortality rate in the industry is the same as across all industry sectors (NIOSH,

NORMS).

PMRs by usual industry for 1990-1999 indicate that workers in industries known and

expected to have high silica exposures were more likely to die from silicosis than would be

predicted based on the occurrence of silicosis mortaltity across all industries combined.

Historically, these industries have included metal mining (PMR = 41.70), miscellaneous

nonmetal mineral and stone products (PMR = 30.72), pottery and related products (PMR =

29.35), nonmetal mining and quarrying (PMR = 29.27), iron and steel foundries (PMR = 21.14),

structural clay products (PMR = 19.72), fabricated metal products (PMR = 5.71), blast furnace

and steelworks (PMR = 3.19), and construction (PMR = 1.26) (NIOSH, 2008c). A PMR of 1.26

for construction indicates that workers in this industry were 26 percent more likely to die from

silicosis than were workers across all industries combined.

For those states (up to 23 at any time) for which industry and occupation codes from

death certificates met NCHS quality criteria for “usual industry” and “usual occupation” during

the 1990-1999 reporting period, Table I-4 shows the number of silicosis deaths reported among

workers in the industries most frequently recorded on death certificates for U.S. residents age 15

and over. For the years 1990-1999 (most recent data available), a total of 118 deaths with

silicosis were reported among construction workers, the largest number of silicosis-related deaths

found for any industry sector (NIOSH, 2008c). This represented 13.4 percent of the 880

silicosis-related deaths identified for which usual industry and occupation were recorded.

Some of the death certificates captured in NORMS include information coded for

occupation. OSHA queried NORMS for the number of silicosis deaths for the ten occupations

most frequently mentioned on death certificates and evaluated the data output. The numbers of

silicosis deaths recorded at the level of detail of the three-digit occupation code are very small

(e.g., the highest number occurs in mining machine operators (138 deaths), next highest is

laborers, except construction (84 deaths), and following that is managers and administrators (34
38

Table I-4. Silicosis: Most frequently recorded industries

on death certificate, U.S. residents age 15 and over, selected

states and years, 1990-1999

CIC Industry

Number

of Deaths Percent

060 Construction 118 13.4

040 Metal mining 86 9.8

041 Coal mining 69 7.8

270 Blast furnaces, steelworks,

rolling and finishing mills

51 5.8

050 Nonmetallic mining and

quarrying, except fuel

48 5.5

271 Iron and steel foundries 48 5.5

262 Miscellaneous nonmetallic

minerals and stone products

44 5.0

392 Not specified manufacturing

industries

33 3.8

331 Machinery, except electrical,

n.e.c.

23 2.6

252 Structural clay products 20 2.3

All other industries 317 36

Industry not reported 23 2.6

Total 880 100

CIC – Census Industry Code n.e.c. – not elsewhere classified

SOURCE: National Center for Health Statistics multiple cause

of death data. NIOSH 2008c, Table 3-6, p. 62

deaths)). All of the other specified occupations listed have 32 or fewer deaths. The occupational

category with the largest number of deaths is “All other occupations,” with 422, almost half of

the total number of deaths. The small number of states reporting industry and occupation codes

from death certificates that met National Center for Health Statistics quality criteria, (e.g., 19

states in 1999), is a major factor in the resulting small numbers of deaths coded for specific

occupations. The small size of the data base limits its utility.

Table I-4 shows that for the years 1990 through 1999, the most frequently recorded

industry on death certificates mentioning silicosis was construction (118 deaths). Linch et al.

(1998) examined OSHA enforcement data for the years 1979-1995, (from OSHA’s Integrated

Management Information System (IMIS)), and found that some of the highest exposures to

respirable crystalline silica in recent years occurred in construction (masonry, heavy

construction, and painting), iron and steel foundries (casting), and in metal services

(sandblasting, grinding, or buffing of metal parts). Exposures were estimated at concentrations

of at least 1, 2, 5, and 10 times the NIOSH Recommended Exposure Limit (REL) of 0.05 mg/m3.

The study found that industries with exposures at least 10 times the REL were: masonry,

stonework, tile setting, and plastering; heavy construction, except highway and street
39

construction; and painting and paper hanging. The industry that was found to have the highest

percentage of workers exposed to at least the NIOSH REL was the cut stone and stone products

industry.

OSHA compiled more recent IMIS data and identified high rates of noncompliance with

OSHA standards, with the non-compliance rate being somewhat higher in construction compared

to general industry. OSHA enforcement data contained in IMIS between 1997 and 2009 (Table

I-5) indicate that 19 percent of silica samples from construction industry and 15 percent for

general industry were at least three times the OSHA permissible exposure level (PEL). For

general industry and construction, about two-thirds of the silica samples contained in IMIS

during inspections in general industry were in compliance with the PEL, while only 58 percent of

the samples collected in construction were in compliance.

Because of the long latency period of chronic silicosis (i.e., the interval between

beginning of exposure to silica and the onset of disease), the deaths that have occurred in the

recent past may be due to exposures that occurred decades ago, so looking at ore current

exposures may predict future trends in silicosis mortality.

Table I-5. Number and Percent of Time-Weighted Average

(TWA) Exposure Respirable Silica Samples for Construction and

General Industry, Compared to the OSHA PEL (OSHA IMIS*

January 1, 1997–December 31, 2009)

Exposure (severity

relative to the PEL)

Construction Other than construction

No. of

samples

Percent No. of

samples

Percent

<1 PEL 972 66% 3,174 67%

1 x PEL to < 2 x PEL 135 9% 576 12%

2 x PEL to < 3 x PEL 80 5% 261 6%

≥ 3 x PEL and

higher(3+)

283 19% 707 15%

Total # of samples 1,470 4,718

*Integrated Management Information System: enforcement database

maintained by OSHA, unpublished data

In summary, the CDC reported a 93 percent decline in mortality associated with silicosis

from 1968 to 2002 (CDC, 2005), and referred to a decline in exposures over that time period as

one likely factor for the dramatic decline in these deaths. The largest percent reduction occurred

in the 1970s, from the first half of the 1970s to the second half. For the years 1995 to 2004, and

for a total of 320 deaths and 2,810 YPPL to age 65, an average of 8.8 YPPL to age 65 was lost

for each silicosis death. Geographically, though deaths with silicosis tend to be concentrated in a

few regions of the country, all fifty states identified at least one silicosis-related death on death

certificates in the 10-year period 1996 to 2005, the last year for which data are available.

Despite the reductions in mortality associated with silicosis, silicosis continues to be identified
40

on death certificates as an underlying or contributing cause of death, with higher mortality seen

in specific industries.

In the states that provide data on the usual industry of decedents, the most frequently

reported industry (1990 to 1999) is construction. OSHA IMIS data for 1992 to 2002 show that

exposures to respirable silica are higher in construction than in industries other than construction

(primarily general industry). As long as exposure to crystalline silica remains high, silicosis

mortality risk is expected to remain higher than average in those industry sectors (e.g.,

construction) and occupations where significant exposures to crystalline silica continue to occur

today.

I.B.2.b. Silicosis morbidity.

With the exception of the NIOSH Coal Workers’ X-Ray Surveillance Program, no

ongoing national surveillance systems exist for occupational respiratory disease morbidity.

Conventional sources of occupational injury and illness data were judged inadequate for

measuring the prevalence of work-related respiratory diseases. For example, the BLS annual

Survey of Occupational Injuries and Illnesses, which relies on employers’ injury and illness logs

for its data, has long been known to under-report incidences of diseases with long latency

periods, such as silicosis, since such diseases are often not recognized or reported by employers.

To improve collection of data on occupational diseases, NIOSH, in association with state

health departments, initiated targeted provider-reporting systems, called SENSOR, (Sentinel

Event Notification System for Occupational Risks) in 1987. These SENSOR systems built on

the experience and capacity that were already present in state health and labor departments

(Baker, 1989).

SENSOR addressed a number of limitations of previously-existing provider-reporting

systems, such as lack of epidemiologic case definitions, lack of formal, defined networks of

sentinel providers with specific responsibility for reporting selected conditions, and lack of

expert guidance. As part of this initiative, NIOSH recommended that each participating state

target a select list of work-related conditions that were significant problems in the state and that

would be appropriate for surveillance under the SENSOR model. NIOSH also developed a list

of work-related conditions of public health importance. Of the initial 10 states participating in

the SENSOR program in 1987, 4 (Michigan, New Jersey, Ohio, and Wisconsin) identified

silicosis as a condition targeted for surveillance. In 1992 these four states were granted

additional five-year cooperative agreements, and three other states (Illinois, North Carolina, and

Texas) were also awarded SENSOR cooperative agreements to establish similar surveillance

systems. During the third SENSOR funding cycle, 1997 to 2002, Ohio and New Jersey were

funded for a third five-year cycle, and Michigan, though not funded, continued to participate and

collaborate. Two of the original silicosis states (Michigan and New Jersey) continue surveillance

for silicosis today. In addition to the SENSOR states, several states funded by NIOSH under

various cooperative agreements to either develop model state-based surveillance systems, called

Expanded Programs, or to develop new state-based surveillance programs, called Fundamental

Programs, chose to focus at least some of their efforts on surveillance for silicosis using the
41

SENSOR model (see http://grants1.nih.gov/grants/guide/rfa-files/RFA-OH-02-007.html.). Both

California and New Mexico were funded during 2002 to 2005 to conduct surveillance for

silicosis.

Summary statistics from these states are compiled and published by NIOSH in electronic

format at eWoRLD (http://www2a.cdc.gov/drds/WorldReportData/) and in the hard copy

WoRLD Surveillance Report (http://www.cdc.gov/niosh/docs/2008-143/pdfs/2008-143a-iv.pdf).

The electronic on-line system and the corresponding WoRLD Report are the most

comprehensive compilation of surveillance data related to indicators of silicosis morbidity in the

U.S. today.

The CDC/NIOSH encourages all states to collect and report silicosis cases and provides

the following reporting guidelines for the purpose of surveillance:

State health departments should encourage physicians, including radiologists and

pathologists, as well as other health-care professionals, to report all diagnosed or

suspected cases of silicosis. These reports should include persons with: a

physician’s provisional or working diagnosis of silicosis, OR a chest radiograph

interpreted as consistent with silicosis, OR pathologic findings consistent with

silicosis (CDC, 2006a).

The CDC/NIOSH has established the following silica case definition for surveillance

purposes: “The following criteria were established for the purpose of defining a case of silicosis:

history of occupational exposure to airborne silica dust and either or both of the following: a

chest radiograph or other imaging technique interpreted as consistent with silicosis; pathologic

findings characteristic of silicosis.”

The CDC/NIOSH provides supplemental information, informing the reader that silicosis

cases can be classified as nodular or acute. Chest radiographs or other images are interpreted as

consistent with nodular silicosis if they have small opacity profusion categories of 1/0 or greater,

as classified by a NIOSH-certified “B” reader under the ILO system. (The ILO classification

system and the NIOSH “B” reader program are described above.) If the largest opacity is >1 cm

in diameter, progressive massive fibrosis [PMF] is present. A bilateral alveolar filling pattern is

characteristic of acute silicosis and may be followed by rapid development of bilateral small or

large opacities.

Pathologic findings characteristic of silicosis consist of fibrotic nodules with a concentric

“onion-skinned” arrangement of collagen fibers, central hyalinization, and a cellular peripheral

zone with lightly birefringent particles seen under polarized light. In acute silicosis, microscopic

pathology shows a periodic acid-Schiff positive alveolar exudate (alveolar lipoproteinosis) and a

cellular infiltrate in the alveolar walls.

For the reporting period 1993-2002, the last year for which data are available, three states

(Michigan, New Jersey and Ohio) recorded 879 cases of silicosis. Hospital discharge records

represent the primary ascertainment sources for all three states (see Table I-6). It should be noted
42

that hospital discharge records most likely include cases of acute silicosis or advanced chronic

silicosis. It is unlikely that, in cases with radiographic diagnoses of ILO category 1/0, there

would be a need for hospitalization. Ascertainment sources for case identification have remained

relatively constant over the years, with hospital reports being the primary source, followed by

physician reports, and death certificates (NIOSH 1999, 2008c). Another source of data is

workers' compensation case data. Demographic, work history, and medical information used for

case confirmation and description were obtained through a combination of the initial case

ascertainment source, a review of medical records, and follow-up telephone interview with the

reported cases or their surviving next-of-kin.

Table I-6. Silicosis: Number of cases by ascertainment source and state, 1993-2002

Source

Michigan New Jersey Ohio Total

No. % No. % No. % No. %

Health care

professional report

108 23.2 2 1.5 13 4.7 123 14.0

Hospital discharge

data

312 67.1 127 94.1 234 83.9 673 76.6

Death certificate

data

10 2.2 2 1.5 9 3.2 21 2.4

Workers’

compensation files

35 7.5 - - 19 6.8 54 6.1

Other - - 4 3.0 4 1.4 8 1.0

TOTAL 465 100 135 100 279 100 879 100

Source: NIOSH, 2008c

Confirmation of a silicosis case would depend upon a record of a chest x-ray or

pathology findings consistent with silicosis and evidence that the worker was exposed to silica.

If no evidence of occupational exposure to silica is found in the existing records, either the

patient or surviving family member can be interviewed to obtain an occupational history.

In addition to its WoRLD Reports, the CDC publishes periodic updates of silicosis

surveillance, including trends and case clusters in its Morbidity and Mortality Weekly Reports.

MMWRs are widely distributed and read by public health practitioners. Cases of silicosis are

reported to CDC by state health departments and can be compiled by the CDC across a number

of states for a specific reporting period (either a single year or a number of years and by year of

case ascertainment or case confirmation) for publication. For example, one publication, CDC,

1997a, reported 256 cases of silicosis that were ascertained (those reported and those confirmed)

between January 1 and December 31, 1993 in seven states. Another, CDC, 1993, reported on

430 cases of silicosis reported by four states (249 cases for Michigan, 89 for New Jersey, 42 for
43

Ohio, and 50 for Wisconsin) for the years 1987 to 1990. Clusters of cases published are

typically observed in the same occupation and/or with similar exposures. Clusters of cases of

silicosis have been reported to CDC by state health departments and published in the MMWR for

sandblasters (Texas) (CDC, 1990), workers involved in abrasive blasting (Ohio) (CDC, 1997b)

and dental laboratory technicians (five states) (CDC, 2004).

Another indicator of morbidity associated with silicosis is the number of persons who

were hospitalized because of silicosis or who had silicosis when hospitalized for other reasons.

The WoRLD Report (NIOSH, 2008c) presents estimated numbers of hospital discharges that

have been abstracted from National Hospital Discharge Survey (NHDS) reports published by the

National Center for Health Statistics (NCHS) (see Table I-7). The NHDS, conducted annually by

NCHS, collects data on the use of short-stay non- Federal hospitals in the United States. In

recent years, data have been abstracted from approximately 270,000 records from about 500

hospitals (NIOSH, 2008c). One limitation of NHDS data is that they represent number of

discharges, not the number of patients (NIOSH, 2008c). Some workers are hospitalized more

than once for pneumoconiosis, and these secondary hospitalizations cannot be excluded (CSTE,

2005). In addition, the NCHS information is available only nationally and by region, but not by

state. Furthermore, the NHDS relies on the completeness of hospital medical records, and

findings can be influenced by diagnostic practices (NIOSH, 2008c).

The Council of State and Territorial Epidemiologists (CSTE), in collaboration with

NIOSH, has published state-level statistics on pneumoconiosis hospitalizations. CSTE’s

statistics also rely on data from the National Hospital Discharge Survey (NHDS) (CSTE, 2005).

Table I-8 shows the number of hospital discharges of persons with silicosis and other or

unspecified pneumoconiosis for thirteen states for the year 2000. The total number of hospital

discharges for the U.S. is estimated by the NCHS from the NHDS.

State-based hospital discharge data is a useful population-based surveillance data source

for quantifying the prevalence of pneumoconiosis, including silicosis, even though only a small

proportion of individuals with pneumoconiosis may be hospitalized for that condition in any

given year. These data show that in the year 2000, 1,128 silicosis-related hospitalizations

occurred indicating that silicosis continues to be a significant health issue and impacts our health

care delivery system in the U.S. Additionally, some of the 952 hospitalizations reported to occur

with “other or unspecified pneumoconiosis” may have been due to silicosis (CSTE, 2005).
44

Table I-7. Estimated number of silicosis-related discharges from short-stay non-federal

hospitals

Source: NIOSH (2008c)
45

Table I-8. Number of Hospitalizations from or with Silicosis and Other/Unspecified Pneumoconiosis, by State

and U.S., 2000

CA CT MA ME MI NC NE NJ NM NY OR WA WI US

Silicosis 67 21 25 6 106 64 <5 47 15 117 18 19 54 1,128

Other and

unspecified

pneumoconio

sis 53 5 18 <5 17 63 <5 22 <10 45 <5 6 <5 952

Data Sources: Number of hospitalizations per state: State hospital discharge data. Estimated

Number of hospitalizations in the U.S.: National Hospital Discharge. Survey Population Statistics

used to calculate rates: Census Bureau Year 2000 U.S. Standard Population.

Source: CSTE, 2005

I.B.2.c. Underreporting of surveillance data.

In this section, OSHA reviews studies that attempt to estimate the degree of silicosisrelated morbidity and mortality after accounting for underreporting. In the absence of active

surveillance systems for silicosis, passive surveillance, which depends upon the health care

community to generate records is likely to underestimate cases of silicosis in the U.S. (Froines et

al., 1989). In clinical settings, occupational diseases, including silicosis, are generally underrecognized and underreported. Physicians play the main role in case-based disease surveillance

by virtue of their unique role in recognizing and diagnosing diseases, but most primary care

physicians do not take occupational histories (Goldman and Peters, 1981; Rutstein et al., 1983).

In addition to the lack of information about exposure histories, difficulty in recognizing

occupational illnesses that have long latency periods, like silicosis, contributes to underrecognition and underreporting by health care providers. Recognizing a history of occupational

exposure to dust containing respirable silica is critical in the identification and reporting of cases

of silicosis. Furthermore, as described above, state-based silicosis surveillance programs rely

heavily on hospital discharge data, which will not capture cases where there are early

radiographic signs of silicosis (i.e., an x-ray classified as ILO 1/0) absent symptoms that would

otherwise trigger a hospital visit.

Identifying silicosis as a cause of death requires that the physician has a readable chest xray or appropriate tissue specimen and then recognizes x-ray changes or pathology evidence as

being consistent with silicosis. Because of the limitations discussed above, physicians often miss

silicosis as a cause of death, resulting in misclassification and underreporting. Furthermore, if

the silicosis is recognized at death, and the decedent resides in one of the states that codes usual

industry and occupation on the death certificate, the state of residence at death may not be the

state in which decedents' exposures occurred, also resulting in a misclassification error. Inability

to verify the coding of usual industry and occupation is another potential limitation of the use of

death certificates. Codes for usual industry and occupation are available only for up to 26 states
46

for the period 1985 to 1999; thus, these data might not be nationally representative. If usual

industry and occupation are not recorded, no exposure information is listed on death certificates;

therefore, no silica exposure-response relationship can be evaluated.

OSHA identified only one study that attempted to evaluate underreporting of silicosis

mortality. Goodwin et al. (2003) estimated, through radiological confirmation, the prevalence of

unrecognized silicosis in a group of decedents presumed to be occupationally exposed to silica,

but whose causes of death were identified as respiratory diseases other than silicosis. In order to

asses whether silicosis had been overlooked and under-diagnosed by physicians, the authors

looked at x-rays of decedents whose underlying cause of death was listed as tuberculosis, cor

pulmonale, chronic bronchitis, emphysema, or chronic airway obstruction, and whose usual

industry was listed as mining, construction, plastics, soaps, glass, cement, concrete, structural

clay, pottery, miscellaneous mineral/stone, blast furnaces, foundries, primary metals, or

shipbuilding and repair.

Any decedent found to have evidence of silicosis with a profusion score of 1/0 was

considered to be a missed diagnosis. Of the 177 individuals who met study criteria, radiographic

evidence of silicosis was found in 15 (8.5%). The authors concluded that silicosis goes

undetected even when the state administers a case-based surveillance system.1 The strength of

this study is its use of existing data from death certificates, hospital records including chest xrays, and the state silicosis registry to estimate the extent of undetected silicosis in one state.

OSHA identified two published papers that estimated the extent of previously undetected

silicosis morbidity. The first of these, Windau et al. (1991), reported on the effort of four states

(California, New Jersey, New York and Wisconsin) to collect hospital discharge data (from

short-term, acute, non-federal hospitals) and compared the ability of hospital discharge records to

identify cases of occupational lung diseases (including silicosis) with the BLS employer-based

system. The second study, Rosenman et al. (2003), used data from death certificates and the

Michigan-based silicosis surveillance system, along with capture-recapture analysis to derive

national estimates of newly-recognized cases of silicosis in the U.S.

Windau et al. (1991) identified seven ICD-9 codes for diseases widely recognized to be

work-related, including silicosis (“pneumoconiosis due to silica or other silicates”) and

“pneumoconiosis due to other organic dust.” They then searched hospital discharge records,

noting those codes on either primary or secondary diagnosis fields, indicating the presence of the

condition at the time of hospitalization (secondary field), even though it may not have been the

primary reason for the hospitalization (primary field). For pneumoconiosis due to silica or

silicates, the number of cases reported by state appears in Table I-9.

1 This study used data collected from hospitals in New Jersey, which administers a case-based surveillance system.
47

In Wisconsin, silicosis was the most prevalent of the seven occupational lung diseases

reported. Data from New York specified the fields where the diagnoses of interest were

captured. Of the 122 hospitalizations with “pneumoconiosis due to silica or other silicates”

listed as a diagnosis, only 20 of these listed silicosis as the primary diagnosis; the others listed

silicosis in the secondary field, indicating the presence of the condition at the time of

hospitalization, even though it was not the primary reason for the hospitalization.

By comparison, almost half (99/200) of the hospitalizations with extrinsic allergic

alveolitis and respiratory conditions due to chemical fumes and vapors were captured in the

primary diagnosis field. The reasons for the difference in the categorization of these two

occupational conditions as they are listed in hospital discharge records are probably related to the

longer latency and more chronic nature of silicosis. In addition to the long latency of silicosis,

this is consistent with death associated with silicosis often being due to cor pulmonale or

obstructive lung disease and other late-stage complications of silicosis progression, which would

be listed in the “immediate” or primary cause of death field, with silicosis coded in secondary

fields.

The authors compared the hospital discharge data from the states to data from the two

BLS data-collection systems that gather information on occupational injuries and illnesses (the

Annual Survey of Occupational Injuries and Illnesses and the Supplementary Data System

(SDS)). The Annual Survey is a sample survey of about 280,000 private sector establishments

nationwide. Sampled employers are required to report all new occupational illnesses and

qualifying occupational injuries for the survey year. States participating in the SDS provide

injury and illness information from state workers’ compensation reports, which reflect cases that

result in death or disability.

For the purpose of comparing the Windau et al. (1991) data with the BLS data, the

Windau data for only one year (1985) are being considered here, since the Windau data report

results for different states for different years, and data from both systems are reported only for

1985. More silicosis cases were captured from the hospital discharge data from two states

reporting in 1985 (204 cases) than were identified from the SDS data for 23 states (128 cases).

The 1985 BLS survey data did not report silicosis cases but did report a total of 1,700 cases of

pneumoconiosis. By comparison, the total number of cases of pneumoconiosis reported in the

Table I-9. No. of Cases of Silicosis Identified Through Hospital

Discharge Records (Windau et al., 1991)

States Years

1980-83 1984 1985

Wisconsin 96

California 132

New Jersey 77 82

New York 122

Total 96 209 204

Source: adapted from Table 3, Windau et al., 1991
48

SDS system in 1985 was 1,191 (for 23 states). However, hospital discharge data from 4 states

reported 2,910 cases (data are for California, 1984; New Jersey, 1985; New York, 1985; and

Wisconsin, 1980-1983 (averaged for the four years, based on estimates)), or more than twice the

number reported from the SDS system for 23 states, and one-and-a-half times the number of

pneumoconiosis cases estimated from the BLS national survey (Windau et al., 1991).

Hopital discharge data, although more comprehensive than either the BLS or SDS

system, still fail to capture all cases since these data identify only those cases in which the person

has been hospitalized, either for the disease of interest or for another condition. On the other

hand, the data reflect the number of hospitalizations, not individuals with silicosis, and it is

possible that some persons with silicosis are hospitalized more than once during any specific

year. Nevertheless, the findings by Windau et al. (1991) show that the incidence of silicosis

cases, as determined from hospital discharge records, is far greater than what would be suggested

by either the BLS survey or the SDS system.

The only attempt to derive a national estimate of the annual incidence of new cases of

silicosis in the U.S. was published by Rosenman et al. (2003). These researchers used data from

death certificates and the Michigan state-based surveillance system along with capture-recapture

analysis to account for sources of under-reporting. The starting point for the analysis was death

certificates for the years 1987 to 1996, which included 2,787 deaths nationwide where silicosis

was listed as either an underlying or contributing cause of death. Of these, 130 were identified

as having occurred in Michigan (NIOSH, 1999). The number of cases identified from the

Michigan surveillance system where silicosis was indicated on the death certificate was 110.

The authors explained that the difference was “presumed to be secondary to differences between

coding by the National Center for Health Statistics and that done by nosologists at the Michigan

Department of Community Health.” For this analysis, the 110 deaths identified by Michigan

were used.

The next step was to determine how many of the silicosis deaths reported in Michigan

could be confirmed. By applying the diagnostic criteria established for surveillance (i.e., a

history of exposure to silica, and either a chest radiograph interpretation showing rounded

opacities of 1/0 or greater profusion as per the ILO classification system for pneumoconiosis, or

a biopsy report of lung tissue showing fibrosis consistent with silicosis), the authors determined

that 85 (or 77.27 percent) of the deaths could be confirmed as silicosis cases. Applying this

proportion to the 2,787 silicosis-related deaths in the U.S., the authors estimated that there would

be 2,154 confirmed silicosis deaths in the U.S. between 1987 and 1996.

The authors then identified living individuals in Michigan with silicosis from one of the

non-death-certificate sources (i.e. hospitals, physicians’ reports, and workers’ compensation)

over the same time period. Cases for which there was a death certificate between 1987 and 1996

and that identified silicosis as a cause of death were excluded to avoid double-counting of cases.

The presence of silicosis in these living cases was confirmed using the same criteria that were

applied to the deceased cases. In all, 547 confirmed cases were identified. Based on the

confirmed silicosis cases from Michigan, the ratio of living to deceased cases was calculated

(547 divided by 85 = 6.4), and applied to the estimated national number of confirmed silicosis
49

deaths (2,154) to yield a national estimate of 13,872 silicosis cases believed to have occurred

between 1987 and 1996, or an average of 1,387 per year. According to the authors, this is the

estimated number of living silicosis cases that would have been reported if there had been a

nationwide surveillance system for silicosis similar to that administered by Michigan.

The investigators used the Michigan surveillance data in a capture-recapture analysis to

account for cases that were likely missed by the surveillance program and to derive an overall

estimate of the annual number of new silicosis cases that occur in the U.S. This analysis

assumes that all silicosis cases have an equal chance of being detected by any one of the data

sources used in the surveillance program (i.e., hospital discharge reports, physicians’ reports, or

workers’ compensation claims). Log-linear regression models were used to control for several

possible interactions between the three data sources, and a range in the estimate of the total

number of new cases in Michigan was derived from the models judged to be the best fit for the

data according to criteria based on the likelihood ratio statistic.

From this analysis, the investigators estimated the total number of living silicosis cases in

Michigan to range from 1,339 to 2,800, or between 2.45 and 5.12 times the actual number of

cases identified from surveillance activities. Assuming that the extent of underreporting is the

same nationwide, the authors estimated that between 33,986 and 71,025 (2.45 or 5.12 times

13,872) silicosis cases occurred in the U.S. for the years 1987-1996, or approximately 3,600-

7,300 new cases per year. The analysis conducted by Rosenman et al. suggests that silicosis

morbidity statistics arising from state-based surveillance programs are under-reported by at least

a factor of 2.5 and possibly by as high a factor as 5. In their study, Rosenman et al. (2003) cite

an abstract by Geidenberger and Socie (1997), who also used capture-recapture analysis with

Ohio data and estimated that the number of actual cases was 3.03-3.18 times the number

identified, which is in close agreement to the Rosenman et al. (2003) study.

Surveillance systems for silicosis mortality and morbidity in the U.S. have been

reviewed. There is no comprehensive, reliable surveillance system for silicosis in the U.S. (i.e.,

there is no a system that captures either all deaths associated with silicosis or all new cases of

silicosis). Mortality data coded for silicosis have been collected by the National Center for

Health Statistics, and are made available in an electronic format by NIOSH in its NORMS

database. Silicosis mortality is reported to have declined dramatically since the 1970s, although

deaths either from or with silicosis still occur today.

Though existing systems are passive and incomplete, cases of silicosis continue to be

reported, where surveillance systems exist. State-based silicosis surveillance systems have

provided more detailed information on a limited number of cases. Both silicosis mortality and

morbidity statistics derived from surveillance efforts likely under-report the true extent of

disease. The one published analysis (Rosenman et al., 2003) of silicosis morbidity and mortality

that accounted for under-reporting estimated that 3,600-7,300 new cases of silicosis occur each

year (based on 1989 to 1998 data) in the U.S. This estimate is about 2.5 to 5 times higher than

the actual number of silicosis cases identified from state-based surveillance efforts.

I.B.3. Progression of Silicosis and Its Associated Impairment.
50

The scientific literature describing the relationships between exposure to crystalline silica

and silicosis is vast and has been reviewed in textbooks and by many authors of scientific review

papers (Davis, 1996; Becklake, 1994; NIOSH, 2002). That exposure to crystalline silica is the

only known cause of silicosis, and that silicosis is with rare exception exclusively an

occupational disease, is without dispute. However, there continues to be much scientific

discussion concerning the relationship between magnitude of exposure and silicosis risk, of the

clinical significance of early radiological signs of silicosis, and the potential for exposure to

increase the risk of pulmonary function decrements associated with the development of chronic

obstructive lung disease (COPD). In reviewing the literature on crystalline silica, silicosis, and

other non-malignant respiratory effects, OSHA identified four principal areas of emphasis

necessary to inform the Agency’s development of an effective revised standard for crystalline

silica. These are:

 The factors that affect the progression of silicosis to more advanced stages and the

clinical significance of disease progression;

 The relationship between pulmonary function decrements and early radiological signs

of silicosis;

 The evidence describing the relationships between exposure to crystalline silica and

pulmonary function decrements and/or development of COPD where radiological

signs of silicosis are largely absent; and

 The quantitative relationship between exposure to crystalline silica and silicosis risk.

The first two areas are discussed immediately below. The literature describing development

of COPD and pulmonary function decrements that are not generally associated with the presence

of radiological findings of silicosis is discussed below in section I.D., Other Non-Malignant

Respiratory Diseases. Finally, several epidemiological studies conducted in several industry

sectors have found positive relationships between cumulative exposure to respirable crystalline

silica and silicosis; many of these studies described quantitative exposure-response relationships

for silicosis morbidity and mortality, as well as for COPD mortality. These are summarized and

discussed in Section II, OSHA’s Preliminary Quantitative Risk Assessment.

I.B.3.a. Factors influencing radiological progression of silicosis.

Numerous epidemiological studies have demonstrated, and it is widely accepted, that

exposure to respirable crystalline silica of sufficient intensity and duration elevates the risk for

developing silicosis. Researchers have made numerous attempts to quantitatively relate the risk

of silicosis to silica exposure, and OSHA discusses the studies that provide quantitative estimates

of the risk of developing silicosis in Section II, Preliminary Quantitative Risk Assessment. This

current section will evaluate the published literature that informs us about the progression of

silicosis, i.e., the factors that affect the progression of silicosis once it has been established.
51

As seen on chest x-ray films, progression is typically described as an increase in

profusion, often but not always according to the ILO scale, although it can also refer to an

increase in the size of opacities. Progression of silicosis has also been described in terms of

increasing functional impairment. In this section, OSHA presents an evaluation of studies that

have examined the relationship between exposure to crystalline silica and progression of silicosis

as determined by radiography, pulmonary function studies, or both. Specifically, this section

reviews scientific literature relevant to the question of which factors influence disease

progression and how radiologic progression relates to progression of functional impairment.

Two broad types of epidemiological studies are reviewed in this section. These include

studies that describe the prevalence of a particular end point in an exposed population at a single

point in time (cross-sectional) and studies that have followed an exposed population forward

over time (prospective). Some cross-sectional studies also employed a “follow-back” feature to

obtain information on how silicosis developed over time in an exposed cohort. Prospective

studies that follow the exposed cohort over a long period of time with periodic examinations can

provide the best information on factors affecting the development and progression of silicosis,

which has a latency period from 10 to 30 years after first exposure (Weissman and Wagner,

2005). Studies that follow the cohort after retirement or other event signifying the end of silica

exposure can inform us of what happens with regard to disease progression in the absence of

further silica exposure. Because silica is a “progressive” disease, all cases seen in a higher

category of profusion (e.g., ILO category 3) have “progressed” from the previous category

(category 2). It is also the case that each worker identified with advanced silicosis was

considered to have acquired simple silicosis at an earlier point in time.

Hughes et al. (1982) studied sandblasters with silicosis in a longitudinal study that

included chest x-rays and pulmonary function studies. Estimates of respirable silica

concentrations were assigned to each job held by a worker, then combined with job histories to

produce estimates of total cumulative silica exposure and average silica dust concentration for

each person, though cumulative exposures were not presented in the published paper.

Employment in blasting ranged from 1 to 32 years, with a mean of 11.3 years. Estimated

average respirable silica concentrations ranged from a low of 0.25 mg/m3(for five participants

who had been exclusively bystanders) to 10 mg/m3, with a geometric mean of 1.98 mg/m3. Ten

persons were exposed to mean concentrations of 1.25 mg/m3or less respirable silica, 40 were

exposed to concentrations of respirable silica between 1.25 and 3.0 mg/m3, and 10 were exposed

to mean concentration of more than three mg/m3respirable silica. Eleven participants had died

since entering the study and eight death certificates were located. For seven, respiratory failure

(or equivalent) was listed as a primary or contributing cause of death, while only three specified

silicosis as a cause of death. Sixty-one of the 83 original participants returned for at least one

follow-up visit. Follow-up ranged from one to seven years.

Criteria for inclusion (and thus for the definition of silicosis) in this study were a majority

reading (by three readers) of small opacities of 1/1 or greater, involvement of both lungs, and a

history of exposure in sandblasting operations. Agreement among the three readers was good:

for final stages of disease (simple or complicated), the three readers completely agreed for 81
52

percent of the cases. For evidence of progression, there was complete agreement for 70 percent

of those with serial films. Length of follow-up was five to 32 years, with a mean of 13 years.

Of the 60 persons with serial chest x-rays available, 38 (63 percent) were judged to have

x-ray evidence of disease progression between initial and latest films. In general, the longer the

time between serial films, the more likely it was that progression had occurred. Those with

larger opacities and/or certain indicators of complication on the ILO scale on initial x-ray had a

higher probability of progression than those with only small opacities. Seventy-two percent of

those with complicated silicosis and 52 percent of those with simple silicosis exhibited evidence

of progression. Of the 10 individuals in the lowest exposure group (< 1.25 mg/m3), 50 percent

(5) progressed; of the 40 persons in the mid-exposure group (1.25-3.0 mg/m3), 59 percent

progressed; and all 10 of those in the highest exposure group (> 3.0 mg/m3) progressed. Though

the sample sizes are small, this study demonstrates a clear exposure-response relationship

between silica exposure concentration and rate of progression of silicosis.

To determine the importance of multiple explanatory variables on the probability of

radiological progression, step-wise logistic regressions were performed in which the following

variables were considered: length of time between films, cigarette smoking (ever or never),

pack-years of cigarette use, age at initial film, age at initial employment in sandblasting

experience, lag time from initial experience, race, initial stage of disease (by chest x-ray),

duration of sandblasting exposure and average silica dust concentration during exposure. The

probability of x-ray progression was significantly related to the length of time between films,

duration and concentration of exposure, initial disease state, race, and age at initial film. After

adjusting for the other variables, those with complicated silicosis initially had a higher

probability of progressing than those in the simple stage, and blacks had a higher probability than

whites. Similarly, the probability of progression increased with increasing length of time

between films, years of sandblasting employment and average silica dust concentration. Thus,

both components of cumulative exposure, duration and concentration, were related to the

likelihood of progression. The coefficient of age was negative; thus, among men who are

comparable for all other variables, older men had a lower probability of progression than

younger ones.

The exposures of these sandblasters were considerably higher than those found in general

today. Most had ceased working by the late 1960s or early 1970s. Nevertheless, numerous cases

occurred among young men with only a few years of recent sandblasting experience, and the

authors reported that five cases had been exposed only as bystanders. For bystanders, exposure

to respirable silica was estimated to be 0.25 mg/m3, well within the range of that experienced by

other workers today.

Ng et al. (1987a) identified a small group (n = 81) of granite quarry workers in Singapore

with silicosis who had been followed at a pneumoconiosis clinic and were still alive at the time

of their study. Subjects had been diagnosed with silicosis in the 1960s and 1970s. The authors

followed the radiologic progression and changes in lung function and attempted to identify likely

determining factors related to disease progression. This study made use of historical data while,

at the same time, benefited from 10 years of follow-up.
53

The authors used historical particle count measurements made in the 1950s and 1960s,

and results of a gravimetric survey done in 1982 to estimate respirable crystalline silica

exposures. Cumulative lifetime exposure to silica and average quartz concentration were

calculated from estimates of jobs and calendar-year-specific silica concentrations and duration of

exposure in each job. On average, the cumulative respirable quartz exposure was 11.3 mg/m3-

years. The mean length of exposure was 23.4 years, and the mean respirable silica concentration

to which they had been exposed was 0.48 mg/m3.

Of the initial group, 52 were no longer working, 11 quit shortly after the initial exam, and

19 remained working for varying lengths of time. Serial radiographs were available for 73

individuals. Follow-up chest x-rays were done between two and ten years during 1975 to 1985.

None of these workers used respiratory protection prior to 1975. All but 11 were no longer

exposed at the start of the study; these eleven continued to work for 4 more years.

At the start of the study, 53 (73 percent) exhibited radiologically simple silicosis, while

20 (27 percent) had complicated disease. Of the 73 for whom serial radiographs were available,

35 (48 percent) showed radiological evidence of progression over the follow-up period ranged

from 2 to 10 years, mean 7.2 years). From the original radiological state of disease, 24 of 53

men (45 percent) who had simple silicosis and 11 of 20 (55 percent) men who had complicated

disease showed evidence of progression. Those with simple silicosis at the start of the study had

lower cumulative respirable silica exposures (11 mg/m3-years) than those with complicated

silicosis (12.7 mg/m3-years).

In this study, simple silicosis was defined as having only small opacities (rounded or

irregular), and complicated if small opacities were present together with large opacities or one or

more signs of other complications. Complications included tuberculosis, pleural thickening, and

emphysema. These authors defined progression as an increase of two or more ILO subcategories

or one step in the size of opacities between the initial and most recent films, or a change from

small to large opacities.

Stepwise logistic multiple regression was used to examine the relationships between

radiological progression and several possible determining factors, including age at initial

examination, initial radiologic category (simple or complicated), smoking history, interval

between initial and most recent radiograph, age at first exposure, average dust concentration, and

duration of exposure. The authors reported that the probability of radiologic progression was

most strongly determined by the average dust concentration, though it was not a statistically

significant variable in the model. The authors did not include cumulative exposure as a variable

in the regression analysis.

These investigators also found that radiologic progression of silicosis was associated with

reduced pulmonary function; these findings are discussed in Section I.B.4 below. In addition,

the estimated exposures are uncertain due to the need to estimate exposures from particle count

data.
54

Lee et al. (2001)studied what appears to be a similar cohort of granite quarry workers in

Singapore, investigating predictive risk factors for progression by comparing an initial and the

most recent radiographs of 141 granite workers diagnosed with silicosis. Although this study

was reported as covering a longer period of time (17 years) than that of Ng et al. (1987a), with

the period of follow-up varying from 2 to 17 years, the reported mean length of follow-up (7.5

years) was the same as in the earlier study.

Silicosis has been a legally notifiable occupational disease since 1970 in Singapore, and

annual chest x-ray films have been required for all granite quarry workers since 1972.

Physicians are required to report suspected cases of silicosis, which are then confirmed on the

basis of chest radiographs of ILO profusion grade of at least 1/1, a definite history of

occupational exposure to silica, and exclusion of other causes of radiological opacities. Once

identified, cases are followed up every 3 years with a chest film and a questionnaire. Of the 260

cases of silicosis identified, 141 who had available serial chest x-ray films of acceptable quality

were selected for study.

Progression was defined as an increase of two or more steps (sub-categories) in the ILO

12-point scale of radiological profusion of small opacities or a one step in the size of small or

large opacities or the development of large opacities not previously present. Agreement between

at least two of the three readers was required.

All study participants had worked in granite quarries where exposure to silica was

considered high. The study reported that historical measurements of dust in granite quarries in

Singapore taken from 1973 to 1987 found exposure to total dust ranged from 0.83 to 3.07 mg/m3

with a mean exposure duration of 27.3 (4-50) years; however, duration of exposure was the only

exposure variable included in the regression model.

Logistic multiple regression was used to examine the relationship between radiological

progression and several possible predictive factors, including age at initial chest radiography,

initial radiological category, smoking history, interval between initial and most recent chest

radiograph, duration of exposure to silica dust, history of pulmonary tuberculosis, and the

duration (or length of time) since exposure ended at the time of the most recent chest radiograph.

Overall, 52 (37 percent) of this cohort showed evidence of progression. From the initial

state of the disease, 24 (31.6 percent) of those with radiological profusion category 1, 15 (37.5

percent) with category 2 and 13 (52 percent) of those classified with complicated silicosis

(including all 7 with category 3) showed evidence of radiological progression during the followup period.

Among those with simple silicosis, 36 (31 percent) had an increase in profusion of small

opacities, 18 (15.5 percent) had an increase in size of small opacities, and 19 (16.4 percent) had

developed large opacities. Nine (22.5 percent) diagnosed with category 2 who had simple

silicosis and 10 (13.2 percent) with category 1 simple silicosis developed large opacities.

Among those with complicated silicosis, 11 (44 percent) had an increase in size of large

opacities, and 5 (20 percent) had an increase in profusion of small opacities, and 5 (20 percent)
55

had an increase in size of small opacities. Multiple logistic regression analysis of risk factors

showed that the probability of radiologic progression was statistically significantly determined

by the presence of large opacities in the initial chest x-ray film (p = 0.01) and the interval

between the two chest radiographs (p = 0.001).

Due to the longer period of follow-up, the authors were able to estimate a 20-percent

increase in odds of progression (by one sub-category of profusion) for every year of follow-up;

however, there was some evidence that radiological progression might slow over longer periods

following the end of exposure. Although the results were of borderline statistical significance,

for those for whom exposure to silica had ceased, there was a 7-percent reduced likelihood of

progression for every year following termination of exposure to silica up to the time of the most

recent chest x-ray. Also of borderline statistical significance, there was an increased likelihood

of silicosis progression when TB was present.

Ogawa et al. (2003) also studied a population whose exposure to silica had ceased. They

reported on two groups of whetstone cutters (200 and 75 men) followed up to 40 years and 15

years, respectively, after cessation of exposure. The smaller group of men were recipients of

disability compensation. Of these, 68 were followed until the end of the study. Although no

exposure data were available for this population, the authors reported that the whetstone cut by

this cohort was approximately 50 percent quartz. Assuming that silicosis prevalence in the

cohort was 42 and 65 percent after 15 and 25 years of service (by averaging prevalences from

duration ranges), respectively, and applying these figures to an exposure-response curve from

data presented by other authors on a different population, exposure concentrations of silica dust

were estimated by Ogawa et al. (2003) to be approximately 0.53 mg/m3silica for 15 years or

0.40 mg/m3silica for 25 years of exposure. Ogawa et al. (2003) stated that this was equivalent to

about 0.9 mg/m3total dust. Duration of service was the only exposure variable analyzed in the

study.

Between 1952 and 1956, at the first examination, 16 percent of the cohort had

radiographic evidence of silicosis. At the third examination, in 1995, after exposure had ceased,

64 percent had silicosis. For workers whose initial x-ray film was classified as ILO categories 1

through 3, the rate of progression over a 15-year period was 50 percent or more. Longer

duration of service and higher category of chest x-ray at the previous examination were the

factors that were most strongly associated with progression. During this same 40-year period of

follow-up, more than half of the 200 workers died due to various diseases, including 29 cases of

silicosis (which included 9 cases of silicotuberculosis) and 6 cases of lung cancer.

Carneiro et al. (2006) also compared clinical and radiologic outcomes between silicotic

gold miners whose exposure to silica had ceased and those for whom exposure continued after

diagnosis. Among the 83 miners, 44 had continued exposure to silica after being diagnosed with

silicosis. Continuation of silica exposure was associated with advanced silicosis (ILO category

3, OR = 6.42, 95% CI = 1.20-34.27), presence of coalescence and/or large opacities (OR = 3.85,

CI = 1.07-13.93), and TB (OR = 4.61, CI = 1.14-18.71). Because this was a retrospective study,

no information was available about the course of radiological progression, i.e. the initial

classification of cases that were later determined to be advanced.
56

Miller et al. (1998) studied men who had worked at a Scottish colliery (coal mine) during

the 1970s, until it closed in 1981. Unlike other coal miner cohorts, these workers were exposed

to higher-than-usual quartz levels (greater than 10 percent freshly-cut quartz) in one of two

seams that operated for a period of time in the 1970s. This study presented more detailed

quantitative exposure data compared to many other epidemiological studies reviewed in this

section because of a pneumoconiosis field research program that was started in the U.K. in the

early 1950s. The data collection program lasted for over 30 years, was based on regular

examination of the workforce at selected collieries, and included detailed descriptions of the

working environments, including extensive dust sampling and mineral compositional analysis,

and regular recording of how long each man spent working in those environments.

The program at this particular colliery began in 1954 and continued until the colliery

closed in 1981. Respiratory health surveys included chest radiography (performed on-site) and a

questionnaire that included smoking habits and (for the 1990/91 follow-up survey only)

occupational history since leaving the colliery. The study reviewed the data from the six

respiratory health surveys, the first in 1954, and the last in 1978. Additionally, attempts were

made to contact all living members of the colliery cohort. Of 1,032 men not identified as

deceased, 547 received a chest x-ray along with the survey. Methods used to collect data for the

follow-up study survey in 1990/91 were based on the earlier surveys, so that results could be

compared.

For each study participant, the radiograph from the 1990/91 follow-up survey, plus any

radiograph taken in the 1974 or 1978 survey were read. If these were not available, then the film

taken in 1970 was used. Each of the three radiograph readers read and classified the follow-up

radiograph independently, then compared the follow-up with the earlier films. The readers were

allowed to revise the classification of the follow-up radiograph based on viewing the earlier

films. The median classification from the three readers was used for the analysis. All

classifications were according to the ILO system.

Respirable dust concentrations were measured at the colliery from 1954 until its closure

in 1981. Dust samples were analyzed for quartz, and mean and maximum exposure to respirable

quartz was estimated for each individual for each time period between respiratory health surveys.

The authors combined the respirable quartz concentrations with the records of time worked to

estimate individual cumulative exposures. The authors reported that for the time period covering

approximately 1964 to 1980, the mean cumulative exposure to respirable quartz was 3.15 gramhours/m3

(ghm3), and the maximum cumulative exposure was 14.4 ghm3. These exposures are

equivalent to 1.8 mg/m3–years and 8.3 mg/m3–years respectively, assuming 1,740 hours worked

per year over the 15-year time period. These cumulative exposure values correspond to mean

concentrations of respirable quartz of 0.12 mg/m3and 0.55 mg/m3, respectively. However,

between 1971 and 1976, workers experienced unusually high concentrations of respirable quartz

in one of the two coal seams in which the miners worked. For some occupations, quarterly mean

quartz concentrations ranged from 1 to 3 mg/m3, and for a brief period, concentrations exceeded

10 mg/m3for one job. Overall, quarterly mean respirable quartz concentrations exceeded 1

mg/m3 more than 10 percent of the time.
57

Based on the median of the three readers’ results on profusion of small opacities, 203

men (38 percent) showed progression of at least one sub-category on the ILO 12-point scale,

between the time of the surveys conducted in the 1970s to the follow-up in 1990-1991.

Progression of one sub-category was found in 75 cases (14 percent), and of two sub-categories in

55 cases (10 percent). A total of 158 men (29 percent) had profusion scored at least 1/0, and 47

(8.6 percent) at least 2/1 at the follow-up survey. Large opacities were recorded as present by at

least two readers for 14 (2.6 percent) of the men. Profusion of small opacities was strongly

related to exposures experienced in the 1970s, and more strongly for quartz than for the nonquartz fraction of the dust.

Of the 547 workers included in the study, the last chest x-ray taken while still working

was classified in major category 0 for 504 workers; of these, 20 percent had progressed to the 1/0

category within 15 years of follow-up, though this transition is probably more specifically

identified as “onset” of radiological silicosis, rather than progression (Hessel et al., 1988). Table

I-10 shows radiologic progression for those workers whose last working chest x-ray was in the

major category 0. The data presented in the paper do not permit an analysis of the rate of

progression for the remaining 36 workers whose last chest film while working was classified in

the major category 1 or higher. Most progression occurred after exposure ended. The best single

predictor of the risk of small opacities at a profusion of 2/1+ was reported to be concentration of

respirable quartz.

Source: Miller et al., 1998

Yang et al. (2006) examined silicosis progression in a retrospective cohort study of

33,640 Chinese workers exposed to silica in tungsten and tin mines and pottery factories. All

subjects had worked for at least one year from 1972 to 1974 and were followed from the first

year of exposure to 1994. Although no information was given on time period of work or year of

first exposure, information was provided that some silicosis cases were diagnosed prior to 1960.

Exposure information was also not provided. Diagnosis was made based on readings by at least

two of three radiologists according to a Chinese national classification system. The classes

included suspected cases (0+), stage I, II, and III silicosis, corresponding to profusion category

Table I-10. Number and percent of British coal

workers exhibiting chest x-ray abnormalities at

follow-up, where the last x-ray taken while working

was classified 0/0 or 0/1.

Results of follow-up x-ray, 1990-91

ILO category No. of workers (%)

0/0, 0/1 382 (76%)

1/0, 1/1, 1/2 97 (20%)

2/1, 2/2, 2/3 21 (4%)

3/1, 3/2, 3/3 4 (0.8%)

Total 504 (100%) (rounded)
58

0/1, 1, 2, and 3, respectively, of the ILO classification system. Only stages I-III were considered

to be silicosis for the purposes of this study.

It was reported that, at the end of the follow-up period (1994), among the 33,640 dustexposed workers, 24,202 (71.9 percent) of the workers were retired or deceased and 7266 (21.6

percent) were still working. In the cohort, 20,660 (61.4 percent) dust-exposed workers had no

silicosis, 5060 (15.0 percent) were suspected cases, and 7920 (23.5 percent) had silicosis. Of

those with silicosis, 45.3, 42.2, and 12.5 percent had stages I, II, and III, respectively. The mean

latency from the year of first exposure to stage I silicosis was 22.9 years and the fifth percentile

was 8.6 years. Of the cases of stage I silicosis, 52.2 percent were diagnosed after silica exposure

had ceased. The time interval from the ceasing of silica exposure to the time of first diagnosis of

silicosis was 9.1 years and the fifth percentile was 1.8 years.

The time interval of silicosis progression was about 5.1 years from 0+to stage I, 4.1 years

(fifth percentile 1.0 years) from stage I to stage II, and 6.8 years (fifth percentile 1.3 years) from

stage II to stage III. The progression rates for 0+to stage I, stage I to stage II, and stage II to stage

III were 48.7, 48.2, and 18.5 percent, respectively. Median survival time (i.e., the interval from

the year of diagnosis to death) of stage I silicosis in tungsten mines, tin mines, and pottery

factories was 21.2, 26.7, and 18.3 years, respectively. However, the survival time of 25 percent

of stage I silicosis was 28.4 to 32.6 years. For those diagnosed at a later stage, the survival time

was shorter. For example, the survival time for stage III was 6.8 years.

Yang et al. (2006) concluded that, while the disease course for silicosis was relatively

long, it progresses quickly once established. Also, they concluded that it was necessary to

handle the cases of 0+as if they had silicosis, by taking measures such as removing them from

exposure, giving them medical examinations every year, and treating them as silicosis patients,

because of their progression rate (48.7 percent) and their quick progression (5.1 years) to stage I.

Thus, some studies have shown evidence of radiologic progression of silicosis after

exposure to silica has ceased (Miller et al., 1998; Ng et al., 1987a; Yang et al., 2006). Hessel et

al. (1988) were also interested in the question of how continued exposure to silica after onset of

silicosis affected the progression of the disease. The objectives of their study were: 1) to

describe/quantify the progression of silicosis in South African gold miners; 2) to determine the

effect of exposure to silica dust on progression; and 3) to compare the silica dust exposures of

those who developed progressive massive fibrosis (PMF) with those who did not.

In South Africa, the Medical Bureau for Occupational Diseases is responsible for

monitoring the health of miners. This includes conducting pre-employment examinations, as

well as annual, benefit and periodic exams for the purpose of determining eligibility for

compensation due to silicosis. Miners with silicosis receive compensation but can continue to

work in dust.

Historical radiographic records were available for the potential cases from benefit records

and records of periodic medical exams. These records were searched and five films were

selected for each case, one record representing an initial chest x-ray, three taken over specified
59

time periods, and the most recent available film. Cases were identified as those with acceptable

films for which two of three readers agreed that silicosis (at least 1/0) was present during the

period 1967-1971, for a total of 631 subjects. Radiographs were coded on a scale from 1 to 10,

with each subcategory in the ILO classification scheme representing a sequential number (e.g.,

0/0, 0/1, 1/0 represented by 1, 2, and 3 respectively). On average, the men were nearly 67 years

old at the time of their last chest x-ray and had been exposed to mine dust for an average of 31.7

years.

Exposure levels for high, moderate and low-dust occupations were defined as 0.97, 0.48

and 0.24 mg/m3respirable crystalline silica, respectively. Cumulative silica exposures were

calculated as the number of shifts worked at each occupation multiplied by the mean silica dust

exposure experienced in that occupation, expressed in mg/m3-shifts. Exposure estimates were

based on measurements of respirable particle counts and estimated quartz content of bulk

material.

The main focus of this study was to look at the effect of continued silica exposure on

progression of silicosis and compare those who continued to have exposure after onset with those

whose exposure had ceased following onset. Overall, 92.4 percent of the silicotics progressed at

least one category on the author’s scale (or one ILO subcategory). The average annual

progression rate was 0.2 minor ILO categories per year. The average length of follow-up was

14.2 years resulting in an average change over the follow-up period of 2.8 minor categories.

Silicotics exposed to silica after onset of disease were only somewhat more likely to progress

(94.6 percent) than those not exposed after onset (88.3 percent), and this difference was not

statistically significant after controlling for year of birth and age at onset.

The younger silicotics experienced a higher rate of progression than older ones. The

older silicotics began with a higher degree of profusion on their initial or earliest x-ray than did

younger silicotics, and workers in all age groups reached nearly the same level of profusion by

the time the last radiograph was taken. However, it cannot be concluded from these data that the

rate of progression decreases with age or that the rate of progression slows as the disease

progresses, since this observation may also reflect faster-progressing contemporaries of the older

silicotics having left the industry, changes in film technique and quality over time, or the fact that

the date of the last radiograph was not fixed by the investigators but was instead based on the

miner’s willingness to travel to the facility and have the examination. In addition, the authors

speculated that workers experiencing slower progression may have continued to come in for

examinations longer than the workers experiencing more rapid progression for reasons related in

part to progression of the disease.

The authors also found that the rate of progression declined with increasing initial

profusion score. For a person whose x-ray film is scored as major category 3, the ability to

progress is limited. However, the authors found this trend to be evident for workers whose initial

film was classified as having category 2 profusion. The authors noted that the group that started

at category 0 in 1957 progressed at a greater rate than the other groups, 2.4 minor categories

during the 10-year period, compared to an average of 2.0 minor categories for those whose initial

x-ray showed evidence of silicosis.
60

The authors stated that cumulative silica dust exposure showed a positive, significant

association with the rate of progression after controlling for covariates. When cumulative silica

dust exposure prior to and subsequent to onset were separated, it was found that exposure after

onset of silicosis was statistically significantly associated with the rate of progression (p <

0.0001) while exposure prior to onset was not.

The silicotics who developed PMF were similar to those who did not develop PMF for

year of birth, year of first exposure, overall cumulative dust exposure and cumulative dust

exposure up to onset of silicosis. PMF cases experienced earlier onset of silicosis and higher

cumulative exposures after onset compared to non-PMF cases. Cumulative exposure after onset

remained a statistically significant predictor of PMF when age at onset was controlled for (p =

0.015).

To summarize, various investigators identified a number of factors that are associated

with an increased probability of progression. These include: 1) degree of profusion seen on

initial films, with higher degrees of profusion associated with lower rates of progression (Hughes

et al., 1982; Lee et al., 2001); 2) increasing length of time between films (Hughes et al., 1982;

Lee et al., 2001); and 3) race (Hughes et al., 1982). In addition, older men experienced lower

rates of progression than did younger ones (Hessel et al., 1988; Hughes et al., 1982).

Similarly, the probability of progression increased with years of employment in silicaexposed occupations (Hughes et al., 1982; Ogawa et al., 2003) and average silica dust

concentration (Hughes et al., 1982; Miller et al., 1998; Ng et al., 1987a). Studies that included

estimates of cumulative exposure found this exposure variable also was associated with

progression (Hessel et al., 1988; Hughes et al., 1982; Miller et al., 1998; Ng et al., 1987a).

OSHA notes that the mining cohort studied by Miller et al. (1998) was exposed to high episodic

exposures of crystalline silica that periodically exceeded 1 mg/m3, and those high peak exposures

could have contributed to the silicosis progression (Buchanan et al., 2003). (See section II for a

detailed discussion of the cumulative dose as the appropriate exposure metric for silicosis and the

evidence of a dose-rate effect.)

At least three studies (Hessel et al., 1988; Miller et al., 1998; Yang et al., 2006) examined

the extent to which silicosis progressed after cessation of exposure. These studies consistently

found evidence of progression absent continued exposure. Silicotics who continued to be

exposed to silica after onset were only somewhat more likely to progress (94.6 percent

progressed) than those not exposed (88.3 percent progressed) (Hessel et al., 1988).

I.B.3.b. Relationship of progression to pulmonary function impairments.

This section discusses epidemiological literature that examines the relationship between

progressive changes observed on radiographs and corresponding declines in lung-function

parameters. Studies that report results of pulmonary function studies along with chest x-ray

results attempt to correlate functional decrements with radiographic changes, both effects of

exposure to respirable silica. Some of the studies that evaluated pulmonary impairment in
61

individuals with silicosis also attempted to characterize the functional impairment as restrictive,

obstructive, or mixed. Some studies also attempted to distinguish between the impairment

associated with silicosis and that related to chronic obstructive pulmonary disease (COPD),

primarily emphysema.

In a 1992 study, Ng and Chan investigated the effects of simple silicosis on lung

function, noting that “(T)here is no doubt that silica exposure is associated in a dose-related

manner with the radiological responses that denote silicosis, and that silicosis in an advanced

stage denoted by large opacities (massive fibrosis) is associated with significant lung function

impairment, usually of an obstructive and/or restrictive type.” The Ng and Chan (1992) study

subjects were current and past workers in two granite quarries who were members of a cohort

defined when all active workers were first given annual radiologic examinations at the start of a

medical surveillance program in 1967, were employed for at least one year between 1967 and

1985, and were initially without silicosis. All the current (n = 206, 91 percent response) and past

workers (n = 132, representing 61 percent of survivors, or 49 percent of all past workers in the

cohort) with or without silicosis were given a questionnaire interview, chest x-ray, and lung

function test.

Detailed work histories were obtained and used to estimate individual cumulative

exposure to respirable quartz based on quarry- and job-specific measurements of past exposures,

as in an earlier companion paper, Ng et al. (1987a). Cumulative exposure to granite dust was

also estimated. Pulmonary function studies and chest x-rays were performed on all the subjects

according to standard procedures. A case was identified when at least 2 of the 3 readers

classified the film as 1/1 or greater by ILO convention.

The lung function values between groups of subjects with and without radiological

opacities were compared with statistical adjustment for age, height, cigarette-years smoked and

cumulative exposure (log-transformed) using analysis of covariance. “Cigarette-years” is

defined as the number of cigarettes smoked per year multiplied by the number of years the

individual smoked. Multiple linear regression techniques were also used to estimate the

independent effects of cumulative exposure to respirable silica or total dust and radiological

opacities on lung function of the study subjects. A total of 320 subjects were available for study.

Irregular and rounded small opacities with a minimum radiological profusion of 0/1 were present

in 79 (25 percent) and 60 (19 percent) subjects, respectively, and large opacities were present in

10 (3 percent) subjects.

Compared to subjects without radiological opacities (category 0/0), subjects with rounded

opacities (indicative of silicosis) had lower values for FEV1 (p < 0.05) and FVC (p < 0.10).

After adjusting for age, height, cigarette-years, and cumulative silica exposure, the adjusted

values in subjects with category 1 profusion were not statistically significantly different from

those with profusion 0/0. However, these were statistically significantly lower for ILO profusion

categories 2 and 3 of small rounded opacities (p < 0.01). As expected, highly significant

reductions in FEV1, FVC, and FEV1/FVC were noted in subjects with large opacities. These

investigators studied lung function by ILO silicosis category; there was no unexposed control

group in this study, nor did the authors compare the values to population-based predicted values.
62

The category 0 group was exposed to a geometric mean of 0.69 mg/m3/yr (GSD 7.5 mg/m3/yr)

respirable silica. This study also included workers who had resigned or retired.

In multiple regression analyses, in which cumulative respirable silica exposure or

profusion of small opacities were entered separately as explanatory variables, each of these

individual factors were significantly associated with decrements in FEV1 and FVC. The authors

concluded that chronic simple silicosis, except that classified as profusion category 1, is

associated with significant lung function impairment. The authors of this study concluded that

lung function loss in silicotics was attributable to fibrotic disease.

In an earlier paper that was discussed in the progression section, Ng et al. (1987a)

identified a small group (n=81) of granite quarry workers in Singapore with silicosis who had

been followed at a pneumoconiosis clinic and were still alive at the time of the study. The

authors followed the radiologic progression and changes in lung function and attempted to

identify likely determining factors related to disease progression in a group of workers who had

silicosis.

Subjects had been diagnosed with silicosis in the 1960s and 1970s. Follow-up chest xrays and pulmonary function testing was done between two and ten years during 1975 to 1985.

Lung function was reduced in men who had complicated disease. For example, FVC in men

with complicated disease was about 13 percent below predicted values whereas for those with

simple silicosis, FVC was only about 4 percent below predicted values. The mean rate of decline

in FEV in one second and FVC were 79 ml./year and 75 ml./year, respectively, in men who had

simple silicosis and 84 ml./year and 88 ml./year, respectively, in those who had complicated

disease.

In both groups (men with simple silicosis and those with complicated disease), those who

showed radiologic evidence of disease progression had significantly greater rates of decline in

lung function than those who did not show such progression. These differences were highly

statistically significant after adjusting for small differences in baseline ventilatory capacity, age,

and smoking habits. Those showing evidence of disease progression experienced mean rates of

decline in FEV1 and FVC of 97 and 95 ml./year, respectively, compared to 64 and 59 ml./year,

respectively, among those not showing evidence of progression.

Bégin et al. (1988) also found a correlation between decreased lung function (FVC and

the ratio of FEV1/FVC) and increases in profusion of opacities. They studied 94 long-term

(more than 20 years) silica-exposed workers in the granite industry or in foundries in Quebec

using computerized tomography (CT scanning) of the chest, chest x-rays and pulmonary function

testing. Chest radiographs were assessed and categorized using the ILO method; CT scans were

also categorized by degree of severity graded on a 4-point scale of increasing severity that was

derived by the investigators.

The subjects were divided into four subsets based on chest x-ray and CT scan of the

thorax: group 1 consisted of 21 subjects who did not meet the criteria for silicosis (category 0

chest x-ray and CT scan); group 2 consisted of 28 subjects with simple silicosis (category 1 on
63

both chest x-ray and CT scan); group 3 consisted of 18 subjects with simple silicosis (category 1

on chest x-ray, but with coalescence or conglomeration or both seen only on CT scan). Group 4

consisted of 27 workers with complicated silicosis on chest x-ray and CT scan of the thorax.

Lung volumes were significantly reduced, but only in the group exhibiting the highest

degree of profusion (group 4) (p < 0.05). Lung compliance, diffusion capacity, and the restexercise P(A-a)O2 gradient were reduced among workers whose images were graded group 3 or

group 4 (p < 0.05). Expiratory flow rates were significantly reduced for those in groups 2, 3 and

4, with the lowest values among those in group 4. The expiratory flow rates among those in

group 3 were significantly lower than for those in group 2. Therefore, this study demonstrated

increasing impairment with higher imaging categories (3 and 4), as expected, but also

impairment (significantly reduced expiratory flow rates) among persons with more moderate

pulmonary fibrosis (group 2).

Moore et al. (1988) also found chronic silicosis to be associated with significant lung

function loss, especially among workers with chest x-rays classified as ILO profusion categories

2 and 3. For those classified as category 1, lung function was not diminished.

Cowie (1998) compared findings on chest x-rays and pulmonary function studies in 242

gold miners to those obtained 4.5 years earlier. At follow-up, 32 were no longer working

underground. A total of 202 men exhibited silicosis on their follow-up chest radiograph (183 on

the initial chest radiograph): 40 (78 on the initial radiograph) with category 1 profusion; 120 (73)

with category 2; and 42 (32) with category 3 nodule profusion. He found that silicotics

progressed one subcategory on chest x-rays (e.g., from 2/1 to 2/2), and that lung function

declined in excess of what was expected for age, and more rapidly in men with silicosis than

those without. Annual loss of FEV1 was 37 ml. in those without silicosis, 57 ml. in those with

category 1 profusion, 100 ml. in those with category 2, and 128 ml. with category 3 nodule

profusion. These changes remained statistically significant after controlling for age, original

lung function, and smoking habits. A similar pattern was noted for FVC.

This study (Cowie, 1998) examined the progression of silicosis in a short period of time

(4.5 years) in gold miners exposed to silica. In addition to the 24 ml./yr. decrements expected

due to aging, this study found an additional loss of 8 ml. of FEV1 per year would be expected

from continued exposure to dust in the mines. The author reported that the men with silicosis

suffered a loss of FEV1, which exceeded the loss in men without silicosis on entry by 210 ml.

over the follow-up period of 4.5 years. However, no exposure information was presented by the

author, limiting the conclusions that can be drawn from this study.

An earlier cross-sectional study by these authors (Cowie and Mabena, 1991) examined

1,197 black underground gold miners who had silicosis and were still working. Each worker

was assigned to an exposure group (high, medium or low), based on knowledge of occupations,

physical demand of the job, and years underground in the gold mine. No industrial hygiene

measurements were obtained. Of those with silicosis, 50 percent were in ILO category 1, 44

percent in category 2, and 6 percent in category 3. There were only small differences in the dust

exposure, smoking and the years underground by category of silicosis. Silicosis (analyzed as a
64

continuous variable) was associated with reductions in FVC, FEV1, FEV1/FVC, and DLco values,

and these relationships persisted after controlling for duration and intensity of exposure and

smoking. The cross-sectional design of this study did not permit comparisons over time. This

study did not include true controls; the men without silicosis on chest radiograph (category 0)

were also underground miners, with 28 percent in the “high dust” exposure category, 53 percent

in the “medium dust” and 19 percent in the “low dust” category.

Other investigators have reported that exposure to crystalline silica is also associated with

pulmonary function decrements or airflow obstruction absent, or independent of, radiological

evidence of silicosis. Although this may reflect the insensitivity of radiologic tools for detecting

silicosis, such findings are consistent with epidemiological and pathological studies that suggest

that exposure to silica dust is associated with chronic obstructive pulmonary disease (COPD), in

the absence of radiological signs of silicosis. Section V.D reviews the evidence that exposure to

crystalline silica increases the risk of COPD and pulmonary impairment absent radiological signs

of silicosis. The following section briefly discusses several studies that found pulmonary

impairment independent of radiological signs of silicosis in workers exposed to silica.

Several studies have reported finding no correlation between decrements in lung function

parameters and degree of nodular profusion seen on chest x-rays. Hughes et al. (1982) studied a

representative sample of 83 silicotic sandblasters, 61 of whom were followed for one to seven

years. A multiple regression analysis showed that the annual reductions in FVC, FEV1 and DLco

were related to average silica concentrations but not duration of exposure, smoking, stage of

silicosis, or time from initial exposure. This same study (Hughes et al., 1982) also found a high

prevalence of respiratory symptoms in this population on initial interview (88 percent with lower

respiratory symptoms, 26 percent with chronic bronchitis, 88 percent with some level of dyspnea

and reduced pulmonary function on initial testing).

Ng et al. (1987b) studied respiratory symptoms, radiographic changes and lung function

in a cross-sectional survey of 218 male gemstone workers in Hong Kong. Cutters and carvers

were exposed to average respirable quartz concentrations of 60 and 30 μg/m3, respectively.

Workers in grinding/polishing and buffing jobs were exposed to average respirable quartz

concentrations of 100 and 160 μg/m3, respectively. Silica flour with quartz content often

exceeding 90 percent was commonly used as an abrasive. All workers had chest x-rays

classified as either Category 0 or 1 for silicosis. The FEV1 and FVC values were not associated

with radiographic category of silicosis after adjustment for years of employment. The authors

concluded that there was an independent effect of respirable dust exposure on FVC, but silicosis

graded as less than category 2 had no effect on lung function after dust exposure was accounted

for.

In a population of 61 gold miners, Wiles et al. (1992) also found that radiographic

silicosis was not associated with lung function decrements. Sixty-one South African gold miners

with radiographic silicosis were matched with 61 miners without radiographic silicosis for age,

date of beginning work, cumulative dust exposure, and smoking. They were all currently

employed and had attended compulsory medical examinations in 1984-1985. The lung function

of the 20 cases in ILO category 1 was not statistically different from that of the referents, and
65

there were no differences between the referents and those with category 2 or 3 silicosis. Wiles et

al. raised the possibility that, in previous studies, two separate effects of exposure to silica have

been demonstrated; one effect being the exposure-response relationship between cumulative

exposure to respirable silica and silicosis, the other perhaps a dose-response relationship between

cumulative silica dust exposure and reduced lung function due to airflow limitation separate

from silicosis. They also noted, however, that those who were still working and had silicosis

may not have been representative of all those with silicosis.

In a re-analysis and follow-up of an earlier study, Hnizdo (1992) found that silicosis was

not a significant predictor of lung function, except for FEV1 for non-smokers.

Wang et al. (1997) observed that silica-exposed workers (both nonsmokers, and

smokers), even those without radiographic evidence of silicosis, had decreased spirometric

parameters and diffusing capacity (DL ). Pulmonary function was further decreased in the

presence of silicosis, even those with mild to moderate (ILO categories 1 and 2). The authors

concluded that functional abnormalities precede radiographic changes of silicosis.

Workers exposed to silica and who have silicosis and impaired lung function may also

have COPD, primarily emphysema. A number of studies have addressed the question of whether

co-existing emphysema could account for the reduced lung function seen in those with silicosis.

Kinsella et al. (1990) compared lung function and computed tomography (CT) findings in

silicotics (both smokers and non-smokers) to determine whether the presence of emphysema in

silicosis was secondary or independent to the development of progressive massive fibrosis

(PMF). Their data suggested that silicosis, in the absence of PMF, does not cause significant

emphysema, and in the presence of both, it is primarily the degree of emphysema rather than the

degree of silicosis that determines the level of pulmonary function.

The authors concluded that the degree of emphysema was the predominant independent

predictor of pulmonary function impairment, and the degree of silicosis was an independent

predictor only for carbon monoxide diffusing capacity. In order to evaluate the independent

effects of cigarette smoking on individuals with silicosis, the authors also compared lung

function in smokers with silicosis and nonsmokers with silicosis. Among subjects who did not

have evidence of PMF, smokers had worse emphysema than did non-smokers. The authors

stated that this was not surprising since cigarette smoking causes emphysema. In patients with

more severe silicosis (PMF), the degree of emphysema in smokers and non-smokers was not

statistically different. The authors reported that their findings suggest that silicosis did not cause

significant emphysemas in the absence of PMF and that it is primarily the degree of emphysema

rather than silicosis that determined the level of pulmonary function in subjects who showed

evidence of both diseases.

In a follow-up to a previous study (Cowie and Mabena, 1991), Cowie et al. (1993)

studied a sample of gold miners who were found to have abnormal lung function, including

airflow obstruction and reduced diffusing capacity. A sample of 70 men from a cohort of older
66

miners with and without silicosis was examined, using CT, lung function tests and routine chest

radiography, to determine whether emphysema accounted for these abnormalities.

On the basis of the chest x-ray findings, 55 of the men had silicosis. A total of 48 men

had emphysema on examination by CT. Emphysema was present in 5 of the 15 men without

silicosis and in 45 of the 55 with silicosis. Diffuse emphysema was present in 2 men without

silicosis (14 percent) and in 25 men with silicosis (45 percent). The proportion of men with

diffuse emphysema increased from 14 percent in those with ILO category 0 nodule profusion to

46 percent in those with category 1, 48 percent in those with category 2, and 67 percent in those

with category 3. Lung function tests showed changes associated with silicosis that could be

explained by the associated emphysema.

The authors noted that in the 1991 study of the same population of men working

underground in gold mines, a relationship between the presence and degree of simple, chronic

silicosis and airflow limitation was observed. This finding persisted after smoking and duration

of exposure to the underground mine environment were controlled for, both factors having been

associated with airflow limitation.

These authors also commented on the low sensitivity of CT scans for detecting silicosis.

They reported finding an association between silicosis and emphysema but were unable to

determine whether silicosis causes emphysema or whether both are caused by exposure to

crystalline silica or some other factor. However, the authors concluded that in this population,

silicosis, as seen on chest x-ray, served as a marker for emphysema and for lung function

decrements in excess of that found in men from the same working environment who did not have

silicosis.

Bégin et al. (1995) studied the prevalence of emphysema in workers with simple silicosis

and asbestosis and in workers exposed to silica and asbestos, but without the pneumoconioses.

The study population consisted of 207 workers evaluated at the Quebec Workman Compensation

Board and who had a radiographic reading of pneumoconiosis in the category 0 or 1 of the ILO

scale, as well as 5 (total) healthy volunteer control subjects. Emphysema was detected, typed,

and graded on high-resolution CT scans independently by three experienced readers. Age, work

experience and industry, smoking habits, and pulmonary function test results were analyzed for

possible associations. The subjects were 58 to 60 years of age and were exposed to mineral dusts

for 25 to 27 years; 31 were lifetime non-smokers and the others were either former- or current

smokers. Ninety-six workers were from primary and 111 from secondary industries and did not

differ otherwise in any parameter.

The three readers were in agreement regarding the extent of pneumoconiosis and

emphysema seen on CT scan for 68 percent and 63 percent (respectively) of the cases. Among

lifetime non-smokers, emphysema was seen in 1 of 20 subjects without pneumoconiosis but in 8

of 11 patients with pneumoconiosis. In smokers without pneumoconiosis, emphysema was

present in 55 percent of patients with silica exposure, but only in 29 percent of patients with

asbestos exposure (p = 0.04). Regression analyses documented that age, smoking, exposure type,

and presence of pneumoconiosis were significant contributing factors for emphysema. In the
67

workers without pneumoconiosis, age, smoking, and exposure to silica were significant

contributing factors.

Regression and contingency analyses relating emphysema and lung function tests showed

that emphysema related best to reductions in FEV1/FVC ratio, maximal midexpiratory flow

(MMEF), and DCO. Patients with emphysema had decreases in FEV1/FVC ratio (8 percent, p =

0.001) and DCO (8 percent, p = 0.001) that were statistically significant compared with the

patients without emphysema. In subjects exposed to silica without silicosis, this study found no

emphysema in lifetime non-smokers but a 55-percent prevalence of emphysema in smokers.

This higher prevalence of emphysema in smokers with silica exposure but without silicosis was

associated with lung dysfunction. These authors (Bégin et al., 1995) found a statistically

significant excess of emphysema on CT scans, associated with lung dysfunction, in Workers

Compensation Board-referred subjects with category 0 or 1 pneumoconiosis. Prevalence of

emphysema was increased in those with pneumoconiosis and in smokers with silica exposure. In

lifetime non-smokers, emphysema was present only in those individuals with pneumoconiosis.

Simple mineral dust exposure, in the absence of smoking, pneumoconiosis, or both did not

increase the prevalence of emphysema, as did silica exposure. The authors concluded that, in

this population of workers, there was a significant excess of emphysema, associated with lung

dysfunction, in those with silicosis (ILO category 1) and in smokers with silica exposure.

Among nonsmokers exposed to silica, only those with silicosis had emphysema. They

concluded that their data supported the concept of an association of emphysema, silicosis, and

reduced lung function.

Gamble et al. (2004) reviewed the relevant studies on the correlation between

radiographic silicosis and reduced lung function by grouping studies by design (i.e., crosssectional, prospective, case-referent, and case series) and by considering the extent to which the

studies attempted to control for smoking, dust exposure, and emphysema, factors that can

confound the association between silicosis and lung function. The authors concluded that the

data suggested a weak association between lung function (mainly obstruction) and dust exposure,

although some studies reviewed had only crude measures of exposure available. In general, the

lung function of those with radiographic silicosis in ILO category 1 was indistinguishable from

those in category 0. Those in category 2 had small reductions in lung function relative to those

with category 0 and little difference in the prevalence of emphysema. There were slightly

greater decrements in lung function with category 3 and more significant reductions with

progressive massive fibrosis. Emphysema was related to the presence of higher categories of

nodular profusion, as well as to smoking. Gamble et al. (2004) believed that silica exposure was

often inadequately controlled in studies examining silicosis and lung function.

Regarding the role of emphysema in silicosis, Gamble et al. (2004) concluded that there

is little evidence that silicosis is related to development of emphysema in the absence of PMF.

Because silicosis and emphysema were evaluated simultaneously in cross-sectional studies, it

was impossible to discern temporal sequence. These authors pointed to the findings of Kinsella

et al. (1990), who found emphysema in areas of the lung both with and without fibrosis, which

led them to conclude that there is another factor that determines susceptibility to both PMF and

emphysema.
68

Gamble et al. (2004) reviewed studies that adjusted for emphysema in addition to

smoking and dust exposure and concluded that, in studies in which information on both silicosis

and emphysema were available, reduced lung function was more strongly associated with

emphysema than with silicosis.

In conclusion, an association between pulmonary function decrements and ILO category

2 or 3 background profusion of small opacities was reported in several studies and appears to be

consistent with the histopathological view that massive fibrosis is formed by the conglomeration

of individual fibrotic nodules (Ng and Chan, 1992). Emphysema may also play a role in

reducing lung function in workers with higher grades of silicosis. Pulmonary function

decrements have not been reported in some studies among workers with silicosis scored as ILO

category 1. However, a number of other studies have documented declines in pulmonary

function in persons exposed to silica and whose radiograph readings are in the major ILO

category 1 (i.e.1/0, 1/1, 1/2), or even before changes were seen on chest x-ray (Bégin et al., 1988;

Cowie, 1998; Cowie and Mabena, 1991; Ng et al., 1987a; Wang et al., 1997).

The literature reviewed above, most convincingly those studies with longitudinal followup of the cohorts, supports a finding of decreased lung function with progression of radiological

silicosis, independent of emphysema. Also, evidence of functional impairment prior to

radiological evidence of silicosis, and the low sensitivity of radiography, particularly in detecting

early silicosis, supports a finding that exposure to silica impairs lung function in at least some

individuals at an earlier point in time than can be detected on chest radiograph.

I.B.4. Pulmonary Tuberculosis.

As silicosis progresses, it may be complicated by severe mycobacterial infections, the

most common of which is tuberculosis (TB). The most common site for TB infection is the

pulmonary (or respiratory) tract. For the purposes of this section, “TB” refers to pulmonary TB.

In workers exposed to silica, TB occurs most frequently when the macrophages are overwhelmed

by silica dust and are unable to kill the infectious organism Mycobacterium tuberculosis

(NIOSH, 2002). The risk of developing TB infection is higher in silicotics than non-silicotics

(Balmes, 1990; Cowie, 1994; Hnizdo and Murray, 1998; Kleinschmidt and Churchyard, 1997;

and Murray et al., 1996). There also is evidence that exposure to silica increases the risk for

pulmonary tuberculosis, independent of the presence of silicosis (Cowie, 1994; Hnizdo and

Murray, 1998; teWaterNaude et al., 2006).

The association between silicosis and the increased risk of TB has been firmly

established by the results of multiple epidemiologic studies conducted prior to the 1990s

(Balmes, 1990; Murray et al., 1996). Later studies strengthened support and added precision and

detail.

Two studies of South African gold miners who were exposed to silica also included

analyses of TB prevalence. Cowie (1994) found that miners with silicosis had an almost threefold incidence of TB (relative risk for TB 2.8 (95% CI, 1.9 to 4.1)) compared to non-silicotic
69

workers of similar age from similar home and work environments. The incidence of TB

increased with increasing severity of silicosis. The miners without silicosis were also observed

to have a three-fold increase in TB incidence compared to the general population of the same

race. This may have been influenced by silica exposure, however, differences in these

populations, including age, gender, and level of TB surveillance make it difficult to assess.

In the other study of South African miners, which was a retrospective study

(Kleinschmidt and Churchyard, 1997), the incidence rate ratio of TB for miners with silicosis

was compared to miners without silicosis (1.54 (95% CI, 1.00 to 2.37)). For workers in

occupations with high dust exposure, such as drilling, the incidence of TB was twice that of

workers in less dusty jobs, including surface and maintenance workers.

A third study of South African gold miners, a prospective study (Hnizdo and Murray,

1998), was designed to investigate specifically whether silica dust, on its own, without the

presence of silicosis, is associated with an increased risk of TB, and if so, whether the risk is

dose-related. This study also looked at the chronological sequence between the development of

pulmonary TB and silicosis after the end of exposure to silica.

Hnizdo and Murray (1998) followed the cohort of 2255 white South African gold miners

for 24 to 27 years, for the incidence of pulmonary TB. During the follow-up period, 1592 (71%)

died. Of these, 1296 (81%) had a necropsy done to determine the presence of silicosis and

pulmonary TB. The investigators studied the incidence of pulmonary TB in the cohort relative to

cumulative dust exposure and the onset of silicosis. For the whole cohort, the factors associated

with increased pulmonary TB were cumulative exposure to dust (mg/m3.yr) (adjusted rate ratio

1.07; 95% CI, 1.04 to 1.10), silicosis diagnosed radiologically (3.96 (2.59 to 6.06)) and tobacco

pack-years (102 (101 to 103)). The rate ratio (RR) for pulmonary TB increased with increasing

quartiles of cumulative exposure to dust 1.0, 1.51 (0.78 to 2.91), 2.35 (1.28 to 4.32), and 3.22

(1.75 to 5.9). In miners who did not have silicosis, the adjusted RR (for pulmonary TB and

cumulative exposure was 1.10 (95% CI, 1.06 to 1.13), and increased with quartiles of exposure.

The authors concluded that exposure to silica dust is a risk factor for the development of

TB in the absence of silicosis, even after exposure to silica ends. The risk of TB increases with

the prevalence of silicosis, and in miners without radiological silicosis, with quartiles of

exposure to dust. The severity of silicosis diagnosed at necropsy was associated with increasing

risk of TB, even if the silicosis had not been diagnosed radiologically. The diagnosis of TB was

on average 7.6 years after the end of exposure to dust. The onset of radiological silicosis

preceded the diagnosis of TB in 92% of the cases with TB who had silicosis.

Charalambous et al. (2001) conducted a case series study of 15 South African gold

miners exposed to silica who presented with TB. Radiological evidence of tuberculosis

remained in 87 percent and 53 percent at 2 and 6 months after treatment. The authors noted that

it is generally accepted that the response to modern TB regimens is rapid and complete

resolution is achieved in most cases. The authors concluded that the combination of previous

silica exposure and TB appeared to have resulted in a more negative outcome (pronounced

response and potentially incomplete radiological resolution of TB) than exposure to TB alone.
70

Sherson and Lander (1990) studied male foundry workers in Denmark to address the

question of whether workers exposed to silica but without silicosis are at a greater risk for TB

than those with silicosis. They found that workers with silicosis had a 10-fold increase in

prevalence rate of TB as compared to a period and age-standardized population of men in

Denmark. Non-silicotic workers with at least 25 years of employment also had a significant, 3-

fold increased incidence rate. The authors discussed possible factors that might explain this

finding: difficulty in diagnosing early silicosis, lack of smoking histories, and social factors such

as housing status, alcoholism, and diabetes could not be evaluated. Percent of foreign workers

was similar to that of the general population. The authors concluded that their findings, in view

of the considerable evidence from epidemiologic and animal studies, suggested that silica dust

exposure, even in the absence of radiographically apparent silicosis, may be responsible for an

increased TB risk. They opined that it therefore may be reasonable to maintain a tuberculosis

surveillance program for silica-exposed workers in spite of diminishing silicosis prevalences.

A study of small-scale pottery workers in India also examined the associations of silica

exposure, silicosis, and tuberculosis. Saiyed et al. (1995) studied the prevalence of silicosis and

tuberculosis in 292 workers in eight small-scale potteries. The overall prevalence of both

diseases was equal at 15.07 percent. The prevalence of TB increased with severity of silicosis.

The stone grinding and glaze spraying departments, which had higher levels of airborne dusts,

also showed a higher prevalence of silicosis and TB. The packing department, which had the

lowest levels of airborne dust with low free silica content, showed the lowest prevalence of

silicosis and TB.

In the U.S., two studies of silica exposure and TB used occupational mortality data to

conduct a proportionate mortality study of persons with TB by occupation for 1979 through 1990

(CDC, 1997b; Chen et al., 1997). Although the study design did not control for confounding, it

identified six occupational groups with potential exposure to silica that had age-adjusted

proportionate mortality ratios (PMRs) for TB that were statistically significant at the 95%

confidence level or greater than 200. The data are broken out by race. The groups with the

highest PMRs include mixing or blending machine operator (black) (376, 95% CI, 122 to 878);

roofers (white) (290, 95% CI, 106 to 630); mining machine operator (white) (276, 95% CI, 207

to 360); grinding, abrading, buffing or polishing machine operator (white) (265, 95% CI, 107 to

547); brick and stone mason (white) (213, 95% CI, 110 to 371) and (black) (159, 95% CI, 80 to

285).

Chen et al. (1997) conducted a case-control study (8,740 cases; 83,338 controls) with

U.S. National Occupational Mortality Surveillance (NOMS) (a precursor to NORMS) data for

1983-1992. The potential for silica exposure was categorized as “high,” “intermediate,” and

“low or no,” based on data from the National Occupational Exposure Survey (NOES) and the

National Occupational Health Survey of Mining (NOHSM) (NIOSH). This study found that

decedents with high potential for exposure to silica and no documentation of silicosis on the

death certificate had a 30-percent greater odds of mortality from TB than decedents with no

potential exposure to silica after adjustment by logistic regression for age, sex, race,

socioeconomic status, potential exposure to active TB, and the presence of silicosis or other
71

pneumoconioses (OR = 1.3; CI, 1.14 to 1.48). The results also suggest an exposure-response

relationship between silica exposure (in the absence of silicosis) and death from TB.

Findings of a study by Calvert et al. (2003) were consistent with those of previous studies

showing an increased incidence of pulmonary TB among nonsilicotic workers with long-term

crystalline silica exposure. In this study using almost five million death certificates, cases with

underlying and contributory causes of death from TB were compared to matched controls with

other causes of death. The potential for silica exposure was determined by three senior industrial

hygienists who conducted independent assessments. Silica exposure categories were defined as

low/no, medium, high, and super-high. Decedents in the super-high category had a significantly

increased risk for TB. In addition, a significant trend of increasing risk of TB with increasing

silica exposure was observed. Analyses were also conducted in which the disease cases with

concomitant silicosis and their associated controls were excluded. These exclusions made little

difference in the findings. Both the presence of silicosis and exposure to silica have been shown

to increase the risk of tuberculosis.

A study by teWaterNaude et al. (2006) of the prevalence of pulmonary tuberculosis

(PTB) in South African gold miners also found that, even in the absence of silicosis, PTB was

significantly associated with dust and silica exposure. In this study, 520 gold miners were

assessed at one time point for a history of PTB, smoking habits, and past chest illness. Each

miner was given a chest x-ray at that time point. A complete job history was obtained and length

of service and exposure measurements were used to calculate cumulative respirable dust and

quartz exposures for each miner. For non-silicotics, there was significant increasing trend for

prevalence of PTB with increasing quintile of cumulative respirable quartz exposure. Since it

was not a confounder in their data, the authors believed that radiologic silicosis was most likely

just a marker for substantial silica exposure.

Studies on the mechanisms of disease development for silicotuberculosis and diseases

caused by silica were summarized by Ding et al. (2002). In discussing silicotuberculosis the

authors noted that it is well documented that exposure to silica can lead to impaired cellmediated immunity. Reduced numbers of T-cells, increased numbers of B-cells, and alterations

of serum immunoglobulin levels have been observed in workers with silicosis.

According to Ng and Chan (1991), silicosis and TB act synergistically to increase fibrotic

scar tissue (leading to massive fibrosis) or to enhance susceptibility to active mycobacterial

infection. Lung fibrosis is common to both diseases and both diseases decrease the ability of

alveolar macrophages to aid in the clearance of dust or infectious particles.

Pulmonary tuberculosis is a widely known complication of chronic silicosis. There is

ample evidence that exposure to silica, even without the presence of silicosis, increases the risk

for pulmonary TB.

I.B.5. Preliminary Conclusions: Silicosis and Disease Progression.
72

Silicosis is a progressive disease affecting the lungs, in some cases progressing to

complications resulting in disability and death. Progression of fibrosis indicative of silicosis can

be observed using chest radiography and computed tomography, though neither technique will

detect the presence of silica-induced lung fibrosis in all affected individuals, particularly in early

stages. However, both imaging techniques are specific enough that they are reliable indicators of

silicosis, once it is detected. Pulmonary function studies are useful in documenting the types of

functional impairment associated with silicosis, which may be mild in the beginning.

A restrictive pattern of airflow limitation, though it initially may be mild, typically

appears early in the development of silicosis. If symptoms (primarily shortness of breath with

exertion) are present, they usually result from restricted airways from the fibrotic scarring in the

alveolar sacs and the ends of the lung tissue. The scarring can be detected from chest x-rays

when the lesions become large enough to be visible opacities. By the time opacities have

coalesced, as viewed on chest x-ray or CT scan, and silicosis has advanced to the “complicated”

stage, it is associated with significant loss of lung volumes, gas exchange function, and increased

airflow obstruction. For the silicotic, this means dyspnea (difficulty breathing), perhaps while

attempting to complete the most simple activities of daily living, and the possibility of a shorter

life span than without silicosis.

Individuals with complicated silicosis exhibited reduced median survival time as

compared with the general population (Infante-Rivard et al., 1991; Ng et al., 1992a; Westerholm,

1980). Data compiled from the National Occupational Respiratory System (NORMS) database

indicate that for persons for whom silicosis is identified as a cause of death, an average of 11.8

years of potential life are lost. Additional predictors of increased mortality in patients with

silicosis included age at diagnosis (younger than age 45 years) and the presence of TB (higher

mortality with TB) (Ng et al., 1992a; Westerholm, 1980). Those with complicated silicosis

(large opacities) (Westerholm, 1980) or who exhibit dyspnea, expectoration, abnormal breath

sounds or low vital capacity as well as silicotics who are current smokers have a much poorer

survival (Infante-Rivard et al., 1991).

When attempting to draw conclusions from the body of literature reviewed here

describing silicosis progression, the largest constraint is the lack of accurate and detailed

exposure data. Of the studies reviewed here, four studies (Hughes et al., 1982; Hessel et al.,

1988; Miller et al., 1998; Ng et al., 1987a) included exposure data that were based on either

current or historical measurements of respirable quartz. The exposure variables most strongly

associated in these studies with progression of silicosis was cumulative respirable quartz (or

silica) exposure (Hessel et al., 1988; Hughes et al., 1982; Miller et al., 1998; Ng et al., 1987a),

though both average concentration of respirable silica (Hughes et al., 1982; Ng et al., 1987a) and

duration of employment in dusty jobs have also been found to be associated with the progression

of silicosis (Hughes et al., 1982; Ogawa et al., 2003).

The study reflecting average exposures most similar to current exposure conditions is

that of Miller et al. (1998), which followed a group of 547 British coal miners in 1990-1991 to

evaluate chest x-ray changes that had occurred after the mines closed in 1981. Between 1964

and 1978, mean and maximum cumulative exposures to respirable quartz were estimated to be
73

1.8 and 8.3 mg/m3-years, respectively, corresponding to average concentrations of 0.12 and 0.55

mg/m3, respectively, over the 15-year sampling period. However, between 1971 and 1976,

workers experienced unusually high concentrations of respirable quartz in one of the two coal

seams in which the miners worked. Buchanan et al. (2003), in a reanalysis of the Miller et al.

(1998) study has shown that short-term exposures to high (>2 mg/m3) concentrations of silica

can have an effect 3 times as great as a cumulative equivalent longer-term exposure to lower

levels.

The Miller et al. (1998) study also provided ILO chest x-ray categories for its

participants, and included workers whose last chest x-ray while they were working was recorded

as either 0/0 or 0/1. Among the 504 workers whose last chest x-ray was classified as ILO 0/0 or

0/1, 20 percent had experienced onset of silicosis (i.e., chest x-ray was classified as ILO 1/0 by

the time of follow up in 1990-1991), and 4.8 percent progressed to at least category 2. However,

there are no data available to continue following the progression of this group because there have

been no follow-up surveys of this cohort since 1991.

The cohorts followed in the other three studies (Hessel et al., 1988; Hughes et al., 1982;

Ng et al., 1987a) were comprised of silicotics (i.e., individuals already diagnosed with silicosis

that were followed further to evaluate disease progression). These studies also reflect exposures

of workers to higher average concentrations of respirable quartz than was the case in the Miller

et al. (1998) study.

With the exception of studies with highly detailed silica exposure measurements and

individual’s exposure times (Buchanan et al., 2003), when exposures are very high, it is difficult

to extrapolate study findings with respect to the extent and rate of disease progression, except in

a very general sense. Some general findings from this body of literature follow. Regarding the

risk of progression of silicosis (defined as changes in chest x-ray), there is strong evidence for

the following findings. First, size of opacities on initial radiograph is a determinant for further

progression. Individuals with large opacities on initial chest radiograph have a higher probability

of progression to chronic silicosis than those with small opacities (Hughes et al., 1982; Lee, et

al., 2001; Ogawa et al., 2003). Second, although silicotics exposed after onset of disease are

more likely to progress than those not exposed (Hessel et al., 1988), once silicosis has been

detected there remains a likelihood of progression in the absence of additional exposure to silica

(Hessel et al., 1988; Miller et al., 1998; Ogawa, et al., 2003; Yang et al., 2006). Silica exposure,

measured as either average concentration (Hughes et al., 1982) or cumulative exposure (Hessel

et al., 1988; Hughes et al., 1982; Miller et al., 1998; Ng et al., 1987a) is the variable that has

most strongly been reported to be related to progression of silicosis.

Additionally, there is some evidence in the literature that the probability of progression is

likely to decline over time following the end of the exposure, although this observation may also

reflect a survivor effect (Hughes et al., 1982; Lee et al., 2001). In addition, of borderline

significance was the association of TB with increased likelihood of silicosis progression (Lee et

al., 2001).
74

Some studies estimated rates of progression as either the number in a cohort who

progressed compared to the total number in the cohort (i.e., as a percentage of the cohort), or as

the number of sub-categories per year on the ILO scale that cohort members were observed to

have progressed. Data from these studies have shown that:

 For a mean respirable silica exposure of 0.48 mg/m3, 45 percent of those with

simple silicosis progressed over a mean of 7.2 years, yielding an annual rate of

progression of 6.2 percent of the cohort (Ng et al., 1987a);

 At an average respirable silica exposure of 0.12 mg/m3, but with high periodic

exposures to freshly fractured silica, of those who had a 0/0 or 0/1 chest x-ray, 29

percent progressed (to at least a 1/0 x-ray) in a follow-up period averaging 16

years (Miller et al., 1998), yielding an average annual progression of almost 2

percent. Additionally, much of this progression most likely occurred after

exposures ceased, since the mine had closed some 9 years prior to follow-up;

 For a mean respirable silica exposure of a 0.98 mg/m3, sandblasters progressed at

an overall rate of 65 percent in a mean of 11.3 years (Hughes et al., 1982),

yielding an average annual progression rate of approximately 6 percent;

 Among South African goldminers, 92 percent progressed in 14 years. (Hessel et

al., 1988). Exposures of high, medium, and low exposure groups were 0.97, 0.48,

and 0.24 mg/m3, respectively; and

 Chinese mine and factory workers categorized as “suspected” silicosis cases i.e.,

0/1, had a progression rate to stage I of 48.7 percent and the interval was about

5.1 years (Yang et al., 2006).

Two studies (Miller et al., 1998; Ng et al., 1987a) provide the information most relevant

to current conditions. The range (0.12 to 0.48 mg/m3) is relatively narrow and falls within the

range of exposures of particular interest to OSHA, because current enforcement data indicate that

exposures in this range or not much lower are common today, especially in construction and

foundries, and sandblasting operations. Both of these studies reported progression in terms of

percentage of workers whose chest x-ray categories progress, and their results are close (2

percent to 6 percent). Based on these data, one can estimate an annual progression rate of 2-6

percent for this exposure range. This means that every year, provided sufficient time has elapsed

since beginning of exposure to account for latency, approximately 2 to 6 percent of workers

exposed to respirable silica dust in the range of 0.12 to 0.48 mg/m3are expected to progress at

least 1 sub-category on the ILO scale (as noted by Hessel et al. (1988), the transition from major

category 0 to the 1/0 category is probably more specifically identified as “onset” of radiological

silicosis, rather than progression).

The following studies provide higher estimates, based on higher historical exposures, and

are provided for comparison:
75

 In a population of gold miners, a 20 percent increased odds of progression was

found for every year of follow-up. In 4.5 years, silicotics progressed one

subcategory on chest x-rays (i.e., from 2/1 to 2/2), for an annual progression rate

of 0.22 subcategories/year (Cowie, 1998) (which is very close to the rate of

progression found by Hessel et al., 1988 of 2.4 minor categories in 10 years); and

 For a mean exposure of 1.4 mg/m3total granite dust for 7.5 years, the overall rate

of progression was 37 percent, for an annual rate of 0.2 categories if large

opacities were present on initial radiograph (Lee et al., 2001).

Regarding the relationship between progression of reduced lung function and its

correlation with chest x-ray changes, there is strong evidence in the literature for the finding that

lung function deteriorates more rapidly in workers exposed to silica, especially those with

silicosis, than what is expected from a normal aging process (Cowie et al., 1998; Hughes et al.,

1982; Malmberg et al., 1993; Ng and Chan, 1992). The rates of decline in lung function were

significantly greater in men whose disease showed evidence of radiologic progression after

adjusting for differences in age, smoking, and baseline value of lung function. Excessive loss of

lung function was noted in relation to progression of chest x-ray changes (Bégin et. al., 1987a;

Cowie 1998; Ng and Chan, 1992; Ng et al., 1987a). Additionally, the deterioration of lung

function seen on average exceeds that in smokers (Hughes et al., 1982).

Two studies attempted to correlate x-ray changes with functional decrements

(progression) and had sufficient data to compare both chest x-rays and PFTs for the same

workers for at least two distinct points in time (Cowie, 1998; Ng and Chan, 1992). Both studies

found statistically significant decrements that exceed the expected values for those men with

chest x-rays consistent with ILO category 2 and 3, and the second study found statistically

significant decrements starting with ILO profusion category 1. Both studies observed

deterioration in lung function in proportion to the degree of silicosis. Both of these studies

included a profusion 0/0 group for comparison, but neither study included an unexposed

comparison group. Other studies (Ng et al., 1987a; Wang et al., 1997) suggested that measurable

changes in pulmonary functions are evident well before the changes seen on chest x-ray.

Left unresolved after this review is the question of whether or not there is a relationship

between silicosis and emphysema, in the absence of PMF. The evidence presented here is

equivocal. Some studies suggest that emphysema is associated with dust exposure and PMF.

Others suggest that emphysema can be a complication of silicosis, even at its earliest stages.

In the next subsection, OSHA presents its discussion of the epidemiologic investigations

that have described lung cancer mortality in workers exposed to crystalline silica. First OSHA

reviews cohort and case control studies of exposed workers, then discusses of large pooled and

national registry studies. This is followed by a review of studies of lung cancer mortality among

workers with silicosis.

I.C. Carcinogenic Effects of Silica (Cancer of the Lung and Other Sites).
76

I.C.1. Introduction.

There has been extensive epidemiological and toxicological study about whether

respirable crystalline silica dust is a risk factor for lung cancer mortality among exposed

workers. In 1997, IARC concluded that “crystalline silica inhaled in the form of quartz or

cristobalite from occupational sources is carcinogenic to humans (Group I).” The working

group noted there was “sufficient evidence” in both the epidemiologic studies and animal data to

support these conclusions (IARC 1997, p.210-Italics in original). In its review, IARC considered

more than 40 lung cancer studies (both cohort and case-control) among silica-exposed workers

and among workers diagnosed with silicosis (silicotics). IARC based its overall finding on

studies of nine occupational cohorts that IARC considered to be the least influenced by

confounding factors, as well as selected studies of registered silicotics with lung cancer. Most of

these studies reported finding an excess lung cancer risk in occupationally exposed populations.

While acknowledging some inconsistency in the studies, IARC stated that “... in view of the

relatively large number of epidemiological studies that have been undertaken and, given the wide

range of populations and exposure circumstances studied, some non-uniformity of results would

be expected” (IARC 1997, p. 208). IARC also noted that some studies demonstrated increasing

risk gradients (positive exposure-response trends) in relation to cumulative silica exposure,

duration of exposure, and/or radiographic-diagnosed silicosis, and that “... these observed

associations could not be explained by confounding or other biases” (IARC, 1997, p. 208).

IARC’s 1997 lung cancer review included many occupational and case-control studies

within many industrial sectors. In four of these industrial sectors, IARC identified nine

occupational studies considered to be the least confounded or biased. These four industrial

sectors and the nine study cohorts were:

1. Stone Quarrying and Granite Works (three studies)

--Danish stone industry workers;

--Vermont granite shed and quarry workers;

--U.S. crushed stone industry workers;

2. Metal Ore Mining (one study)

--U.S. gold miners;

3. Ceramics, Pottery and Refractory Material (four studies)

--United Kingdom pottery workers;

--Chinese pottery workers;

--Chinese refractory brick workers;

--Italian refractory brick workers;

4. Diatomaceous Earth (one study)

--U.S. diatomaceous earth workers.

No foundry studies were selected as the least confounded studies by the IARC panel,

because foundry workers are generally exposed to multiple occupational carcinogens, (e.g.,

PAHs, aromatic amines and metals).
77

Relying largely on the same information as IARC, the U.S. National Toxicology Program

(NTP) also concluded that respirable crystalline silica is a known human carcinogen (NTP,

2000). The National Institute for Occupational Safety and Health (NIOSH) (2002) also reviewed

the health effects of occupational exposure to respirable crystalline silica and stated “NIOSH has

reviewed the studies considered by IARC and American Thoracic Society (ATS), and NIOSH

concurs with the conclusions of IARC (1997) and ATS (1997).”

Since the IARC panel review, a number of the studies initially reviewed by IARC have

been updated with the benefit of additional mortality follow-up, or IARC has supplemented the

original research by conducting a nested case-control study, or improving upon the quantification

and analysis of exposure data. Also, new research has been conducted in other industrial sectors,

including the industrial sand industry, the silicon carbide industry, and the construction industry.

OSHA has made every attempt to be as inclusive in its review of the literature pertaining

to health effects associated with silica exposure as possible. In this section, OSHA presents its

review of epidemiologic studies, including those contained in IARC and NIOSH reviews. To

identify relevant literature published subsequent to these reviews, OSHA conducted literature

searches and relied on other published reviews. The most comprehensive and thorough of these

were by Steenland et al. (2001a), Mannetje et al. (2002a, b), Birk et al. (2003), HSE (2003) and

Pelucchi et al. (2006). OSHA reviewed other seminal papers including: Finkelstein (2000),

McDonald et al., (2001), Checkoway and Franzblau (2000), Hessel et al. (1990, 2000), Soutar et

al. (2000), Steenland (2005b), and Stayner (2007). In addition, OSHA has evaluated selected

studies and six meta-analyses that investigated lung cancer mortality among workers who

developed silicosis. OSHA’s review also includes the pooled multi-center analyses conducted

by Steenland et al. (2001a), and Mannejte et al. (2002a), a pooled, multi-centered European

Union case-control study (Cassidy et al., 2007), as well as two large national registry studies

(Calvert et al., 2003; Pukkala et al., 2005). Table I-11 lists approximately 60 epidemiological

that have been reviewed by OSHA. This table summarizes the design, properties, and findings

from the studies presented in this health effects section, and is organized by industrial sector,

cohort or study population, author(s), and year of publication. This literature base reflects the

study of more than 30 occupational cohorts in a wide range of industries.

OSHA’s evaluation of the cancer literature reflects a weight-of-evidence approach where

studies are given greater weight and consideration when they include a robust number of workers

in the study population; have adequate length of follow-up since onset of exposure; have

sufficient power to detect modest increases in lung cancer incidence and mortality; use

quantitative exposure data of sufficient quality to minimize serious misclassification of exposure;

evaluate exposure-response relationships between exposure to silica and lung cancer; and

consider confounding factors including smoking and exposure to other carcinogens. The studies

meeting these criteria were considered to be most reliable for evaluating whether exposure to

crystalline silica increases the risk of lung cancer. Where studies provided adequate data on

exposures and lung cancer response, they were further examined in the quantitative risk

assessment detailed in Section II (Preliminary Quantitative Risk Assessment).
Table I-11. Summary of Cancer Studies

78

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Granite and stone quarrying and processing

Danish stone workers Cohort study of

incident cases in

Danish registries.

N = 2,071 (1,081

stonecutters, 990

unskilled workers)

Mass concentration of

respirable crystalline silica

and particle count taken

between 1948 and 1980:

median exposures 0.16mg/m3

for road material industry;

0.05mg/m3for stone cutting

industry; 0.26mg/m3for stone

crushing industry

44 cases among

stone cutters, 24

among unskilled

workers

SIR 2.00 (CI 1.49-2.69)

for stonecutters, 1.81

(CI 1.16-2.70) for

unskilled; SIR for

highest subgroup of

stonecutters was

8.08 (CI 1.16-2.70)

Smoking data not

available. Stone

workers not exposed to

other carcinogens.

Guénel et al.,

1989a, 1989b

U.S. (Vermont)

granite shed and

quarry workers –

Proportional

mortality study.

N = 969, 1 yr. min.

employment from

1952-1978.

From 1924-1966, particle

counts of respirable particles

with conversion to mass:

0.075mg/m3per mppcf. From

1970-1976, mass

concentration of respirable

crystalline silica.

62 PMR 120 (90-105) PMR increased with

cumulative exposure for

silicosis and TB, but

not for lung cancer.

Davis et al.,

1983

Cohort study.

N = 5,414

employed at least 1

year between 1950

and 1982.

Exposure data not used in

analysis.

53 deaths among

those hired

before 1930; 43

deaths among

those hired after

1940.

SMR 129 for pre-1930

hires (not stat. sig.);

SMR 95 for post-1940

hires (not stat. sig).

SMR 181 (stat. sig) for

shed workers hired

before 1930 and with

long tenure and latency.

Dust controls employed

between 1938 and 1940

with continuing

improvement

afterwards.

Costello and

Graham, 1988
Table I-11. Summary of Cancer Studies

79

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Cohort study

(update of Costello

and Graham,

1988).

N = 5,414

employed at least 1

year between 1950

and 1982.

Followed through

1996.

Exposure data not used in

analysis.

91 deaths among

those hired

before 1940; 120

deaths among

those hired after

1940.

SMR 118 overall

(stat.sig.). SMR 126

for pre-1940 hires (stat.

sig.). SMR 113 for

post-1940 hires (not

stat. sig.). SMRs stat.

sig. elevated for both

pre- and post-1940 shed

worker hires.

Higher SMRs for

workers who smoking

habits could be

confirmed. SMRs were

elevated for silicosis

and TB, but most

deaths occurred among

pre-1940 hires.

Graham et al.,

2004

Cohort study.

N = 5,414

employed at least 1

year between 1950

and 1982.

Followed through

1994.

From 1924-1966, particle

counts of respirable particles

with conversion to mass:

0.075mg/m3per mppcf. From

1970-1976, mass

concentration of respirable

crystalline silica. Mean

cumulative exposure was 2.1

mg/m3-yrs (SD = 3.8).

201 overall SMR 117 (p < 0.05)

overall.

SMRs were 77, 98, 126,

125, 133, 147, 170, and

116 respectively for

increasing exposure

groups.

Found a positive

exposure-response

relationship based on

Poisson regression.

Attfield and

Costello, 2004

U.S. crushed stone Cohort study.

N = 3,246,

employed at least 1

year between 1940-

1980. Follow-up

from 1979-1981.

Geometric mean concentration

of respirable particles (αQuartz component): 0.6mg/m3

for granite operations, 0.4

mg/m3for trapwork and

limestone operations.

51 SMR 129 (CI 96-170)

overall. SMR 150 (CI

95-225) for limestone

workers and 335 (CI

134-690) for granite

workers.

Not exposed to other

carcinogens. Only

counted deaths where

work histories could be

confirmed.

Costello et al.,

1995
Table I-11. Summary of Cancer Studies

80

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Finnish granite

workers

Cohort and nested

case-control

studies.

N = 1,026, follow

up from 1972-

1981, extended to

1985 (Koskella et

al., 1990) and 1989

(Koskella et al.,

1994).

Personal sampling data

collected from 1970-1972

included total and respirable

dust and respirable silica

sampling. Average silica

concentrations ranged form

0.3-4.9 mg/m3.

31 through 1989. Through 1989, SMR

140 (CI 98-193). For

workers in two regions

where silica content of

rock was highest,

SMRs were 126 (CI 71-

208) and 211 (CI 120-

342), respectively.

Smoking habits similar

to other Finnish

occupational groups.

Minimal work-related

exposures to other

carcinogens.

Koskela et al.,

1987, 1990, 1994

Refractory brick industry

Chinese refractory

brick workers

Cohort study

N = 6,266 workers

employed before

1962. Follow up

through 1985.

No exposure data presented. 610 SRR 1.49 (p < 0.01)

overall and 2.10 (p <

0.01) for silicotics.

No statistically

significant excess

cancer risk among nonsilicotics.

Dong et al., 1995

Case-control study.

Cases worked 10

years or more and

were diagnosed

between 1987-

1993.

No exposure data presented. 40 OR 2.9 (CI 1.4-5.9) for

workers with 15 or

more years of work.

Possible confounding

by asbestos exposure.

Xu et al., 1996b

Italian refractory

brick workers

Cohort study.

N = 231 workers

employed as of

Jan. 1 1960.

Follow up through

1979.

No exposure data presented. 11 SMR 183 (CI 91-327) No asbestos exposure;

PAH levels were

considered to be

minimal.

Puntoni et al.,

1988
Table I-11. Summary of Cancer Studies

81

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Cohort study.

N = 1,022 workers

employed at least 6

months between

1954-1977

(included

population studied

by Puntoni et al.,

1988). Follow up

through 1986.

No exposure data presented. 28 SMR 151 (CI 100-218)

overall. SMR 177 (CI

103-284) among

workers hired prior to

introduction of dust

controls; SMR 123 (61-

220) among workers

hired afterwards.

No asbestos exposure;

PAH levels were

considered to be

minimal.

Merlo et al.,

1991

Gold mining

South African (white)

gold miners

Case-control study.

N = 133 cases

selected between

Jan. 1979 and Oct.

1983. Two

controls per case.

Occupations grouped into four

levels of dustiness.

133 No association with

silica exposure index,

duration of

employment, or number

of shifts worked in high

dust.

ORs for lung cancer

and silicosis declined

with increasing

exposure to dust.

Hessel et al.,

1986

Case-control study.

N = 231 lung

cancer deaths, 318

controls that died

between 1975 and

1986.

Same as Hessel et al., 1986. 231 Reported no difference

in cumulative exposure,

intensity of exposure,

number of shifts

worked, or number of

shifts in high-dust jobs

between case control

and cancer deaths

Odds ratio was adjusted

for smoking. Authors

found no association

between exposure to

silica, silicosis and lung

cancer.

Hessel et al.,

1990
Table I-11. Summary of Cancer Studies

82

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Cohort and casereferent study.

N = 3,971 white

miners employed at

start of 1970.

Followed for 9

years.

Cumulative dust exposures 530 SMR 161 (CI 115-220)

overall. From casereferent study, RR of

1.14 (CI 0.63-2.05) per

10 years employment

underground and 1.77

(CI 0.94-5.31) per 10

particle-years

underground exposure.

RR estimates from

case-referent study

adjusted for smoking.

Wyndham et al.,

1986

Cohort and nested

case-control study.

N = 4,925 white

male miners

employed at start

of 1970. Followed

through 1989.

Two controls per

case.

Particle count data converted

to respirable dust mass

(Beadle and Bradley, 1970,

and Page-Shipp and Harris,

1972). Average cumulative

exposure of subjects in casecontrol study was 3.7 mg/m3

-

yrs respirable dust.

143 deaths

observed in

cohort. 159

cases selected for

case-control

study.

SMR 139.8 (CI 117.8-

164.6) overall. Casecontrol study showed

no relationship between

lung cancer and dust

exposure.

Smoking history

included in model.

Authors concluded that

risk factors such as

unhealthy life-style

contributed to excess

risk as well as silica

exposure.

Reid and SluisCremer, 1996

Cohort study.

N = 2,209 white

male miners

employed between

1936 and 1943.

Followed from

1968-1986.

Particle count data from

Beadle (1971).

77 RR 1.023 (CI 1.005-

1.042) per 1,000

particle-years of

exposure based on Cox

proportional hazards

model.

Model adjusted for

smoking and year of

birth. Lung cancer was

associated with silicosis

of the hilar glands not

silicosis of lung or

pleura. Possible

confounding by radon

exposure among miners

with 20 or more years

experience.

Hnizdo and

Sluis-Cremer,

1991
Table I-11. Summary of Cancer Studies

83

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Nested casecontrol study from

population study

by Hnizdo and

Sluis-Cremer,1991.

N = 78 cases, 386

controls.

Particle count data converted

to respirable dust mass

(Beadle and Bradley, 1970,

and Page-Shipp and Harris,

1972).

78 RR 2.45 (CI 1.2-5.2)

when silicosis was

included in model.

Lung cancer mortality

associated with

smoking, cumulative

dust exposure, and

duration of

underground work.

Latter two factors were

most significantly

associated with lung

cancer with exposure

lagged 20 years.

Hnizdo et al.,

1997

Western Australia

gold miners -

Cohort study.

N = 1,974 miners

that participated in

medical surveys in

1960 and 1961.

Follow up through

1975.

No exposure assessment

conducted.

59 O/E ratio 1.4 (p < 0.01)

overall.

RR 1.41 (CI 0.069-

2.96): comparing

below-ground workers

to above-ground

workers

Arsenic and radon

exposures were wellbelow levels associated

with cancer risk.

Observed interaction

between smoking and

duration of

underground exposure.

Armstrong et al.,

1979

Cohort and nested

case-control study.

N = 2,297, follow

up of Armstrong et

al. (1979). Follow

up through 1993.

Expert ranking of dustiness by

job.

Nested case

control of 138

lung cancer

deaths

SMR 126 (CI 107-159)

lower bound; SMR 149

(CI 126-176) upper

bound. From casecontrol, RR 1.31 (CI

1.10-1.7) per unit

exposure score.

Association between

exposure and lung

cancer mortality not

stat. sig. after adjusting

for smoking, bronchitis,

and silicosis. Authors

concluded lung cancer

restricted to miners who

received compensation

for silicosis.

de Klerk and

Musk, 1998
Table I-11. Summary of Cancer Studies

84

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

U.S. gold miners Cohort study.

N = 440 miners

employed at least 5

years. Follow up

from 1960 to 1973.

Exposures assessed by particle

count and quartz analysis of

airborne and settled dust.

Exposures deemed to be

below the OSHA standard.

SMR 370 (p < 0.01) for

pulmonary

malignancies

Arsenic, chromium and

nickel were present in

trace amounts. Authors

believed cancer excess

related to exposure to

asbestos-like fibers.

Gillam et al.,

1976

Cohort study,

extension of

GIllam et al.

(1976).

N = 3,328 workers

followed through

1977.

Same as above 43 No excess lung cancer

mortality reported.

Brown et al.,

1986

Cohort and nested

case-control study,

same population as

Brown et al.

(1986); workers

with at least 1 year

underground work

between 1940 and

1965. Follow up

through 1990.

Particle count data, conversion

to mass concentration based

on Vt. Granite study,

construction of JEM. Median

quartz exposures were 0.15,

0.07, and 0.02 mg/m3prior to

1930, from 1930-1950, and

after 1950 respectively.

115 SMR 113 (CI 94-136)

overall. SMRs

increased for workers

with 30 or more years

of latency, and when

local cancer rates used

as referents. Casecontrol study showed

no relationship of risk

to cumulative exposure

to dust.

Smoking data available

for part of cohort,

habits comparable to

general US population;

attributable smokingrelated cancer risk

estimated to be 1.07.

Steenland and

Brown, 1995a,

1995b
Table I-11. Summary of Cancer Studies

85

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Other Mining

Chinese Tin,

Tungsten, and

Copper miners

Cohort study.

N = 54,522

workers employed

1 yr. or more

between 1972 and

1974. Follow up

through 1989.

Measurements for total dust,

quartz content, and particle

size taken from 1950’s1980’s. Exposures

categorized as high, medium,

low, or non-exposed.

SMRs 198 for tin

workers (no CI reported

but stat. sig.). No stat.

sig. increased SMR for

tungsten or copper

miners.

Non-statistically

significantly increased

risk ratio for lung

cancer among silicotics.

No increased gradient

in risk observed with

exposure.

Chen et al., 1992

Nested casecontrol study.

Same population as

Chen et al., 1992.

JEM based on total dust

sample data and quartz content

of settled dust (Dosemeci et

al., 1993).

87 among tin

miners, 93,

among tungsten

miners

OR 1.5, 1.9, 3.1 for

low, medium, and highexposure groups,

respectively (p for trend

= 0.004)

Correction for smoking

did not influence

observed trend with

silica exposure.

McLaughlin et

al., 1992

Same as above,

examination of

interactions with

other carcinogens

and silicosis.

Same as above. OR for lung cancer

increased with severity

of silicosis, OR of 1.4

(CI 1.1-2.0) overall.

Cancer risk not

increased with

increasing exposure.

Cancer risk among

silica-exposed more

evident absent exposure

to nickel, radon, and

PAH’s. No influence

observed from arsenic

or cadmium.

Cocco et al.,

2001
Table I-11. Summary of Cancer Studies

86

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Nested casecontrol study. N =

7,855 tin miners

included in

McLaughlin et al.,

1992. Followed

through 1994.

Total dust measurements and

quartz content of settled dust.

Conversion to respirable

crystalline silica measures

based on side-by-side

sampling (Zhuang et al., 2001)

130 lung cancer

cases (627

controls)

Strong positive

exposure-response

trend with total dust

and arsenic exposure.

No excess of lung

cancer among workers

in mine where arsenic

concentrations were

lowest, despite high

prevalence of silicosis.

Authors concluded

arsenic and smoking

were most important

factors for lung cancer

risk.

Chen and Chen,

2002

Cohort study.

Same tin miner

population as in

Chen et al., 1992.

Follow up through

1994

Total dust measurements and

quartz content of settled dust.

Conversion to respirable

crystalline silica measures

based on side-by-side

sampling (Zhuang et al., 2001)

138 SMR 249 (CI 209-294)

overall. RR 3.55 (p <

0.01) for exposed

miners compared to

unexposed.

Lung cancer mortality

increased with

increasing cumulative

total dust exposure and

cumulative respirable

silica exposure. Role of

arsenic could not be

ascertained.

Chen et al., 2006

British Coal workers Cohort study.

N = 17,820 miners

from 10 colliaries.

Quartz exposure assessed

from personal respirable dust

samples.

973 Significant relationship

between cumulative

silica exposure (lagged

15 years) and lung

cancer mortality VIA

Cox regression.

Adjusted for smoking. Miller et al,

2007; Miller and

MacCalman,

2009
Table I-11. Summary of Cancer Studies

87

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Industrial sand industry

North American

industrial sand

workers

Cohort and nested

case-control study.

N = 4,626 workers.

Follow up from

1960-1996.

Exposure assessment based on

4,269 compliance dust

samples taken from 1974-

1996 and analyzed for

respirable quartz. Exposures

prior to 1974 based on particle

count data and quartz analysis

of settled dust and dust

collected by high-volume air

samplers, and use of a

conversion factor (1 mppcf =

0.1 mg/m3).

109 deaths

overall.

SMR 160 (CI 131-193)

overall. Positive trends

seen with cumulative

silica exposure (p =

0.04 for unlagged, p =

0.08 for lagged).

Smoking data from 358

workers suggested that

smoking could not

explain the observed

increase in lung cancer

mortality rates.

Steenland and

Sanderson, 2001

Cohort study.

N = 2,670 workers

employed for 3

years or more prior

to 1980 (overlaps

with Steenland and

Sanderson (2001)

cohort). Followed

through 1994.

Exposure assessment not

utilized.

83 SMR 150 (p = 0.001)

for deaths occurring 20

years or more from

hire, based on U.S.

rates. SMR 139 (p =

0.001) based on

regional rates.

Observed excess due to

4 plants in two states,

no excess lung cancer

seen in plants in three

other states or in

Quebec.

McDonald et al.,

2001
Table I-11. Summary of Cancer Studies

88

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Case-control study

from McDonald et

al. (2001) cohort.

Assessment based on 14,249

respirable dust and silica

samples taken from 1974 to

1998. Exposures prior to this

based on particle count data.

Adjustments made for

respirator use (Rando et al.,

2001).

95 cases, two

controls per case.

OR 1.00, 0.84, 2.02 and

2.07 for increasing

quartiles of exposure p

for trend = 0.04).

Adjusted for smoking.

Positive association

between silica exposure

and lung cancer.

Median exposure for

cases and controls were

0.148 and 0.110 mg/m3

respirable silica,

respectively.

Hughes et al.,

2001

Cohort and nested

case-control study.

Follow up of

McDonald et al.,

2001 cohort (minus

Canadian workers)

through 2000.

102 deaths

overall in cohort.

SMR 147 (p = 0.001)

overall for workers who

died 20 or more years

after hire.

From case-control, ORs

of 1.00, 0.94, 2.24, and

2.66 for increasing

quartiles of (lagged)

exposure (p for trend =

0.006)

Exposure-response

analysis adjusted for

smoking. Lung cancer

was related to average

silica concentration but

not duration of

employment.

McDonald et al.,

2005

United Kingdom

industrial sand

workers

Cohort study.

N = 2,703 workers

employed at least

one year between

1950 and 1986.

Follow up through

2001.

Assessment based on 2,429

personal and 583 area samples

analyzed for respirable dust

and silica. Earlier exposures

estimated by linear

extrapolation. GM of

exposures was 0.09 mg/m3

respirable silica.

No association between

cumulative silica

exposure and lung

cancer.

No smoking data

available. Mean

cumulative exposure of

cohort was 0.31 mg/m3-

yrs. Over half of cohort

deaths had less than 10

years service.

Brown and

Rushton, 2005a,

2005b
Table I-11. Summary of Cancer Studies

89

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Pottery industry

United Kingdom

pottery workers

Cohort study.

N = 3,669 workers

under age 60 and

employed in 1970-

1971. Follow up

through 1985.

Mean exposures to respirable

quartz were 0.01mg/m3–

0.2mg/m3.

60 SMR 140 (CI 107-180)

nationally adjusted rate;

and SMR 132 (CI 100-

169) locally adjusted

rate

Found increasing SMR

with increasing quartile

of cumulative exposure

and with duration of

employment. Smoking

information available.

Winter et al.,

1990

Proportionate

mortality study.

N = 7,020 workers

born between 1916

and 1945. Follow

up to June 30,

1992.

PMR 124 (CI 106-144);

PMR 122 (CI 104-143)

after exclusion of

asbestos exposure

Asbestos as

confounding factor, but

adjusted for in analysis.

70 percent of deaths

came from one town

with high background

rate of lung cancer.

McDonald et al.,

1995

Cohort and nested

case-control study.

N = 5,115 workers

first employed

between 1929-

1982.

Assessment based on >1,000

personal air samples for

respirable dust taken from late

1960’s to 1992. Also used

particle count data from 1950

to the 1960’s.

JEM included 569 jobs in 11

job processes; used to estimate

maximum, cumulative, and

average lifetime exposures to

respirable crystalline silica.

52 lung cancer

cases were

included

(excluded 36

cases)

SMR 191 (CI 148-242)

based on national rates,

SMR 128 (CI 99-162)

based on local rates.

Smoking-adjusted ORs

were elevated (stat.

sig.) for mean

concentration of silica,

but not for cumulative

exposure nor duration

of employment.

Cherry et al.,

1998
Table I-11. Summary of Cancer Studies

90

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Chinese pottery

workers

Cohort study.

N = 13,719

workers employed

in 1972-1974.

Follow up through

1989.

Measurements of job-specific

total dust and quartz content

of settled dust used to classify

workers into one of four total

dust exposure groups.

SMR 58 (p < 0.05)

overall. RR 1.63 (CI

0.8-3.4) among

silicotics compared to

non-silicotics.

No reported increase in

lung cancer with

increasing exposure.

Chen et al.,

1992,

Nested casecontrol study.

N = 62 cases from

Chen et al. (1992)

cohort.

Assessment based on total

dust area measurements taken

from 1950 to 1987, and

estimates of percent respirable

dust and quartz content

(Dosemeci et al. 1993).

OR 1.0, 1.8, 1.5, and

2.1 with increasing

cumulative exposure

(not stat. sig.).

ORs adjusted for

smoking. Authors

found positive but

inconsistent trends of

lung cancer risk with

exposure.

McLaughlin et

al., 1992

Dutch ceramic

workers

N = 1,794 workers

employed in 1972-

1986 and who

worked more than

two years. Follow

up to 1991.

No quantitative exposure data:

used qualitative categories of

exposure based on job

description.

30 SMR = 88 161 deaths total in

cohort (9 percent of

cohort). Stat. sig.

excess of lung cancer

among those with

simple pneumoconiosis.

Meijers et al.,

1996

German stone, quarry

and ceramic workers

case-control study

Population-based

case-control study.

Cases diagnosed

between 1980 and

1994.

N = 133 cases vs.

231 controls (stone

quarry); 114 cases

vs 564 controls

(ceramic)

Exposures classified as either

above or below the thenGerman MAK (0.15 mg/m3

respirable silica) based on

available exposure

measurements and

professional judgment.

Cristobalite exposure in

ceramics industry not

assessed.

No exposure-related

trends with lung cancer

observed.

All controls selected

from silica-exposed

populations; cases and

controls with silicosis

were eliminated.

Ulm et al., 1999
Table I-11. Summary of Cancer Studies

91

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Diatomaceous earth industry

U.S. Diatomaceous

earth workers

Cohort study.

N = 2,570 workers

employed at least 1

year between 1942

and 1987.

Exposures were to cristobalite.

Semi-quantitative assessment

based on exposure

measurement records, review

of process history, interview

of employees. Adjusted to

account for increased

respirator use after 1950.

59 SMR 143 (CI 109-184);

RR = 2.88 (CI 1.13-

7.33) for workers with

20 or more years

experience compared to

low-exposed referent

group.

RR increased for

increasing exposure

groups. Incomplete

smoking data available

but analysis of potential

effect of smoking could

not explain observed

excess lung cancer

mortality. Asbestos a

potential confounding

factor.

Checkoway et

al., 1993

Cohort study, reanalysis of

previous study.

N = 2,266 workers

from 1 plant for

whom quantitative

exposure estimates

could be derived.

Included quantitative

assessment of silica and

asbestos exposures.

52 SMR 141 (CI 105-185).

RR for increasing

categories of silica

exposure were 1.00,

1.37, 1.80, and 1.79

(15-year lag).

ORs adjusted for

cumulative asbestos

exposure.

Checkoway et

al., 1996
Table I-11. Summary of Cancer Studies

92

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Cohort study.

Same as

Checkoway et al.,

1993, excluding

317 workers whose

exposures could

not be

characterized, and

including 89

workers with

asbestos exposure

who were

previously

excluded from the

1993 study.

Follow up through

1994.

Assessment based on almost

6,400 samples taken from

1948-1988; about 57 percent

of samples represented

particle counts, 17 percent

were personal respirable dust

samples. JEM included 135

jobs over 4 time periods

(Seixas et al., 1997)

77 SMR 129 (CI 101-161)

based on national rates,

and SMR 144 (CI 114-

180) based on local

rates. Risk ratios by

exposure quintile were

1.00, 0.96, 0.77, 1.26,

and 2.15, with the latter

being stat. sig.

RR = 2.15 and 1.67

Smoking history

available for half

cohort. Under worstcase assumptions, the

risk ratio for the highexposure group would

be reduced to 1.67 after

accounting for

smoking.

Checkoway et

al., 1997

Cohort study.

N = 1,809 workers

selected from the

1993 study for

whom chest x-ray

films were

available.

Same as above. SMR 157 (CI 43-403)

for silicotics compared

to non-silicotics. Nonsilicotics had increasing

cancer mortality with

increasing cumulative

silica exposure (p for

trend = 0.02).

Checkoway et

al., 1999
Table I-11. Summary of Cancer Studies

93

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Foundry industry

Danish foundry

workers

Cohort study.

N = 6,144 workers

participating in

silicosis

surveillance

program in 1967-

1969 and 1972-

1974. Follow up

through 1985.

No quantitative exposure data;

used years employment as

proxy for exposure.

166 cases

diagnosed.

SIR 1.30 (CI 1.12-

1.51). Upward trend in

SIR with increasing

employment duration.

Other confounders not

addressed in study.

Sherson et al.,

1991

U.S. (Michigan)

foundry workers

Cohort and casecontrol studies.

N = 5,337 white

males; 2,810 nonwhite males; 627

females. Workers

employed at least 6

months from 1950

to 1979. Follow up

through 1984 and

1989.

Silica exposure index created

from available exposure data.

220 deaths in

case-control

study; 2,220

controls.

SMR 1.23 (CI 0.96-

1.54) for whites; SMR

1.32 (CI 1.02-1.67) for

non-whites (1984

follow up). ORs

decreased with

increasing exposure

quartile.

Other confounders were

disclosed but not

adjusted for in study.

Andjelkovich et

al., 1990, 1992,

1994
Table I-11. Summary of Cancer Studies

94

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Chinese iron and

steel workers

Case control study.

All lung cancer

deaths occurring

between 1980 and

1989 among

workers in

industry.

Cumulative exposure to total

silica dust.

610 deaths, 610

controls

OR 1.8 (CI 1.1-2.8)

among foundry

workers. Modest

increasing trend in OR

with cumulative silica

exposure among steel

workers (p for trend =

0.007).

Lung cancer among

foundry workers

increased with

benzo(a)pyrene

exposure.

Xu et al., 1996b

(case-control)

Swedish aluminum

foundry workers

Nested casecontrol study.

N = 5,016 workers.

Study used 31

cases and 233

controls.

Used cross-sectional exposure

data; used “correction” factors

to estimate respirable

crystalline silica levels.

46 deaths in

cohort.

No statistically

significant trend with

exposure.

No smoking data

provided.

Westberg and

Bellander, 2003

Silicon carbide industry

Norwegian silica

carbide workers -

Cohort study.

N = 2,620 workers

with at least 6

months in one of

three plants.

Follow up started

from the latter of

1953 or after 6

months of

employment,

through 1966.

Combination of particle count,

total dust, and respirable silica

measurements. Constructed

JEM for all plants.

74 lung cancer

cases total.

SIR 1.9 (CI 1.5-2.3) Exposures were to

silica, cristobalite, silica

fibers, PAHs; possibly

asbestos. Exposures to

various dusts highly

correlated. Poisson

analysis indicated that

SiC fiber exposure was

a stronger predictor of

lung cancer incidence.

Romundstad et

al., 2001
Table I-11. Summary of Cancer Studies

95

Industry

Sector/Population

Type of Study and

Description of

Population

Exposure Characterization

No. of Lung

Cancer Deaths/

Cases

Risk Ratios

(95% CI)

Additional Information

Source

Canadian silica

carbide workers -

Cohort study.

N = 585 workers

employed at any

time from 1950-

1980. Follow up

through 1989.

Limited to total dust

measurements.

24 SMR 169 (CI 109-252) Co-exposures to other

carcinogens.

Infante-Rivard et

al., 1994

Construction and building materials

Finnish road paving

and asphalt workers

Cohort study.

N = 5,676 workers

employed at least 6

months before

1985. Follow up

from 1964-1994.

Used IARC protocol to

estimate exposures and

construct JEM; respirable

quartz data available.

SMR 145 (CI 103-198)

for asphalt workers and

SMR 139 (CI 103-184)

among building/ground

construction workers.

Exposure to silica

showed non-stat. sig.

trend for lung cancer.

Kauppinen et al.,

2003

Canadian Bricklayers Cohort study.

N = 10,953 union

members followed

from 1950 through

1993.

No exposure data available;

used proxy data (length of

employment or union

membership).

100 SMR 162 for workers

with 20-29 years

experience; SMR 150

for workers with 30+

years experience.

Possible exposures to

hexavalent chromium

and asbestos.

Finkelstein and

Verma, 2005
96

I.C.2. Evaluation of Cohort Studies.

I.C.2.a. Danish stone industry workers.

This was a cohort study of 2,175 Danish stone workers who met the following

criteria: 1) they were alive on or after January 1, 1943; and 2) they were less than 65

years old at the time they were first identified from one of the six data sources used.

Ninety-five percent of the initial cohort was successfully traced, resulting in a total of

2,071 stone workers included in the study (Guénel et al., 1989b). The cohort was

comprised of two separate populations, including 1,081 skilled stonecutters (carving

tombstones and ornamental building materials) dispersed throughout Denmark in smaller

shops, and 990 unskilled workers (581 in the road materials industry from one company

and 409 in the stone cutting industry). The skilled stonecutters typically remained in

their trade for many years and tended to have lower exposures to crystalline silica, as

opposed to the unskilled workers who predominated in the road and building materials

industry. The analysis of cancer incidence in the study was carried out separately for the

skilled and unskilled workers because of the differences in work tasks and length of

employment (Guénel et al., 1989b).

Exposures to silica dust among workers in the stonecutting and stone road

building industries were assessed from data collected between 1948 and 1980, which was

available in the archives of the Danish National Institute of Occupational Health. Details

of exposure data summarizing current and historical measurements appeared in a separate

paper (Guénel et al., 1989a). There were a total of 197 measurements, of which 108 were

mass measurements (mg/m3) and 87 were by particle count (particles/cm3). Most

measurements (163) were taken from three operations in the road material and building

industry (crushing, sieving, and drilling), while only 34 measurements were taken from

two operations in the stonecutting industry (hand cutting and surface finishing). The

median respirable silica exposure in the road material industry was 0.16 mg/m3, with 70

percent exceeding 0.10 mg/m3. Respirable silica exposure in the stonecutting industry

was more moderate, with a median exposure of 0.05 mg /m3and 45 percent exceeding

0.10 mg/m3. Crushing was associated with the highest median respirable silica exposure

(0.26 mg/m3), while the lowest median exposure level was found for cutting operations

(0.05 mg/m3). Median exposures for workers engaged in sieving and drilling were 0.1

and 0.09 mg/m3, respectively (Guénel et al., 1989a).

Smoking data were not available for the cohort. The expected numbers of lung

cancer cases were based on the Danish national incidence rates for men, after adjustment

for region. A total of 44 lung cancer cases were observed for the cohort of skilled

workers and 24 lung cancer cases for the cohort of unskilled workers. The standardized

incidence ratio (SIR) for lung cancer was 2.00 (95% Confidence Interval (CI) 1.49-2.69)

for all skilled stone workers, and 1.81 (95% CI 1.16-2.70) for all unskilled stone workers.

The highest SIRs were observed for the subgroups of skilled sandstone cutters (SIR =

8.08; 95% CI 3.23-16.16) and skilled granite stone cutters (SIR = 4.04; 95% CI 2.02-

23.0) from Copenhagen (Guénel et al., 1989b). The authors noted that the excess risk of

lung cancer among the Copenhagen stone cutters was higher for those workers hired
97

before 1940, prior to improvements in ventilation, but there was no detailed information

provided on the relationship between incidence and magnitude or duration of exposure.

Based on observing a lower-than-expected incidence of bladder cancer among the

workers, the investigators concluded that smoking alone was unlikely to explain the

excess risk of lung cancer. They also commented that stone workers in this study had not

been exposed to other known lung carcinogens in the workplace and therefore believed

that the results of the study suggested a relationship between exposure to crystalline silica

and increased lung cancer mortality (Guénel et al., 1989b).

I.C.2.b. U.S. granite shed and quarry workers.

Vermont granite shed and quarry workers have been studied extensively since

recognition in the 1930’s of high silicosis and TB rates among them. The silica content

in respirable dust was approximately 9 percent (Theriault et al., 1974a), and granite rock

contained approximately 30 percent crystalline silica or quartz. Davis et al. (1983) were

among the first researchers to investigate the possible association between silica exposure

and lung cancer mortality.

Measurement of airborne concentrations took place from 1924 to 1977, including

six surveys. Those measurements taken from 1970 to 1976 were of respirable dust and

silica, analyzed by gravimetric analysis and XRD and/or infrared spectrometry (IR),

respectively. The previous four surveys, conducted from 1924 to 1966, were particle

count measurements collected by using either standard or midget impingers, with quartz

analysis by petrographic, colorimetric or XRD techniques (Davis et al., 1983; Theriault et

al., 1974a). Exposure measurements made in 1965-1966 and again in 1972 comparing

particle count measurements to respirable mass sampling, with analysis for silica by XRD

and IR, provided an empirical basis for converting particle count to respirable dust mass

and respirable quartz percentage of the dust (Ayer et al., 1973). In Davis et al. (1983),

respirable mass measures were converted to particle counts by comparing matched pairs

of particle count and respirable mass measurements taken concurrently. Results of these

two experiments, combined with measurements of the percent crystalline silica in the

samples, yielded the following relationship: 10 mppcf = 0.075 mg/m3respirable silica.

The Davis et al. (1983) study was a proportional mortality study of 969 deceased

white male granite workers employed in granite quarries and sheds, who worked 1 year

or more from 1952 through July, 1978. Davis et al. (1983) observed 28 deaths due to

silicosis (vs. none expected), 65 deaths due to tuberculosis (vs. 6.5 expected), 22 deaths

from emphysema (vs. 16.9 expected), and 62 deaths of lung cancer (vs. 52.6 expected).

The proportionate mortality ratios (PMRs) for all of these causes of death were

statistically significantly elevated, except for lung cancer (PMR = 120, 95% CI 90-105).

When subjects were grouped into quartiles by cumulative exposure to respirable silica

(identified as low, medium, high, and very high), PMRs for silicosis and tuberculosis

increased with increasing exposure, but PMRs for other causes of death, including lung

cancer, did not. All but one of the deaths from silicosis and all deaths from tuberculosis

occurred among workers who had started work before dust controls began to be

implemented in the late 1930’s, after which exposure was significantly reduced. In
98

summary, this study did not find a consistent association between respirable silica

exposure and lung cancer.

Costello and Graham (1988) conducted a cohort mortality study of 5,414 Vermont

granite workers (1,527 death certificates traced) employed between 1950 and 1982 to

evaluate the relationship between silica exposure and lung cancer mortality. This was an

improvement over the Davis et al. (1983) study of this population since death rates were

evaluated longitudinally, and because the number of deaths in the cohort had increased by

558 since the Davis et al. study. There was limited discussion of exposure

measurements, but exposure data were not used in the analysis. Cohort mortality was

compared with white male U.S. population rates. The standardized mortality ratios

(SMR) for all workers for silicosis and tuberculosis were significantly elevated (SMR =

636 and 586, respectively) and the SMR for shed workers was approximately twice that

for quarry workers, reflecting the generally higher exposures to respirable quartz

experienced by shed workers. There was a limited amount of smoking data.

Dust controls were developed and introduced into the industry between 1938 and

1940, with continuing improvement in dust control such that exposures to silica were

reduced approximately ten-fold in the mid-1950’s (Theriault et al., 1974a). These quasiexperimental conditions allowed separation of workers into groups having higher or

lower exposures. As expected, the standardized mortality for silicosis and tuberculosis

was significantly elevated for workers hired before 1930; the SMR for tuberculosis was

893.9 (116 deaths) and the SMR for silicosis was 999.0 (36 deaths). For workers hired

after 1940, the SMRs for tuberculosis and silicosis were 60 and 94, respectively,

suggesting the efficacy of controls (as well as population-wide measures to reduce

mortality from tuberculosis).

The SMR for lung cancer among workers hired before 1930 was also elevated

with an SMR of 129 (53 deaths) but was not statistically significant. For workers hired

after 1940, the SMR for lung cancer was 95 (43 deaths). Additional analysis of SMR for

lung cancer for workers classified by latency and tenure revealed a statistically significant

excess number of deaths for shed workers with more than 30 years tenure and more than

40 years latency (SMR = 181; 47 deaths) and for shed workers with 10-29 years tenure

and 25-39 years latency (SMR = 164; 21 deaths). These workers had been hired before

1930 (thus experiencing high exposure to silica), and all 84 workers (of 118) whose

smoking habits could be determined, had been smokers. The authors concluded that

these findings suggest “that granite dust exposure does not act as a carcinogen by itself”

(Costello and Graham, 1988).

Graham et al. updated this study in 2004 based on 2,436 deaths among cohort

members (vs. 1,527 in the 1988 report). The study design was similar to that of the

earlier one. Death rates were evaluated among workers hired both before and after 1940,

which corresponded to periods before and after dust controls began to be implemented.

Available exposure data was not analyzed quantitatively. SMRs for tuberculosis and

silicosis were elevated for the group as a whole, but nearly all such deaths occurred

among the granite workers hired before 1940. The SMR for cancer of the trachea,
99

bronchus, and lung for the entire group was statistically significantly elevated (SMR =

118; 211 deaths). For all granite workers hired before 1940, the SMR for lung cancer

was statistically significantly elevated (SMR = 126; 91 deaths); for workers hired after

1940, the SMR was elevated but was not statistically significant (SMR = 113; 120

deaths). The SMR for lung cancer was elevated overall for shed workers (SMR = 131,

193 deaths) and was statistically significantly elevated for both shed workers hired before

1940 (SMR = 148, 95% CI 119-182, 90 deaths) and after 1940 (SMR = 124, 95% CI

102-151, 103 deaths). When comparing the lung cancer mortality experience of shed

workers segregated by job tenure and latency, Graham et al. (2004) concluded that the

mortality experience of shed workers hired before 1940 was similar to those hired after

1940, despite the fact that the earlier group of shed workers had been exposed to higher

dust levels. The authors concluded that these “results do not support the hypothesis that

granite dust exposure has a causal association with lung cancer.”

Attfield and Costello (2004) analyzed the occurrence of lung cancer deaths among

the same population studied by Graham et al. (2004) but used quantitative exposure data

to evaluate relationships between exposure to respirable crystalline silica and lung cancer

mortality. According to the authors, and as noted by IARC (1997), the previous 1998

study by Costello and Graham used proxies for exposure based on date-of -hire and job

tenure, with the potential of exposure misclassification and a lessened ability to evaluate

quantitative exposure response.

Airborne concentrations were measured in six surveys from 1924 to 1977.

Attfield and Costello (2004) adapted the job exposure matrix (JEM) developed by Davis

et al. (1983) discussed previously and classified three eras as pre-, intermediate-, and

post-dust control periods for the time periods before 1940, from 1940 to 1950, and after

1950, respectively. Most of the 203 unique job and department title combinations were

grouped into 13 similarly exposed job groups which represented 75 percent of the work

history entries. Each job group or unique job title was assigned an exposure for one of

the three time periods and linked to individual workers’ employment histories to calculate

cumulative exposure measured in mg/m3-years. Particle counts were converted to

respirable mass using the conversion equation reported by Davis et al. (1983), i.e., 10

mppcf = 0.75 mg/m3.

The authors calculated SMRs and Standardized Risk Ratios (SRRs) for all causes

of death using national death rates from 1940 to 1999 as the reference group. Poisson

regression was used to fit various models. Details of Attfield and Costello (2004)

quantitative exposure-response analysis and accompanying estimates of lung cancer risk

associated with exposure to crystalline silica are provided in Section II, Preliminary

Quantitative Risk Assessment.

Attfield and Costello (2004) found SMRs of 210 for pneumoconiosis including

silicosis, 1288 for respiratory tuberculosis, and 141 for diseases of the respiratory system

(p < 0.01 for all values, confidence interval or number of deaths not provided).

Cumulative exposure was divided into eight exposure groups ranging from <0.25 to >6.0

mg/m3-years with an approximately equal number of lung cancer cases in each exposure
100

category. The mean cumulative exposure was 2.1 mg/m3–years. The rates of nonmalignant respiratory disease increased with increasing cumulative exposure and were

statistically significant among all groups exposed to 1.0 mg/m3–years or more for

respiratory tuberculosis and among all groups exposed to 1.5 mg/m3–years or more for

pneumoconiosis and diseases of the respiratory system.

When all silica dust exposure categories were included in the analysis for lung

cancer mortality, the investigators obtained a statistically significant trend when

cumulative exposure was log-transformed (p < 0.01), but not for untransformed exposure.

For untransformed cumulative exposure, with a 15-year exposure lag, SMRs were 77, 98,

126, 125, 133, 147, 170, and 116 for the respective exposure groups of <0.25, 0.25-<0.5,

0.5-<1.0, 1.0-<1.5, 1.5-2.0, 2.0-3.0, 3.0-<6.0 and >6.0 mg/m3-years. Lung cancer

mortality was observed to rise reasonably consistently through the first seven increasing

exposure groups, but fell in the highest exposure group. Attfield and Costello (2004) also

conducted analyses omitting the highest cumulative exposure group (6.0 mg/m3-years or

more). With the highest exposure group omitted, a strong positive exposure-response

trend was found for either untransformed or log-transformed cumulative exposure (p <

0.005). Attfield and Costello (2004) concluded that their quantitative analysis provided

clear evidence that exposure to crystalline silica in the range of cumulative exposures

experienced by the cohort increased the risk of lung cancer. The authors justified their

conclusions from results that excluded the highest exposure group based on the following

considerations:

 Data for the seven lower exposure groups comprised about 85 percent of

the total number of deaths in the cohort and demonstrated a monotonic

exposure-response relationship;

 The highest exposure group was believed to have exerted a

disproportionate influence over the observed exposure-response

relationship, yet the underlying exposure data for this exposure group was

more likely to include unreliable exposure estimates given that 83 percent

of these workers had 20 or more years of exposure before the introduction

of controls, when exposure measurements were most uncertain. (The

authors also noted in this highest exposed group the potential of “a highly

selected healthy worker” effect and that lung cancer may have been

obscured as a cause of death by competing high rates of silicosis and

tuberculosis deaths.)

 Exposure levels of interest today (i.e., cumulative exposures in the range

of 2 to 4 mg/m3–years reflecting exposure to current standards and

recommended exposure limits) fell within the range of the six remaining

exposure groups in the cohort; and

 Estimates of risk derived from the exposure-response relationships

excluding the highest exposure group were consistent with risk estimates
101

reported in other studies (i.e., Rice et al., 2001 for diatomaceous earth

workers).

Graham (2004) questioned the appropriateness of eliminating the highest

exposure group from the Attfield and Costello (2004) exposure-response analysis. He

argued that trends in the SMRs for silicosis and tuberculosis validated the exposure

measurements and that the absence of elevated risk for the highest exposure group

weakened the claim that silica causes lung cancer. Attfield (2004) responded, explaining

further that such anomalies were commonly seen in cohort studies. The authors reiterated

that exposure levels of greatest concern were in the range where the exposure-response

relationship was monotonic. They also referred to Stayner et al. (2003) who described

several other reported instances where epidemiological studies of occupational hazards

found non-monotonic exposure-response relationships resulting from an observed

reduction in mortality rate among the most highly exposed workers compared to the

remaining cohort members. Stayner et al. (2003) explained that this could arise because

of a healthy worker effect, depletion of susceptible individuals in the population, a

natural limit in the occurrence of disease with a high background rate, exposure

misclassification, or other factors.

Finally, Attfield and Costello (2004), in absence of most participants’ smoking

data, discussed why they believed cigarette smoking was unlikely to explain the observed

association of increased silica exposure and lung cancer. They argued that it was

unlikely that smoking would be correlated with exposure to crystalline silica (for

example, that shed workers, who were highly exposed to silica, would smoke more often

than quarry workers). They also stated that there is an extensive literature on the limited

capacity of smoking to cause confounding, particularly when using quantitative data and

internal references for relative risk estimates as was done in their study, and they further

stated that elevations in the incidence of diseases typically associated with smoking were

not observed among the more highly exposed workers. Instead, non-malignant disease

(bronchitis, emphysema, ischemic heart disease) mortality was higher in the quarry

workers (lower exposed group) than they were in shed workers. This is the opposite of

what one would expect if excess lung cancer mortality was due to smoking.

OSHA believes that the finding by Attfield and Costello (2004) of a positive

exposure-response relationship for lung cancer among granite workers is more

convincing than are the results from the Graham et al. (2004) study. In particular, OSHA

believes it likely that some of the workers hired after 1940 continued to be exposed to

dust levels that, although somewhat lower than before 1940, were still appreciably higher

than those that resulted after dust controls had been fully implemented after 1950. For

example, Attfield and Costello (2004) summarized respirable quartz levels for several

granite shed jobs and reported that for cutter/marker/surfacer jobs, respirable quartz

airborne concentrations averaged 0.37 mg/m3prior to 1940, 0.22 mg/m3between 1940

and 1950, and 0.07 mg/m3after 1950. Similarly, crane operators, which included shed

derrickmen, were exposed to average quartz levels of 0.14 mg/m3before 1940, 0.09

mg/m3between 1940 and 1950, and 0.03 mg/m3after 1950. OSHA notes that in Graham

et al.’s 2004 analysis, about one-fourth of the lung cancer deaths among post-1940 hires
102

were associated with 40 or more years of latency, indicating that these workers were, for

the most part, hired between 1940 and 1950 and, therefore, had intermediate exposures.

In essence, the post 1940 sub-cohort was not limited to those having among the lowest

exposures; this could have contributed to the observed lack of a statistically significant

difference in the mortality outcomes between the pre and post 1940 hires. Given these

considerations, OSHA believes that the finding by Attfield and Costello (2004) of a

positive exposure-response relationship among granite workers, which was based on a

quantitative assessment of the exposure of each cohort member, provides evidence of a

causal relationship between exposure to crystalline silica and lung cancer.

I.C.2.c. U.S. crushed stone industry workers.

This study is a cohort mortality study of 3,246 males employed 1 year or longer

between 1940 and 1980 at 20 crushed stone operations (including limestone, granite,

traprock, sandstone, marble and shale) (Costello et al., 1995). Crushed stone operations

were selected from a Mine Safety and Health Administration (MSHA) listing of active

establishments in 1978. Crystalline silica in the form of alpha-quartz was found to be a

component of respirable dust at all operations, comprising 37 percent, 11 percent, and 15

percent by weight of the personal respirable dust samples collected at granite, limestone,

and traprock operations, respectively. Geometric mean airborne concentrations of

respirable silica were 0.6 mg/m3for granite operations and 0.4 mg/m3for both trapwork

and limestone operations (Kullman et al., 1995). Personal work histories were obtained

from the companies’ personnel records. Workers were excluded from the analysis if their

company records were missing, date of birth was unavailable, or did not meet the entry

requirements for the cohort. Underlying cause of death was coded according to the ICD

8

th revision. SMRs were calculated by employing U.S. white male mortality rates for

whites and U.S. nonwhite male rates for nonwhites.

The overall lung cancer SMR was not statistically significantly elevated (SMR =

129; 95% CI 96-170). The SMR for lung cancer among traprock workers was not

elevated (SMR = 63; 95% CI 13-184). The overall lung cancer SMR for limestone

workers was elevated, although this was not statistically significant (SMR 150; 95% CI

95-225). The overall lung cancer SMR for granite workers was elevated and, although

based on a small sample size (7 deaths), was statistically significant (SMR 335, 95% CI

134-690). The workers in granite facilities with 20 or more years latency and more than

10 years of tenure had a statistically significantly elevated lung cancer SMR of 354 (95%

CI 142-729). In general, the U.S. crushed stone workers were not exposed to other

suspected pulmonary carcinogens (with the exception of one operation where asbestos

exposure was found). Smoking data were not available for the cohort.

I.C.2.d. Finnish Granite Workers.

In this study, Koskela et al. (1987) examined lung cancer mortality in a cohort of

1,026 granite workers. Follow-up was from 1972 to 1981 with a total of 20,165 personyears of observation. The SMR for lung cancer mortality was elevated for the cohort

overall (SMR = 129, 22 deaths), but the report did not state whether this increase was
103

statistically significant, nor was the confidence interval provided. Mortality from lung

cancer was increased for workers with at least 15 years of job tenure (SMR = 221, p <

0.01, 21 deaths).

Airborne concentration data was available predominately from 1970 to 1972,

from air sampling conducted by the Finnish Institute of Occupational Health. Most of the

airborne concentration measurements were from personal sampling using a cyclone preselector. Airborne concentration ranges were provided for major work operations such as

drilling, pneumatic hammering, rock surfacing and other activities. Airborne

concentration monitoring, according to Mannetje et al. (2002a), was of total and

respirable dust and respirable silica content as determined by XRD. This is a relatively

small cohort with only 9 years of average exposure to relatively high silica airborne

concentration levels ranging from 0.3 – 4.9 mg/m3. The referenced exposure study was

in Finnish and has not been reviewed by OSHA.

There was minimal potential confounding in this study by other occupational

carcinogens. Smoking histories were obtained from relatives retrospectively and may

therefore be subject to recall bias. The authors stated that smoking rates were similar to

those of other occupational cohorts of a similar time period (data not provided).

Koskela et al. (1990) extended follow-up from 1981 to 1985 for a total of 13 years

of follow-up. The SMR for lung cancer mortality was 156 (31 observed deaths, 95% CI

106-221) and for workers followed for at least 15 years, the SMR was 220 (28 observed

deaths, 95% CI 147-319). Geometric mean quartz concentrations were reported by the

authors to range from 1.0 to 1.5 mg/m3based on the data described by Koskela et al.

(1987). Smoking and previous non-quarry occupational exposure histories were analyzed

by questionnaire. Confounding due to previous exposure to other occupational

carcinogens for more than 5 years was limited to only 33 workers and smoking data were

obtained for 75 percent of the cohort and indicated that smoking habits were similar to

other Finnish workers (Koskela et al., 1990).

Koskela et al. (1994) extended follow-up from 1981 to 1989 and conducted a

case-control study of lung cancer mortality. This study also conducted a detailed

assessment of the type and qualities of granite mined including the percentage of quartz

content. The SMR for lung cancer mortality was 140 (31 observed deaths, 95% CI 98-

193). A nested case-control for lung cancer mortality was conducted for the 31 lung

cancer deaths with two referents for each case matched by age, year of entry and quality

of available industrial hygiene data. Geometric mean concentration was reported by the

authors as being between 1.0 to 1.5 mg/m3. Historical airborne concentration data were

reconstructed by an industrial hygienist, but details on the approach were not provided.

Pairwise comparison showed that only nine cases had clearly higher exposures than did

individual referents (Koskela et al., 1994). The authors examined mortality patterns by

region, type of granite, and relative percentage of silica in the granite. Workers for one

region that had low or no silica content in its granite rock experienced no elevated lung

cancer mortality rates. For workers in other regions the risk of lung cancer mortality

reflected workers’ estimated silica exposures. In the Vehma and Kuru regions, where
104

native rock contains a high percentage of silica, SMRs for lung cancer mortality were 126

(CI 71-208) and 211 (CI 120-342), respectively (Koskela et al., 1994, Table 4).

The studies conducted by Koskela et al. (1987, 1990, and 1994) demonstrated an

increased risk of lung cancer in granite workers. However, the quality of the airborne

concentration estimates is difficult to evaluate given the limited information provided in

the reports. As part of their IARC multi-center exposure-response study, Steenland et al.

(2001a) conducted an additional seven years of follow-up and reported finding a slight

positive exposure-response trend. However, a re-analysis of that data conducted as part

of an OSHA-sponsored uncertainty analysis (Toxichemica, Inc., 2004) found no apparent

exposure-response relationship between crystalline silica exposure and lung cancer

mortality after correcting a small number of errors in the assignment of cumulative

exposure values. It does not appear that lung cancer mortality was associated with

cumulative exposure to respirable silica dust in this cohort.

I.C.2.e. Chinese refractory brick workers.

Dong et al. (1995) conducted a retrospective cohort mortality study of 6,266 male

workers (silicotics and non-silicotics) employed before 1962 at 11 brick refractory plants

in China and followed between 1963 and 1985. Demographic and employment history

data were obtained through an interview and an examination of the personal records of

each plant (Dong et al., 1995). No airborne concentration monitoring results were

reported in the study. All deaths were determined from funeral allowance records at each

refractory plant and the underlying cause of death was obtained from medical records or

certificates and coded according to the Chinese classification of diseases. The

investigators calculated the standardized risk ratios (SRR) by comparing the mortality

rates of silica-exposed workers with those of a population of male steel workers. In order

to minimize confounding, steel workers ever exposed to known occupational carcinogens

or silica dusts were excluded from the referent population (methodological details not

provided). The investigators evaluated the smoking status, latency period, radiological

status, silicosis, and duration of employment in silica brick or silica clay brick

manufacturing. For the total cohort and for silicotics (as determined by chest X-ray,

profusion category 1 or higher), there were statistically significant excesses for lung

cancer mortality (SRRs of 1.49 (p < 0.01) and 2.10 (p < 0.01), respectively). Dong et al.

(1995) found a statistically significant excess of lung cancer mortality for both smoking

and nonsmoking silicotics (SRRs of 2.34 (p < 0.01) and 2.13 (p < 0.05), respectively).

Non-silicotics (48 percent of the population) showed an elevated but not statistically

significant SRR for lung cancer (SRR = 1.11).

These results suggested that, in this cohort, the workers with silicosis appeared to

be at a higher lung cancer risk. The investigators also found that the lung cancer risk

increased with increasing latency for the silicotics, but not for those who did not have

silicosis. There was a clear gradient for lung cancer by three Chinese radiological

categories (I, II, III) of silicosis (SRRs of 1.97, 2.34, and 2.55, respectively), as well as by

latency period (data not presented). To summarize, there was a statistically significant

excess risk of lung cancer in Chinese refractory brick workers who had radiographic
105

silicosis. The authors suggested that the excess lung cancer mortality observed may have

underestimated the true risk to the extent that workers with silicosis prematurely died of

that disease (Dong et al., 1995). Although the prevalence of silicosis in this cohort is

high (52 percent), the study presents no exposure data. Thus, it is not helpful in

ascertaining any dose-response relationship.

Xu et al. (1996b) in a case-control study found an increased odds ratio for lung

cancer mortality among refractory brick maintenance workers. Incident lung cancer

cases were defined as those having worked at the steelworks for 10 years or more and

diagnosed between 1987 and 1993. The refractory brick maintenance workers were a

subpopulation of 40 cases within a larger case-control study of 610 incident lung cancer

cases within a large iron and steelworks facility. Xu et al. (1996b) noted that refractory

brick workers with 15 years or more of work had a statistically significantly elevated

incidence of lung cancer (OR = 2.9, CI 1.4-5.9). Xu et al. (1996a, 1996b) noted it was

not possible to adequately distinguish the carcinogenic effects of silica from other dusts

as both silica and asbestos exposures were present in the refractory brick area.

I.C.2.f. Italian refractory brick workers.

A cohort of 231 workers actively employed as of January 1, 1960 was assembled

by Puntoni et al. (1988) from one refractory brick (firebrick) plant in Genova, Italy.

Follow-up was through the end of 1979 with the vital status being determined for the

entire cohort. Job assignment analysis was not conducted because of high employee

mobility between departments. No analysis by latency and length of exposure was

possible since neither the date of hire nor the age at hire were available. Smoking data

was not available and only limited cross-sectional airborne concentration data were

presented but not used in data analysis. Mortality for the brick worker cohort was

elevated for cancer of the lung, bronchus, trachea and pleura (SMR = 183, CI 91-327, 11

deaths) and for nonmalignant respiratory disease (SMR = 304, CI 177-486, observed

deaths 17, 11 of which were silicosis). This cohort was incorporated into a larger cohort

assembled by Merlo and discussed below.

Merlo et al. (1991) conducted a retrospective cohort study of 1,022 male

refractory brick workers employed for at least 6 months between 1954 and 1977 and

followed through 1986. The plant was opened in 1931 with production interrupted

between 1952 and 1957 to improve production and environmental controls. The authors

stated that worker exposures to crystalline silica prior to the mid-1950s were higher than

in later years. There was likely to be little chance of exposure to other carcinogens since

asbestos had never been used in the production processes and polyaromatic hydrocarbons

(PAH) levels were minimal (Merlo et al., 1991). Smoking information was not available

for the whole cohort but indirect adjustment for smoking had virtually no effect on

results. A marginally statistically significant excess of lung cancer mortality was

observed for brick workers (SMR 151, 95% CI 100-218, 28 deaths) compared to the

Italian male population. Analysis by year of employment revealed that the workers first

employed before 1957 (year of dust control introduction) had a statistically significantly

elevated SMR of 177 (95% CI 103-284, 17 deaths). Those employed after 1957 had a
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non-statistically significantly elevated SMR of 123 (95% CI 61-220, 11 deaths). A

statistically significant increase in lung cancer SMR was observed in the subgroup of

workers with 19 or more years since first exposure (SMR 201, 95% CI 107-344, 13

deaths). Brick workers’ mortality from other respiratory diseases, excluding silicosis,

was almost double the mortality rate due to lung cancer (respiratory disease SMR = 403,

lung cancer SMR = 224; CI not provided), in a highly exposed sub-cohort, that worked

prior to 1957 and had more than 19 years of plant experience.

Although cross-sectional industrial hygiene data were presented for respirable and

silica dust for areas of the brick plant for 1973 and 1975, they were not available for prior

years. There was no exposure analysis by job title, exposure groups or job-exposure

matrix presumably because of the job mobility reported by Puntoni et al. (1988). The

authors concluded that their findings supported a relationship between exposure to

crystalline silica and increased lung cancer mortality. This was particularly true for those

who worked prior to 1957, when exposures were higher, and for those who had greater

than 19 years of work.

I.C.2.g. South African gold miners.

There are a number of studies of lung cancer among South African gold miners,

including two case-control studies by Hessel et al. (1986, 1990) and three studies of two

different cohorts. The larger cohort was first investigated by Wyndham et al. (1986) with

a follow-up and cohort redefinition and accompanying nested case-control study by Reid

and Sluis-Cremer (1996). A smaller cohort study was conducted by Hnizdo and SluisCremer (1991), with a nested case-control study by Hnizdo et al. (1997).

Each of these studies relied on extensive dust concentration measurements and

engineering control observations compiled by Beadle and Bradley (1970), and published

by Page-Shipp and Harris (1972). These environmental assessments were conducted in

20 mines between 1956 and 1959 using three dust measurement techniques, which

included:

 Hand-held Konimeter samples taken at 10-minute intervals throughout the

shift (22,000 samples, all of which were ignited, acid treated, and

counted);

 Modified thermal precipitator samples (e.g., fitted with elutriators) taken

at 10-minute intervals throughout the shift (22,000 samples analyzed

before and after acid treatment with a photoelectric sensor to measure

surface area of respirable dust); and

 Standard thermal precipitator samples taken continuously throughout the

shift (650 area samples) analyzed before and after acid treatment by highpower light microscopy for particle count in at least 15 size ranges.
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Measurements were made while following approximately 650 gold miners

representing 11 occupational exposure groups throughout their work shifts. The

summary by Page-Shipp and Harris (1972) provided mean particle count and particle

surface area data as well as estimates of respirable dust mass concentration, which was

based on theoretical calculations using the surface area data.

Beadle and Bradley (1970) estimated that the percentage of quartz content of total

mine dust was 31 percent with high variability in the mines. The mine mean values

measured within 6 mines ranged from 14 percent to 57 percent. More recently,

Churchyard et al. (2004) reported that in South African gold mines the silica content of

respirable dust ranges ranged from 12 percent (SD = 5.6) to 16 percent (SD = 5.8) based

on two separate series of measurements using cyclonic air sampling and analysis by Xray diffraction.

One of the first investigations into whether exposure to respirable silica dust was

a risk factor for lung cancer was a case-control study by Hessel et al. (1986). Cases and

controls were selected from all deaths reported to the miners’ pension fund between

January 1979 and October 1983; this included all white miners with at least 15 years of

service, as well as some with less than 15 years of service if they chose to remain in the

fund. Two controls for each of the 133 lung cancer cases identified were matched by

year of birth and by smoking history. Exposure to silica for each case and control was

quantified by multiplying the number of shifts worked in an occupation with a weighting

factor assigned to reflect the relative degree of dustiness of that occupation. Occupations

were grouped into four levels of dustiness (non-dusty, low, moderate, and high). The

presence of silicosis was assessed by both radiographic and autopsy findings.

The authors found no association between lung cancer and a silica exposure

index, duration of employment, or number of shifts worked in high dust. The odds ratios

for lung cancer and either radiological or parenchymal silicosis at autopsy declined with

increasing exposure to dust. The authors also reported finding a non-statistically

significant trend toward increasing severity of parenchymal silicosis among lung cancer

cases, which they believed indicative of an increased susceptibility to silicosis among

lung cancer cases.

Hessel et al. (1990) conducted an expanded case-control study of necropsied

miners that included 231 primary lung tumor cases and 318 controls that died from 1975

to 1986 (excluding deaths that occurred in the same time frame as the earlier study).

Cases and controls were matched by age at death. Their findings showed no differences

between cases and controls in cumulative dust exposure, dust intensity, shifts employed

underground and shifts in high dust jobs. The odds ratio (OR) (adjusted for age at death,

smoking, and cumulative dust exposure by conditional logistic regression) for silicosis of

the parenchyma was 1.10 (95% CI 0.79-1.60); for silicosis of the pleura the OR was 0.80

(95% CI = 0.54-1.20); and for silicosis of the hilar lymph glands the OR was 1.29 (95%

CI = 0.83-2.00). No case-control differences were noted for any of the exposure

indicators, including cumulative dust exposure, total dusty shifts, and shifts in high dust.
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The authors conclude there is no apparent association between either silica dust exposure

or silicosis and lung cancer in this study population.

Wyndham et al. (1986) studied a cohort of 3,971 white South African gold miners

born between 1916 and 1930 who were alive and actively employed at the start of 1970

(ages 39-54), and who were followed for nine years. SMRs were based on mortality rates

of white South African males as the comparison population. There were 530 deaths

within the cohort with an SMR for all causes equal to 118. SMRs were statistically

significantly elevated for chronic respiratory disease (SMR = 165, 95% CI 108-243),

nephritis (SMR = 381, 95% CI 164-751) and heart disease (SMR = 115, 95% CI 100-

140). There were elevated risks for lung cancer (SMR = 161; 95% CI 115-220) and

gastric cancer (SMR = 157; 95% CI 78-281). The authors used a case-referent approach

to examine gold miner risk factors such as cumulative dust exposure and years employed

underground to further explore lung cancer, chronic respiratory disease and heart disease.

Smoking history was included in the model. For lung cancer mortality, the smokingadjusted risk ratio (RR) was 1.14 per 10 years employed underground (95% CI 0.63-2.05)

and 1.77 per 10 particle-years of underground exposure (95% CI 0.94-3.31). The authors

concluded that years employed underground was not a sensitive indicator of risk.

Reid and Sluis-Cremer (1996) published an 11-year follow-up study of the cohort

studied by Wyndham et al. (1986). This paper included a cohort and nested case-control

study of mortality comprised of 4,925 white-male South African gold miners to

determine whether dust exposure contributed to risk of lung cancer, chronic obstructive

pulmonary disease (COPD), or ischemic heart disease (IHD).

The cohort definition was less restrictive than that of Wyndham et al. (1986),

resulting in a larger study group, 4,925 versus 3,971. The cohort comprised white gold

miners, aged 39 to 54 at the start of 1970, who were still working as of January 1, 1970

and who had attended the Medical Bureau for Occupational Diseases for a required

physical exam in 1969. As such, the cohort represented virtually all of the miners who

were working in the region of interest as of the beginning of 1970. The Reid and SluisCremer (1996) study included workers of contractors and of mines who were not

members of the Mining Provident (Insurance) Fund. The vital status of the cohort was

followed through the end of 1989 (20 years of follow-up), and mortality was compared to

standardized ratios for all white male South Africans.

In the case-control study, cases included those miners who had died from any of

the three diseases of interest. For lung cancer and COPD cases, two controls for each

case were randomly selected from the cohort who was born the same year as the case and

who survived the case; one control was selected for each case of IHD. Under the

randomization procedure used by the authors, it was possible for a case for one disease to

be a matched control for a case for one of the other diseases of interest, and a miner could

have been selected as a control for two different disease cases. For the case-control

analysis, the authors presented the results only for miners who had at least 85 percent of

their service in gold mines and who worked underground for at least 15 percent of their

gold mining service. Eighty-seven percent of the cohort fulfilled these criteria. These
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case-control selection criteria were also used by Wyndham et al. (1986) with 93 percent

of the cohort having had more than 85 percent of their service in the gold mines. It

appears then that the broader cohort definition used by Reid and Sluis-Cremer (1996)

somewhat diluted the intensity of exposure of the overall cohort but would not likely

have affected the case-control analysis.

Airborne dust concentrations for the case-control analysis were estimated from

thermal precipitator particle count (after acid washing) data converted to respirable dust

mass, presumably the same data as described by Beadle and Bradley (1970) and PageShipp and Harris (1972). Seven occupational groups were defined based on degree of

dustiness and cumulative exposure for each case and control was determined by linking

occupation-specific mean dust exposure estimated for these seven occupation categories

with the miner’s occupational history and expressing the miner’s exposure as yearsmg/m3

. Cumulative exposure was calculated from the start of employment up to 5 years

before the death of each case for each case-control set; the average cumulative exposure

of subjects included in the case-control study was 3.7 mg/m3-years respirable dust over

an average of 27 years of service. Duration of employment was used as a surrogate for

exposure to radon and its progeny. Smoking history was abstracted from the physical

exam conducted in 1969. Analysis of the relationships between cumulative exposure,

number of shifts in underground mining, smoking history, and mortality was conducted

using conditional logistic regression (Reid and Sluis-Cremer, 1996).

The overall SMR for the 2,032 miners who had died was 129.6 (95% CI 124.0–

135.4), significantly higher than expected. The principal causes of excess mortality were

lung cancer (SMR = 139.8; 95% CI 117.8–164.6), ischemic heart disease (SMR = 124.1;

95% CI 115.0–133.7), COPD (SMR = 198.0, 95% CI 162.1–219.0), cirrhosis of the liver

(SMR = 155.3; 95% CI 113.3–207.9), and renal failure (SMR = 163.5, 95% CI 104.7–

243.3). The authors also observed additional causes of statistically significant excess

mortality involving the pulmonary system. These included: tuberculosis, bronchitis,

emphysema, chronic obstructive airways, pneumoconiosis, and corpulmonale. The casecontrol study indicated the principal risk factor for COPD, IHD, and lung cancer was

cigarette smoking. Cumulative exposure to respirable dust had a modest but not a

statistically significant effect on lung cancer mortality, with reported odds ratios of 1.08

(95% CI 0.94–1.2) and 1.12 (95% CI 0.97–1.3) excluding and including smoking,

respectively. Cumulative exposure was associated with a statistically significant increase

in COPD (OR = 1.23, 95% CI 1.0–1.5 without smoking in the model; OR = 1.20, 95% CI

1.0–1.4 with smoking in the model). However, the authors reported that none of the

COPD cases were non-smokers, suggesting to them that, in this study, exposure to dust

could cause COPD only in conjunction with smoking. Number of shifts of underground

service was not shown to increase lung cancer, COPD, or IHD mortality.

Reid and Sluis-Cremer (1996) concluded that little of the 30-percent excess

mortality seen in this cohort was likely attributable to dust exposure and that the excess

was better explained by a greater prevalence among miners of unhealthy lifestyles

compared to South African white males, given that 86 percent of the cohort had smoking

histories and that the main causes of mortality (lung cancer, IHD, COPD, liver cirrhosis)
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are known to be associated with smoking and excessive alcohol consumption. The

authors also suggested that lifestyle factors could have interacted with risk factors in the

mine environment to increase the risk of some of these diseases, such as the combination

of dust exposure and smoking to produce COPD.

Hnizdo and Sluis-Cremer (1991) studied 2209 South African white male gold

miners who began mining between 1936 and 1943 and who were evaluated for

respiratory disease between 1968 and 1971. Mortality was followed from 1968 to 1986.

The study objectives were:

 To evaluate dose-response relationships between exposure to silica dust

and lung cancer risk;

 To examine the combined effect of exposure to silica dust and smoking;

and

 To investigate the association between lung cancer and silicosis detected

at necropsy.

Miners were selected for the cohort only if they were between the ages of 45 and

54 at the time of the pulmonary disease survey and had a minimum of 10 years of

underground gold mining experience. Vital status was ascertained using files of several

South African sources, and causes of death were determined from the best available

evidence, including the extensive postmortem records maintained for medico-legal

purposes (84 percent of deceased subjects had an autopsy). Of the 945 deaths (43 percent

of the cohort), there were 77 lung cancer deaths accepted (66 confirmed by necropsy, five

by biopsy, and six from the death certificate). To estimate silica exposures for the cohort,

the authors relied on mean respirable particle count data for 11 occupational groups, as

developed by Beadle (1971) and described above. Cumulative dust measures were

calculated by multiplying the number of shifts worked in each occupation by the mean

respirable dust count for that occupational group; cumulative exposures were expressed

as respirable particle-years. Smoking information was obtained from the 1968-71

pulmonary disease survey and was checked for changes in smoking status from the

miners' longitudinal medical files. Overall, the authors showed that, in contrast with the

rest of the cohort, the 77 cases of lung cancer had higher cumulative silica exposures,

smoked more, and had a greater percentage of miners who had ever smoked (96% vs.

88%), had poorer pulmonary function, and had more respiratory disease than the rest of

the cohort.

Using a Cox proportional hazards model, smoking produced a highly significant

(p < 0.001) correlation with lung cancer risk in models that adjusted for age. In models

that adjusted for age and cigarette equivalent pack-years (to account for pipe smoking),

the following four cumulative dust variables were statistically significant predictors of

lung cancer mortality: particle-years accumulated to 1949 (p < 0.01); particle years

accumulated to 1959 (p < 0.05); particle-years accumulated to start of follow-up in 1968

(p < 0.01); and particle-years accumulated to end of follow up in 1986 (p <0.05). There
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was an increasing trend in the relative risk for lung cancer for both increasing cumulative

exposure and smoking. Based on the proportional hazards model, the authors estimated a

relative risk for lung cancer of 1.023 (95% CI = 1.005 to 1.042) per 1,000 particle-years

of exposure, after adjusting for smoking and year of birth. This means that the most

veteran white gold miners (all employed more than 10 years) exposed to 50,000 particleyears of silica dust would have 3.18 times greater risk of dying from lung cancer than

those exposed to only 15,000 particle-years. Analysis using a general relative risk model

indicated that the combined effect of exposure to silica dust and smoking was greater

than the sum of individual effects. The synergy appeared to be greatest for miners with

more than 35 pack-years of smoking history and more than 30,000 particle-years of

exposure (Hnizdo and Sluis-Cremer, 1991).

Of the 945 deaths in the cohort, autopsy reports were available for 745 that

permitted the investigators to examine lung cancer risk and the presence of silicosis.

After adjusting for age at death, cumulative exposure, and pack-years, lung cancer was

found to be associated with silicosis of the hilar glands (OR = 1.2, 95% CI 10.7-2.0) but

not with silicosis of the lung or of the pleura (OR = 0.9, 95% CI 0.5-1.6).

Hnizdo and Sluis-Cremer (1991) concluded that their study showed a statistically

significant exposure-response relationship between exposure to silica dust, pack-years of

smoking, and lung cancer mortality. The results of this study were consistent with those

of another cohort study (Wyndham et al., 1986), but not with the two case-control studies

conducted up to that time (Hessel et al., 1986, 1990). Hnizdo et al. (1991) suggested that

since exposure to silica is known to increase all-cause mortality, it is possible that

controls from the Hessel studies had sufficient exposure to result in overmatching of

cases and controls with respect to exposure, making it more likely that a weak association

would go undetected.km

Hnizdo and Sluis-Cremer (1991) also raised the possibility that radon exposure

may have confounded the associations reported with silica dust. Although they

acknowledged that radon exposure was generally considered to be low (an average

working level of 0.4 WL ranging from 0.1 to 3.0 WL) miners having more than 20 years

of experience at least theoretically could accumulate a level of radon exposure that has

been associated with an increased risk of lung cancer.

Hnizdo et al. (1997) conducted a nested case-control study from their earlier

cohort study (Hnizdo and Sluis-Cremer, 1991) to investigate relationships between lung

cancer mortality and smoking, cumulative silica dust exposure, years of underground

mining, silicosis, lung cancer cell type, and history of uranium ore exposure. The authors

identified 78 cases of lung cancer (for which necropsy data were available for 69) and

386 controls (5 controls per case). The controls were matched for year of birth and

survival of the case. Mean exposures to respirable dust were estimated for nine

occupational categories based on the measurements that had been taken in the 1960’s and

estimates of the average time spent underground in each occupation (Page-Shipp and

Harris, 1972). Dust exposure for each study subject was determined by combining
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his/her occupational history with the estimated average respirable dust exposure for each

of the occupation categories. The measures of exposure were cumulative dust exposure

(CDE = ∑DiTi, with CDE = cumulative dust exposure [mg/m3-years], Di = dust for ith job

and Ti, = time spent in the ith job) or years spent in dusty jobs. Exposures were lagged 0,

5, 10, and 20 years. Exposure to radon gas and its progeny was estimated indirectly

based on mine-specific data on annual uranium production and grade of uranium ore.

Smoking habits were obtained from questionnaires administered during each miner’s

regular medical evaluation. The presence of radiological silicosis was assessed from

chest X-ray films; year of onset of silicosis was defined as the earliest film categorized as

ILO 1/1 or higher up to three years prior to death.

Lung cancer mortality was found to be associated with cigarette smoking,

cumulative dust exposure (with and without a 20-year lag), silicosis, and duration of

underground mining (with and without a 20-year lag). The most significant predictors

showing a dose-response trend were cumulative dust exposure and duration of

underground mining, both lagged by 20 years prior to the death of the case. When

silicosis was added to the model, lung cancer mortality was associated with the

occurrence of silicosis (RR = 2.45, 95% CI 1.2-5.2) and smoking but was no longer

associated with cumulative exposure and years of underground mining. Although Hnizdo

et al. (1997) acknowledged that this finding might suggest that silicosis is a more

important risk factor for lung cancer than silica exposure, they pointed out that the

relationship between cumulative exposures, years in underground mining, and silicosis is

complex, and that these variables are highly correlated. Thus, it is not possible to say

with certainty that these results indicate silicosis, and not just exposure to silica, increases

the risk of lung cancer. In addition, the results of this study showed a multiplicative

effect of smoking and silicosis on lung cancer; the cohort study (Hnizdo et al., 1991)

showed a similar multiplicative effect of smoking and cumulative silica exposure on lung

cancer mortality.

The authors found no significant association of lung cancer with variables

representing uranium production and the grade of the uranium ore. As discussed above,

the level of radon exposure in this cohort was low (average = 0.4 WL) compared to other

cohorts of uranium miners, but high enough to potentially have some confounding effect

on a silica-lung cancer association.

According to the authors, the correlations between exposure and silicosis

variables in this study make it difficult to draw causal inferences. They suggested their

results are consistent with three possible causal relationships: (1) subjects with high dust

exposure who develop silicosis are at increased risk of lung cancer; (2) high levels of

exposure to silica dust on its own is important in the pathogenesis of lung cancer and

silicosis is coincidental; and (3) the increased lung cancer risk reflects time spent working

underground in high levels of dust and with potential radon exposure.

Overall, two cohort studies (Reid and Sluis-Cremer, 1996 and Wyndham et al.,

1986, with essentially the same cohort, and Hnizdo et al., 1991) demonstrated excess

lung cancer mortality among South African miners exposed to respirable silica-
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containing dust; however, in each of these studies, potential confounding by smoking

and/or exposure to radon cannot be ruled out. Of the four case-control studies (Hessel et

al., 1986, 1990; Hnizdo et al., 1997; Reid and Sluis-Cremer, 1996), only that by Hnizdo

et al. (1997) found statistically significant increases in lung cancer risk that were

associated with increases in dust exposure, time spent underground, or radiographic

silicosis. Although Reid and Sluis-Cremer (1996) did not find a statistically significant

correlation between lung cancer and dust exposure, their reported elevated odds ratios

were nearly so, both with and without including smoking as a co-variable. As such,

OSHA believes that their results are not wholly inconsistent with the findings of the casecontrol study by Hnizdo et al. (1997). The earlier case-control studies by Hessel et al.

(1986, 1990) also failed to find statistically significant associations between dust

exposure and increased lung cancer risk, but Hnizdo et al. (1991, 1997) have suggested

that these studies might have been biased towards the null by overmatching for exposure

and including smoking as a matching criteria (in Hessel et al., 1986), or by not matching

on date of birth (in Hessel et al., 1990). Furthermore, OSHA notes that the Hnizdo et al.

cohort (1991) and case-control (1997) studies used the most detailed approaches for

estimating miners’ cumulative exposures in terms of defining occupational categories and

estimating their respective mean exposure levels, thus reducing the potential for exposure

misclassification that would make it more difficult to see a modest association between

lung cancer and exposure to silica dust. Although not conclusive in isolation, OSHA

believes the body of evidence from the South African studies is suggestive of an

exposure-related association with lung cancer.

I.C.2.h. Western Australia gold miners.

Armstrong et al. (1979) conducted a cohort study of 1974 gold miners and 213

coal miners in the Kalgoorlie area of Western Australia. This discussion will be limited

to the findings of the gold miner cohort. The cohort was defined as underground and

above-ground gold miners that participated in respiratory medical surveys in 1960 and

1961 that included a questionnaire on respiratory, smoking and occupational histories and

radiological evidence of pneumoconiosis. Follow-up was to the end of 1975 for 13-14

years of follow-up. The gold miner cohort experienced 500 deaths, slightly less than 25

percent of the cohort for a total of 15,551 man-years of follow-up. Within this cohort,

there was statistically significant (p < 0.01) excess mortality for lung cancer (ratio of

observed to expected cases (O/E ratio = 1.4, 59 deaths) silicosis (O/E ratio = 6.4, 11

deaths) and accidental death (O/E ratio = 2.9, 13 deaths). Underground miners had

increased risk of respiratory cancer mortality in comparison to above-ground miners (RR

= 1.41, 95% CI 0.69-2.96). There was an observed trend of increased respiratory cancer

mortality with increased employment duration underground but the trend was not

statistically significant. There was a slight, but not statistically significant, association

between radiographic evidence of silicosis and death from respiratory cancer (RR = 1.13,

95% CI 0.64-1.98).

Potential confounding by arsenic and radon was addressed by the authors.

Average levels of arsenic from bulk samples of mine rock was 49 parts per million with a

maximum concentration of 335 parts per million. Air measurements were not provided.
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Maximum air measurements of radon and radon daughters were 11 picocuries (pci) for

radon and a working level of 0.045 pci for radon daughters. Armstrong et al. (1979)

explained that even the maximal levels measured were substantially below those that

have been associated with lung cancer in other studies.

No exposure assessments for respirable dust or silica were conducted or

discussed, nor were analyses conducted by job title or mine work area as a surrogate for

exposure. Respiratory cancer mortality was strongly associated with cigarette smoking

and smoking prevalence was higher among gold miners (66.3%) than for an external

south-west Australia reference group (53.2%). The authors provided evidence of an

interaction between lifetime smoking and duration of underground exposure (Table 6 of

Armstrong et al., 1979) and stated that cigarette smoking probably explained at least part

of the respiratory cancer mortality excess.

De Klerk and Musk (1998) conducted a follow-up of a slightly larger cohort of

2,297 gold miners from Kalgoorlie in Western Australia who participated in surveys of

respiratory symptoms, and smoking, and employment histories in 1961-1962 and 1974-

1975; it was estimated that 95 percent of miners participated in these surveys. The cohort

was followed to the end of 1993 for 30 years of follow-up for lung cancer mortality and

incidence of compensation for silicosis.

Complete work histories obtained from the clinic conducting the respiratory

surveillance were used to develop an exposure matrix. Detailed measurements of dust

counts were not available for the period 1925 to 1976. Semi-quantitative estimates of

average and cumulative dust exposure were made by a panel of experts who ranked jobs

based on dustiness on a scale of 1 to 10 of increasing dustiness, taking into account

changes in dust control technology and procedures. Estimates of average and cumulative

exposure to silica were made separately for underground and surface mining activity as

the sum of the products of each miner’s time spent in each job and the dustiness rank for

each job.

More than half (1,386) of the cohort had died by the end of the follow-up, and 631

had been compensated for silicosis. Eighty-four percent of the men in the cohort had

smoked at some time and 66 percent were current smokers. The median number of

months employed in gold mining was 192 (range 0-594) underground and 50 (range 0-

586) in surface activities.

SMRs were calculated using Western Australia mortality rates (specific for age,

calendar period, and gender) and using two alternative methods for censoring data from

subjects lost to follow-up (257) to provide lower- and upper-bound estimates of the true

SMR. The lower- and upper-bound estimates of the SMR for lung cancer were

statistically significantly increased (lower SMR 126, 95% CI 107-159; upper SMR 149,

95% CI 126-176). A nested case-control analysis of 138 lung cancer deaths showed that

lung cancer mortality was associated with log cumulative silica exposure (RR = 1.31 per

unit of log (exposure-score year); 95% CI 1.01-1.70) after adjustment for smoking and

bronchitis; however, the association between log cumulative silica exposure and lung
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cancer mortality was not statistically significant after adjustment for smoking, bronchitis

and occurrence of silicosis, although the relative risk was still increased [RR = 1.20 per

unit of log (exposure-score year); 95% CI 0.92-1.56]. The effect of the silicosis variable

in the logistic regression model became slightly less influential with increasing time since

diagnosis, and had its strongest effect 0 to 1 years after diagnosis. Duration of

underground employment was not statistically significantly related to lung cancer

mortality (p > 0.15) after adjustment for smoking and bronchitis. There was no

discussion of potential confounding due to other potential occupational exposures,

although Armstrong et al. (1979) partially addressed arsenic exposure and thoroughly

addressed radon exposures.

The authors concluded that their findings showed significantly increased lung

cancer and pneumoconiosis mortality in this cohort and that the increase in lung cancer

mortality was restricted to miners who had received compensation for silicosis. Since

silicosis had its strongest effect on lung cancer mortality almost immediately following

diagnosis and compensation, the authors believed it possible that lung cancer arose in

these subjects from localized immune suppression caused by silicosis. However, since

compensated silicosis was strongly associated with cumulative dust exposure, the authors

noted that the results could not definitively confirm the role of silicosis or dust exposure

in lung cancer mortality.

I.C.2.i. U.S. gold miners.

A number of studies were conducted that examined the health risk to workers

employed at the Homestake Gold Mine in Lead, South Dakota (Brown et al., 1986;

Gillam et al., 1976; Steenland and Brown, 1995a, 1995b). The first by Gillam et al.

(1976) was a retrospective cohort study of 440 male miners who were employed for at

least 5 years in underground jobs and who had never worked in another underground

mine. These men were followed from 1960 to 1973. A SMR of 370 (p < 0.01) was

reported for pulmonary malignancies. The authors reported that crystalline silica

concentrations were not apparently elevated and arsenic, chromium, and nickel were

present in trace concentrations; radon daughters were not detected. The authors

postulated that the lung cancer excess was related to exposure to asbestos-like

cummingtonite-grunerite fibers in combination with cigarette smoking and a possible

additive role for crystalline silica was proposed. In contrast, Brown et al. (1986) failed to

find an excess of lung cancer mortality among 3,328 miners followed through June 1977,

nor was there a trend with estimated cumulative exposure to silica or with latency.

Steenland and Brown (1995a) studied the same cohort as Brown et al. (1986) and

extended the follow-up period by 14 years, through 1990. There were a total of 1,551

deaths in the cohort (47%), including 115 from lung cancer (compared to 861 total deaths

(26%) and 43 lung cancer deaths reported by Brown et al., 1986). The cohort included

workers who worked underground for at least 1 year between 1940 and 1965; most of the

cohort was first employed before 1950.
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Cumulative exposures were estimated using a job-exposure matrix in which

underground jobs were grouped into five major categories based on similarities in job

function and exposure to dust. A sixth category included all jobs that were not full time.

Average dust exposures were calculated for each job category using company

measurements of particle count concentrations taken between 1937 and 1975. The silica

content of respirable dust was estimated to be 13 percent, while that of settled dust was

estimated to be 39 percent (Zumwalde et al., 1981). Prior to 1950, the silica exposure

levels were estimated to range from 10 to 30 mppcf, which was about 1 to 3 times higher

than the then-recommended ACGIH TLV, but lower than dust levels reported for other

industry sectors. After implementation of dust controls in 1950, dust levels fell below the

TLV. Using a conversion factor derived from studies of the Vermont granite sheds,

where silica content was similar to that seen in the gold mine, the authors estimated the

median of the miners’ average exposure levels to be 0.05 mg/m3respirable quartz. The

medians of the average exposure levels prior to 1930, between 1930 and 1950, and after

1950 were estimated to be 0.15, 0.07, and 0.02 mg/m3, respectively.

Miners were also exposed to a variety of non-asbestiform minerals, principally

cummingtonite-gunnerite and tremolite-actinolite. Exposure to the potential lung

carcinogens arsenic and radon were below the existing OSHA and MSHA standards,

respectively, when measured in the mid-1970s.

Smoking data were available for 602 men aged 35 to 64; these data indicated only

small differences in smoking habits between the gold mine workers and the general U.S.

population and lung cancer rates were estimated to reflect these differences. SMRs were

calculated using U.S. or local rates for overall mortality. In addition, the authors

conducted a nested case-control study selecting five age-matched controls for each case.

The researchers found a slight excess of lung cancer (not statistically significant)

for the cohort as a whole (SMR = 113 with 95% CI 94-136 based on the national rate)

and no evidence of an exposure-response association, even though a clear exposureresponse trend was found for respiratory tuberculosis and pneumoconiosis. The SMRs

for lung cancer among workers followed for 30 or more years from the first underground

employment and for workers in the highest exposure category were 127 (95% CI 102-

155) and 131 (95% CI 87-189), respectively. Trends with duration of exposure were

inconsistent. When local county or South Dakota rates were used as the referent rates,

SMRs for lung cancer were 125 (95% CI 103-151) for workers followed for 30 or more

years and 159 (95% CI 131-192) for the most highly exposed workers. A nested casecontrol analysis of the 115 lung cancers and a set of matched controls failed to show a

relationship between lung cancer and cumulative dust exposure (Steenland and Brown,

1995a). There was also no apparent relationship between lung cancer and the mention of

silicosis on death certificates. Based on the available smoking data, Steenland and

Brown (1995a) estimated the lung cancer risk ratio attributable to smoking to be 1.07.

The authors reported finding elevated mortality from a variety of other causes,

including nonmalignant renal disease, arthritis, systemic lupus, sclerosis, lupus and

scleroderma. Renal disease mortality was elevated among the most highly exposed
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workers (those hired prior to 1930) and showed a significant exposure-response trend.

The authors concluded that there was an excess of lung cancer in the cohort but that the

excess was not related to estimated cumulative dust exposure, a finding in contrast to

other studies of gold miners (de Klerk and Musk, 1998; Hnizdo and Sluis-Cremer, 1991;

Wyndham et al., 1986). Although the reasons for this discrepancy are not known, the

authors suggested differences in the biological activity of minerals present in the mines

and potential confounding in the positive studies by exposures to radon or arsenic as

explanations.

I.C.2.j. Chinese tin and tungsten miners.

A series of mortality and nested case-control studies have been conducted on a

cohort of Chinese tin miners. The early studies in the series (Chen et al., 1992;

McLaughlin et al., 1992) also included other metal mining and pottery workers. The

cohort was comprised of over 68,000 workers from 21 mines and 8 factories, including

10 tungsten mines (n = 28,481), six copper/iron mines, 8 potteries, 1 clay mine, and 4 tin

mines (n = 7,875). The results for the pottery workers will be discussed in Section 3.n

below.

The first study in the series (Chen et al., 1992) was a mortality study of tin and

tungsten mineworkers were employed for at least one year between 1972 and 1974 with

follow-up through 1989. Operations in all the workplaces began before 1949, although

there were government reorganizations and expansion between 1952 and 1957. The

mean age at entry into the cohort in 1972 to 1974 was 34 years. Less than 2 percent of

the cohort had begun employment before 1950, 50 percent began during 1950 to 1959,

and 47 percent began during 1960 to 1974. Historic data from workplace air sampling

for total dust (mg/m3), percent free silica, and particle size from the 1950s through the

1980s were used to estimate an exposure level for every dust-exposed job in each of

several calendar-year periods. Based on job-specific exposure estimates, each cohort

member was classified into one of four total dust exposure levels: high (43 percent of

cohort), medium (15 percent), low (7 percent), and non-exposed (35 percent). If a worker

had more than one job, their exposure estimate was based on the job having the highest

dust exposure level provided the worker worked in that job for at least one year. Vital

status and cause of death information was obtained mainly from employment registers,

accident records, and medical records. Silicosis registries had been required in all

workplaces where silica exposure occurred after 1963 and annual chest x-rays were

routinely taken.

Lung cancer mortality was statistically significantly increased only for tin miners

(not for other miners) for the periods 1972 to 1989 (SMR = 198) and for 1985 to 1989

(SMR = 262). (Confidence intervals not provided.) The authors also reported a rising

trend in the risks for lung cancer with increasing dust exposure only for tin miners: the

relative risks and 95 percent confidence intervals for medium- and high-exposure groups

relative to non/low-exposure groups were 1.15 (0.4-3.3) and 1.72 (1.1-2.7), respectively.

For the cohort overall, there was no increased relative risk for lung cancer (SMR = 78)

nor an increased gradient of risk for the medium- and high-exposure groups relative to
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the low-exposure groups. Also, for the cohort overall there was a non-statistically

significant excess risk of lung cancer in silicotics (RR = 1.22, 95% CI 0.9-1.6).

McLaughlin et al. (1992) conducted a nested case-control study of lung cancer in

the same cohort of silica-exposed Chinese workers as was studied by Chen et al. (1992).

The analysis was based on a job-exposure matrix developed by Dosemeci et al. (1993).

Total dust exposure data was available from routine company surveys between 1950 and

1987. All dust exposure data were static area total dust measurements with sample time

intervals of 20 to 30 minutes and were analyzed gravimetrically. Approximately 2

million dust measurement records were abstracted for tin, tungsten, copper and iron

mines. Assignments of exposure were by plant, job, and calendar year. Approximately

51 percent of the exposure assignments for workers in tin mines, tungsten mines and

potteries were based on quantitative data. This ranged from 1 to 2 percent for the early

1950s to approximately 70 percent in the 1980s. For exposures prior to 1950, the 1950

exposure data were applied. Less than 2 percent of the workforce started work prior to

1950 (McLaughlin et al., 1992).

The percentage of silica in the dust was less well characterized as it was based on

134 settled dust samples and was only available for 14 percent of the exposure

assignments with the earliest exposures being more poorly characterized than later

exposures. Data regarding the silica content of the total dust were available at the facility

level only due to lack of specific measurements historically by job title or process type

(Dosemeci et al., 1993; Zhuang et al., 2001).

In 1988 to 1989, side-by-side measurements using the Chinese method for total

dust sampling and the U.S. method for sampling respirable dust were done in 9 potteries

and 20 mines as a special sampling survey conducted by the Tongji Medical College,

China, and NIOSH, USA. Three sampling sites were selected at each mine or pottery to

be distinct exposure zones representative of high, medium, and low dust levels as

determined from historic Chinese sampling data. Respirable dust samples were obtained

gravimetrically from 10-mm nylon cyclone samples collected over 8-hour shifts.

Sampling lasted typically two days per mine or plant with three respirable samples per

day for a total of 120 respirable personal air samples (tin mines - 10, tungsten mines - 56,

and potteries - 54). The cyclone samples were analyzed both gravimetrically and by

XRD to determine respirable dust and respirable silica dust concentrations, respectively.

A conversion factor was developed to convert Chinese settled dust silica estimates into

crystalline silica content of respirable dust collected by 10 millimeter cyclone and

analyzed by XRD. The Chinese method washes the sample with phosphoric acid,

removing most non-crystalline silica and then analyzing the residual by colorimetric

analysis. The ratio of the silica content between the two methods is applied to the

historical estimates of the percentage of crystalline silica in each mine. In general, bulk

samples contain a higher percentage of crystalline silica then a corresponding respirable

air sampling, but this can vary by industrial process (Dosemeci et al., 1993; Zhuang et al.,

2001).
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Job-specific data from workplace air samplings for total dust (mg/m3) and the

percentage of silica by mine as collected in settled dust were multiplied together for each

cell in the job exposure matrix for each of several calendar-year periods. Based on these

job-specific exposure estimates, each case or control was classified without knowledge of

disease status into one of four silica exposure levels: high, medium, low, and nonexposed (McLaughlin et al., 1992).

The authors analyzed the mortality data by cumulative exposure to dust and

arsenic, via categorical analyses (3 categories for dust, 4 categories for arsenic).

Extensive dust measurements over time allowed the development of an accurate jobexposure matrix for dust. In contrast, historical data on arsenic exposure were very

limited given that no arsenic air measurements were taken prior to 1988. Therefore, for

exposures prior to 1988, the job-exposure matrix for arsenic was based on the percentage

of arsenic in settled dust samples, for which limited historical data were available.

The tin miner nested case-control study consisted of 87 cases and 371 controls

and the tungsten miner study consisted of 93 cases and 400 controls. Up to four controls

from the cohort were selected for each case and matched based on working in the same

mine and by decade of birth (age).

The highest risks for lung cancer mortality were seen in tin miners, followed by

pottery workers (discussed separately below). A reverse trend of decreasing risk with

increasing exposure was observed in tungsten miners. Odds ratios for tin miners were 1.5

(no-low exposure, 0.1-8.69 μg/m3-yr), 1.9 (medium exposure, 8.70-26.2 μg/m3-yr), and

3.1 (high exposure, >26.3 μg/m3-yr) for cumulative respirable silica exposure and were

statistically significant (p for trend = 0.004). Among tin miners, increasing exposure to

arsenic was significantly associated with the risk of lung cancer, whereas exposures to

polyaromatic hydrocarbons (PAHs) were less consistently linked to increased risk of lung

cancer. Arsenic and PAHs were highly correlated with silica exposures (r = 0.80). This

prevented the authors from adjusting for these confounders in the analysis. Cigarette

smoking was associated with lung cancer in all the cohorts studied, but the correction for

smoking did not influence the association between silica and lung cancer (McLaughlin et

al., 1992).

An additional examination of the interaction of other carcinogens (cadmium,

nickel, radon daughters, arsenic, and polyaromatic hydrocarbons) with silicosis in this

cohort was conducted by Cocco et al. (2001) using data from the nested case-control

study of McLaughlin et al. (1992). In this study, data from all 29 worksites were pooled.

The authors were able to obtain, for each worker, information on silicosis stage at first

diagnosis, any subsequent changes in radiological diagnosis and staging, and the dates of

diagnosis. A “modest” association was observed between silica exposure and lung

cancer risk, with a statistically significantly increased odds ratio of 1.6 (95% CI 1.1-2.4)

in the third quartile of cumulative exposure to respirable silica (10.8-26.9 mg/m3-yr).

However, although the odds ratio for exposure in the fourth quartile (≥ 27 mg/m3-yr) was

elevated, it was not statistically significantly increased (1.2, 95% CI 0.8-1.9). These risk

estimates associated with silica exposure did not change with limiting the analysis to non-
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silicotics or with radiological stage of silicosis. A “modest” association was also

observed between silicosis and lung cancer risk (OR 1.4, 95% CI 1.1-2.0). Although

odds ratios for lung cancer among silicotics were not increased with cumulative exposure

to respirable silica, the odds ratios increased by severity of silicosis. The trend was

statistically significant among workers in the first three levels of cumulative silica

exposure but not among those in the higher exposure group. This association did not

vary by severity of silicosis, disease progression, or level of silica exposure. Among

silicotics, lung cancer risk was significantly increased only with co-exposure to cadmium

and polyaromatic hydrocarbons. In the cohort overall, lung cancer risk associated with

silica exposure stratified by exposure to the other carcinogens noted above showed that

lung cancer risk was more evident among workers exposed to silica but unexposed to

nickel, radon daughters, or poly aromatic hydrocarbons. Risk associated with silica

exposure did not vary among workers by exposure to arsenic and cadmium. Cocco et al.

(2001) believed, however, that strong correlations between exposures to the different

agents prevented a detailed evaluation of the role of individual agents. Also, no isolated

exposure to the other lung carcinogens occurred in the study. The authors called for

further research to resolve the issues involving this complex pattern of interactions.

Chen and Chen (2002) analyzed the same cohort for the four Chinese tin mines (n

= 7,855) as were analyzed by McLaughlin et al. (1992). Mortality follow-up was

extended through 1994 and the cohort had experienced 1034 total deaths (13% of the

cohort) by the end of the follow-up period. The investigators used a nested case-control

analysis that included 130 lung cancer deaths and 627 controls. Up to five controls were

individually matched to cases based on date of birth, gender, and mine. Smoking data

were collected from next-of-kin. The previously discussed exposure matrix created by

Dosemeci et al. (1993) was modified for use in this study.

Chinese exposure data from 1990 to 1992 were added to the job-exposure matrix

that developed by Dosemeci et al. (1993). Zhuang et al. (2001) estimated conversion

factors for converting Chinese total dust measurements to current respirable silica dust

measurements based on the side-by-side samples and by calculating the ratio of respirable

silica measurements to the total dust measurements. The intent was to create an

appropriate composite correction factor for each industry. The industry-wide composite

conversion factors for converting Chinese total dust to US respirable silica dust was

0.0429 for tin mines. Respirable fraction of total dust was estimated to be 25 percent ± 4

percent and respirable silica concentration was estimated to be 3.6 percent ± 0.8 percent

of the total dust concentration (Gao et al., 2000; Zhuang et al., 2001).

Airborne arsenic concentrations were measured only after 1988. For the period

before that, arsenic concentration was estimated by multiplying the total dust

concentration by the arsenic content of the settled dust. Analyses were by contingency

tables and logistic regression. Chen and Chen (2002) analyzed the mortality data by

cumulative exposure to dust and arsenic, via categorical analyses (3 categories for dust, 4

categories for arsenic). Extensive dust measurements over time allowed the development

of an accurate job-exposure matrix for dust. In contrast, historical data on arsenic
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exposure were very limited given that no arsenic air measurements were taken prior to

1988.

Chen and Chen (2002) found strong, statistically significant positive exposureresponse trends for both total dust containing silica and arsenic. These values were

highly correlated (r = 0.82), making it difficult to separate the effects of arsenic- and

silica-containing dust. However, arsenic concentrations appeared to be low when

compared to historical studies showing arsenic exposure levels associated with lung

cancer. Measured arsenic (14 samples) among workers in “high” exposure jobs taken in

1988 or later showed a mean of 10μg/m3, which is the current permissible OSHA

standard. However, descriptive data presented in the paper indicated a mean cumulative

exposure of about 500 μg/m3-years for arsenic with a mean duration of exposure of 14

years, implying an average exposure concentration of 35 μg/m3. When a categorical

analysis was conducted comparing the effects of total dust and arsenic, the authors found

a statistically significant odds ratio of 2.0 (95% CI 1.1-3.7) for lung cancer mortality

among workers in the lowest arsenic exposure category compared with those having no

arsenic exposure. The authors also noted that the mean estimated level of arsenic

exposure in the lowest exposure category was 3.7 μg/m3; an exposure level where excess

lung cancer would not be expected.

These data were also analyzed using a number of unconditional logistic regression

models to assess the importance of various factors, including smoking, confounding

exposures, and the presence of silicosis. These models confirmed that smoking,

cumulative exposure to dust, duration of exposure to dust, and cumulative exposure to

arsenic were associated with the risk of lung cancer. Of the four tin mines studied, a

much lower arsenic concentration was found in one mine compared to the others. No

excess of lung cancer was found among workers from this mine despite there having been

a high prevalence of silicosis (as was also true of workers from the other mines). Dust

concentrations and percentages of silica in the dust were similar in the four mines. Chen

and Chen (2002) concluded that exposure to arsenic and smoking played a more

important role than silica exposure in lung carcinogenesis among these tin miners and

that silicosis seemed unrelated to the observed increased risk of lung cancer. The authors

believed that their results provided little support for the hypothesis that respirable silica

causes lung cancer.

Chen et al. (2006) conducted a five year follow-up through 1994 of the cohort

mortality study of Chen et al. (1992). Fourteen percent of the cohort had died by the end

of 1994 with the SMR for all causes of death similar to that of the national average.

Malignant neoplasm was the leading cause of death with elevated SMRs for cancer of the

nasopharynx (SMR = 341, CI 219-508, 24 deaths), liver cancer (SMR = 197, CI 163-235,

119 deaths), lung cancer (SMR = 249, CI 209-294, 138 deaths), and leukemia (SMR =

231, CI 129-382, 15 deaths) being statistically significantly elevated. Mortality from

pneumoconiosis was markedly high (SMR = 3389, CI 2691-4212, 81) and was

statistically significant.
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In contrast to the earlier study (Chen et al., 1992), this study utilized new data to

estimate exposure in quantitative units, rather than semi-quantitative units (Chen et al.,

2001). In a categorical analysis of four cumulative total dust exposure groups

(<0.1mg/m3-years, 0.1-29.99 mg/m3-years, 30-69.99 mg/m3-years, >70 mg/m3-years)

consistent increased mortality trends were noted in overall mortality and mortality due to

lung cancer, pneumoconiosis, pulmonary tuberculosis, and cardiovascular disease. In

comparison to the mortality in non-exposed miners, exposed miners experienced elevated

mortality for lung cancer (RR = 3.55; p < 0.01), respiratory disease (RR = 23.45; p <

0.01) and pulmonary tuberculosis (RR = 5.98; p < 0.01). The study also found that there

was a significant increase in lung cancer among silicotics in comparison to non-silicotics.

However, lung cancer mortality was also observed to increase with cumulative dust

exposure among workers without silicosis.

The authors concluded that their findings indicated “a positive dose-response

relation between exposure to cumulative dust and the mortality of lung cancer. High

arsenic content in dust particles, together with crystalline silica, may play an important

role in causing increased mortality from lung cancer” (Chen et al., 2006). Unlike the

previous paper on this cohort (Chen and Chen, 2002), no attempt was made to

disentangle the highly correlated exposures between arsenic and silica. However,

separate analyses were done for three mines from Dachang where arsenic concentrations

were high and one mine in Limu where there was much lower arsenic exposure. There

were differences observed in the trends for lung cancer risk between the Dachang and

Limu mines. The cumulative risk of lung cancer was significantly elevated in Dachang

mines but only slightly elevated in the Limu mine. The authors suggested that this

finding may have been due to the higher arsenic levels in the Dachang mine particles

since both Limu and Dachang particles had similar silica levels. However, since arsenic

exposure was highly correlated with silica dust exposures (r = 0.82), further isolating or

quantifying the effect of respirable silica in this cohort was not possible.

Three papers concerning principally arsenic and uranium exposures in Chinese tin

mines also reviewed silicosis or silica exposure in reference to lung cancer. Qiao et al.

(1997) raised the issue of either silicosis or silica exposure as posing a risk for lung

cancer in a study of Yunnan province tin miners who had elevated exposures to radon

and arsenic; the age adjusted relative risk for lung cancer mortality for radon was 3.91

and for arsenic, it was 4.94 when comparing workers in the highest to the lowest

exposure quartile. When the authors conducted a single variable analysis, the relative

risk of lung cancer for silicotics was 1.46 (95% CI 1.02-2.09), suggesting to the authors

that “silicosis appears to be in age-adjusted analysis to be a lung cancer risk factor...(and)

will require more detailed assessment of exposure to silica and adjustment for potential

confounders”.

Hua et al. (1992, 1994) published a cohort and a nested case-control study,

sequentially. In both papers no specific reference is made to silica exposure, but the

authors did examine silicosis as a risk factor in the case-control study. The cohort

consisted of 1,113 male Daching tin miners in which the authors found an exposureresponse relationship between metal ore dust exposure and lung cancer and an interaction
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between smoking and metal ore dust exposure. In the 1994 case-control study, Hua et al.

found that the presence of silicosis did not independently contribute to predicting risk in

the presence of other variables.

I.C.2.k. British coal miners exposed to respirable quartz.

Miller et al. (2007) and Miller and MacCalman (2009) reported on a follow-up of

a mortality study of British coal miners originally conducted by Miller et al. (1997). The

two follow-up reports on mortality analyzed a cohort of 17,800 miners and extended the

analysis through the end of 2005. By that time there were 516,431 person years of

observation, an average of 29 years per miner, with 10,698 deaths from all causes.

Causes of deaths of interest included pneumoconiosis, other non malignant respiratory

diseases (NMRD), lung cancer, stomach cancer, and tuberculosis. The authors noted that

no additional exposure measurements were included in the updated analysis, since all the

mines had closed by the mid 1980’s. However, some of these men might have had

additional exposure at other mines or facilities, not reported in this study. (One of these

coal mines has already been discussed in Section I.3.a, above, for the relationship of

silica exposure and silicosis progression and morbidity among 547 miners exposed to

high levels of quartz during the early to mid 1970’s.)

For this cohort mortality study there were analyses using both external and

internal controls. The external controls used British administrative regional age-time and

cause specific mortality rates from which to make standardized mortality rate (SMR)

calculations. The internal controls from the mines used Cox’s proportional hazards

regression methods, which allowed for each individual miner’s measurements of age and

smoking status, as well as the individual’s detailed dust and quartz time-dependent

exposure measurements. Cox regression analyses were done in stages, with the initial

analyses used to establish what factors were required for baseline adjustment.

For the analysis from external mortality rates, the all-cause mortality SMR from

1959 through 2005 was 100.9 (95% CI, 99.0-102.8), based on all 10,698 deaths.

However, these death ratios were not uniform over time. The period from 1990-2005 had

an all-cause SMR of 109.6 (106.5-112.8), while the ratios for previous periods were

<100. This pattern of recent 1990-2005 increasing SMRs was also seen in the recent

cause-specific deaths from chronic bronchitis, SMR = 330.0 (268.1-406.2); tuberculosis,

SMR = 193.4 (86.9-430.5); cardiovascular disease, SMR = 106.6 (102.0-111.5); all

cancers, SMR = 107.1 (101.3-113.2); and lung cancer, SMR = 115.7 (104.8-127.7).

SMR from overall NMRD was 142.1 (132.9-152.0) in this recent period, and remained

highly statistically significant. In their previous analysis on mortality from lung cancer,

reflecting follow-up through 1995, Miller et al. (1997), had not found any increase in

lung cancer mortality risk.

Among the strengths of this study are the availability of detailed time-exposure

measurements of both quartz and total mine dust, detailed individual work histories, and

individual smoking histories. All these data were used in the internal analyses using Cox

regression methods. Using these analyses, Miller and MacCalman (2009) estimated
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relative risks (RR) for a cumulative lifetime exposure of 5 gram-hours/m3(ghm-3)

respirable quartz (equivalent to approximately 0.055 mg/m3for 45 years) and/or 100 ghm3

total dust. They presented estimated relative risks for various causes of death -

pneumoconiosis, COPD, ischemic heart disease, lung cancer, and stomach cancer - based

on models with either single (dust or quartz) exposures or to simultaneous exposures to

both, either with or without 15-year lag periods. Generally, the risk estimates are slightly

greater using 15 year lag periods. For the models using only quartz exposures with a 15-

year lag, only pneumoconiosis, RR = 1.21 (1.12-1.31); COPD, RR = 1.11 (1.05-1.16);

and lung cancer, RR = 1.07 (1.01-1.13) showed statistically significant increased risks.

Exposure to coal dust was not a predictor of lung cancer mortality; exposure to

crystalline silica remained statistically significantly associated with excess lung cancer

risk when both coal dust and silica dust exposure were included in the regression model.

According to Miller and MacCalman (2009), other analyses conducted have not shown

that exposure to radon or diesel fume is associated with an increased cancer risk among

British coal miners.

OSHA believes that this study of a large British coal mining cohort provides

convincing evidence of the carcinogenicity of crystalline silica. This large cohort study

with almost 30 years of follow-up demonstrated a positive exposure-response after

adjusting for smoking histories, and there was no evidence that exposure to the potential

confounders radon and diesel were associated with excess lung cancer risk. Because of

the strengths of this study, OSHA has included it in its Preliminary Quantitative Risk

Assessment (Section II), where the quantitative aspects of the study are presented in

greater detail.

I.C.2.l. North American industrial sand workers.

Steenland and Sanderson (2001) analyzed a cohort of 4,626 U.S. industrial sand

workers (18 plants, 11 different states) who had worked at least 1 week and had adequate

personal and work history data. Mortality follow-up was from 1960 to 1996. The

mortality experience of these workers was evaluated based on SMRs, using the general

U.S. population as reference, or as standardized risk ratios (SRRs), using the lowest

quartile exposure group of the cohort as the referent population.

A follow up nested case-control study was also conducted that was analyzed by

conditional logistic regression to evaluate the relationships between lung cancer mortality

and cumulative exposure, average exposure, duration, and peak exposure. In the

analysis, each lung cancer case (n = 75) was matched with 100 controls on age, gender,

race and survival time. The average year of first employment was 1967, with an average

length of employment of 8.8 years

The method of determining exposure and developing a job exposure matrix was

reported by Sanderson et al. (2000). Exposure data were based on 4,269 compliance dust

samples taken from 1974 to 1996 by the Mine Safety and Health Administration (MSHA)

and prior to 1977, U.S. Bureau of Mines (Sanderson et al., 2000). A cross-sectional
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industrial hygiene survey conducted for the National Industrial Sand Association in 1946

(Hatch et al., 1947) was used to estimate exposure for prior years. In these earlier

surveys, counts of particles smaller than 5 μm were made from midget impinger samples,

and the percent quartz was determined by XRD from dust collected from high volume air

samples as well as from settled dust. A total of 125 area samples were taken by Hatch et

al. (1947) at 19 sand plants characterizing 8 broad job classifications. The particle count

data were converted to equivalent job-specific measures of respirable mass of quartz

using methods described by Ayer et al. (1973), Rice et al. (1984), and Sheehy and

McJilton (1987). This method assumes a constant factor to convert particle counts to

gravimetric respirable dust mass equivalents (1 mppcf = 0.1 mg/m3); respirable silica

mass was then estimated based on the quartz content as documented in Hatch et al.

(1947). The results reported by Hatch et al. (1947) indicate that the silica content of

quartz particles of less than 5μm in size ranged from 90 percent or greater in the

pulverizing mill and crusher operations to 24 and 32 percent in some screening and

drying operations, as analyzed by XRD of settled air sample particulate of less than 5μm.

Steenland and Sanderson (2001) characterized exposure for 10 job categories, 8 of

which were the same job categories as were used in Hatch et al. (1947) and an additional

2 categories (administrative and other) drawn from the 1974 to 1988 data analysis to

characterize exposure. A job exposure matrix was created containing 120 cells reflecting

3 time periods, 4 plant groupings, and the 10 job titles. The 1947 data from Hatch et al.

were characterized similarly by 10 job groups and four plant groups. Exposure estimates

between 1946 to 1974 were made by linear extrapolation from the 1974 to 1988 data

back to the 1946 data; exposure for years prior to 1946 was assumed to be the same as

that in 1946 (Sanderson et al., 2000).

The authors were not able to identify any significant exposure to other

occupational lung carcinogens. Limited data on smoking for 358 workers aged 25 to 64

years were used to estimate the impact of smoking differences on lung cancer rates for

the cohort versus the U.S. population, but the data were not sufficient to directly adjust

risk estimates. Exposure-response trends were analyzed based on a subcohort of workers

for which detailed work histories were available (n = 4,027). The authors also reanalyzed

the data restricted to those workers with six or more months employment (n = 3,361) in

order to eliminate short-term workers who might have had high excess mortality for

reasons unrelated to occupational exposures (Steenland and Sanderson 2001).

Compared to the U.S. male general population, there was an increased mortality

from all causes combined (SMR 123; 2,819 deaths), all cancers (SMR 128; 416 deaths),

and other diseases. In particular, mortality from cancers of the lung/trachea/bronchus

were statistically significantly increased (SMR 160; 95% CI 131-193, 109 deaths).

Smoking data analysis revealed a higher prevalence of smoking in the cohort compared

with the U.S. population. This would have been expected to cause a 10 to 20 percent

increase in lung cancer mortality, which is insufficient to explain the observed 60 percent

excess. There was also a large excess of deaths from silicosis (SMR 6,630) or

unspecified pneumoconiosis (SMR 777).
126

Elimination of short-term workers (< 6 months of employment) reduced, but did

not eliminate, the overall lung cancer mortality excess (SMR 149, 95% CI 117-187).

According to the authors, internal SRR analyses for lung cancer showed a positive, but

not statistically significant, trend in SRRs, (p for trend = 0.07) for cumulative silica

exposure lagged 15 years. Analysis of the lung cancer mortality by duration of

employment did not show a consistent trend. Positive exposure-response trends were

found for lung cancer mortality with unlagged cumulative silica exposure (p = 0.04) and

with cumulative silica exposure lagged 15 years (p = 0.08). A slightly more pronounced

positive exposure-response trend (See odds ratios in Table I-12) was observed in quartile

analysis of average respirable silica exposure (p = 0.003). Average is defined by

Steenland and Sanderson (2001) as “cumulative exposure divided by duration of

exposure.” There was a twofold excess risk for those in the highest quartile of either

average or cumulative exposure. In contrast, duration of exposure with and without a

time lag did not show a trend with lung cancer risk. The authors concluded that this study

supports the IARC determination that crystalline silica is a lung carcinogen.

Table I-12. Industrial Sand Workers: Odds Ratios from a Nested Case-Control Study of Lung

Cancer Mortality by Quartile of Cumulative and Average Exposure to Respirable Quartz for

Males Working Six Months or Greater in 18 Industrial Sand Plants

Exposure Quartiles p-value for Trend

Q1 Q2 Q3 Q4

Cumulative Exposure

Range of Exposure Quartile

in mg/m3-years

0-

0.18

>0.18-

0.59

>0.59-

1.23 >1.23

Odds Ratio – unlagged (# of

cases)

1.0

(16)

1.28

(20)

0.73

(12)

1.70

(27) 0.04

Odds Ratio –15-year lag (# of

cases)

1.0

(20)

1.35

(21)

1.63

(18)

2.00

(16) 0.08

Average Exposure **

Range of Exposure Quartile

in mg/m3

0-

0.023

>0.023-

0.046

>0.046-

0.065 >0.065

Odds Ratio (# of cases) 1.0

(15)

0.92

(12)

1.44

(20)

2.26

(28) 0.003

*Adapted from Steenland and Sanderson (2001, Table 6)

** Average exposure is defined as cumulative exposure divided by duration.

McDonald et al. (2001) conducted a cohort study that overlapped with the

industrial sand cohort (18 plants, 4,626 workers) studied by Steenland and Sanderson
127

(2001). The cohort included 2,670 men employed before 1980 for three years or more in

one of eight North American (7 U.S. and 1 Canadian) sand-producing plants and 1 large

associated office complex. Information on cause of death was obtained for 99 percent of

the deceased workers for a total 1,025 deaths representing 38 percent of the cohort. A

case-control analysis based on 95 lung cancer deaths from this cohort was also conducted

by Hughes et al. (2001). Both of these studies relied on an analysis of exposure

information published by Rando et al. (2001).

Six (6) of the nine (9) facilities from which the cohort was defined were also

studied by Steenland and Sanderson (2001), and some cross-checking of data indicated

that approximately two-thirds of the subjects studied by Hughes et al. (2001) were

included in the Steenland and Sanderson (2001) study (personal communication, K.

Steenland, 2003).

The cohort study by McDonald et al. (2001) showed a statistically significantly

elevated SMR for trachea/lung/bronchus cancer (SMR = 150, p = 0.001, based on U.S.

rates) for deaths occurring 20 or more years from hire. The SMR for

trachea/lung/bronchus cancer declined slightly when regional cancer mortality rates were

used (SMR = 139, p = 0.001, 83 deaths). SMRs for trachea/lung/bronchus cancer, using

U.S. rates, increased with increasing time since hire (87, 127 and 162 for <20, 20-30 and

≥ 30 years, respectively), but not with duration of employment. There was no consistent

correlation between duration of employment and lung cancer risk in this cohort. SMRs

for NMRD and tuberculosis were statistically elevated for deaths occurring 20 years or

more from hire (SMR = 178 (97 deaths) and 393 (8 deaths), respectively; p < 0.01).

McDonald et al. (2001) also noted a statistically significant elevation in chronic renal

disease (SMR = 212; 16 deaths; p < 0.002).

The exposure assessment conducted by Rando et al. (2001) was a comprehensive

historical reconstruction and was based on substantial exposure data. There were 14,249

respirable dust and silica samples from 9 plants taken from 1974 to 1998. Rando et al.

(2001) relied on similar historic data used by Sanderson et al. (2000) in developing a job

exposure matrix. Historic samples were taken with the Greenburg-Smith impinger and

particles with diameter less than 5.0 μm were counted microscopically. Job-specific

samples (346) were taken from the National Industrial Sand Association during 1946 at

19 plants in the U.S. with another survey conducted in 1954 and 1955 (Hatch, 1954;

Hatch et al., 1947; Hatch and Schreibis, 1955; Hatch and Wellington, 1955). Exposure

estimates prior to 1946 were made based on plant walkthroughs and written

documentation, site-specific exposure data for one-half of the cohort, and interviews with

plant managers and employees to develop the job-exposure matrix. Overall, Rando et

al.’s (2001) assessment was based on exposure measurements that were available for 31

site-specific processes in three large plants representing one-half of the cohort. Industry

wide process-specific mean exposure values were used to estimate historical exposure for

the workers at the six remaining plants. Finally, adjustments in exposure were made for

the use of respirators between 1974 and 1996, considering both the protection factor of

respirators and an estimate of the frequency of respirator use.
128

In reference to the older exposure data, conversion from particle counts to

respirable mass was not possible from empirical data because side-by-side samples were

not available. Consequently, the authors developed a computational algorithm that

considered particle size distribution and collection efficiencies of the impingermicroscope method of counting particles and the cyclone-filter method of measuring

respirable mass. A conversion factor of 274 μg/m3per million particles per cubic foot

(mppcf) was used to convert historic dust measurements to mass respirable dust

equivalents which, according to Rando et al., “[m]ay be positively biased to some

(unknown) extent...” Rando et al. (2001) acknowledged that other investigators show

smaller industry-specific conversion factors: 110 μg/m3per mppcf for Vermont granite

sheds (Ayer et al., 1973) and 90-180 μg/m3per mppcf for U.S. diatomaceous earth

(Seixas et al., 1997). The effect of using a relatively high conversion factor in estimating

exposure to respirable quartz from particle-count data will be to overstate the historic

exposure estimate.

The percentage of silica in the historic sampling conducted by Hatch et al. (1947),

Hatch and Schreibis (1955) and Hatch and Wellington (1955) was partially determined

from settled dust. Rando et al. (2001) elected to create a profile of percent silica (type of

profile not specified by author) based on more current respirable air samples and X-ray

diffraction analysis. According to Rando et al. the settled dust samples “... [a]ppear

extraordinarily high and are possibly unreliable. On the other hand, silica assays in the

modern database are likely to be negatively biased, since high loadings derive primarily

from particles released from the sand as it is being processed.” This would tend to

underestimate historic exposures. OSHA notes that these two potential biases of the

exposure estimate might, to some extent, be offsetting.

Hughes et al. (2001) conducted a nested case-control study of 95 lung cancer

deaths of the cohort studied by McDonald et al. (2001). Two controls were selected per

case, matched on plant and date of birth, and outliving the case. There was no indication

in the paper that the exposure history of controls was appropriately truncated when it

extended beyond the age when the index case failed. Both categorical analyses and

conditional logistic regression were used to examine relationships with cumulative

exposure, log of cumulative exposure, and average exposure, although results from the

categorical analysis were emphasized in the report. Smoking data were collected from

medical records supplemented by information from next of kin or living subjects for 91

percent of cases and controls. Exposure levels over time were estimated via a jobexposure matrix developed for this study. The 50th percentile (median) exposure level of

cases and controls for lung cancer were 0.149 and 0.110 mg/m3respirable silica

respectively, slightly above the current OSHA standard. Silicosis mortality showed a

positive exposure-response trend for lung cancer with cumulative exposure and average

exposure concentration, tending to validate the exposure estimates. Statistically

significant positive exposure-response trends for lung cancer were found for both

cumulative exposure (lagged 15 years) and average exposure concentration, but not for

duration of employment, after controlling for smoking. With exposure lagged 15 years

and after adjusting for smoking, increasing quartiles of cumulative silica exposure were

associated with lung cancer mortality odds ratios of 1.00, 0.84, 2.02 and 2.07 (p for trend
129

= 0.04). This monotonic increase was seen for both lagged and unlagged cumulative

exposure, when the four upper exposure categories were collapsed into two. There was

no indication of an interaction effect of smoking and cumulative silica exposure (Hughes

et al., 2001).

McDonald et al. (2005) conducted a follow-up study extending the observation

period by six years, from 1995 to 2000. The primary aim of the follow-up study was to

determine if death from chronic renal disease was related to silica exposure and to

determine whether the previous findings of lung cancer and silicosis in McDonald et al.

(2001) and Hughes et al. (2001) were confirmed. This discussion is limited to the followup on lung cancer and silicosis mortality (See Section I.E for a discussion on silicarelated renal disease). In the original study, there were 990 deaths among a cohort of

industrial sand workers employed in nine plants. The follow-up study was limited to

workers in eight U.S. plants, eliminating the Canadian plant, and identified an additional

231 deaths for a total of 1205 deaths (49 percent of the cohort). Vital status and cause of

death was obtained and determined for 99 percent of the cohort. Exposure estimation and

case-control selection and analysis were similar to the original study. Difference in

smoking was analyzed by conditional multiple regression and exposure categories were

the same as in the original study (McDonald et al., 2005).

The findings of the follow-up study confirmed the findings of the original studies.

SMRs for all causes of death, based on U.S. male death rates, for workers who died 20 or

more years after hire were elevated in the follow-up (SMR = 142; p < 001) as compared

to the initial study (SMR = 118; p < 0.001). Elevated SMRs were also identified for lung

cancer (SMR = 147, p = 0.001, 102 deaths) and NMRD (SMR = 164; p = 0.001, 116

deaths of which 26 were silicosis deaths) for workers who died 20 or more years after

hire. These values were not significantly different than the initial study.

A nested case control analysis found that, with exposure lagged 15 years,

increasing quartiles of cumulative silica exposure were associated with increases silicosis

mortality, with odds ratios of 1.00 (N = 7), 2.54 (N = 7), 4.55 (N = 8), and 5.16 (N = 8) (p

for trend = 0.017). Regarding the association between cumulative silica exposure and

silicosis mortality, the authors stated “Taking into account the very small numbers (of

cases), the original and updated (odds) ratios agree reasonably well, especially in those

lagged 15 years, which demonstrated a clear and statistical trend. Further analysis of

more recent data showed that the risk of death from silicosis was independently related to

both duration and intensity of exposure and was strongly related to smoking...”

(McDonald et al., 2005). In the initial and follow-up studies for both lagged and

unlagged exposure, the association between lung cancer and cumulative silica exposure

were very similar. For the updated study, with exposure lagged 15 years and after

adjusting for smoking, increasing quartiles of cumulative silica exposure were associated

with lung cancer odds ratios of 1.00 (14), 0.94 (15), 2.24 (31), and 2.66 (30) (p for trend

= 0.006). The slope of the exposure-response was slightly greater than was described in

the earlier Hughes et al. (2001) study.
130

As was observed in the original studies, the follow-up study found that the risk of

lung cancer was related to average silica concentration but not to the length of

employment. Smoking was independently and strongly related to silicosis and lung

cancer. The odds ratio for silicosis among smokers versus nonsmokers was 5.09 (95% CI

1.29-20.07). The respective odds ratio for lung cancer among smokers versus

nonsmokers was 5.37 (95% CI 2.33-12.35).

The results of the Hughes et al. (2001) study support the thesis that silica

exposure is positively associated with increased lung cancer mortality risk. Furthermore,

the two sets of industrial sand studies (four papers by McDonald, Hughes, and Rando,

and two papers by Steenland and Sanderson), despite the differences in the cohorts,

mutually reinforce each other in terms of their positive findings. Given the quality of the

underlying exposure and job history data available for the Hughes et al. (2001) study, and

the ability of the study to adjust for smoking history, OSHA considers this study

particularly suitable for inclusion in its Preliminary Quantitative Risk Assessment. The

McDonald et al. (2005) study is equally convincing and yielded results similar to those of

Hughes et al.; however, as explained in the risk assessment section, only the Hughes et al.

study contained sufficient information upon which to construct a quantitative exposureresponse model.

I.C.2.m. United Kingdom industrial sand workers.

This is a retrospective cohort mortality study of 2,703 United Kingdom (UK)

industrial sand workers in seven plants who were employed for at least one year from

1950 to 1986 (Brown and Rushton, 2005b). The cohort was followed until 2001 by

which time there were 764 deaths representing 28 percent of the cohort. The overall

mortality rate for the cohort was lower than expected in the general population, likely the

result of a healthy worker effect. Mortality rates for all cancers, including lung cancer,

circulatory diseases, and non-malignant respiratory disease were not elevated. Only two

deaths were attributable to pneumoconiosis, one of which was confirmed silicosis.

Mortality from lung cancer did not show a correlation with cumulative exposure to

respirable silica. Smoking data were not available.

In a separate paper, Brown and Rushton (2005a) developed the job-exposure

matrix (JEM) from personal records and a total of 2,429 personal and 583 static area

respirable silica measurements that were collected from the seven plants between 1978

and 2000. All exposure measurements were made using current methods for collecting

and analyzing respirable silica samples. The JEM profile had five quarry types and three

time periods and 12 grouped job titles. Each worker was assigned to job categories based

on their work histories and cumulative respirable silica exposures were estimated from

the JEM profile. No exposure data were available for between 1950 and 1977; for this

period, exposure was estimated by linear extrapolation with the highest exposure

assumed to have occurred in 1950 and with exposure decreasing linearly through 1977.

The high exposure areas, greater than 0.3 mg/m3, were predominately located in the dry

and silica flour areas. Fifteen (15 percent) of the samples taken within the “dry areas

(baggers, dryers, other) and silica flour” areas of the plant exceeded 0.3 mg/m3and 90
131

percent of the samples that exceeded 0.3 mg/m3plant wide were in these areas. The

authors noted in their discussion that the geometric mean exposure of 0.09 mg/m3 was

higher than the geometric mean exposures reported in the two U.S. sand cohorts (0.026

mg/m3from Sanderson et al., 2000 and 0.042 mg/m3from Rando et al., 2001) during

similar time periods (Brown and Rushton, 2005b).

This study did not find an association between cumulative silica exposure and

lung cancer, a result that is inconsistent with the U.S. industrial sand studies (Hughes et

al., 2001; McDonald et al., 2005; Steenland and Sanderson, 2001). In a letter review,

Steenland (2005a) identified two issues that may explain this discrepancy. First, as

indicated by IARC (1997), positive findings for lung cancer have not been consistently

reported across studies, possibly reflecting differences in specific mineral properties and

toxicities of silica in different workplaces. More importantly, Steenland (2005a) noted

that the cumulative exposures of the workers studied by Brown and Rushton (2005b) was

significantly lower compared to those experienced by the 10 cohorts used by Steenland et

al. (2001a) in the pooled analysis. The Brown and Rushton study (2005a) reported a

mean cumulative exposure of 0.31 mg/m3-years and the maximum exposure quartile

consisted of workers exposed to more than 1.0 mg/m3-years. (The exact distribution of

the highest exposure group is not provided by Brown and Rushton, 2005a.) By

comparison, the mid-quintile of cumulative silica exposure reported by Steenland et al.

(2001a) was 2.0-5.4 mg/m3-years which is the lowest quintile showing increased relative

risk. (Steenland et al., 2001a, pooled analysis had RRs of 1.0, 1.0, 1.3, 1.5, and 1.6 for

<0.4, 0.4-2.0, 2.0-5.4, 5.4-12.8 and >12.8 mg/m3-years.) Steenland (2005a) suggested

that the low silicosis mortality reported by Brown and Rushton (2005b) reflects the

overall low cumulative exposure in this cohort.

A third consideration, as was noted by Brown and Rushton (2005b), is that a large

portion of the cohort had relatively short service times in the industry, with over one-half

the cohort deaths and almost three-fourths of the lung cancer mortalities having had less

than 10 years service. Considering the apparent high turnover in this industry and the

absence of prior occupational histories, exposures from work experience other than in the

industrial sand industry could be a significant confounder. This is reinforced by data in

Table 1 of Brown and Ruston (2005b), which indicates that 34 of the 81 lung cancer

deaths (41%) occurred among workers less than five years after the start of employment,

representing less than 10 percent of the person-years at risk. Similarly, only 8 (<10%) of

the lung cancer deaths occurred among workers more than 20 years after the start of

employment, where an effect might most be expected. Steenland (2005a) also

commented on the eight lung cancer deaths occurring in workers with greater than 20

years of employment, noting that the overall deficit in lung cancer could be attributed to

workers in one plant, where there was a deficit in all causes of mortality, possibly due to

workers from this plant having less follow-up time and exhibiting a greater healthy

worker effect. Brown and Rushton (2005b) also noted that the absence of smoking data

is another potential confounding factor, but this was minimized by internal comparison

between quartiles as previously discussed. Lastly, the authors indicated that this is a

relatively young cohort and the use of case-control study design would allow for more

detailed exposure reconstruction, prior work history, and process control history.
132

OSHA believes that the industrial sand study conducted by McDonald et al.

(2001), Hughes et al. (2001) and Rando et al. (2001) with a recent follow-up study by

McDonald et al. (2005) are the most thorough and complete of the industrial sand studies.

Reasons include the availability of exposure data based on modern methods of collection

and analysis; exposures were ascertained for individual cohort members; smoking

histories were available; the cohort had long-term work experience averaging 19 years

(compared to the Steenland and Sanderson, 2001 average of 9 years and Brown and

Rushton, 2005a, 2005b, average employment time not provided); and use of a nested

case-control design. Furthermore, OSHA believes that the findings of the Brown and

Rushton study should be discounted due to the low cumulative exposure profile; the

unusual distribution of lung cancer deaths among relatively short-tenured workers; the

relative youth of the cohort having inadequate accumulation of exposure years; and

possible confounding or misclassification caused by the absence of smoking data, prior

work exposures in an apparently highly transitory cohort, and the absence of a more

discerning nested case-control study.

I.C.2.n. United Kingdom pottery workers.

Winter et al. (1990) published preliminary findings from a cohort of workers

employed as of 1970/1971 and assembled from a sample of 40 plants based on a national

cross-sectional survey of the British pottery industry. The cohort was followed until

1985. Because of the difficulties in tracing older cohort members, the analysis was

restricted to 3,669 men under 60 years of age at the time of the survey. This limitation

was of concern to the authors because of the potential for selection bias given the long

latency of lung cancer, and was noted in IARC’s 1997 review. A total of 60 lung cancer

deaths were observed with associated SMRs of 140 (95% CI 107-180) and 132 (95% CI

100-169) based on national and locally adjusted rates, respectively. Smoking information

and exposure measurements were also obtained from the 1970/1971 cross-sectional

survey (Winter et al., 1990). Radiographic findings and analysis were not presented. The

exposure data varied by industry subtype and job groupings and mean respirable quartz

exposures ranged from 0.01-0.20 mg/m3. The authors used a simplified cumulative

exposure model based on job title exposures derived from cross-sectional environmental

sampling multiplied by the total number of years worked at the plant by each employee

per 1970/1971 job title. Cumulative exposure was grouped into four quartiles for

analysis.

There were no excesses of lung cancer mortality by product or job group.

However there was an indication of increased lung cancer mortality with increased

cumulative exposure (SMR = 108, 99, 162, and 151 for each of the exposure quartiles).

There was also a trend of increased lung cancer with increased duration of employment

(neither confidence limits or p values were provided).

McDonald et al. (1995) conducted a preliminary analysis of proportionate

mortality in a cohort of 7,020 male pottery workers born between 1916 and 1945 with

mortality follow-up to June 30, 1992. Dates and causes of death were confirmed and
133

copies of death certificates were obtained for 92.5 percent of the cohort. The

investigators calculated the proportional mortality ratios (PMR) for lung cancer based on

deaths from lung cancer in England and Wales, 1961-1992, standardized for the

quinquennium of date of birth and age at death. In these analyses, the authors use 90

percent confidence intervals and probabilities based on a one-tailed distribution of the

chi-square. The overall PMR for lung cancer was 124 (90% CI 106-144). After

exclusion of known asbestos exposure, the PMR for lung cancer was reduced to 122

(90% CI 104-143) but was still statistically significantly increased. Excluding those with

pneumoconiosis on the death certificate resulted in a PMR of 123 (90% CI 105-144),

which was also statistically significantly increased. For those with pneumoconiosis also

on the death certificate, the PMR increased to 175 (90% CI 70-360), but this increase was

not statistically significant. The authors noted, however, that 70 percent of the deaths in

the cohort came from one town that had a high background mortality rate for lung cancer.

When they computed the lung cancer PMR of their cohort relative to that of this town in

1979-1983, the PMR was estimated to be 104 (confidence interval not reported).

McDonald et al. (1995) also conducted a nested case-referent study in order to

assess the effect on lung cancer mortality of smoking, duration of exposure, asbestos

work, and ILO X-ray score for small opacities. Since there was a substantial difference

in smoking habits between cases and referents, the authors decided to compare just the 47

cases and 47 referents that were smokers and for which x-ray readings were available.

The results showed a statistically significant effect for silica exposure duration (≥10

years), for pottery work (OR = 2.8, 90% CI 1.1-7.5), and for past asbestos work (OR =

3.8, 90% CI 1.1-12.8), but not for small opacities (OR = 0.8, 90% CI 0.2-3.6), suggesting

that the risk of lung cancer was not associated with radiologically-defined silicosis.

Cherry et al. (1995) also conducted a person-years analysis restricted to 470

deaths occurring between January 1985 and June 1992. This analysis resulted in a lung

cancer SMR of 128 (90% CI 104-157) compared to local rates.

Cherry et al. (1998) published a full description of results that had been reported

in a preliminary manner by McDonald et al. (1995) and Cherry et al. (1995) previously.

The investigators excluded men who had been living outside the pottery areas at the time

of the first medical examination, worked previously with asbestos or in foundries, or who

had been employed for more than one year in coal mining or exposed to other dusts,

limiting the analysis to 5,115 male workers. The date of first employment ranged from

1929 to 1982, with 80 percent employed before 1970. Only 52 of 88 identified lung

cancer cases met the criteria for inclusion in the nested case-control study due to

destroyed work records, evidence of job histories in other industries with expected silica

exposure, and in one case, only 10 years of employment since first exposure. Three or

four controls were matched to each case on date of birth and date of first exposure

making a total of 247 controls.

A job-exposure matrix (JEM) consisting of 569 job titles in 11 major process

groups expressed over six decades 1930-1990’s was used to calculate individual

maximum, cumulative, and average lifetime exposure to crystalline silica. This was
134

based on employment records, a detailed knowledge of process control and modifications

over time and available exposure data (Burgess, 1998). Extensive exposure records were

available for the period from the late 1960s to 1992. Over 1,000 personal samples had

been taken with a cyclone pre-selector. Infrared analysis was first conducted between

1960 and 1975, followed by x-ray diffraction from 1975 to1980. From the 1950s to the

1960’s, approximately 350 particle count samples were taken with a static area sampler.

Air sampling was collected using a thermal precipitator and particle counting conducted

post incineration. Exposures post-1960 generally ranged from 50 to 200 μg/m3of

respirable silica (Burgess et al., 1997; Cherry et al., 1998). Burgess et al. (1997) elected

to use the conversion factor developed by Rice et al. (1984). Two data transformations

were necessary to express particle counts from a thermal precipitator as cyclonic

gravimetric data: (1) the conversion from thermal precipitator to impinger (thermal

precipitator expressed in particles per cubic centimeter (ppcc) being equivalent to an

impinger measurement = 0.02832 million particles per cubic foot (mppcf); based on Jahr

(1969) and (2) the conversion of impinger particle count measurements to gravimetric

data using the conversion factor developed by Rice et al. (1984) for the North Carolina

dusty trades (1 mppcf = 0.09 mg/m3of respirable dust). The conversion factor formula as

provided by Burgess (1998) was 50 ppcc x 0.09 x 0.02832 = 0.127 mg/m3(Burgess,

1998).

The authors also estimated the percentage of quartz to be 12 percent (+/-2%), for

typical respiratory dust in potteries (Bloor et al., 1971) and a post-firing estimate of the

percentage of cristobalite of 6 percent (HSE, 1990).

Documentation of historic process modifications, ventilation controls, and rates of

production were used to extrapolate exposures for the 1930s and 1940s where exposure

data were not available. Burgess et al. (1997) conducted a pilot study on a sub-sample of

the larger cohort to determine the sensitivity of the JEM to discern a dose-response for

ILO radiological scoring for silicosis prior to conducting the full study. This study

indicated prominent increases in silicosis mortality risk with increasing exposure and the

p-value for trend was statistically significant for the reported exposure gradients (Burgess

et al., 1997).

For the overall cohort, the lung cancer SMRs based on background rates for

England/Wales and for local rates were 191 (95% CI 148-242) and 128 (95% CI 99-162),

respectively (Cherry et al., 1998). Although the SMR based on local rates barely missed

being statistically significant, the authors noted that the observed number of cases

differed significantly from expectation (χ

2

= 3.91; p < 0.05). The nested case-control

analysis calculated separate odds ratios for cumulative exposure, duration of exposure,

and mean concentration. This resulted in smoking-adjusted ORs of 1.67 (95% CI 1.13-

2.47), 1.66 (95% CI 1.14-2.41) and 1.60 (95% CI 1.11-2.31) for mean concentration

lagged 0, 10, and 20 years, respectively. Only mean concentration of exposure was

positively related to lung cancer (p < 0.008 for all three lag periods). Neither cumulative

exposure nor duration of employment was positively related to lung cancer. Mean

exposure concentrations of silica were 21 percent higher for cases than for controls and

were consistently higher for those with employment durations less than 20 years. The
135

findings also revealed no evidence of an association between radiological pulmonary

opacities and lung cancer. The authors concluded that their findings indicated that the

exposure to crystalline silica in the pottery industry carries an increased risk of lung

cancer mortality.

I.C.2.o. Chinese pottery workers.

Chen et al. (1992) conducted a mortality study of 13,719 pottery workers

employed from 1972 to 1974 at eight pottery factories in south central China with followup through 1989. The original study included workers from tungsten, tin, clay, copper

and iron mines, but only the study involving the pottery worker subcohort was considered

by IARC (1997) to be among the least confounded studies because pottery factories had

higher dust levels compared to the mines and more importantly, the exposure to potential

confounding pulmonary carcinogens was minimal.

In the cohort study, historic data from workplace air sampling for total dust and

quartz analysis of settled dust were used to estimate job-specific exposures in each of

several calendar-year periods (Wu et al. 1992; Zhuang et al. 2001). Based on job-specific

exposure estimates, each cohort member was classified into one of four total dust

exposure levels: high, medium, low, and non-exposed.

A low lung cancer mortality rate (SMR = 58, p < 0.05) among pottery workers

was found using national mortality rates for comparison; however, an unknown

percentage of these workers were considered non-exposed (estimated to be 50 percent by

Steenland et al., 2001a). The cohort analysis did not show an increased risk for lung

cancer with increasing dust exposure (data not provided). The relative risk for lung

cancer mortality among silicotics relative to nonsilicotics was 1.63 (95% CI 0.8-3.4) in

pottery workers.

McLaughlin et al. (1992) conducted a more quantitative nested case-control study

from the same cohort of 62 male pottery workers who died from lung cancer before 1990.

Cases were matched with 238 controls on age (decade of birth) and factory. Exposure to

silica dust (expressed as a cumulative exposure measure) was assigned for each study

subject based on historical industrial hygiene records and a job-exposure matrix

developed by Dosemeci et al. (1993). Exposure data were available from routine

company surveys between 1950 and 1987. All exposure data were total-dust area

measurements using a gravimetric method with sample times of 20 to 30 minutes.

Records were available for approximately 1,000 area samples collected with high flow

pumps operating at approximately 25 liters/minute. Assignments of exposure were by

plant, job and calendar year. In the case-control study, approximately 51 percent of the

assignments were based on quantitative total dust data. This ranged from 1 to 2 percent

during the 1950s to approximately 70 percent in the 1980s. For exposures prior to 1950,

the 1950 exposure data were applied (McLaughlin et al., 1992). Percentages of respirable

dust and silica content of the total dust estimated at the facility level only, due to lack of

specific measurements for job titles or process areas were used to estimate silica exposure

(Dosemeci et al., 1993; Zhuang et al., 2001).
136

Vital status and cause of death were determined for each worker. Smoking data

were obtained by interviews of the subjects or their next of kin (McLaughlin et al., 1992).

The authors found a positive, but not consistent, relationship between cumulative

respirable silica dust exposure and lung cancer among pottery workers. When data were

adjusted for age and smoking, there was a suggestive trend with increasing quartiles of

respiratory crystalline silica exposure (OR equal to 1, 1.8, 1.5 and 2.1 for cumulative

exposures of none, low, medium, and high, respectively). The exposure-response

gradient did not reach statistical significance and confidence limits were not provided.

The IARC panel (1997) provided an independent calculation of confidence limits which

is presented in Table I-13.

Table I-13. Odds ratios reported by McLaughlin et al.

(1992) for Chinese pottery workers, with confidence

intervals provided by IARC

Cumulative Respirable

Silica (μg/m3 - years) OR No. 95% CI*

None --- 1.0 11

Low (0.1-8.69) 1.8 17 1.04-2.87

Medium (8.70-26.2) 1.5 27 0.99-2.18

High (> 26.3) 2.1 7 0.80-4.12

*CI = confidence interval

McLaughlin et al. (1992) found the relationship between cumulative silica

exposure and lung cancer mortality of interest because only polyaromatic hydrocarbons

(PAHs) were present as a potential confounder and adjustment for PAHs did not reduce

the association between lung cancer mortality and exposure to silica. Despite the high

prevalence of silicosis, there was no evidence of an increased risk of lung cancer among

silicotics compared to non-silicotics; silicosis was present in 13 percent and 12 percent of

cases and controls, respectively.

McLaughlin et al. (1992) concluded that the findings of their study provide some

evidence of an association between silica and lung cancer but that the dose-response

relationship did not show a strong trend.

I.C.2.p. Dutch ceramic workers.

Meijers et al. (1996) conducted a retrospective cohort mortality study in male

Dutch ceramic workers. The cohort was selected from subjects identified in a nationwide

cross-sectional silicosis survey. Most of the workers were drawn from two large

mechanized companies, with the remainder coming from 76 small ceramic workshops.

In this survey, subjects received a thorough medical examination which included a chest

radiograph and questionnaires on job history, respiratory symptoms and smoking habits.

If the initial chest radiograph was suggestive of silicosis, a second larger radiograph was
137

taken and graded according to the ILO scale. In total, 1,794 male workers were selected

for the cohort who had worked in the ceramics industry between 1972 and 1982 for more

than two years. The cohort was followed up to the end of 1991. SMRs were calculated

using the Dutch male population as the referent group.

No quantitative information on exposure to respirable crystalline silica was

available. However, the level of exposure was judged to be highly correlated to the stage

of production of ceramic ware. This allowed the authors to assign each subject to a

qualitative category of average exposure (none, low, moderate or high) based on job

description. However, this categorization was based on each subject’s job at the time of

the medical survey and took no account of possible movement between different jobs

during their employment, which could potentially impact significantly cumulative

exposure estimates over the period of the study. In fact, subjects identified with simple

pneumoconiosis were medically removed from jobs where respirable silica exposure

occurred, so a worker might have been classified as having high exposure but could have

spent much of his/her later employment time in a job with no or minimal exposure. This

is a weakness in the study design and renders the exposure assessments very unreliable.

There was no information on the extent to which these subjects may have been exposed

to cristobalite as distinct from quartz. The authors did not identify any problems with

confounding exposures. There was limited use of talc dust in the molds, but exposure to

talc was not considered to be significant.

The mean length of follow-up was 14 years, and mean age at the start of the

follow-up period was 40 years. Follow-up was complete for virtually all (99.8 percent)

subjects. Around half of the workers had worked for more than 10 years in the industry.

There were 124 subjects (around 7 percent of the cohort) with radiographically apparent

opacities (simple pneumoconiosis), but in all cases the ILO grading was higher than 1/1.

Smoking data suggested that around 80 percent of the cohort smoked, but the absence of

a clear excess of lung cancer (SMR = 88 based on 30 lung cancer deaths in the entire

cohort) suggests that they may not have been heavy smokers. The prevalence of workers

with opacities in the different exposure categories was not stated.

There were 161 total deaths (around 9 percent of the cohort), which was

significantly less than expected (SMR = 70) suggesting the presence of a healthy worker

effect. There were no statistically significant correlations between mortality from all

causes or lung cancer and duration of employment, smoking status or exposure category.

There was a statistically significant excess of lung cancer in subjects with simple

pneumoconiosis (SMR =220, 10 observed deaths) compared to a deficit in those without

pneumoconiosis (SMR = 68). There were more deaths from lung cancer among smokers

than non-smokers, but the number of deaths were similar to or less than expected (SMR =

97 for smokers (27 deaths) and 49 for non-smokers (3 deaths)). This study is limited by

lack of quantitative exposure data, low overall mortality, and the relatively short period

of follow-up of only 14 years. However, the results did reveal a statistically significant

excess of lung cancer in those with simple pneumoconiosis. It did not appear that this

excess could be attributed to smoking.
138

I.C.2.q. German stone and ceramic workers.

Ulm et al. (1999) conducted a population-based case-control study of workers in

the stone, quarry and ceramic industries diagnosed with lung cancer in the Bavarian

district of Germany between 1980 and 1994. There were 133 cases and 231 controls

from the stone and quarry industry and 114 cases and 564 controls from the ceramic

industry. Cases were identified from insurance and hospital records. Controls were

selected differently for the quarry and ceramic cohorts. In the ceramic industry, controls

were selected from a silicosis surveillance program affecting almost all employees at

multiple plant locations, while in the quarries controls were selected from records of

accidents that happened either at work or traveling to or from work. For each industry,

cases were matched to controls on gender, age, area of residence, industry type, and

smoking habits. Smoking status was determined from medical files and personal

interviews. According to the authors “[a]ll controls had been occupationally exposed to

silica dust” (Ulm et al., 1999). The study by design eliminated cases and controls that

had silicosis, as defined by the requirement for compensation (ILO radiological category

≥ 1/1 and reduced lung function). Ulm et al.’s (1999) intent was to eliminate those with

underlying silicosis to determine “whether silica dust itself can induce lung cancer or

only via silicosis.”

In Ulm et al. (1999), details of the exposure assessment were only briefly

presented. Analysis by job title as a proxy for exposure is not conducted in the analysis.

Exposures were estimated by industrial hygienists using complete occupational histories,

available exposure measurements, and differences in exposure caused by changes in

plant, type of occupation, or technical equipment. If no exposure measurements were

available, the level of exposure was estimated by hygienists familiar with the workplace.

It is not possible to evaluate the quality of exposure estimation since information on the

number of plants in the study, process descriptions, job or exposure distributions, and

sampling and analytical methods used to determine respirable crystalline silica levels

were not provided. Cristobalite exposures were also not evaluated in the ceramics

industry. Exposures were classified as either high-exposed or low-exposed with the

German MAK value of 0.15 mg/m3being used as the cut-off point. In a further analysis,

exposure indices were classified into four semi-quantitative categories to allow the

exploration of exposure response relationships.

Approximately 30 percent of cases and controls were considered exposed to a

potentially confounding occupational carcinogen, but there was no clear distinction

between cases and controls with the exception that 13 percent of cases were exposed to

diesel exhaust compared to 9.2 percent for controls. Even though smoking had been used

as a matching criterion, cases as compared to controls had a higher smoking rate (82.4

percent to 66.1 percent) for smoking more than 10 cigarettes per day and controls stopped

smoking 10 years earlier than cases.

Three exposure indices were used: median TWA exposure, cumulative exposure,

and peak exposure. Odds ratios for lung cancer were calculated for the different

measures of exposure, adjusted for age at onset of exposure, year of first exposure,
139

duration of exposure, latency, and exposure to other occupational carcinogens. No odds

ratios were statistically significantly increased. To assess the possible exposure response

relationship, ORs for both industries were calculated for four categories of cumulative

and average TWA exposure. No trend with either cumulative, average, or peak exposure

was observed. The authors concluded that their study showed no association between

exposure to crystalline silica and lung cancer.

This paper reflected the mortality experience of populations having relatively low

exposures to crystalline silica because (1) the exclusion of subjects with radiographic

opacities would tend to over-select those workers with the lowest exposures, and (2) the

limited exposure information presented suggests that exposure in these industries in the

later decades were less than OSHA’s current PEL of approximately 0.1 mg/m3respirable

crystalline silica. In fact, the mean exposure estimate in the ceramic industry prior to

1940 is estimated to be 0.07 mg/m3(Ulm et al., 1999). The authors acknowledged that

the low exposures of the cohorts may have reduced the power of the study to detect a

small risk. Potential exposure misclassification, as noted above, could further reduce the

power of the study. OSHA believes the results of this study should be discounted due to

low exposures experienced by the cohort, the limited size of the cohort, and the imprecise

methods of exposure classification.

I.C.2.r. U.S. diatomaceous earth industry workers.

Checkoway et al. (1993) conducted a cohort study of 2,570 white male workers at

two diatomaceous earth (DE) plants in California who were employed at least one year

and who worked at least one day between 1942 and 1987. Vital status was ascertained

for 91 percent of the cohort and death certificate information was retrieved for 94 percent

of identified deaths. The major exposure of concern in these plants was cristobalite, a

polymorph of crystalline silica. Workers who had experienced previous occupational

exposure to asbestos from earlier employment were excluded from the main study cohort.

The health outcomes of interest in this study were lung cancer and non-malignant

respiratory diseases (NMRD). Smoking data were incomplete so investigators decided to

examine whether smoking was a confounding factor in two ways: (1) inspection of

mortality risks for other smoking related diseases and (2) by hypothetical estimation of

the extent of confounding required to produce spurious observed excesses. The most

important finding was an excess of lung cancer mortality (SMR = 143, 95% CI 109-184,

59 deaths) for diatomaceous earth workers compared to U.S. population rates. The SMR

for lung cancer was also elevated when using lung cancer rates from local counties (SMR

= 159). The largest SMRs were found for workers hired before 1930 (SMR = 263, 95%

CI 112-515, 8 deaths). The cohort’s NMRD mortality, defined by the authors as

excluding infectious disease and pneumonia, was also increased (SMR = 259, 95% CI

196-336, 56 deaths).

According to the authors, the crystalline silica exposure index was “semiquantitative,” combining information on duration, differences of exposure between jobs

and calendar periods, the crystalline silica content of various plant processes and product

mixes, and the use of respirators. Exposure intensity was determined from a review of
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process history, industrial hygiene records, and implementation of engineering controls

by review of plant records and discussion with knowledgeable employees. Exposures

were categorized as none, low, moderate, or high over five time periods with exposure

reducing over time. Exposure estimates were also adjusted to account for the increased

use of respirators beginning in 1950. The percentage of crystalline silica in respirable

dust was estimated to be 1 percent in the diatomaceous earth pre-treatment area and 10 to

25 percent in calcined and flux-calcined processes. An index of cumulative exposure was

computed as the sum of the product of the time spent in different jobs adjusted for

differences in exposure intensity by job, by time period, by respirator use, and the

percentage of crystalline silica in respirable dust.

The investigators found the strongest exposure-response gradients for lung cancer

mortality, assuming a 15-year latency, for the workers exposed 20 or more years

compared with a reference group of workers with less than 5 years of exposure (RR of

2.88 with 95% CI 1.13-7.33, 6 deaths). The study also found positive exposure-response

trends for lung cancer and NMRD with duration of employment in dust-exposed jobs,

and with cumulative crystalline silica exposure index. The relative risks for lung cancer

with silica exposure lagged 15 years were 1.00, 1.19, 1.37, and 2.74 for the none, low,

moderate and high exposure groups, respectively. The authors concluded that the excess

of lung cancer could not be attributed solely to smoking.

Checkoway et al. (1996) re-analyzed these data to assess more thoroughly

potential confounding by exposure to chrysotile asbestos, which had been used in limited

quantities in some operations of the two plants. The reanalysis was limited to 2,266

white male workers from the larger plant who had been employed after 1930 and for

whom quantitative exposure estimates could be derived. The exposure characterization

of asbestos and the development of a job exposure matrix were conducted independently

without industrial hygiene personnel knowing the mortality outcome of individual

workers or their previous silica exposure classification. There were 52 cases of lung

cancer mortality in this subcohort. Lung cancer was stratified according to cumulative

respirable silica and asbestos fiber exposure, and mortality rates were compared to those

of the U.S. male population. The SMR for lung cancer mortality of the cohort was 141

(95% CI 105-185). With exposure lagged 15 years, the SMRs for the four categories of

increasing silica exposure among workers not exposed to asbestos were 113, 87, 214, and

200, respectively. After adjustment for age, calendar year, duration of follow-up,

ethnicity, and cumulative asbestos exposure, risk ratios for the increasing categories of

silica exposure were 1.00, 1.37, 1.80, and 1.79, respectively, with a 15-year lag. The

authors concluded that asbestos exposure was not an important confounder of the

observed association between exposure to respirable silica and lung cancer mortality in

this cohort.

A detailed, quantitative job-exposure matrix (JEM) was developed by Seixas et al.

(1997) and used by Checkoway et al. (1997) in a 7-year extended cohort analysis to

evaluate quantitative exposure-response relationships. Five thousand seven hundred and

nine (5,709) computerized samples collected from 1962 to 1988 and 686 sample results

taken from 41 written documents from 1948 to 1962 were used to characterize exposure
141

primarily at one plant. The samples were collected by plant industrial hygienists over a

40-year timeframe from 1948 to 1988. Specific estimates of exposure were made for

each individual in the cohort from 135 job titles covering four time intervals (Seixas et

al., 1997). The exposure of concern was to cristobalite. Historical plant exposure was

determined from particle count data and gravimetric measurements of total and respirable

dust. Only 1,069 of the 6,395 samples (17%) were personal respirable mass

measurements and approximately 15 percent were either personal or area total (nonrespirable) dust samples. Approximately 57 percent of all samples represented particle

counts. The investigators could not determine whether approximately 5 percent of the

samples were area or personal samples and these were classified as unknown. Most of

these unknown samples were from the 41 written reports and reflected particle count

data.

Sampling data were available representing 140 workstations that allowed the

investigators to compare particle count results with gravimetric results for total and

respirable dust (160 matched mean values) and develop mathematical models to

transform the various exposure measures to a respirable mass equivalent. Plant

documents, industrial hygiene data, and employee interviews identified four time periods,

three for which exposure could be characterized quantitatively. There were no exposure

data for the fourth period between 1902 and 1947. A subjective scaling factor of 2.5 (log

scale) developed by industrial hygienists and others familiar with the plant was used to

estimate exposures for time periods prior to 1944 when bagging operations changed from

using paper to using less dusty burlap bags (Seixas et al., 1997). The percentage of the

cohort’s cumulative exposure prior to 1944 is not known. The JEM consisted of

respirable dust exposure estimates covering 135 jobs over 4 time periods. The percentage

of silica in respirable dust was estimated based on knowledge of plant process and

product mix as was previously described by Checkoway et al. (1993).

The 1993 cohort study was updated (Checkoway et al., 1997) to investigate the

quantitative dose-response associations of exposure to respirable cristobalite with lung

cancer mortality. The investigators in this study: (1) extended mortality follow-up for

seven years through 1994; (2) extended job history data for seven additional years for

those still working; and (3) used the JEM described above to estimate cumulative

exposures of individuals in the cohort. The cohort definition was similar to that from

Checkoway et al. (1993) with two exceptions: (1) three-hundred and seventeen (317)

workers who were employed in the smaller plant were excluded from the later study

because their exposures could not be adequately quantified, and (2) eighty-nine (89)

workers who were also exposed to asbestos and thus previously excluded from the cohort

were included in the analysis because quantification and adjustment for their asbestos

exposure was possible. Cumulative exposure for respirable dust and respirable

crystalline silica was divided into quintiles with the lowest quintile serving as the

comparison group. Respirable silica exposure categories were: <0.5, 0.5-<1.1, 1.1-<2.1,

2.1-<5.0 and 5.0 or greater mg/m3-years.

The overall findings were similar to the results from the 1993 paper; based on 77

deaths from cancer of the trachea, lung, and bronchus, the SMR was 129 (95% CI 101-
142

161) and 144 (95% CI 114-180) based on rates for U.S. and local county males,

respectively. The authors noted that nonmalignant respiratory disease (NMRD) had

relatively higher mortality (SMR = 201, 95% CI 156-255, 67 deaths) than lung cancer.

The largest NMRD mortality excess occurred among workers hired between 1920 and

1939. The NMRD among workers hired since 1960 suggested a persistent risk,

according to the authors, even as exposures decreased over time. This finding was in

contrast to that for lung cancer where the excess mortality was apparently limited to

workers hired before 1960 (Checkoway et al., 1997).

The authors found a positive, but not monotonic, exposure-response trend for lung

cancer. The risk ratios for lung cancer with increasing quintiles of respirable crystalline

silica exposure were 1.00, 0.96, 0.77, 1.26 and 2.15 with a 15-year exposure lag. Lung

cancer mortality was only statistically significantly elevated for the highest exposure

category (RR = 2.15; 95% CI 1.08-4.28). The authors also found a strong, statistically

significantly increasing trend for NMRD, noting that the dose-response trends for lung

cancer were considerably weaker than those detected for NMRD. Checkoway et al.

(1997) also found no evidence that asbestos exposure in the diatomaceous earth industry

confounded the observed associations with lung cancer. The positive dose-response

relationship between cumulative respirable silica exposure and lung cancer was not

diminished when adjusted for cumulative asbestos exposure.

Smoking history was available for about one-half of the cohort. The available

data suggested that the prevalence of smoking was higher in higher exposure categories

when compared to the lowest exposure category (prevalence by increasing exposure

category was 0.64, 0.81, 0.84, 0.84, 0.84). Using the method described by Axelson

(1978), the authors made a worst case estimate (assuming 20 times greater lung cancer

risk in smokers compared to non-smokers) and indirectly adjusted the relative risk (RR)

estimates for lung cancer for differences in smoking rates. With exposures lagged 15

years, the worst case effect would be to reduce the RR for lung cancer in the highest

exposure group from 2.15 to 1.67. Checkoway et al. (1997) concluded that the

association between respirable silica exposure and lung cancer was unlikely to be

confounded by smoking or asbestos exposure.

A recent study by Checkoway et al. (1999) was designed to investigate the

relationship between radiological silicosis and lung cancer. A subset of 1,809 men from

the 1993 cohort were selected based on the availability of chest x-rays of adequate

quality. This study demonstrated a trend of increasing lung cancer risk with increasing

cumulative silica exposure even in the absence of radiological silicosis. Specifically, 81

members of the cohort (4.5%) had radiological silicosis. The overall mortality from lung

cancer was higher in silicotics, (SMR = 157; 95 % CI 43-403) compared to non-silicotics

(SMR = 119; 95% CI 87-157), although neither increase was statistically significant. In

non-silicotics, there was a statistically significant increase (p for trend = 0.02) in lung

cancer mortality with increasing cumulative silica exposure (based on national rates).

The authors concluded: “The dose-response relation observed between cumulative

exposure to respirable crystalline silica and lung cancer mortality among workers without

radiological silicosis suggests that silicosis is not a necessary co-condition for silica
143

related lung carcinogenesis. However, the relatively small number of silicosis cases in

the cohort and absence of radiographic data after employment limit interpretations”

(Checkoway et al., 1999). Although smoking history data were limited, the authors

indicated that the available smoking data suggested that confounding due to smoking was

not likely to explain the findings.

Rice et al. (2001) conducted a re-analysis and a quantitative risk assessment of the

diatomaceous earth cohort and found exposure to respirable crystalline silica was a

significant variable in several relative risk models examined. OSHA discusses this

analysis in detail in Section II, Preliminary Quantitative Risk Assessment.

OSHA notes that the Checkoway et al. (1993) study had been previously

reviewed by IARC (1997) and found to be one of the least confounded of the studies

evaluated. The investigators had access to 40 years of exposure data for dust, silica and

asbestos, which enabled them to quantify exposure in detail, develop a job exposure

matrix, and control for potential asbestos confounding in the analysis. Furthermore, the

investigators were able to use smoking history data for part of the cohort to rule out

smoking as a serious confounder. Thus, OSHA believes that the studies of diatomaceous

earth workers, and in particular the quantitative exposure-response analysis by Rice et al.

(2001), are appropriate for inclusion in the preliminary risk assessment.

I.C.2.s. Danish foundry workers.

Sherson et al. (1991) studied 6,144 Danish foundry workers who were invited to

participate in a silicosis surveillance program from 1967 to 1969 and from 1972 to 1974,

with follow-up through 1985. This survey was actually a census as it included virtually

all Danish foundries. There were 647 total tumors diagnosed within the cohort and ageand gender-adjusted Danish incident rates were used to calculate SIRs (standard incident

ratio). No exposure measurements were reported as part of the study, as no data was

provided. A significantly increased standardized incident ratio (SIR) was observed for all

cancers (SIR = 1.09, 95% CI 1.01-1.18, 647 cases) and for lung cancer (SIR = 1.30, 95%

CI 1.12-1.51, 166 cases). A systematic trend in SIRs was seen with duration of work for

lung cancer. The SIR was 0.99, 1.19, 1.28 and 1.85 for durations of employment of <10

years, 10-19 years, 20-29 years, and >30 years, respectively. According to the authors,

this study suggests that occupational exposure, as represented by duration of

employment, in Danish foundry workers is associated with an increased lung cancer

incidence. It is not possible to isolate the effect of silica from other potential

confounding workplace carcinogens since these were not addressed in the study design

and analysis.

I.C.2.t. U.S. (Michigan) foundry workers.

Andjelkovich et al. (1990, 1992, and 1994) conducted a mortality study of 5,337

white men, 2,810 non-white men, and 627 women who had been employed in a grey iron

foundry in Michigan for at least six months from 1950 to 1979. Mortality was followed

through 1984 and vital statistics and death certificates were determined for more than 97
144

percent of the cohort. Age, gender, and race adjusted mortality rates for the U.S. and

local counties were used to calculate SMRs. A description of other carcinogenic

exposures typically found in the plant was provided but was not used to adjust risk

estimates. Non-white employees experienced higher mortality rates for all cancers,

including lung cancer. All cancer SMRs for white workers was 0.98 and for non-white

workers was 1.16 (not statistically significantly elevated). Lung cancer SMRs were

elevated for white males and non-white males (SMR-w = 1.23, CI 0.96-1.54 and SMRnw = 1.32, CI 1.02-1.67), but only the SMR for nonwhites was statistically significantly

elevated.

A follow-up study, extended five additional years to 1989, and a nested casecontrol study was conducted (Andjelkovich et al., 1994). The study consisted of 220

lung cancer cases and 2,220 controls. Smoking history was obtained by medical records

or by questionnaire of the employee or surviving relative. A silica exposure index was

created and the odds ratio for lung cancer mortality determined for increasing exposure

quartiles with the initial quartile serving as the reference. The odds ratios for lung cancer

decreased with increasing exposure quartile (OR = 1.0, 1.27, 1.14, and 0.90; all values

not statistically significantly elevated) and do not reflect an association between silica

exposure and lung cancer.

I.C.2.u. Chinese iron and steel workers.

Xu et al. (1996b) identified all deaths during the decade 1980 to 89 for workers

employed in the iron and steel industry in Anshan, China. There were 610 lung cancer

cases diagnosed from 1987 to 1993 and 292 incident cases of stomach cancer (1989-

1993). There was one control for each case. Controls were matched by age and gender.

Cases and controls had to have worked in the steel complex for at least 10 years. Lifetime

occupational histories and smoking data were available. Cumulative dust and cumulative

silica exposure, as well as benzo(a)pyrene exposure, a marker for polycyclic aromatic

hydrocarbon (PAH) exposures, was established from historical records and available

industrial hygiene sampling data.

The risk of lung cancer was increased among foundry workers (OR = 1.8, CI 1.1-

2.8). This study also noted that refractory brick workers working 15 years or more had a

statistically significantly elevated incidence of lung cancer (OR = 2.9, CI 1.4-5.9).

Cumulative exposure to total silica dust and benzo(a)pyrene showed trends of increased

lung cancer with increased exposure. For the entire steel complex, a modest nonmonotonic trend was noted with increased cumulative silica exposure; OR = 1.7, 1.5, 1.5

and 1.8 for exposures ranging, respectively, from <3.7 to >27.72 mg/m3-years of

respirable dust with a p for trend = 0.007. The authors stated “[W]e could not adequately

distinguish the carcinogenic effects of silica vs. other dusts.” For example, in the

refractory brick area Xu et al. (1996b) indicated that there was a combination of silica

and asbestos exposure. IARC in its 1997 review was uncertain if the gradients for lung

cancer were adjusted for potential confounding by PAH exposures

I.C.2.v. Swedish aluminum foundry workers.
145

Westberg and Bellander (2003) conducted a nested case control study of Swedish

aluminum foundry workers. The initial cohort consisted of 5,016 foundry workers of

which 46 deaths from lung cancer were identified. There were 31 cases and 233 controls

in the final study with one year or greater of employment. Controls were matched to

cases by gender and age up to time of disease and analyzed as matched pairs. The

authors focused on creating an exposure model where there was good current crosssectional exposure data and relatively sparse historical data. Historical exposure data was

available as total dust samples in comparison to the current method of collecting

respirable dust with a cyclone. Therefore, a correction factor was necessary since “the

quartz concentrations were usually twice as high [in the total dust samples] as with the

present cyclone separation method...” (Westberg and Bellander, 2003). Regression

models using the determinants of job title, time period, foundry type, and size of

production were used to generate process-year historical total dust and crystalline quartz

exposure estimates.

These estimates were used to calculate individual cumulative exposures. Testing

of model variables was done by multiple linear regression analysis, which indicated that,

while total dust explained much of the variation (r2= 0.58), only a small portion of the

variation (r2= 0.13) was explained by respirable crystalline quartz exposure estimates.

No smoking data were provided in the paper, and even though other potentially

confounding occupational carcinogens were discussed, no adjustments were made in the

analysis. Odds ratios for total dust and silica showed a non-statistically significant trend

for increasing lung cancer mortality with increasing cumulative exposure. The maximum

cumulative exposure for respirable quartz in the high exposure group was 2.4 mg/m3-

years.

I.C.2.w. Norwegian silica carbide workers.

Romundstad et al. (2001) studied lung and other cancer incidence among workers

in the Norwegian silicon carbide (SiC) industry. The final study cohort consisted of

2,620 men who worked at least six months in one of three plants: plant A the largest,

started operation in 1913, plant B started operation in 1963 and plant C started operation

in 1965. Follow-up of cancer incidence started after six months of employment or from

1953, which ever was later, and continued to the end of 1966. Death certificates were

obtained from multiple sources with 2 percent either dying prior to follow-up or 3 percent

not being traceable.

Silicon carbide is a combination of quartz and finely ground coke that is heated in

an electrical resistance-type furnace at high temperatures ranging from 2,2000C to

2,5000C creating exceedingly hard materials. The nature of the production process is

very dusty and creates multiple exposures, including total dust and respirable quartz in

the preparation and mixing areas; SiC fibers and SiC particles, quartz, cristobalite, and

small amounts of PAHs in the furnace firing and post-furnace process areas; and potential

asbestos fiber exposure to maintenance personnel.
146

A JEM was created of all three plants. Plant A was the largest and the longestoperating facility. Therefore, workers in plant A contributed most of the person-years of

exposure and experienced most of the lung cancer cases (60 cases in plant A versus 8 and

6 cases plant C).

Since 1950 more than 6,000 dust samples had been taken at the three plants. Until

1974, a Watson thermal precipitator was used, taking time-weighted average area

samples (n = 4,200) for particle counts. From 1974 to 1996, gravimetric personal

measurements of total dust samples were taken. Fewer samples were available

characterizing the dust, with 200 measurements of crystalline silica (quartz and

cristobalite) analyzed by infrared spectroscopy prior to 1980 and supplemented by XRD

after 1980, and 216 short-term SiC fiber measurements analyzed by an optical phase

contrast microscope. Romundstad et al. (2001) reported that quartz and cristobalite were

present in roughly equal quantities in the oven and sorting departments. Gravimetric

measurements for total dust adjusted for the percentage of silica and a correction factor to

estimate respirable dust exposure were used to characterize exposures from 1975 to 1996.

During the time period 1950 to 1974, thermal precipitator measurements along with

changes in work patterns were used to estimate cumulative exposure to respirable

crystalline silica. Prior to 1950 when plant A was the only plant operating, there were no

exposure measurements. Estimation of pre-1950 exposures were principally based on

knowledge of changes of work patterns and the introduction of technology. Romundstad

et al. (2001) did not try to estimate gravimetric exposures from particle count data.

Instead, four cumulative exposure quartiles were created with an arbitrary scale of 1, 2, 3,

and 4, representing ranked exposures of zero, lowest, medium and highest exposures.

Categorical smoking data (never, former, current) was available from medical records

kept at the plants. Poisson regression analysis was used to investigate internal doseresponse relationships and to evaluate potential confounding by smoking.

The cohort’s total cancer incidence was elevated (SIR = 1.2, 95% CI 1.0-1.3).

This excess was mainly due to lung cancer (SIR = 1.9, 95% CI 1.5-2.3), but the rate of

stomach cancers (SIR = 1.5) and cancers of the upper respiratory tract (SIR = 1.7) were

increased, though the increase was not statistically significant. Lung cancer was elevated

at all three plants with SIRs of 1.9 (60 cases) in plant A, 1.7 (8 cases) in plant B, and 2.0

(6 cases) in plant C. Cumulative exposures to different types of dust were associated

with an increase in lung cancer. However, exposure levels to the various dusts and fibers

were highly correlated (r = 0.7-0.9). As stated by Romundstad et al. (2001) “[T]otal dust,

SiC fiber, SiC particle and crystalline silica exposure measures all showed essentially the

same pattern, [referring to the dose-response relationship] possibly because of a strong

correlation between these exposures...” In essence, it was difficult to separate out the

effects of respirable silica from SiC fibers and total dust, because these dust exposures

were associated with similar processes. In the highest exposure category the SIR for SiC

fibers was 3.5 (95% CI 2.1-5.6) with comparable results for respiratory crystalline silica

and SiC dust (SIR = 3.6 for both). When Poisson regression analysis in which both

crystalline silica and SiC fibers were included in the exposure model, the analysis

indicated that SiC fiber exposure was a stronger predictor of lung cancer risk than was

exposure to crystalline silica. The authors believed that this analysis should be
147

interpreted cautiously because of the strong correlation between these exposure

measurements. Romundstad et al. (2001), after performing an internal regression

analysis, concluded that smoking was not a significant confounder in this cohort.

I.C.2.x. Canadian silica carbide workers.

A Canadian study by Infante-Rivard et al. (1994) found an SMR of 169 (95% CI

109-252) for lung cancer mortality and an SMR of 203 (95% CI 121-322) for nonmalignant respiratory disease among silica carbide workers. A slight increase in lung

cancer deaths with increasing cumulative exposure to total dust was noted, with the risk

ratios being 1.67 and 1.48 for middle and high exposure categories, respectively. This

study had less exposure data available than did Romundstad et al. (2001) and was limited

to total dust measurements. As was the case with the Romundstad et al. (2001) study,

this study is difficult to interpret due to the existence of co-exposures of potential

occupational carcinogens, which were probably inherent to the production processes.

I.C.2.y. Finnish road paving and asphalt workers.

Kauppinen et al. (2003) conducted a cohort study of Finnish road paving and

asphalt workers. The cohort was defined as all workers who worked at least six months

before 1985 for one of six road paving companies. Follow-up was from 1964 through

1994 with an average duration of employment of 17 years. Detailed individual job

histories were available from company records for 1969 to 1994. A total of 5,676 male

workers, including bitumen workers, building/ground construction workers primarily

from one large company, and others met the cohort criteria with 666 deaths occurring by

the end of 1994. This study was part of the broader IARC Multicenter Study on Cancer

among European Asphalt Workers and Kauppinen et al. (2003) followed the IARC

protocol in developing an exposure matrix but developed a more detailed job

classification and used only Finnish exposure data.

In addition to respirable quartz exposure, road pavers are exposed to bitumen

(asphalt) fume, organic vapor, and benzo(a)pyrene, and building construction workers are

exposed to asbestos. Available Finnish exposure data were limited to two studies of road

paving, two studies of waterproof /roofing of rubberized roof sheets, and studies of two

roof sheet factories. Semi-quantitative exposure estimates for respirable quartz and other

chemicals were derived by a team of occupational hygienists from structured interviews

and available exposure data, and these results were specific for time period, job class,

company history, and chemical agent(s) used. A questionnaire to obtain smoking and

lifetime occupational histories was administered to 635 living cases of the cohort, which

had a 41 percent response rate.

This cohort experienced a total mortality SMR of 111 (95% CI 103-120), which

was mainly driven by accidents and violence, malignant neoplasm, and non-malignant

diseases of the respiratory system (SMR 123, CI 84-174, 32 deaths). Cancers of trachea,

bronchus, and lung were statistically significantly elevated for asphalt workers (SMR =

145, CI 103-198) and among building/ground construction workers (SMR = 139, CI 103-
148

184). When categorical exposure data were analyzed, no statistically significant trends

were noted, principally due to the small number of deaths, but exposure to silica showed

a non-statistically significant trend with the highest exposure category having a RR of

2.26 (95% CI 0.89-5.76). The authors noted that the smoking rate among

building/ground construction workers was similar to that of the overall Finnish male

population. Multivariate Poisson regression models with a 15-year exposure lag

suggested exposure-related trends for coal tar, organic vapors, silica dust, diesel exhaust

and bitumen fume. In their discussion, Kauppinen et al. (2003) noted “Exposure to silica

dust in construction works and asphalt mixing may partially explain the lung cancer

excess. The contribution of diesel engine exhaust cannot be ruled out, because the

exposure occurs often simultaneously with exposure to silica dust.”

I.C.2.z. Canadian bricklayers and associated crafts.

Finkelstein and Verma (2005) conducted a retrospective cohort analysis of 10,953

male brick and stone masons who were members of the International Union of

Bricklayers and Allied Craftworkers in the Province of Ontario, Canada. Subjects

entered the cohort on the date of joining the union or 1950, whichever was later, and

follow-up continued through the end of 1999. Ontario members of the plumbers’ union

served as the comparison group. The study did not have access to exposure

measurements or smoking data but used number of years and type of union membership

as a proxy for type of exposure and duration of exposure.

All cause mortality rates were less than expected prior to 30 years of work

(SMR10-19 yrs = 75 and SMR20-29 yrs = 88) but was statistically significantly elevated after

30 years or more of membership (SMR = 120, 95% CI 104-130). With 20 or more years

of union membership, statistically significant elevations of lung cancer (SMR20-29 yrs =

162, 50 deaths; SMR30+yrs = 150, 50 deaths), stomach cancer (SMR20-29 yrs = 200, 8 deaths;

SMR30+yrs = 260, 11 deaths), and colorectal cancer (SMR20-29 yrs = 180, 18 deaths

SMR30+yrs = 150, 17 deaths). When the data were broken down by members of refractory

locals compared to all locals there was no difference in lung cancer mortality rates

between members of these locals. Finkelstein and Verma (2005) indicated that besides

respirable silica, other occupational carcinogens may have been present in bricklayers’

work environments, including asbestos, exposure as a bystander to brick removal

operations, and hexavalent chromium present in the cement mixture (although hexavalent

chromium was found to be below the detection limit in air monitoring of the mixing of

cement by Ontario construction workers (Finkelstein and Verma, 2005)). After adjusting

for place of birth, age, and year of death, lung cancer rates were higher among bricklayers

than plumbers (OR = 1.14), but the difference was not statistically significant. The

authors concluded, “[l]ung cancer mortality reflect smoking habits and occupational

exposure [to silica]” and noted that plumbers were perhaps not the best comparison group

since they were exposed to asbestos and welding fume, both lung carcinogens, which

would deflate the lung cancer mortality risk estimate for silica.

I.C.3. Pooled IARC-Sponsored Multicenter Exposure-Response Analyses for Lung

Cancer.
149

As discussed in the introduction to this section, IARC (1997) noted that there

were some inconsistencies in exposure-response findings of studies carried out to

investigate the relationship between exposure to crystalline silica and lung cancer risk.

This finding led Steenland et al. (2001a) to conduct a comprehensive quantitative

exposure-response study of lung cancer mortality risks. This study, which was sponsored

by and coordinated through IARC, relied on raw data from previously published

epidemiological studies for which there were adequate quantitative data on crystalline

silica exposures to perform exposure-response analyses. The goal of this study was to

estimate exposures to crystalline silica across all studies using a common metric and

conduct a pooled analysis of resulting exposure-response trends to determine if the cohort

studies overall provide evidence of an exposure-response relationship between crystalline

silica and lung cancer. The results of the Steenland et al. (2001a) quantitative exposureresponse analysis and the exposure assessment reported by Mannetje et al. (2002a) are

described in detail in Section II, Preliminary Quantitative Risk Assessment, but are

summarized here.

The pooled analysis relied on data obtained from studies of 10 occupational

cohorts, all of which are described in Section I.C.4 above. These cohorts were:

 U.S. gold miners;

 U.S. diatomaceous earth workers;

 U.S. (Vermont) granite workers;

 Chinese pottery workers;

 South African gold miners;

 Australian gold miners;

 Chinese tungsten miners;

 Chinese tin miners;

 Finnish granite workers; and

 U.S. industrial sand workers.

Studies of three other cohorts were also identified as having adequate quantitative

exposure data but were excluded due to unavailability of the data (Dutch ceramic workers

in Meijers, 1996 and South African gold miners in Reid and Sluis-Cremer, 1996) or

because the data were incompatible with the case-control design of the study (English

pottery workers in McDonald et al., 1995).

These ten cohorts (5 mines and 5 industrial plants) included 65,980 workers and

1,072 lung cancer deaths (Steenland et al., 2001a). The follow-up period for five cohorts

(U.S. gold miners, Chinese pottery workers, Chinese tungsten miners, Chinese tin miners

and Finnish granite workers) was extended by 5 to 9 years beyond the original follow-up

period described in the original studies. Quantitative exposure data were either already

available or developed specifically by a co-investigator (Mannetje et al., 2002a) to

estimate cumulative exposures to respirable crystalline silica using cohort-specific

conversion factors based on silica content of the dust or results of side-by-side dust

sampling data. Mannetje et al. (2002a, 2002b) reported finding a positive, monotonic
150

exposure-response trend with silicosis mortality, indicating that the exposure assessment

was reasonable and unlikely to have resulted in significant misclassification of exposures.

Steenland et al. (2001a) conducted a nested case-control analysis on each cohort

using conditional logistic regression. Each case was matched to 100 controls who had

survived to at least the same age as the case. Matching was based on race, gender, and

date of birth and by research study. Categorical analyses of lung cancer rates by

cumulative and average exposure (defined as cumulative exposure averages of the whole

exposure period) were conducted by quintiles of cumulative exposure (<0.4, 0.4-2.0, 2.0-

5.4, 5.4-12.8, 12.8+) and analysis of cumulative exposure as a continuous variable was

performed using a log-linear relative risk model both with and without log transformation

of cumulative exposure and with lags of 0, 5, 10, 15, or 20 years. (Details of the results

of the risk modeling are presented in Section II, Preliminary Quantitative Risk

Assessment).

Tests for heterogeneity revealed that there was considerable heterogeneity

between studies for cumulative exposure and average exposure, and use of logtransformed cumulative exposure significantly reduced heterogeneity between studies.

There was no clear explanation for the observed heterogeneity. The authors speculated

that potential confounding by radon exposure in the South African gold miner cohort

leading to a relatively large exposure-response coefficient and possible physical

differences in crystalline silica particles in the various work environments might have

caused the differences in toxicity.

Steenland et al. (2001a) found a monotonic increase in lung cancer odds ratios

with quintiles of cumulative exposure, cumulative exposure lagged 15 years, and average

respirable silica concentration, but not with duration or log duration of exposure. For the

pooled categorical analysis with cumulative exposure lagged 15 years, the odds ratios and

95% confidence intervals for ascending quintiles of exposure were 1.0 (CI 0.83-1.3), 1.3

(CI 1.0-1.6), 1.5 (CI 1.2-1.8), and 1.5 (CI 1.2-1.9). Use of the log-linear model with log

cumulative exposure (unlagged or lagged 15 years) resulted in no substantial

heterogeneity between data sets and both yielded positive pooled exposure coefficients

suggesting the presence of a positive association between exposure to respirable silica

and lung cancer risk. Exposure-response trends were found to be similar between mining

and non-mining cohorts. Use of a spline model, which is essentially unconstrained and

does not impose a shape to the exposure-response curve, resulted in both an improved fit

and a reasonably monotonic increase in lung cancer risk with log cumulative exposure.

Eliminating the South African cohort, which had the strongest exposure-response

relationship of the studies, resulted in only slight changes in the results from the

categorical and continuous analyses. Analysis performed with and without the three

Chinese studies, where there was concern over potentially confounding exposure to other

carcinogens, did not cause any appreciable change in the pooled exposure coefficient.

Of the ten studies used by Steenland et al. (2001a), six had no information on

smoking histories of cases and controls. Steenland et al. (2001a) elected to leave the data

unadjusted for the other four studies, stating that the use of internal comparisons between
151

high- and lower-exposed workers within the cohort reduces the concern of confounding

by smoking since both high- and lower-exposed groups would presumably have had

similar smoking histories. The authors further stated, “[I]n those studies where complete

or partial smoking data were collected and considered in exposure-response analyses

either little confounding of exposure response trends were observed (South African and

Australian gold miners, diatomaceous earth workers, Finnish granite workers) or smoking

was actually a negative confounder (English pottery workers).” The authors concluded:

Silica appears to be a weaker carcinogen than other lung carcinogens

measured by mass in air. [Compared to the exposure-response curves seen

for hexavalent chromium, soluble nickel, arsenic, and cadmium,] silica

appears the weakest of the five, with lower relative risks and a lower slope

of the exposure-response curve.

Despite this relatively shallow exposure–response trend, overall our

results tend to support the recent conclusion by IARC (1997) that inhaled

crystalline silica in occupational settings is a human carcinogen, and

suggest that existing permissible exposure limits for silica need to be

lowered (Steenland et al., 2001a).

Steenland and Bartell (Toxichemica, Inc., 2004) also conducted a quantitative

uncertainty analysis at OSHA’s request in which data from some of the cohorts were

updated and follow-up periods extended. Additional quality control revealed a few errors

in the original assignments of exposures to cohort members. After correcting for these

errors and repeating the analysis using the same log-linear models as before, Steenland

and Bartell found only small changes in the exposure-response coefficients derived from

each cohort with the exception of the Finnish granite cohort, which changed from

positive to negative. There was no appreciable change in the pooled exposure coefficient

after updating the cohort data and correcting errors (0.060 from the model based on log

cumulative exposure and a 15-year lag, compared to 0.062 as originally reported by

Steenland et al., 2001a). In addition, repetitive implementation of the log-linear model

with log cumulative exposure using a Monte Carlo method to reflect random errors in

estimating exposures of cohort members to respirable silica resulted in a mean pooled

exposure coefficient only slightly below the coefficient originally reported by Steenland

et al. (2001a), with a variance around the estimate of the mean comparable to the level of

statistical uncertainty associated with the use of the log-linear model in the original

analysis. This suggests that uncertainties in the underlying estimates of exposure were

not likely to be so great as to call into question the finding from the original pooled

analysis of an overall exposure-related increase in lung cancer risk. This Steenland and

Bartell analysis (Toxichemica, Inc., 2004) strengthens OSHA’s confidence in the

available data and provides both a qualitative and quantitative estimate of the data’s

stability, even when subject to systematic error. The methods used in the uncertainty

analysis and results obtained are described in detail in Section II, Preliminary

Quantitative Risk Assessment.

I.C.4. Multi-National Pooled Population and National Death Certificate Studies.
152

I.C.4.a. U.S. national (27 states) case-control study.

Calvert et al. (2003) conducted a case-control study using 4.8 million death

certificates from the National Occupational Mortality Surveillance data set. Death

certificates were taken from 27 states covering the period from 1982 to 1995. Cases were

persons who had died from any of several diseases of interest: silicosis, tuberculosis, lung

cancer, chronic obstructive lung disease (COPD), gastrointestinal cancers, autoimmunerelated diseases, or renal disease. Five controls who had not died from a disease of

interest were selected from the same data set for each case and were matched on gender,

race, age, state, and year of death. Industry and occupation listed on each death

certificate were used to categorize exposure to crystalline silica as no/low, medium, high,

or super-high. This assessment was performed by three senior industrial hygienists who

were not informed as to whether subjects were cases or controls. Cases and controls

assigned to the high and super-high exposure categories were considered to have had

exposures at or above the OSHA PEL for silica (approximately 0.1 mg/m3). Secondary

mortality was also evaluated for persons who died of silicosis, which was considered to

be a less ambiguous marker of exposure. The mortality odds ratios were calculated for

each of the diseases of interest and are shown in Table I-14 by exposure group. Those

subjects thought to have had exposure to silica (medium, high or super-high categories)

had a significantly elevated risk of death for silicosis, chronic obstructive pulmonary

disease (COPD), tuberculosis, and rheumatoid arthritis (p < 0.05). The association with

silicosis validated the exposure classification system. There was also a significant trend

of increasing risk of mortality from these conditions as well as from lung cancer with

increasing exposure.

Table I-14. Mortality Odds Ratios by Silica Exposure Category and

Cause of Death from a U.S. Death Certificate Study*

Cause of Death

Exposure Category

p for

Trend

**Ever

v

Low/no

Med v

low/no

High v

low/no

Super

High v

low/no

Silicosis 4.98 2.91 6.84 30.5 <0.001

Pulmonary Tuberculosis 1.47 1.34 1.60 2.48 <0.001

COPD 1.12 1.02 1.29 1.47 <0.001

Lung Cancer 0.99 0.88 1.13 1.13 <0.001

*Adapted from Calvert et al. (2003)

**Medium, high and super high pooled and compared to low/no group

***Super high exposure
153

When associations between exposure and risk of disease are not strong – as is the

case with lung cancer and exposure to crystalline silica – it becomes more difficult to

detect the association because errors in measurement of either exposure or outcome tend

to bias results toward the null. Such problems can be overcome either by having high

quality data or by studying a very large population. The report by Calvert et al. (2003)

adopts the latter strategy by evaluating exposure among 4.8 million deaths, with positive

results that are generally consistent with other findings discussed in this section.

The study by Calvert et al. (2003) is consistent with earlier reports showing a

strong exposure-related increase in the risk of death from silicosis and tuberculosis and a

lesser increase in risks for other lung disease (in this case, COPD) and lung cancer. The

authors acknowledged the potential for confounding by higher smoking rates for cases

compared to controls, and partially controlled for this by eliminating white-collar workers

from the control group in the analysis. Upon reanalysis, the investigators reported

slightly lower, but still statistically significantly elevated, lung cancer mortality ORs of

1.07 (95% CI 1.06-1.09) and 1.08 (95% CI 1.01-1.15) for the high- and super-high

exposure groups, respectively (Calvert et al., 2003).

I.C.4.b. Finnish nationwide job exposure matrix (FINJEM).

Pukkala et al. (2005) wrote a methods paper that evaluated the FINJEM protocol

and evaluated the extent and magnitude of occupational exposure among persons

employed in several occupations over one or more time periods. Crystalline silica was

chosen as an example of a “known” occupational lung carcinogen and prostate cancer

was used as a negative control. Crystalline silica was also chosen for study because of the

large number of persons exposed, over 60,000 workers or 3 percent of the workforce.

Approximately 90 percent of those exposed were men. The cohort consisted of all Finns

born between 1906 and 1945 who participated in a national population census on

December 31, 1970. Follow-up of the cohort was through 1995. According to the

authors, Finland has excellent public health registries and associated databases.2The

census files contained updated information on death and migration, allowing for precise

calculations of person-years of exposure. In addition, data were available on job tenure,

socioeconomic class, and cigarette smoking rates. The Finnish cancer registry has

collected incident cancer cases since 1953. Between 1970 and 1995, there were 30,137

cases of incident lung cancer among men and 3,527 among women. The number of

incident prostate cancer cases was 18,744.

The basic data elements used for exposure assessment for FINJEM are

occupation, chemical agent, and calendar time periods of employment. The version of

FINJEM used in this study had data for 43 chemical agents and 311 job categories. To

make these job categories more homogenous 30 job categories were further subdivided

into 2 to 9 industry subgroups, resulting in a total of 393 job categories defined from the

database. Exposure data from 1972 to 2000 was collected by the Finnish Institute of

2 Reporting by the medical community is mandatory with nearly 100 percent coverage by the registry with

a high accuracy rate (Pukkala et al., 2005).
154

Occupational Health (FIOH) (>5,000 samples of respirable quartz or quartz-containing

dust) and when such data were not available, exposures were estimated based on the

opinions, experiences, and historical knowledge of technological changes of about 20

experts from FIOH. Default cumulative exposure categories for respirable quartz were

defined as follows: <1.0 mg/m3-years (low), 1.0 – 9.9 mg/m3-years (medium) and >10

mg/m3-years (high). Job-specific exposures were estimated for two time periods, 1945 to

1959 and 1960 to 1984.

For men, over 18 percent of the 30,137 lung cancer cases worked in occupations

with potential exposure to silica dust. After adjusting for socio-economic class, the SIRs

for lung cancer in men assigned to no, low, medium, and high exposure categories were

0.97 (95% CI 0.96-0.99), 1.10 (95% CI 1.06-1.14), 1.17 (95% CI 1.12-1.21), and 1.31

(95% CI 1.10-1.55), respectively. For women, the prevalence of exposure was 4 percent

with only 5 cases assigned to the highest exposure group. After merging the high

exposure group with the medium exposure group and adjusting for socio-economic class,

the SIRs for lung cancer in women were 0.99, 1.03, and 1.48 (95% CI 1.19-1.82) for the

no, low, and medium/high exposure groups, respectively, with only the SIR for the

medium/high exposure being statistically significantly elevated.

In reviewing independent variables in their model, Pukkala et al. (2005) found

that age and period of follow-up were poor predictors of lung cancer incidence, but

smoking and socioeconomic class had measurable independent effects, as was expected.

These two variables were highly correlated in the various models examined. Increasing

the lag time (years of latency) within the model resulted in a more pronounced exposureresponse association, with 18 years being the latency yielding the strongest exposureresponse relationship. Asbestos exposure was also included in the models preferred by

the authors.

In their discussion section, Pukkala et al. (2005) reported that exposure studies of

respirable quartz in Finnish working populations indicated that exposures greater than 0.1

mg/m3 were frequently found in metal and nonmetal mines, granite quarrying and

processing, crushed stone, foundry, ceramic, and the construction industries. Statistically

significant exposure-related trends for lung cancer risk were reported for all of these

industry groups except workers in foundries and workers in glass and ceramic industries.

The authors interpreted their findings “as signs of causality” between exposure to

respirable silica and lung cancer and viewed the results as consistent with the findings of

IARC (1997).

I.C.4.c. European multi-center community-based case-control study.

Cassidy et al. (2007) studied 2,852 newly diagnosed lung cancer cases and 3,104

controls, matched on gender and age from 1998 to 2003 in seven primarily Eastern

European countries. By investigating new cases, the authors were able to obtain detailed

job histories focusing on multiple exposures in jobs held longer than one year and to

obtain lifestyle information (by questionnaire), including smoking, socio-demographic

information and medical histories from 84 percent of the cases and 85 percent of the
155

controls. Furthermore, local experts knowledgeable in industrial hygiene assessed

exposures for up to 70 chemical agents, based on a protocol adopted from Siemiatycki et

al. (1990), without knowledge of case or control status. Detailed silica exposure data

were available for approximately 15 percent of the study population. The assessment of

silica exposure was principally done by assigning cases and controls to one of three

exposure categories, “low”, “medium”, and “high” and assigning ranges of exposure

levels to each of the categories in order to obtain “standardization in the application of

the intensity index”. There were 15 centers involved in this study, 2 of which used

population controls and 13 that used hospital-based controls, which excluded other

cancers and diseases related to smoking and tobacco use.

Statistical analysis was based on unconditional regression modeling of the

relationship between silica exposure and lung cancer, adjusted for age, study center,

tobacco consumption (ever/never smoked and pack-years), and highest school grade

completed (a socioeconomic variable). All other occupational agents assessed (70) were

considered as potential confounders and were evaluated by fitting dichotomous variables

for these agents consecutively. Various approaches were used to quantify exposure to

silica, including duration of exposure (years), weighted duration (hours per year by

frequency of exposure), and cumulative exposure, which was estimated from the assigned

exposure categories. Besides silica dust, only two other occupational exposures, wood

dust and insulation dust (including asbestos), were appreciably associated with lung

cancer incidence. These variables were added to the unconditional regression model used

in the analysis. All lung cancer risk estimates are expressed as adjusted odds ratios (ORs)

with 20-year lag periods.

Occupational exposure to crystalline silica, estimated by semi-quantitative

methods, was associated with an increased risk of lung cancer (OR = 1.37, 95% CI 1.14-

1.65). The risk was most apparent for the duration of exposure (OR = 1.73, CI 1.26-

2.39), the weighted duration of exposure (OR = 1.88, CI 1.35-2.61) and upper third

(tertile) of cumulative exposure (OR = 2.08, 95% CI 1.49-2.39), p < 0.0001 for trends.

Increased rates of smoking were more common among cases than controls. The

proportion of ever smoked was 90 percent for cases and 64 percent for controls. The

study design allowed for adjustment of this and other study confounders as well as

permitting a detailed analysis of the interaction of smoking and silica exposure as risk

factors for lung cancer.

Categorical analysis showed a 41 percent increased lung cancer risk (OR = 1.41,

95% CI 1.07-1.87) when comparing current smokers ever-exposed to silica to current

smokers who were unexposed. Similarly, increased lung cancer risks were also observed

for silica-exposed ex-smokers (OR = 1.31) and never smokers (OR = 1.41) when

compared to those who were unexposed. The authors concluded “Although smoking was

by far the largest risk for lung cancer, our results did not suggest an interaction between

tobacco smoking and exposure to silica on the risk of lung cancer beyond a multiplicative

model” (Cassidy et al., 2007).
156

Cassidy et al. (2007) observed elevated risks of lung cancer for persons who were

ever-exposed to silica in the construction (OR = 1.27, 95% CI 1.01-1.60), manufacturing

(OR = 2.03, 95% CI 1.30-3.17) and mining (OR = 1.48, 95% CI 1.02-2.13) industries. In

addition, clear linear trends of increasing ORs were observed for construction (p =

0.005), manufacturing (p for trend = 0.003) and mining (p = 0.03). The authors stated,

“[o]ur results show that silica is associated with an increased lung cancer risk,

independent of the source of silica. An increased risk has been observed in mining,

manufacturing, and construction industries, with a clear dose-response relationship in the

latter” (Cassidy et al., 2007).

In OSHA’s view, this study has a number of strengths. The first is the high power

achieved by pooling data in a multi-centered, multinational study to assemble a large

number of cases evaluated using a uniform protocol. There were 2,417 lung cancer cases

of which 435 had greater than 20 years of silica exposure, comprising a very large study.

Only one country out of the seven countries included in the study, Slovakia, contributed a

sufficient number of cases to observe a statistically significantly elevated lung cancer risk

(OR = 1.72 95% CI 1.05-2.83). Second, the authors of this incidence study were able to

obtain valuable personal lifestyle risk and demographic data (smoking and social class)

which is typically not available in many retrospective occupational cohort studies of

silica mortality. Third was the use of industrial hygiene experts to assess exposures to up

to 70 chemical agents semi-quantitatively using detailed job histories and available

industrial hygiene data, which enabled the investigators to rank exposure to silica dust

and several possible confounders. This study demonstrated that exposure to silica was a

risk factor for lung cancer among employees in a broad range of industries.

OSHA believes that the population-based design of this study combined with its

statistical power, control of confounding factors and use of exposure algorithm and local

industrial hygiene expertise to assess exposures make the findings of exposure-related

trends particularly compelling for the purpose of evaluating the causal relationship

between exposure to crystalline silica and lung cancer; however, because of the semiquantitative nature of the exposure assessment, OSHA believes that the data are not

suitable for evaluating quantitative exposure-response relationships.

I.C.5. Studies of Lung Cancer Risk Among Silicotics.

In this section, OSHA reviews studies that have investigated the relationship

between lung cancer mortality and the presence or absence of radiological silicosis.

Findings of an increased lung cancer risk among silicotics adds to the evidence of a

causal relationship between exposure to respirable crystalline silica and an increased lung

cancer risk since silicosis by definition, can only arise from such exposure. However, the

more difficult question is whether such findings suggest that silicosis itself is a necessary

precursor to lung cancer, or whether associations between silicosis and an increased lung

cancer risk simply reflect an increased risk among workers who have had a history of

significant exposure to crystalline silica.
157

IARC (1997) identified two data sets among the numerous silicotic cohort studies

as being the most complete and with the least bias and confounding. These were the

North Carolina dusty trades cohort (Amandus et al., 1991, 1992) and silicotics in Finland

(Partanen et al., 1994). The range of relative risk estimates were higher in these silicotic

cohorts compared to risk measures reported in the previously reviewed cohort studies

above. This is perhaps not surprising given that silicotics would have had higher

cumulative silica exposures as a group than was experienced by the exposed cohorts,

which included both silicotics and non-silicotics. For example, the North Carolina dusty

trades study, conducted by Amandus et al. (1992), undertook a reanalysis of 306

technically acceptable radiographs from an initial registry of 760 white male silicotics

and reported relative risks (RR) for lung cancer mortality ranging from 2.3 for jobs with

expected silica exposure only to a RR of 3.4 for silicotics who had ever smoked.

Silicotics with simple pneumoconiosis (small opacities with profusion 1, 2 or 3.) had a

RR of 2.5. By comparison, most of the studies of exposed cohorts discussed above

reported risk ratio measures generally at or below 1.5.

The Finnish study was much larger and covered 811 silicotics over a 40-year

period (1936 to 1977). The lung cancer incident ratio (SIR) for all silicotics was 2.9.

Statistically significantly elevated SIRs were found by industry and were 1.8 for casting

and foundries, 3.7 for mining and quarrying, and 3.3 for the glass and ceramic industry.

Statistically significant SIRs were also noted in the construction trades with the SIR for

excavation and foundation work being 5.8 and the SIR for building construction being

10.4 (based on 2 cases). Smoking data were available in 40 percent of the population

with the authors reporting no evidence of confounding by cigarette smoking in this subsample.

Some of the cohort and case-control studies reviewed earlier in this section looked

specifically at the lung cancer mortality rate of silicotics and/or non-silicotics (those who

did not have evidence of silicosis). In general, these studies have not consistently found

associations between the presence or absence of radiological silicosis and elevated lung

cancer risk. A number of these studies reported finding no increases in the expected

number of lung cancer cases among non-silicotics (de Klerk and Musk, 1998; Dong et al.,

1995; Ulm et al., 1999). Other studies that reported finding an association between

exposure to silica and increased lung cancer mortality did not find such associations with

radiological silicosis. In the study of British pottery workers (Cherry et al., 1998) no

evidence was found of a relationship between pulmonary opacities and lung cancer, the

prevalence of opacities being 6 percent and 5 percent, respectively, for cases and

controls. Among Chinese pottery workers, despite the high prevalence of silicosis

observed (in 13 percent of lung cancer cases and 12 percent of controls) there was no

evidence of an increased risk of lung cancer among silicotics versus non-silicotics

(McLaughlin et al., 1992).

Studies of South African miners involving three separate populations examined

the presence of silicosis and lung cancer at autopsy. In a study by Hessel et al. (1990),

there was no clear exposure-response trend in odds ratios for lung cancer among subjects

showing signs of silicosis of the parenchyma or pleura, and a negative exposure-response
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trend was found among those with signs of silicosis in the hilar glands. In a cohort study

by Hnizdo and Sluis-Cremer (1991) and a follow-up nested case-control study by Hnizdo

et al. (1997), the authors found no clear relationship between silicosis and the risk of lung

cancer as determined by autopsy. Miners with silicosis in the lung parenchyma and

pleura did not show an increased risk of lung cancer compared to those without evidence

of silicosis at these sites. However, the results did show a statistically significantly

higher risk of lung cancer in miners with evidence of silicosis of the hilar glands, a

finding that contrasts with that reported by Hessel et al. (1990). Hnizdo et al. (1997)

reported that they could not disentangle the relative contributions of silica exposure and

silicosis in increasing lung cancer risk because of the strong association between

exposure and silicosis. Studies of Chinese miners also reported mixed results, with

silicotics (defined by Chinese radiological categories) from tin and copper/iron mines but

not tungsten mines, showing higher lung cancer mortality compared to non-silicotics

(Chen et al., 1992). Overall, the mining studies do not show a consistent pattern with

respect to the lung cancer mortality experience of silicotics.

Since the IARC (1997) review, there have been several individual studies and

meta-analyses on silicotics designed to examine the relationship between silicosis and

lung cancer. A brief review of this literature follows. A study by Chan et al. (2000),

consisting of 1,490 male silicotics from Hong Kong (of whom approximately 90 percent

were construction workers) concluded that smoking was the predominant risk factor for

lung cancer in this cohort and that silica dust contributed little to the lung cancer risk.

Although the authors reported a lung cancer SMR of 194 (95% CI 135-270) for the

cohort overall, the proportion of workers who ever smoked was 90.6 percent compared to

49.8 percent for the male Hong Kong population. Using Axelson’s model and assuming

a 20-fold risk factor for smokers versus non-smokers, the authors estimated that the SMR

would equal 175 from smoking alone in this cohort, which was close to the observed

SMR of 194 (Chan et al., 2000).

Carta et al. (2001) conducted a study of 724 Sardinian male patients who were

current or former mine and quarry workers and who were first diagnosed with silicosis

between 1964 and 1970. Chest x-ray films categorized by the ILO classification system

were available for all patients, as were smoking histories, tests of lung function

(FEV1/VC(vital capacity)), and detailed work histories. Mortality follow-up was through

the end of 1997. Detailed exposure data were available for silica from 1945 and for

radon from 1972. Exposures were reconstructed back to the 1920s by a team of industrial

hygienists based on an analysis of mining techniques, annual production/figures, and

documentation of changes in ventilation and drilling techniques. Individual employee

cumulative exposure estimates were classified in one of three exposure groups for

respirable dust and one of three exposure groups for respirable crystalline silica (<5

gh/m3, 5-10 gh/m3, and >10gh/m3). Radon exposure data was only available from 1972

forward and the cumulative exposures were grouped as either greater than or less than

120 WLM (working level months). The analysis consisted of categorical analysis with

SMR values being derived from regional mortality rates supplemented by regression

analysis using multivariate proportional hazards modeling and stepwise regression

analysis. Carta et al. (2001) also included a nested case-control of 34 lung cancer deaths
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with 4 controls randomly selected from the cohort for each case, matching on age and

year of entry into the workforce.

Standard mortality rates from NMRD (non-malignant respiratory disease) and

tuberculosis (TB) were 603 (95% CI 544-669, 278 deaths) and 2,200 (95% CI 1,738-

2,784, 33 deaths), respectively, which largely contributed to an all-cause mortality of

SMR 134 for the cohort. The SMR for lung cancer mortality was elevated but was not

statistically significant (SMR = 137, 95% CI 98-191, 34 deaths). Non- statistically

significant trends of increased lung cancer mortality were observed with increased

cumulative exposure to silica and ILO radiographic profusion category. These trends

became more pronounced after incorporating a 20-year latency period into the analysis

but were still not statistically significant. The authors reported that a clearer trend (data

not provided) existed between exposure to radon and lung cancer mortality than silica

exposure and lung cancer mortality. The highest SMR for lung cancer mortality was

found among ever smokers with evidence of obstructive impairment measured by

spirometry at initial diagnosis (SMR = 329 95% CI 223-483).

According to the authors, the analysis showed that smoking, severity of airflow

obstruction, and cumulative exposure to radon daughters were the only significant

explanatory variables for lung cancer mortality. The nested case-control analysis

confirmed a statistically significant association between exposure to radon daughters and

lung cancer (OR = 2.21, 95% CI 1.01-4.85 for exposures greater than 120 WLM). In

contrast, ORs for lung cancer were not statistically significantly elevated. For example,

for the highest ILO radiological category and the highest cumulative silica exposure

category, the OR was 1.30 (95% CI 71-268).

Finkelstein (1998) re-analyzed data from a nested case-control study conducted

from a cohort of workers under surveillance for silicosis in Ontario, Canada. There were

42 lung cancer cases with 3 matched controls for each case. Smoking histories and chest

x-ray films were available from the surveillance program, and x-ray films were analyzed

independently by two readers with a very high concordance of classification. Particular

attention was given to potential confounding by smoking, using computer simulations

since only 1 out of 42 lung cancer cases had never smoked. The relative risk of lung

cancer mortality was 3.27 (95% CI 1.32-8.2) for subjects whose films were classified 1/0

or greater (based on the 1980 ILO system), compared to those whose films were

classified 0/1or 0/0. The authors concluded that there was an association between the

presence of radiographic silicosis and increased lung cancer mortality and that

radiographic silicosis should be considered a marker for increased lung cancer risk

among workers exposed to silica.

The study of diatomaceous earth workers by Checkoway et al. (1999) was

specifically designed to investigate the relationship between the classification of

radiological silicosis and lung cancer mortality. The study demonstrated a trend of

increasing lung cancer mortality with increasing cumulative exposure to crystalline silica

in the absence of silicosis. In this study, 81 workers (4.5 percent) in the cohort had

radiological silicosis. The overall mortality from lung cancer was found to be higher
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among these silicotics, (SMR 1.57 95 % CI 0.43-4.03) compared to non-silicotics (SMR

1.19 95% CI 0.87-1.57), although neither increase was statistically significant. Among

non-silicotics, there was a statistically significant increase in lung cancer mortality

(compared to national rates) with increasing cumulative exposure (p for trend = 0.02).

The authors concluded, “ [t]he dose-response relation observed between cumulative

exposure to respirable crystalline silica and lung cancer mortality among workers without

radiological silicosis suggests that silicosis is not a necessary co-condition for silicarelated lung carcinogenesis. However, the relatively small number of silicosis cases in

the cohort and absence of radiographic data after employment limit interpretations.”

Several meta-analyses and pooled cohort studies designed to explore relationships

between silicosis and lung cancer mortality have been performed (Kurihara and Wada,

2004; Lacasse et al., 2005; Pelucchi et al., 2006; Smith et al., 1995; Steenland and

Stayner, 1997; Tsuda et al., 1997). Smith et al. (1995) and Tsuda et al. (1997) performed

meta-analyses on cohort and case-control studies of silicotic workers. Smith et al. (1995)

originally abstracted data from 29 epidemiologic studies published between 1966 and

1994. Six of these studies were eliminated due to design flaws or unquantifiable biases,

leaving 23 studies. The method developed by Greenland (1987) was used to derive a

pooled relative risk (RR) estimate for lung cancer among silicotics. This method weights

each study’s RR measure in a manner inversely proportional to the variances of each

study-specific estimate. The pooled RR estimate for the 23 studies was 2.2 (95% CI 2.1-

2.4). The pooled RR estimates by study design were 2.0 (95% CI 1.8-2.3) for cohort

studies and 2.5 (95% CI 1.8-3.3) for case-control studies (Smith et al., 1995). There was

significant heterogeneity between the studies used in the analysis. The authors concluded

that the results of the analysis provided evidence of an increased risk of lung cancer in

silicotics who do not smoke, and that these findings could be due to either a modifying

effect of silicosis or to a direct effect of crystalline silica exposure.

Tsuda et al. (1997) also conducted a meta-analysis to explore the relationship

between silicosis/pneumoconiosis and lung cancer mortality. Lung cancer RR measures

were pooled from 32 eligible studies (6 from the Japanese literature) published from 1980

to 1994. The pool of studies was thus broader but had better-defined inclusion criteria

than those of Smith et al. (1995). The Greenland (1987) method was used to derive the

pooled estimate of relative risk. The overall estimated risk ratio was somewhat higher

than those obtained by Smith et al. (1995) (RR = 2.7, 95% CI 2.6-2.9). The RRs for lung

cancer mortality by study type were 2.8 (95% CI 2.6-2.9) for cohort studies and 2.7 (95%

CI 2.3-3.6) for case-control studies. Tsuda et al. (1997) calculated pooled RRs for lung

cancer among workers in four separate industry categories and found similar estimates

for each (pooled RR 2.68, 2.65, 2.61, and 2.6 for silicotics in mining, quarrying, foundry,

and pottery/ceramic work, respectively). Although the authors did not find an association

between lung cancer mortality and increasing silicosis severity (determined by ILO

profusion category), they concluded that silicosis was causally related to lung cancer

mortality with the lung cancer risk being about three times greater among silicotics than

in the general population.
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Steenland and Stayner (1997) conducted a meta-analysis of 19 studies of silicotics

and 16 studies of silica-exposed populations. The process for selecting studies was not

described, and the pooled RR was estimated by weighting each risk measure from each

study in inverse proportion to the variance of the risk estimate and using a random effects

model. The pooled RR for silicotic populations was 2.3 (95% CI 2.2-2.4). Steenland and

Stayner (1997) also reviewed 16 studies of silica-exposed workers, which had a pooled

RR of 1.3 (95% CI 1.2-1.4), suggesting a higher risk among silicotics compared to silicaexposed working populations. The authors pointed out that it was unlikely that

confounding by smoking was responsible for the observed excess risk because a number

of the studies included in their analysis controlled for smoking, either directly or

indirectly (Steenland and Stayner, 1997).

Kurihara and Wada (2004) conducted a meta-analysis that compared the

estimated relative risks of lung cancer among workers exposed to crystalline silica versus

those with silicosis. The investigators evaluated studies published between 1966 and

2001 and excluded those studies in which the confounding exposures to asbestos, radon

and other potential carcinogens were apparent or where potential confounding by

smoking was not sufficiently addressed. A panel of three independent reviewers

performed a quality screen to select studies for analysis with differences resolved by

consensus. Thirty studies (17 cohorts and 13 case-controls) in 25 papers were selected to

evaluate the relationship between exposure to silica and lung cancer and 16 studies (11

cohort and 5 case-control) were reviewed to evaluate the relationship between lung

cancer risk and the presence of radiological silicosis. Risk measures were weighted by

the inverse of their variances and combined using a random effects model. There was no

indication of publication bias (tendency not to publish negative studies) when

observations were made by funnel analysis.

The pooled lung cancer RR for silica-exposed populations was 1.32 (95% CI

1.24-1.41), a finding similar to that of Steenland and Stayner (1997). The pooled RR for

cohort and case-control studies were 1.29 (95% CI 1.20-1.40) and 1.42 (95% CI 1.22-

1.65), respectively. For studies of silicotic populations, the pooled lung cancer RR was

2.37 (95% CI 1.98-2.84). The pooled lung cancer RR among non-silicotic subjects with

silica exposure was not found to be elevated (pooled RR = 0.96, 95% CI 0.81-1.15). The

investigators also reported that the pooled risk in smokers with silicosis (pooled RR 4.47,

95% CI 3.17-6.30) was twice as high as the pooled risk among non-smokers with silicosis

(pooled RR 2.24, 95% CI 1.46-3.43). The degree of radiographic progression as

determined by ILO classification of the chest x-ray films was not associated with an

increased relative risk of lung cancer in this study.

The authors suggested that silicosis, rather than exposure to crystalline silica

itself, increased the lung cancer risk among silica-exposed workers. The authors further

suggested that exposure control to reduce silicosis and implementation of smoking

cessation programs among silicotics would greatly reduce lung cancer mortality. The

authors acknowledged that the sample number (N=8) in their analysis was small and

therefore, could not definitively determine whether “exposure to crystalline silica directly

increases lung cancer risk.”
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Lacasse et al. (2005) reviewed the international epidemiological literature on

silicosis as a potential causative agent or marker of lung cancer mortality published

between 1966 and 2004 to identify original cohort and case-control studies. Proportional

mortality, autopsy, and case series studies were excluded. Two of the authors

independently reviewed each study and reached consensus or involved a third reviewer in

determining a paper’s inclusion in the meta-analysis. Selected papers underwent a funnel

analysis, and the authors determined that publication bias was slight. Three separate

meta-analyses were conducted: one for the unadjusted SMR; another for the adjusted

SMR, according to the method of analysis proposed by Axelson (1978) to account for

smoking-related risk; and a third restricted to studies of non-smokers. The SMR values

were weighted by the inverse of their variance and pooled using a random effects model.

A dose-response analysis also compared ILO category of radiological diagnosis of chest

x-rays with the risk of lung cancer mortality.

Thirty-one studies (27 cohort and 4 case-control studies) met the inclusion

criteria. Without any adjustment for smoking, the meta-analysis for the cohort studies

estimated a pooled SMR = 245 (95% CI 163-366), with a high degree of heterogeneity in

underlying risk factors present (p < 0.0001). When four of the cohort mortality results

were adjusted for smoking in accordance to Axelson’s method, the pooled SMR was

reduced to 160 (95% CI 133-193), with no significant heterogeneity (p = 0.52). When

the data were restricted to four studies of silicotics who had never smoked, the pooled

SMR was estimated at 152 (95% CI 102-226), a result comparable to that found in the

analysis that adjusted for smoking (Lacasse et al., 2005).

The authors also found that lung cancer risk increased incrementally with

increased profusion of opacities on x-ray, with the lung cancer RR increasing

incrementally by 1.33 (95% CI 1.16-1.53) for each major ILO profusion category (i.e.,

ILO 1, 2, or 3). Lung cancer risk also increased incrementally with size of opacities with

the incremental RR equal to 1.67 for each ILO size category (i.e., ILO categories a, b, or

c).

In their discussion, Lacasse et al. (2005) acknowledged that their meta-analysis

probably represents an overestimate of the real risk of lung cancer among silicotics

because of the inherent biases of observational studies to meet the inclusion criteria.

Nevertheless, separate meta-analyses of non-smoking silicotics and the dose-response

observed between lung cancer mortality and silicosis severity suggested a true association

between silicosis and lung cancer mortality. The authors also stated that it could not be

determined from the available literature whether respiratory fibrosis directly increased the

risk of lung cancer or, alternatively, whether an increased lung cancer risk could be

attributed to exposure to respirable crystalline silica.

Pelucchi et al. (2006) reviewed approximately 45 studies published from 1996 to

2005, including 28 cohort and 15 case control studies. Approximately half of these casecontrol studies were nested within occupational or silicotic cohorts. Each study was
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categorized by the authors as being either a study of silicotics only, silicosis status

undefined, or a study of non-silicotics.

The pooled RRs of lung cancer were 1.69 (95% CI 1.32-2.16) in cohort studies of

silicotics only, 1.25 (95% CI 1.18-1.33) in cohorts where silicosis status was undefined,

and 1.19 for non-silicotics (1 study, RR not statistically significant). The authors

concluded that an association between silicosis and lung cancer mortality was

established, in agreement with other primary studies and meta-analyses, but that the issue

remained open on whether exposure to respirable silica itself was associated with lung

cancer. Pelucchi et al. (2006) also performed a pooled analysis of studies of exposed

populations by industrial sector, with the industrial sector characterization being similar

to that used by IARC (1997). These are presented in Table I-15.

Table I-15. Pooled Relative Risk (RR) for Lung Cancer Mortality from

Pelucchi et al. (2006), by Homogeneous Industry Types

Industry Grouping Cohort

Studies Case-Control Studies

No. RR* (95%

CI)** No. RR* (95% CI)**

Miners (underground

and surface) 3

1.17 (1.03-

1.32) 4 1.47 (1.19-1.82)

Industrial sand worker 3 1.29 (1.03-

1.61) 0 --

Ceramic, diatomaceous

earth, and refractory

brick

4

1.40 (1.11-

1.75) 3 1.26 (0.99-1.62)

Other Miscellaneous

exposures

10 1.17 (1.12-

1.22) 9 1.24 (1.02-1.52)

Adapted from Pelucchi et al., 2006, Table 1

* RR = relative risk ** 95% CI = 95 percent confidence intervals

Pelucchi et al. (2006) reviewed these findings and the quality of some of the

underlying studies and found the relative risk estimates to be equivocal as to whether

exposure to crystalline silica causes lung cancer, particularly due to the weakness of the

case-control studies. OSHA notes that the pooled RR estimates for the four industry

groups are modest but nevertheless statistically significantly elevated.

In summary, many studies of silicotic cohorts consistently reported higher

mortality rates for lung cancer than were seen among non-silicotic or mixed cohorts.
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Some of these studies (Kurihara and Wada, 2004; Steenland and Stayner, 1997) also

showed an increase in lung cancer mortality among exposed workers absent evidence of

radiographic silicosis, although these risks tended to be smaller than those reported for

diagnosed silicotics.

The previously cited diatomaceous earth study by Checkoway et al. (1999) also

found a statistically significant exposure-response relationship for lung cancer among

non-silicotics, and no difference in lung cancer RRs were noted between silicotics and

non-silicotics in the pottery industry studies. Checkoway and Franzblau (2000), in

reviewing the international literature, found that all epidemiological studies conducted to

that point were insufficient to conclusively determine the role of silicosis in the etiology

of lung cancer. The authors proposed that the question of whether silicosis is a necessary

precursor for lung cancer “[i]s virtually unanswerable from currently available

epidemiological literature, and is unlikely to be addressable in future epidemiological

studies.” Similarly, OSHA believes that meta-analyses designed to investigate this issue

demonstrate that workers with radiological silicosis are at higher risk of lung cancer

mortality than non-silicotics but that it is not possible with available data to determine

whether the increased lung cancer mortality risk reflects higher exposure among silicotics

or whether it indicates that silicosis itself plays an etiologic role in the development of

lung cancer.

I.C.6. Preliminary Conclusions from the Lung Cancer Evidence.

OSHA conducted an independent review of the epidemiological literature on

exposure to respirable crystalline silica and lung cancer, covering more than 30

occupational groups in over a dozen industrial sectors. In addition, OSHA reviewed a

pooled case-control study, a large national death certificate study, two national cancer

registry studies, and six meta-analyses. In all, OSHA’s review included approximately

60 primary epidemiological studies (See Table I-1).

Based on its review, OSHA preliminarily concludes that the human data

summarized in this section provides ample evidence that exposure to respirable

crystalline silica increases the risk of lung cancer among workers. The strongest

evidence comes from the worldwide cohort and case-control studies reporting excess

lung cancer mortality among workers exposed to respirable crystalline silica dust as

quartz in various industrial sectors; the 10-cohort pooled case-control analysis by

Steenland et al. (2001a) confirms these findings. A more recent clinic-based pooled casecontrol analysis of seven European countries by Cassidy et al. (2007) as well as two

national death certificate registry studies (Pukkala et al., 2005 in Finland and Calvert et

al., 2003 in the United States) support the findings from the cohort and case-control

analysis.

I.C.6.a. Overall and industry sector-specific findings.

Associations between exposure to respirable crystalline silica and lung cancer

have been reported in worker populations from many different industrial sectors. The
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IARC panel (1997) identified four industry sectors in which studies were judged to be the

least confounded that reported findings consistent with this hypothesis (quarries and

granite works, ceramic or pottery industries, refractory brick industries, and the

diatomaceous earth industry). Based on these and other findings, IARC (1997)

concluded that crystalline silica is a confirmed human carcinogen. NIOSH (2002) also

determined that crystalline silica is a human carcinogen after evaluating updated

literature.

OSHA believes that the strongest evidence for carcinogenicity comes from studies

in five industry sectors. These are:

 Diatomaceous Earth Workers (Checkoway et al., 1993, 1996, 1997, and

1999; Seixas et al., 1997);

 British Pottery Workers (Cherry et al., 1998; McDonald et al., 1995);

 Vermont Granite Workers (Attfield and Costello, 2004; Graham et al.,

2004; Costello and Graham, 1988; Davis et al., 1983);

 North American Industrial Sand Workers (Hughes et al., 2001; McDonald

et al., 2001, 2005; Rando et al., 2001; Sanderson et al., 2000; Steenland

and Sanderson, 2001); and

 British Coal Mining (Miller et al., 2007; Miller and MacCalman, 2009).

OSHA credits these studies because in general, they:

 Are of sufficient size and have adequate years of follow up;

 Have sufficient quantitative exposure data to reliably estimate exposure of

cohort members;

 Were either unlikely to be confounded by exposure to other occupational

carcinogens, or potential confounding by co-exposures was addressed and

found to be unlikely;

 For the most part, were able to obtain smoking history data, which

permitted controlling for potential confounding or indirectly estimate an

independent effect of smoking; and

 Were absent of any apparent selection bias, including choice of referent.

The studies above were all retrospective cohort or case-control studies that

demonstrated positive, statistically significant exposure-response relationships between

exposure to crystalline silica and lung cancer mortality. Except for the British pottery

studies, where exposure-response trends were noted for average exposure only, lung
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cancer risk was found to be related to cumulative exposure. There was limited

confounding due to other occupational exposures. Where potential confounding could

occur, e.g., asbestos in a subset of diatomaceous earth workers or U.S. crushed stone

workers; this potential confounding was addressed in the study design or data analysis.

As part of their analyses, the authors of these studies also found positive exposureresponse relationships for silicosis, indicating that underlying estimates of worker

exposures were not likely to be substantially misclassified.

A series of studies of the diatomaceous earth industry (Checkoway et al., 1993,

1996, 1997, 1999) demonstrated positive exposure-response trends between cristobalite

exposures and lung cancer as well as non-malignant respiratory disease mortality

(NMRD). Checkoway et al. (1993) developed a “semi-quantitative” cumulative exposure

estimate that demonstrated a statistically significant positive exposure-response trend

between duration of employment or cumulative exposure and lung cancer mortality.

Checkoway et al. (1996) conducted a re-analysis to address criticisms of potential

confounding due to asbestos and again demonstrated a positive exposure response risk

gradient when controlling for asbestos exposure and other variables. Rice et al. (2001)

conducted a re-analysis and quantitative risk assessment of the Checkoway et al. (1997)

study, which is used by OSHA as part of its assessment of lung cancer mortality risk (See

Section II, Preliminary Quantitative Risk Assessment).

In the British pottery industry, excess lung cancer risk was found study to be

associated with crystalline silica exposure among workers in a PMR study (McDonald et

al., 1995) and in a cohort and nested case-control study (Cherry et al., 1998). In the PMR

study, elevated PMRs for lung cancer were found after adjusting for potential

confounding by asbestos exposure. In the study by Cherry et al., odds ratios for lung

cancer mortality were statistically significantly elevated after adjusting for smoking.

Odds ratios were related to average, but not cumulative, exposure to crystalline silica.

The findings of the British pottery studies are supported by other studies within their

industrial sector. Winter et al. (1990) reported a statistically significant increase in the

SMR for lung cancer among British pottery workers, and a non-monotonic increase in

lung cancer mortality with increasing cumulative exposure. (This was a crude estimate of

cumulative exposure based on job title during cross-sectional environmental sampling

multiplied by the total number of years worked at the plant.) A nested case-control study

of 13,719 Chinese potters also showed a modest increase in lung cancer mortality

associated with increasing quartile of cumulative exposure to respiratory crystalline silica

(McLaughlin et al., 1992).

Costello and Graham (1988) and Graham et al. (2004) in a follow-up study found

that Vermont granite workers employed prior to 1930 had an excess risk of lung cancer,

but lung cancer mortality among granite workers hired after 1940 (post-implementation

of controls) was not elevated in the Costello and Graham (1988) study and was only

somewhat elevated (not statistically significant) in the Graham et al. (2004) study.

Graham et al. (2004) concluded that their results did not support a causal relationship

between granite dust exposure and lung cancer mortality. Attfield and Costello (2004)

looking at the same population developed a quantitative estimate of cumulative exposure
167

(8 exposure categories) adapted from a job exposure matrix developed by Davis et al.

(1983). They found a statistically significant trend with log-transformed cumulative

exposure. Lung cancer mortality was observed to rise reasonably consistently through

the first seven increasing exposure groups, but fell in the highest cumulative exposure

group. With the highest exposure group omitted, a strong positive dose-response trend

was found. Attfield and Costello (2004) concluded that their quantitative analysis

provided clear evidence that exposure to crystalline silica in the range of cumulative

exposures typically experienced by contemporarily exposed workers have an increased

risk of lung cancer mortality. OSHA believes that the study by Attfield and Costello

(2004) is of superior design that allowed for the quantification of exposures by exposure

group, along with a detailed explanation of why the lack of smoking data in this cohort

had a small probability of affecting the results. The conclusions of the Vermont granite

worker study (Attfield and Costello, 2004) are supported by the findings in studies of

workers in the U.S. crushed stone industry (Costello et al., 1995) and Danish stone

industry (Guénel et al., 1989a, 1989b).

Studies of overlapping cohorts in the industrial sand industry (Hughes et al., 2001;

McDonald et al., 2001, 2005; Rando et al., 2001; Sanderson et al., 2000; Steenland and

Sanderson, 2001) reported comparable results. They both found a statistically

significantly increased risk of lung cancer mortality with increased cumulative exposure

in both categorical and continuous analyses. The cohort of McDonald et al. (2001)

entered the workforce, on average, a decade earlier than the Steenland and Sanderson

(2001) study; it has more years of exposure in the industry (19 versus 8.8 years); and is

more concentrated working within eight plants. The Steenland and Sanderson (2001)

cohort worked in 16 plants, 7 of which overlapped with the McDonald, et al. (2001)

cohort. McDonald et al. (2001), Hughes et al. (2001), and Rando et al. (2001) had good

smoking histories for the cohort and access to plant records, processes, and modern and

historic exposure measurements to conduct historical reconstructions and develop a job

exposure matrix. Steenland and Sanderson (2001) had less access to plant facilities, less

detailed historic exposure data, and used MSHA enforcement records for estimates of

recent exposure. The findings of these studies (Hughes et al., 2001; McDonald et al.,

2005; Steenland and Sanderson, 2001) are mutually reinforcing in that they show very

similar exposure response patterns of increased lung cancer mortality with increased

exposure gradients.

Excess lung cancer mortality was reported in a large cohort study of British coal

miners (Miller et al., 2007; Miller and MacCalman, 2009). These studies examined the

mortality experience of 17,800 miners through the end of 2005. By that time there were

516,431 person years of observation, an average of 29 years per miner, with 10,698

deaths from all causes. Overall lung cancer mortality was elevated and a positive

exposure-response relationship with crystalline silica exposure was determined from Cox

regression after adjusting for smoking history. Three of the strengths of this study are the

detailed time-exposure measurements of both quartz and total mine dust, detailed

individual work histories, and individual smoking histories. For lung cancer, analyses

based on these Cox regression methods provide strong evidence that, for these coal
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miners, quartz exposures were associated with increased lung cancer risk, but that

simultaneous exposures to coal dust did not cause increased lung cancer risk.

Studies of lung cancer mortality in metal ore mining populations are more mixed.

Many of these mining studies were subject to confounding due to exposure to other

potential carcinogens such as radon and arsenic. IARC (1997) noted that in only a few

ore mining studies was confounding from other occupational carcinogens taken into

account. IARC (1997) also noted, where confounding was absent or accounted for in the

analysis (gold miners in the U.S., tungsten miners in China, and zinc and lead miners in

Sardinia, Italy), an association between silica exposure and lung cancer was absent.

OSHA believes that many of the studies conducted since IARC’s 1997 review more

strongly implicate crystalline silica as a human carcinogen. Pelucchi et al. (2005), in a

meta-analysis of studies conducted since IARC’s (1997) review, reported statistically

significantly elevated relative risks in underground and surface miners in three cohort and

four case-control studies (See Table I-15). Cassidy et al. (2007), in a pooled case-control

analysis, showed a statistically significant increased risk of lung cancer mortality among

miners. Cassidy et al. (2007) also demonstrated a clear linear trend of increasing odds

ratios for lung cancer with increasing exposures.

Among workers in Chinese tungsten and iron mines, mortality from lung cancer

was not found to be statistically significantly increased (Chen et al., 1992; McLaughlin et

al., 1992). In contrast, studies of Chinese tin miners found increased lung cancer

mortality rates and positive exposure-response associations with increased silica exposure

(Chen et al., 1992). Unfortunately, in many of these Chinese tin mines, there was

potential confounding from arsenic exposure, which was highly correlated with exposure

to crystalline silica (Chen and Chen, 2002; Chen et al., 2006).

Gold mining has been extensively studied involving four separate cohort and

associated nested case-control studies conducted in three different countries and two

independent case-control studies conducted in South Africa. Similar to other metal

mining, gold mining lung cancer risk is subject to confounding, particularly from radon

exposure. The U.S. gold miner study (Steenland and Brown, 1995a) did not find an

increased risk of lung cancer, while the western Australian gold miner study (de Klerk

and Musk, 1998) showed a statistically significant elevated SMR. Logistic regression

analysis of the western Australian case control data showed that lung cancer mortality

was statistically significantly associated with log cumulative silica exposure after

adjusting for smoking and bronchitis. The authors concluded that their findings showed

statistically significantly increased lung cancer mortality in this cohort but that the

increase in lung cancer mortality was restricted to silicotic members of the cohort.

Four studies of gold miners were conducted in South Africa. Two case control

studies (Hessel et al., 1986, 1990) reported no significant association between silica

exposure and lung cancer, but these two studies were subject to underestimating risk,

according to Hnizdo and Sluis-Cremer (1991). Two cohort studies (Reid and SluisCremer, 1996 and Hnizdo and Sluis-Cremer, 1991) and their associated nested casecontrol studies found elevated SMRs and odds ratios, respectively, for lung cancer. Reid
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and Sluis-Cremer (1996) attributed the increased mortality due to lung cancer and other

non-malignant respiratory diseases to cohort members’ lifestyle choices. However,

OSHA notes that the study reported finding a positive, though not statistically significant,

association between cumulative crystalline silica exposure and lung cancer, as well as

statistically significant association with renal failure, COPD, and other respiratory

diseases that have been implicated with silica exposure. Thus, OSHA believes that this

study is not wholly inconsistent with others that have reported increased lung cancer

mortality among silica-exposed workers.

In contrast, Hnizdo and Sluis-Cremer (1991) found a positive exposure-response

gradient between cumulative exposure and lung cancer mortality after accounting for

smoking. In a nested case-control study from the same cohort, Hnizdo et al. (1997) found

a statistically significant increase in lung cancer mortality that was associated with

increased cumulative dust exposure and time spent underground. These studies were the

strongest South African studies in terms of their rigorous methodology and quantification

of exposure. Consequently, OSHA believes that exposure misclassification was less

likely to occur in these latter two studies. Although not conclusive in isolation, OSHA

considers the mining study results, particularly the gold mining and the newer mining

studies, as supporting evidence of a relationship between exposure to silica and lung

cancer risk.

Further evidence for a causal relationship between exposure to respirable

crystalline silica and lung cancer mortality comes from the pooled analysis of 10

occupational cohorts (5 mines and 5 industrial facilities) conducted by Steenland et al.

(2001a), which demonstrated an overall positive exposure-response relationship between

the log cumulative exposure to silica and lung cancer mortality.

OSHA also reviewed a center-based case-control study (Cassidy et al., 2007),

which pooled cancer incidence data from seven European countries in 15 regional

centers. This large study, with 2,852 newly diagnosed cases, was able to obtain good

personal data on smoking as well as good exposure estimates of exposure to silica dust

and other potentially confounding occupational exposures. The authors concluded: “Our

result(s) support the hypothesis that silica is an important risk factor for lung cancer.

This risk could not be explained by exposure to other occupational carcinogens or

smoking” (Cassidy et al., 2007).

In addition, a recent analysis of 4.8 million death certificates from 27 states within

the U.S. for the years 1982 to 1995 showed a statistically significant pattern of increased

mortality risk due to lung cancer as well as increased mortality due to silicosis,

tuberculosis, and NMRD among persons with occupations in industries with medium and

high exposure to respirable crystalline silica as determined by an expert panel of

industrial hygienists (Calvert et al., 2003). A national records and death certificate study

was also conducted in Finland by Pukkala et al. (2005) who found a statistically

significant increase in incidence rates of lung cancer among men and women with

estimated medium and heavy exposures.
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OSHA believes that these large national death certificate studies and the pooled

European community-based case-control study strongly supportive of the previously

reviewed epidemiologic data and supports the conclusion that occupational exposure to

crystalline silica is a risk factor for lung cancer mortality.

I.C.6.b. Smoking, silica exposure, and lung cancer.

Smoking is known to be a major risk factor for lung cancer. However, OSHA

believes it unlikely that the observed exposure-response trends reported in most of these

studies are explained by smoking. This is particularly true in retrospective cohort or

nested case-control studies that demonstrate a gradient of increased disease risk with

increasing exposure, as is the case with studies of diatomaceous earth, British pottery,

Vermont granite, British coal, South African gold, and industrial sand workers. Also, the

fact that these positive associations are found in multiple studies in multiple sectors is

supportive of crystalline silica being an independent risk factor from smoking, since it

becomes increasingly unlikely that smoking alone could explain the observed exposureresponse trends across a large group of studies.

Studies by Hnizdo et al. (1997), McLaughlin et al. (1992), Hughes et al. (2001),

McDonald et al. (2001, 2005), Miller and MacCalman (2009), and Cassidy et al. (2007)

had detailed smoking histories with sufficiently large populations and sufficient time

from first exposure for lung cancer to become manifest to quantify the interaction

between crystalline silica exposure and cigarette smoking. In a cohort of white South

African gold miners (Hnizdo and Sluis-Cremer, 1991) and in the follow-up nested casecontrol study (Hnizdo et al., 1997) found that the combined effect of exposure to

respirable crystalline silica and smoking was greater than additive, suggesting a

multiplicative effect. This synergy appeared to be greatest for miners with greater than

35 pack-years of smoking and higher cumulative exposure to silica. In the Chinese

nested case-control studies reported by McLaughlin et al. (1992), cigarette smoking was

associated with lung cancer, but correction for smoking did not influence the association

between silica and lung cancer in the mining and pottery cohorts studied. The studies of

industrial sand workers by Hughes et al. (2001) and British coal workers by Miller and

MacCalman (2009) found positive exposure-response trends after adjusting for smoking

histories. Cassidy et al. (2007) found that current smokers ever exposed to silica had

approximately a 40 percent increased incidence of lung cancer (OR = 1.41, 95% CI 1.07-

1.87) than unexposed current smokers. Similar estimates of increased risk were observed

among exposed ex-smokers and non-smokers, but these results were not statistically

significant for these populations. Cassidy et al. (2007) “[d]id not observe any interaction

beyond a multiplicative model between tobacco smoking and silica exposure.”

In reference to control of potential confounding by cigarette smoking in

crystalline silica studies, Stayner (2007), in an invited journal commentary, stated:

“Of particular concern in occupational cohort studies is the difficulty in

adequately controlling for confounding by cigarette smoking. Several of

the cohort studies that adjusted for smoking have demonstrated an excess
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of lung cancer, although the control for smoking in many of these studies

was less than optimal. The results of the article by Cassidy et al. presented

in this journal appear to have been well controlled for smoking and other

workplace exposures. It is quite implausible that residual confounding by

smoking or other risk factors for lung cancer in this or other studies could

explain the observed excess of lung cancer in the wide variety of

populations and study designs that have been used. Also, it is generally

considered very unlikely that confounding by smoking could explain the

positive exposure-response relationships observed in these studies, which

largely rely on comparisons between workers with similar socioeconomic

backgrounds.”

Given the findings of investigators who have accounted for the impact of

smoking, the weight of the evidence reviewed here implicates respirable crystalline silica

as an independent risk factor for lung cancer mortality. This finding is further supported

by animal studies demonstrating that exposure to silica alone can cause lung cancer (e.g.,

Muhle et al., 1995).

I.C.6.c. Silicosis and lung cancer risk.

In general, studies of workers with silicosis, as well as meta-analyses that include

these studies, have shown that workers with radiologic evidence of silicosis have higher

lung cancer risk than those without radiologic abnormalities or mixed cohorts. Three

meta-analyses attempted to look at the association of increasing ILO radiographic

categories of silicosis with increasing lung cancer mortality. Two of these analyses

(Kurihara and Wada, 2004; Tsuda et al., 1997) showed no association with increasing

lung cancer mortality, while Lacasse et al. (2005) demonstrated a positive dose-response

for lung cancer with increasing ILO radiographic category. A number of other studies,

discussed above, also found increased lung cancer risk among exposed workers absent

radiological evidence of silicosis (Cassidy et al., 2007; Checkoway et al., 1999; Cherry et

al., 1998; Hnizdo et al., 1997; McLaughlin et al., 1992). For example, the diatomaceous

earth study by Checkoway et al. (1999) showed a statistically significant exposureresponse for lung cancer among non-silicotics. Checkoway and Franzblau (2000),

reviewing the international literature, found all epidemiological studies conducted to that

date were insufficient to conclusively determine the role of silicosis in the etiology of

lung cancer. OSHA preliminarily concludes that the more recent pooled and metaanalyses do not provide compelling evidence that silicosis is a necessary precursor to

lung cancer and might simply reflect that more highly exposed individuals are at a higher

risk for lung cancer.

Animal and in vitro studies have demonstrated that the early steps in the proposed

mechanistic pathways that lead to silicosis and lung cancer seem to share some common

features. This has led some of these researchers to also suggest that silicosis is a

prerequisite to lung cancer. Some have suggested that any increased lung cancer risk

associated with silica may be a consequence of the inflammation (and concomitant

oxidative stress) and increased epithelial cell proliferation associated with the
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development of silicosis. However, other researchers have noted that other key factors

and proposed mechanisms, such as direct damage to DNA by silica, inhibition of p53,

loss of cell cycle regulation, stimulation of growth factors, and production of oncogenes,

may also be involved in carcinogenesis induced by silica (see Section II.F. for more

information on these studies). Thus, OSHA preliminarily concludes that available animal

and in vitro studies do not support the hypothesis that development of silicosis is

necessary for silica exposure to cause lung cancer.

I.C.6.d. Relationship between silica polymorphs and lung cancer risk.

The current OSHA standard reflects a once-held belief that cristobalite is more

toxic than quartz (i.e., the PEL for cristobalite is one-half the PEL for quartz). Available

evidence indicates that this does not appear to be the case with respect to the

carcinogenicity of crystalline silica. A comparison between cohorts having principally

been exposed to cristobalite (the diatomaceous earth study and the Italian refractory brick

study) with other well conducted studies of quartz-exposed cohorts suggests no

difference in the toxicity of cristobalite versus quartz. The data indicates that the SMRs

for lung cancer mortality among workers in the diatomaceous earth (SMR = 141) and

refractory brick (SMR = 151) cohort studies are within the range of the SMR point

estimates of other cohort studies with principally quartz exposures (quartz exposure of

Vermont granite workers yielding an SMR of 117; quartz and possible post-firing

cristobalite exposure of British pottery workers yielding an SMR of 129; quartz exposure

among industrial sand workers yielding SMRs of 129, (McDonald et al., 2001) and 160

(Steenland and Sanderson, 2001)).

OSHA believes that the current epidemiological literature provides little, if any,

support for treating cristobalite as presenting a greater lung cancer risk than comparable

exposure to respirable quartz. Furthermore, available toxicological literature no longer

supports the hypothesis that cristobalite has a higher toxicity than quartz, and quantitative

estimates of lung cancer risk do not suggest that cristobalite is more carcinogenic than

quartz. (See Section I-F, Physical Factors that May Influence Toxicity of Crystalline

Silica, for a fuller discussion of this issue.) OSHA preliminary concludes that respirable

cristobalite and quartz dust have similar potencies for increasing lung cancer risk; this

position is consistent with previous positions taken by IARC (1997) and NIOSH (2002).

I.C.7. Cancer of Other Sites.

Respirable crystalline silica exposure has also been investigated as a potential risk

factor for cancer at other sites such as the larynx, nasopharynx and the digestive system

including the esophagus and stomach. Although many of these studies suggest an

association between exposure to crystalline silica and an excess risk of cancer mortality,

most are too limited in terms of size, study design, or potential for confounding to be

conclusive. Other than for lung cancer, cancer mortality studies demonstrating a doseresponse relationship are quite limited. Also, most of the better quality studies reviewed

above (Vermont granite, British pottery, industrial sand, and diatomaceous earth) did not

find statistically significant excess cancer mortality rates for sites other than the
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respiratory system. In their silica hazard review, NIOSH (2002) concluded that,

exclusive of the lung, an association has not been established between silica exposure and

excess mortality from cancer at other sites. A brief review of the relevant literature is

presented below.

I.C.7.a. Cancer of the larynx and nasopharynx.

There are several studies that have hinted at an increased incidence of laryngeal

cancer among workers exposed to crystalline silica. In part due to the small size of the

occupational cohorts studied, none of these studies found statistically significant results.

In addition, many of these studies did not control for smoking, an important potential

confounder for laryngeal cancer. One of the earliest cancer studies among Vermont

granite workers looked at the proportion of deaths due to cancers at various sites (Davis

et al., 1983). The authors reported an overall increase in respiratory cancer mortality as

well as mortality from cancer of the larynx. The proportionate mortality ratio (PMR)

values were 130 (95% CI 100-160) for respiratory cancer mortality, 190 (95% CI 80-440,

5 cases observed) for laryngeal cancer mortality and 120 (95% CI 90-150) for lung

cancer mortality. However, later studies of this population with extensive follow-up

failed to find excess mortality from laryngeal cancer (Costello and Graham, 1988;

Graham et al., 2004).

Another early study by Selikoff (1978) of New York City tunnel workers reported

finding an SMR for laryngeal cancer mortality of 3.80 (3 observed). No industrial

hygiene monitoring was provided, but the author indicated that asbestos exposure, if any,

was small and that these workers experienced high silica quartz exposures. A population

based study by Neuberger and Kundi (1990) in Vienna, Austria, of the dusty trades

(foundries, metal working, and glass, brick and stone work, etc.) found increased

mortality from lung cancer (SMR = 148, 175 observed), laryngeal cancer (SMR = 143, 4

observed), and stomach cancer (SMR = 166, 77 observed).

Puntoni et al. (1988) reported finding an SMR of 405 (95% CI 83-1182, 3

observed) for laryngeal cancer among refractory brick plant employees. Puntoni et al.

(1988) noted that laryngeal cancer was limited only to the silicotic population, whereas

lung cancer was more evenly distributed among the study population. Sorahan and

Cooke (1989) in a cohort of 10,491 United Kingdom foundry workers reported increases,

though not statistically significant, in nose and naval cavity cancers and cancer of the

larynx. The SMRs were 251 (4 observed/1.6 expected) for the nose and nasal cavity and

116 (8 observed 6.9 expected) for the larynx. Cherry et al. (1998) and Chen et al. (1992)

did not observe an increased rate of esophageal cancer among British or Chinese pottery

workers, respectively. Chen et al. (1992) found statistically significantly increased

mortality from nasopharyngeal cancer among Chinese tungsten and tin miners, but not

among Chinese pottery workers. Two well-done studies of U.S. cohorts (diatomaceous

earth and industrial sand workers) reported increases, though not statistically significant,

in laryngeal cancer mortality (Checkoway et al., 1997; McDonald et al., 2001).
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In summary, many of these initial studies, including three of the better-quality

lung cancer studies (Checkoway et al., 1997; Davis et al., 1983; McDonald et al., 2001)

suggest an association between exposure to crystalline silica and increased mortality from

laryngeal cancer. However, the evidence for an association is not strong due to the small

number of cases reported and lack of statistical significance of most of the findings.

I.C.7.b. Gastric (stomach) cancer.

In their 2002 hazard review of respirable crystalline silica, NIOSH identified

numerous epidemiological studies and reported statistically significant increases in death

rates due to gastric or stomach cancer. The following cancer studies were reviewed and

cited in NIOSH (2002). The studies are listed below by industry author and date (see

NIOSH, 2002 for full bibliographic references):

 Iron ore miners (Lawler et al., 1985; Mur et al., 1987; St. Clair Renard,

1984);

 Canadian gold miners (Kusiak et al., 1993; Miller et al., 1983; Muller et

al., 1983; Shannon et al., 1987);

 Lead and zinc miners (Belli et al., 1989);

 Brick workers (Katnelson and Mokronosova, 1979);

 Foundry workers (Newberger and Kundi, 1990);

 Jewelry workers (Dubrow and Gute, 1987; Hays et al., 1993; Sparks and

Wegman, 1980); and

 Farmers/farmworkers (Blair and Zahm, 1991, 1993).

Moshammer and Neuberger (2004) reported on a prospective community based

study examining the long term disease effects of occupational non-fibrous dust(s)

exposure (including crystalline silica) on life expectancy and specific causes of death.

Subjects were 3,260 male Viennese workers, selected at a mean age of 54 during

preventive check-ups between 1950 and 1960 and who were followed prospectively until

death (50 years of follow-up during which essentially the entire cohort had died). Half of

the subjects (1,630) were exposed at work to non-fibrous, mineral particulates and were

matched for year of job entry, age, and smoking status, with non-exposed workers.

Average life expectancy of those exposed to dusty occupations was 1.6 years less than

that of non-exposed workers (p < 0.001). Only a small part of this decrease in life

expectancy was related to “acknowledged occupational diseases such as silicosis and

silicotuberculosis” and other pneumoconiosis (SMR = 6,712). Chronic obstructive

pulmonary disease (COPD) (SMR = 182 95% CI 130-256), bronchial cancer mortality

(SMR = 142 95% CI 114-176), and stomach cancer mortality (SMR = 177 95% CI 125-

251) were found more frequently among those exposed to dust. The authors postulated
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that the finding of an increased incidence of stomach cancer might be related to particles

swallowed after clearance from the airways. By design, this study could not distinguish

the differences between exposure to crystalline silica and other mineral dusts.

PMRs and proportionate cancer mortality ratios (PCMRs) were evaluated for

12,873 members of the Operative Plasterers' and Cement Masons' International

Association who died between 1972 and 1996, using United States age-, race-, and

calendar-specific death rates (Stern et al., 2001). Among cement masons, statistically

significant elevated mortality was observed for cancer of the stomach (PCMR = 133 p <

0.01) and benign neoplasm (PMR = 132 p < 0.01). This was an initial study and was

suggestive of elevated stomach cancer mortality among cement masons who would

presumably have been exposed to crystalline silica (Stern et al., 2001).

Finkelstein and Verma (2005) conducted a preliminary retrospective cohort study

of 10,953 male members of International Union of Bricklayers and Allied Craftworkers

from Ontario, Canada, who were exposed to silica and other inorganic dusts. The

comparison group was comprised of Ontario members of the plumbers’ union. The study

did not have access to exposure measurements or smoking data but used type of union

local and years of union membership as proxies for type of exposure and duration of

exposure.

Elevation of lung cancer, pneumoconiosis, and stomach cancer mortality was

noted among union members. For workers with 20 or more years of union membership,

the SMR for lung cancer was 158 (95% CI 130-190, 100 observed) and for stomach

cancer was 235 (95% CI 140-370, 19 observed). Stomach cancer mortality rates also

increased with increasing decade of union membership, but the increase was statistically

significant only for those with more than 30 years of membership (11 observed deaths).

The studies by Stern et al. (2001) and Finkelstein and Verma (2005) suggest that

exposure to dust from construction materials such as brick and concrete are a risk factor

for stomach cancer.

Parent et al. (1998) conducted detailed population-based case-control analyses of

incident gastric cancer cases identified between 1979 and 1985. The analysis included

250 male cases, aged 35 to 70 years, residing in Montreal, Canada, who were diagnosed

with gastric cancer with histological confirmation. This was part of a larger study of

cancer cases at 19 anatomical sites, from which 533 age-stratified controls were selected,

but excluded cancer of the lung and esophagus. A two-part interview was conducted

with each case or control: a structured questionnaire on socio-demographic variables and

personal habits and a second semi-structured questionnaire obtaining a detailed job

history. In total, 16 occupation and industry categories and 32 substances that were

identified either in exploratory analyses or in previous studies as potential risk factors for

gastric cancer were evaluated. A panel of chemists and industrial hygienists, blinded to

the case or control status of the subject, ranked the likelihood, frequency, and intensity of

the expected exposure based upon the detailed job histories. Unconditional logistic

regression was used in the analysis with smoking status, years at school (measure of

socioeconomic status), and birthplace or country of origin treated as covariates.
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Among cases who had worked at least 10 years as excavators or pavers or as

electric or electronic workers, the authors found an increasing risk of gastric cancer with

increasing years of work. Crystalline silica was one of three exposures that was

statistically significantly associated with increased stomach cancer mortality (OR = 1.7

95% CI 1.1-1.7, N = 25); the other substances were grain dust (OR = 1.9 CI 1.2-3.1, N =

23) and leaded gasoline (OR = 2.0 CI 1.2-3.3, N = 22). For crystalline silica, the risk of

gastric cancer increased with the frequency and concentration of exposure, but there was

no evidence of an exposure-response pattern based on the duration of exposure (Parent et

al., 1998).

Tsuda et al. (2001) conducted a population-based case-control study to examine

the effect of silica exposure on gastric and esophageal cancer mortality. Both cases and

controls were selected from cancer death certificates, controls being colon and other

types of cancer exclusive of lung cancer. The study was restricted to male subjects from

the Tobi area of Japan. For gastric cancer, the age and smoking-adjusted OR was 1.22

(95% CI 0.74-2.01) and for esophageal cancer, the OR was 1.53 (95% CI 0.87-6.23).

Although results did not reach a statistically significant level, the authors concluded that

the results suggest that an increased mortality associated with gastric and esophageal

cancers was related to silica exposure.

In a study by Koskela et al. (1987) of 1,026 Finnish granite workers exposed to

silica from 1940 to 1985, mortality from gastrointestinal cancer was significantly

increased (SMR of 200 95% CI 110-380, 15 deaths observed). No other Finnish cohorts

had statistically significant increased rates of gastrointestinal cancer.

González et al. (1991) conducted a population-based study consisting of 354 cases

of gastric carcinoma diagnosed among the residents of four regions of Spain. The cases

were matched by age, sex, and geographical area. The subjects were interviewed to

obtain information on bio-demographic characteristics, work history, and occupational

exposures to inorganic and organic dusts (no exposure measurements). The risk of

stomach cancer was statistically significantly increased for employment in coal mining,

construction, and the leather industries as well as occupations with expected silica or

other mineral exposure after adjusting for potential confounding by socioeconomic status

and consumption of vegetables and fruits.

Xu et al. (1996b) conducted a nested case-control of stomach (292 incident cases)

and lung cancer among iron and steel workers in Anshan, China. For lung and stomach

cancer a statistically significant dose-response was observed for total dust and

benzo(a)pyrene exposure, but not for the silica fraction of total dust. (In China, routine

sampling for silica is conducted as a total dust area measurement, supplemented by silica

content of settled dust.) For stomach cancer, after adjusting for consumption of pickled

vegetables, prior gastric diseases, family history of stomach cancer, low intake of fruits

and vegetables and education level, the risk of stomach cancer was statistically

significantly elevated for those employed 15 or more years in the fire resistant brick

factory (OR = 2.5, 95% CI = 1.1-5.8), in general (dusty) loading (OR = 3.2, CI = 1.2-8.9),
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as boiler workers and cooks (OR = 2.6, CI = 1.2-5.6), and as coke oven workers (OR =

5.4, CI = 1.8-16.0). This confirmed an earlier PMR study by Xu et al. (1996a) that

showed an increase in stomach and esophageal cancer mortality among refractory brick

workers. In contrast, Chen et al. (1992), found no excess stomach cancer mortality in tin,

iron and copper mining, and the ceramic industry. Chen et al. (1992) also found a

statistically reduced mortality in tungsten mining (SMR = 48) in a cohort of 68,000

Chinese workers of primarily metal mining and the ceramics industry. Dong et al. (1995)

in a retrospective cohort of silica and clay brick workers in 11 refractory plants found a

slight non-statistically significant increase in mortality due to stomach cancer (SMR =

130) among 6,266 male workers.

In summary, OSHA preliminarily concurs with observations made previously by

Cocco et al. (1996) and the NIOSH (2002) crystalline silica hazard review that the vast

majority of epidemiology studies of silica and stomach cancer have not sufficiently

adjusted for the effects of confounding factors or have not been sufficiently designed to

assess a dose-response relationship (e.g., Finkelstein and Verma, 2005; Moshammer and

Neuberger, 2004; Selikoff, 1978, Stern et al., 2001). Other studies did not demonstrate a

statistically significant dose–response relationship (e.g., Calvert et al., 2003; Tsuda et al.,

2001). Therefore, OSHA believes the evidence is insufficient to conclude that silica is a

gastric carcinogen.

I.C.7.c. Esophageal cancer.

Wernli et al. (2006) evaluated the associations between occupational exposures in

the textile industry and the risks of esophageal cancer and stomach cancer. The authors

conducted a case-cohort study nested in a cohort of predominately female textile workers

in Shanghai, China. One hundred two (102) incident esophageal cancer and 646 incident

stomach cancers diagnosed between 1989 and 1998 were compared with an age-stratified

reference subcohort (n = 3,188). Work histories were obtained for all study subjects from

factory personnel records or interviews. Exposures were reconstructed for chemicals and

dusts by linking work history data with a job exposure matrix. Twenty-three (23)

chemical or dust groupings and 12 specific hazardous agents, including silica dusts, were

evaluated. Cox proportional hazards modeling was used to estimate RRs. Information

about personal risk factors, including smoking history, (ever/never) alcohol consumption,

and reproductive history was obtained in a baseline questionnaire administered from

1989 to 1991.

Risk of esophageal cancer was associated with long-term exposure to silica dust

(>10 years) in a metal foundry setting that was part of the textile complex (hazard ratio =

15.8, 95% CI 3.5-70.6) as well as exposure to metals (hazard ratio = 3.7, 95% CI 1.9-

7.1). There was also a modest increase of esophageal cancer risk associated with

exposure to acids, bases, and caustics. Increased risks of stomach cancer were modest,

with either no or erratic trends with increased duration of these exposures. The authors

acknowledged that the increase in risks may be attributed to exposure to PAHs

(polycyclic aromatic hydrocarbons) that were not assessed in this study.
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Yu et al. (2005) conducted a mortality study of esophageal cancer in a cohort of

2,789 male silicotic workers in Hong Kong during 1981 to 1999. The registry of

silicotics primarily consisted of construction workers who either worked within caissons

and tunnels or those who worked in surface construction occupations. The SMR for

esophageal cancer for the entire cohort was 222 (95% CI 136-343, based on 20 deaths).

For a subgroup of caisson workers who had a higher exposure to silica dust, the SMR

was 421 (95% CI 181-830, based on 8 deaths). The RR of esophageal cancer for caisson

workers with silicosis was reduced to 234 (95% CI 101-462) after adjustment, using the

indirect method proposed by Axelson, for the effects of smoking and alcohol drinking.

For non-caisson silicotic workers, no excess risk of esophageal cancer was observed after

indirect adjustment for the effects of smoking and alcohol drinking.

The authors believed that the excess risk of esophageal cancer mortality among

caisson workers with silicosis could best be explained by the very heavy exposure to

respirable crystalline silica dust in their working environment, reported by the authors to

be greater than hundred times the TLV. Exposure data for respirable silica and other

possible exposures (welding fumes, combustion products) for caisson or surface

construction workers was available, but not used, in the analysis. The authors stated, “no

measurements were taken during pneumatic rock drilling because extremely high dust

concentrations led to absorption of alpha particles and rendered counting inaccurate.”

The authors also referenced Lam et al. (1988) who reported a wide range of radon and

radon daughters concentrations in caissons. OSHA believes that if radon particles are

absorbed by the dust and dust is inhaled and partially cleared or has a longer residence

time in the lung and esophagus due to overloading, excess alpha radiation would be

expected to be delivered to these organ areas leading to lung or esophageal cancer.

Using duration (years) of exposure and severity of silicosis as surrogates of

exposure, Yu et al. (2005) noted a non-statistically significant dose response trend for the

eight caisson workers who died of esophageal cancer for both the duration of exposure

and severity of silicosis. The authors have accounted for other known confounders such

as smoking and alcohol by indirect adjustment and still maintain a statistically significant

result among caisson workers. They noted that the differences of esophageal cancer

mortality rates between caisson work and surface construction work is unlikely to be

caused by socioeconomic confounding as these construction workers are generally of the

same socioeconomic class.

In this study we have presumably a moderate to heavily exposed population

represented by the non-caisson workers and a very heavily exposed workforce

represented by the caisson workers. Yu et al. (2005) attribute the excess lung cancer to

the very heavy silica exposure of caisson workers. However, OSHA believes that results

of this study may not be applicable to the broader population of silica exposed workers as

the presence and absorption of radon onto dust particles from pneumatic drilling may

result in confounding.

Pan et al. (1999) conducted a nested case-control design within a cohort of

industrial workers who were exposed to refractory brick dust in a large iron-steel
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complex in China. Esophageal cancer cases (125 cases) and 250 controls were identified

from the death registry file of the company and matched on age. Past exposure

information was obtained through the development of a job-exposure matrix via the

reconstruction of work histories from work files. Dust exposures were categorized into

eight broad categories of dust exposure, dust/chemical exposure, or non-exposed. This

included relatively “pure” silica dust exposures defined in this study as exposure to

refractory grade quartz and possibly cristobalite during the making, laying and repairing

of blast furnaces. However, OSHA notes that refractory repair of blast furnaces may also

be associated with exposure to metals such as chromium, vanadium, arsenic and other

residues on old refractory brick ILO (1983). Smoking, drinking, and eating habits were

determined from interviews with next of kin (>95% for cases and controls). In the initial

bivariate analysis ORs were unadjusted but were later adjusted for confounding factors in

the multivariate analysis using unconditional logistic regression.

After adjusting for confounders, occupational exposure to refractory grade silica

dust was the most important risk factor among all the variables investigated (OR = 2.8,

95% CI 1.4-5.7) and there was a clear dose-response by duration of exposure. For those

exposed to refractory silica dust for 25 years or greater, the excess risk was statistically

significant (OR = 8.7, 95% CI of 1.7-47.1). Drinking of alcohol (OR of 1.8) and cooking

with coal (OR of 2.0) were also risk factors for esophageal cancer. High consumption of

a fruit diet (OR of 0.5) and a meat diet (OR of 0.6) were protective factors. Thus, the

relationship between occupational exposure to silica dust and the risk of esophageal

cancer found in an earlier SPMR study (Xu et al., 1966a) was also seen here. The authors

suggested that ingestion of silica particles after lung clearance may increase the risk of

esophageal cancer among workers exposed to silica.

Cucino and Sonnenberg (2002) analyzed data files from the National Center for

Health Statistics of the U.S. to study the causes of death by occupation and industry. The

number of deaths from esophageal cancer was retrieved from computerized U.S. vital

statistics. Mortality by occupation or industry was expressed as standardized

proportional mortality ratio (PMR), adjusted for age, gender, and ethnicity. Between

1991 and 1996, 63,717 subjects died from esophageal squamous cell carcinoma.

Mortality was particularly high among non whites and men. Mortality from esophageal

squamous cell carcinoma occurred more frequently among subjects exposed to silica

dust, such as brick masons and stonemasons (PMR = 137, 95% CI 111-163), concrete

and terrazzo finishers (PMR = 164, 95% CI 117-211), roofers (PMR = 142, 95% CI 101-

183), and construction laborers (PMR = 112, 95% CI 100-115). It was also high in such

industries as unspecified machinery or manufacturing (PMR = 116, CI 105-126) and such

occupations as unspecified material handlers, janitors, or cleaners (PMR = 111, CI 101-

121). The authors concluded that mortality from esophageal squamous cell carcinoma

appeared to be low in occupations associated with less consumption of alcohol and

tobacco and was high among occupations potentially associated with exposure to silica

dust and chemical solvents or detergents.

In a similar PMR study, Fillmore et al. (1999) analyzed death certificate data on

occupation and industry from 24 states in the U.S. between 1984 and 1993 (NOMS
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database). The authors’ primary purpose was to compare PMRs for men and women

exposed to silica. Industry and primary job titles as they appear in death certificates, a

crude estimate of exposure, were used to define “possible” and “probable” silica

exposure. Approximately 20,000 women and 500,000 men were estimated to be exposed

using these criteria. Both men and women had higher than expected PMRs for

respiratory diseases, lung cancer, and esophageal cancer. The PMR for esophageal

cancer with possible silica exposure in women did not reach statistical significance (PMR

=121, 95% CI 92-157, 59 deaths) while the PMR in men was lower, but statistically

significant (PMR = 105, 95% CI 102-109, 3,488 deaths). With probable silica exposure

(both industry and job title with expected exposure) the PMR for esophageal cancer was

more robust for women, but still not statistically significant (PMR = 266, 95% CI 97-579,

6 observed deaths) while the PMR for esophageal cancer for men was essentially similar

as those possibly exposed (PMR = 108, 95% CI 102-115, 1,028 observed deaths). This

study and the previously reviewed study by Cucino and Sonnenberg (2002) are

considered by OSHA to be preliminary due to the crude estimates of exposure. Also,

confounding by non-occupational factors (smoking and alcohol use) was not adjusted for

in either study.

Calvert et al. (2003) conducted a large case control study using a similar, but

somewhat expanded database (NOMS 27 states, 1982 to 1995) as Fillmore et al. (1999).

The study evaluated the mortality risk for a number of cancers and respiratory and other

diseases previously associated in the literature with crystalline silica exposure. The

methodology of this study was reviewed in depth in the previous section on lung cancer.

The odds ratios (OR) for esophageal and stomach cancer were 0.94 and 0.98,

respectively, with a slight, but not statistically significant, dose response (increasing

disease with increasing ranked exposure estimates) for esophageal cancer.

Weiderpass et al. (2003) conducted a census-based study of incident cases for

gastrointestinal and esophageal cancer, including 389 esophageal cancer cases of 413,817

predominately industrial and service Finnish female workers identified between 1971 and

1995. The relative rates for new cases of esophageal and other cancers were determined

from a job exposure matrix for 183 job titles over four time periods for 25 chemical

agents ranked into three exposure categories (zero or reference, low, and medium/high).

Liver and esophageal cancer rates were adjusted for alcohol use. The authors found no

statistically significant association between any of the agents analyzed and esophageal

and liver cancer (389 cases each). The RR for esophageal cancer was slightly elevated at

1.57 (95% CI 0.85-2.91, p = 0.51). The results of this study are similar to those of

Calvert et al. (2003) with neither study supporting an association between silica exposure

and esophageal cancer.

In summary, three well-conducted nested case-control studies of Chinese workers

indicated an increased risk of esophageal cancer mortality attributed by the study’s

authors to respirable crystalline silica in refractory brick production, boiler repair, and

foundry workers (Pan et al., 1999; Wernli et al., 2006) and caisson construction work (Yu

et al., 2005). Each study demonstrated a dose-response association with some surrogate

measure of exposure, but confounding due to other occupational exposures is possible in
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all three work settings (heavy metal exposure in the repair of boilers in steel plants, PAH

exposure in foundry workers, radon and radon daughter exposure in Hong Kong caisson

workers). Other less well-constructed studies also indicated elevated rates of esophageal

cancer mortality with silica exposure (Tsuda et al., 2001; Xu et al., 1996a).

In contrast two large national mortality studies in Finland and the United States,

using qualitatively ranked exposure estimates did not show a positive association

between silica exposure and esophageal cancer mortality (Calvert et al., 2003;

Weiderpass et al., 2003). OSHA preliminarily concludes that the epidemiological

literature is not sufficiently robust to attribute increased esophageal cancer mortality to

exposure to respirable crystalline silica.

I.C.7.d. Other miscellaneous cancers.

In 2002, NIOSH conducted a thorough literature review of the health effects

potentially associated with crystalline silica exposure including a review of lung cancer

and other carcinogens. NIOSH noted for workers who may have been exposed to

crystalline silica, there have been infrequent reports of statistically significant excesses of

deaths for other cancers. A summary of these cancer studies as cited in NIOSH (2002)

have been reported in the following organ systems (see NIOSH, 2002 for full

bibliographic references):

Table I-16, Miscellaneous Cancers

Cancer Type Lead Author, Year Published

Salivary gland Zheng et al. 1996

Liver Chen et al. 1992

Hua et al. 1992

Bone Steenland and Beaumont 1986

Forastiere et al. 1989

Pancreatic Kauppinen et al. 1995

Skin Partenan et al. 1994

Rafnsson and Gunnarsdottir 1977

Lymphopoetic or hematopoietic Redmond et al. 1981

Silverstein et al. 1986

Steenland and Brown 1995

Brain Rafnsson and Gunnarsdottir 1977

Bladder Bravo et al. 1987

According to NIOSH (2002), an association has not been established between these

cancers and exposure to respirable crystalline silica. OSHA believes that these isolated

reports of excess cancer mortality at these sites are not sufficient to draw any inferences

about the role of silica exposure. The findings have not been consistently seen among

epidemiological studies and there is no evidence of an exposure response relationship.

I.D. Other Nonmalignant Respiratory Disease.
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In addition to causing silicosis, exposure to crystalline silica has been associated

with increased risks of other nonmalignant respiratory diseases (NMRD), primarily

chronic obstructive pulmonary disease (COPD). COPD is a disease state characterized

by airflow limitation that is not fully reversible. The airflow limitation is usually

progressive and is associated with an abnormal inflammatory response of the lungs to

noxious particles or gases. In patients with COPD, either chronic bronchitis or

emphysema may be present or both conditions may be present together. Chronic

bronchitis is defined clinically (and typically ascertained by questionnaire reporting of

symptoms) as chronic productive cough for three months in each of two successive years

in a patient in whom other causes of productive chronic cough have been excluded.

Emphysema is defined pathologically (generally examined either at autopsy or

radiographically) as the presence of permanent enlargement of the airspaces distal to the

terminal bronchioles, accompanied by destruction of their walls and without obvious

fibrosis. The relative contribution of chronic bronchitis and emphysema to the COPD

process is often difficult to discern (ATS, 2004). The following presents OSHA’s

discussion of the literature describing the relationships between silica exposure and

nonmalignant respiratory disease.

I.D.1. Emphysema.

Longitudinal studies of South African gold miners have been conducted by

Hnizdo and coworkers (1991, 1994). In a retrospective cohort study, Hnizdo et al. (1991)

conducted a post-mortem examination of the lungs of 1,553 South African gold miners in

order to make quantitative estimates of increased risk of emphysema in relation to

cumulative respirable dust exposure. For each miner, information was available on the

number of shifts worked in each occupation and mine. The average respirable dust level

of each occupation had been previously evaluated (Beadle, 1971). Hnizdo et al. (1991)

grouped occupations into five categories that were assigned dust factors proportional to

these previously evaluated respirable dust measurements. The respirable dust exposure

for each miner was calculated by number of dusty shifts, years spent in high-dust

occupations, and cumulated dust index calculated as the sum of the product of the

number of shifts in an occupation and the occupational dust factor, divided by 1,000.

These three dust measurements were then cumulated up to 35, 45, and 55 years of age

and to death. Dust was measured by standard thermal precipitator and then treated with

heat and acid. The authors noted in a later report that the respirable dust after this

treatment contained about 30 percent silica (Hnizdo and Sluis-Cremer, 1993).

In the current study, the authors estimated that, based on a 30-percent silica

content, exposures of the cohort ranged from 0.05 to 0.8 mg/m3respirable crystalline

silica. For miners working in high dust occupations, such as “shaft sinkers” and

“developers,” the average cumulative respirable dust exposure over an 8-hour shift was

about 3.12 mgh/m3. Hnizdo et al. (1991) found that both panacinar and centriacinar

emphysema were positively related to respirable dust exposure. Centriacinar emphysema

was also related to the presence of silicosis. Of the exposure variables, cumulative

respirable dust exposure to 45 years of age was found to be the strongest predictor of
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emphysema. A logistic regression model showed a statistically significant association

between emphysema and years of employment in high-dust occupations. The authors

estimated that a gold miner with 20 years of exposure in high-dust occupations up to 45

years of age has a 3.5 (95% CI 1.7 to 6.6) times higher odds of having a significant

degree of emphysema at autopsy than a miner not in a dusty occupation when the

coefficient for the cumulative dust index was used, and a 2.1 (95% CI 1.5 to 2.82) times

higher odds when the coefficient for years in high-dust occupations was used. There

were only four non-smokers with a significant degree of emphysema found in the cohort,

and there was no such association found for nonsmokers. Oxman et al. (1993) has

calculated that the cumulative exposure of a miner in this group with 20 years of

exposure in high-dust occupations up to 45 years of age would be “roughly” 22 gh/m3

respirable dust containing about 30 percent free silica. To provide an estimate of how

this cumulative exposure might be acquired from an average exposure concentration,

expressed in mg/m3, OSHA performed the following calculations:

22 gh/m3= 22,000 mgh/m3; 20 years x 2000 h/year = 40,000 hours total work; so,

22,000 mgh/m3∕ 40,000 h = an average concentration of 0.55 mg/m3respirable

dust over the work tenure; so,

0.55 mg/m3respirable dust x 0.3 (percent silica) = 0.165 mg/m3average exposure

to respirable silica.

This figure is less than twice the current OSHA permissible exposure limit (PEL). Thus,

these findings suggest that workers exposed to average respirable silica levels in the

range of the current OSHA PEL for 20 years may have an increased risk of developing

emphysema. However, uncertainties concerning the exposure measurements in this study

and the role of other respirable dust components of mine dust in the etiology of

emphysema caution against drawing firm conclusions based on these data.

Hnizdo et al. (1994) conducted a retrospective cohort study, this time of only lifelong non-smoking South African gold miners. The 242 miners had 23.1 mean years of

mining (SD = 11.0, range 1-48) with a mean cumulative respirable dust exposure

(mg/m3-years) of 6.8 (SD 2.4, range 0.5-20.2). Only a minimal, insignificant degree of

panacinar emphysema was found at autopsy and the degree was not associated with a

statistically significant degree of lung function impairment nor with respirable dust

exposure (years of gold mining or cumulative dust index). The degree of emphysema

was also not associated with parenchymal silicosis but was associated with the degree of

hilar gland nodules (p < 0.05), which the authors suggested might act as a surrogate for

exposure to silica. The authors concluded that the slight degrees of emphysema found in

lifelong non-smokers exposed for many years to silica dust at the level to which these

miners were exposed is unlikely to cause a statistically significant impairment of lung

function. However, based on their earlier study (Hnizdo et al., 1991), the authors also

concluded that the statistically significant association between exposure to silica dust and

the degree of emphysema in smokers suggested that tobacco smoking potentiates the

effect of silica dust.
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Hnizdo et al. (2000) conducted a longitudinal study of 724 South African gold

miners. The main purpose of the study was to determine and quantify whether COPD

determined at autopsy was related to lung function that had been measured years earlier.

The study subjects were selected through a complex process. Subjects were selected

from a database containing the results of autopsies of the hearts and lungs of miners and

ex-miners on death. Subjects were selected only if they met these criteria: (1) autopsy

between 1975 and 1986; (2) 80 percent of mining service in gold mines; (3) less than one

year asbestos mining; (4) lungs inflated at autopsy; (5) tissue adequately preserved to

enable histological assessment of bronchiolitis and bronchitis; and (6) lung function tests

undergone within five years of death.

There were 8,462 subjects who satisfied the first four criteria and 6,035 who

satisfied criteria one through five. Of this group of 6,305, 2,651 had COPD and 3,384

did not. A sample of 500 was drawn from the 3,384 who did not have COPD. From this

group of 500 and the 2,651 that did have disease, the researchers excluded those without

lung function tests within five years of death (criterion six) and cases of cardiac failure,

leaving 724 subjects eligible for study. Results showed that emphysema diagnosed at

autopsy was the main determinant of airflow impairment. The age- and smokingadjusted emphysema score, however, decreased with increased categories of silicosis and

cumulative respirable dust exposure. This was the opposite of the findings of other

studies. The authors suggested that the complex selection process had resulted in an

unrepresentative sample of miners and that this was likely to have affected the

association between cumulative dust exposure and COPD outcomes, such as emphysema,

but not to have affected the association between the autopsy findings and clinical findings

for COPD.

The other studies that have examined the relationship of silica exposure to

emphysema have been cross-sectional (prevalence) or case-control studies. Becklake et

al. (1987) conducted an unmatched case control study of a cohort of white South African

gold miners. There were 44 cases of emphysema (ascertained at autopsy) and 42 controls

without emphysema. The presence and grade of silicosis was similar in both groups.

This study showed that cases were, on average, older, had worked more high-dust

exposure shifts, and had smoked more heavily (average daily cigarette use) than had

controls throughout their lives. A multiple logistic regression analysis confirmed that the

strongest predictors of emphysema at autopsy were number of shifts worked in high dust

jobs, smoking, and age. Although the variables of presence or severity of silicosis were

related to the total number of shifts worked in high dust jobs, these variables were not

responsible for the predictive value of high dust mining in the model.

Using this model, Becklake et al. (1987) determined that a miner who had worked

in high dust jobs for 20 years had approximately a 13-times greater chance of having

grade 2 or higher emphysema at autopsy than a miner who had never worked in high

dust. In a later study designed to examine the potential for selection bias, de Beer et al.

(1992) added back a number of cases and controls that had been excluded from the

original study due to missing data. The cases that had been originally excluded worked

fewer shifts in high-dust jobs. There was no difference in number of shifts in high-dust
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jobs between the controls in the initial data and those added back. The exposure of

interest (high dust) was associated with poor initial information on cigarette smoking and

medical examinations during which features such as cough, sputum, and rhonchi and/or

wheezing were recorded. This resulted in the systematic exclusion of cases with none or

low numbers of shifts in high-dust jobs. After including these new cases, miners who

had worked in high-dust jobs for 20 years still had a statistically significantly greater

chance of having emphysema at autopsy, but the odds ratio decreased from 12.70 (95%

CI 3-52) to 3.06 (95% CI 1.14-8.23). The authors concluded that their study “highlights

the need to maximize the inclusion of eligible subjects and the danger of differential

exclusion of subjects in an analytical study.”

One study of gold miners failed to demonstrate a relationship between number of

years of employment in gold mines, an indicator of silica exposure, and emphysema. In a

study of a random sample of 70 black underground gold miners, taken from a larger

cross-sectional study (Cowie and Mabena, 1991, reviewed below in the section on

bronchitis and above in Section V.B), Cowie et al. (1993) demonstrated, using

computerized tomography, that 48 out of the 70 men who had worked underground for an

average of 29 years in the gold mining industry had emphysema. There was no

relationship between presence and grade of emphysema and number of years of mining.

The association of presence and grade of emphysema with silicosis found in this study is

discussed above in Section I.B.

Begin et al. (1995) studied the prevalence of emphysema in workers with simple

silicosis or without silicosis and exposed to silica. Aspects of this study, especially those

concerned with workers with silicosis, have been discussed above in section I.B. Briefly,

the study population consisted of 207 workers evaluated for possible pneumoconiosis at

Quebec Workman Compensation Board and who had a radiographic reading of

pneumoconiosis in the category 0 or 1 of the ILO scale, as well as 5 control subjects.

Emphysema was detected, typed, and graded on high-resolution CT scans. Age, work

experience and industry, smoking habits, and pulmonary function test results were

analyzed for possible associations. The subjects were 58 to 60 years of age and were

exposed to mineral dusts for 25 to 27 years; 31 were lifetime nonsmokers and the others

were either ex- or current smokers.

In lifetime non-smokers, emphysema was seen in 1 of 20 subjects without

pneumoconiosis but in 8 of 11 patients with pneumoconiosis. In smokers without

pneumoconiosis, emphysema was present in 55 percent of patients with silica exposure,

and only in 29 percent of patients with asbestos exposure but comparable smoking

histories (p = 0.04). In the workers without pneumoconiosis, age, smoking, and exposure

to silica were significant predictors of reduced pulmonary function.

Experimental (animal) studies have suggested that silica dust-induced emphysema

could precede silicosis and airway disease in humans. For example, it was shown that in

rats exposed to silica dust, emphysema occurred at lower silica doses than did fibrosis in

small airways or the appearance of early silicotic nodules (Wright et al., 1988).
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I.D.1.a Summary and conclusions for emphysema.

OSHA has considered a series of longitudinal studies of white South African gold

miners conducted by Hnizdo and co-workers. Hnizdo et al. (1991) found a significant

association between emphysema (both panacinar and centriacinar) and years of

employment in a high dust occupation (respirable dust was estimated to contain 30

percent free silica). There was no such association found for non-smokers, as there were

only four non-smokers with a significant degree of emphysema found in the cohort. A

further study by Hnizdo et al. (1994) looked at only life-long non-smoking South African

gold miners. In this population, no significant degree of emphysema or association with

years of exposure or cumulative dust exposure was found. However, the degree of

emphysema was significantly associated with the degree of hilar gland nodules, which

the authors suggested might act as a surrogate for exposure to silica. The authors

concluded that the minimal degree of emphysema seen in non-smoking miners exposed

to the cumulative dust levels found in this study (mean 6.8 mg/m3, SD 2.4, range 0.5 to

20.2, percent free silica 30%) was unlikely to cause meaningful impairment of lung

function.

From the two studies above, Hnizdo et al. (1994) concluded that the statistically

significant association between silica dust and the degree of emphysema in smokers

suggests that tobacco smoking potentiates the effect of silica dust. A later study by

Hnizdo et al. (2000) of South African gold miners found, in contrast to their previous

studies, that emphysema was decreased in relation to dust exposure. The authors

suggested that selection bias was responsible for this finding.

The findings of several cross-sectional and case-control studies were more mixed.

Becklake et al. (1987), in an unmatched case-control study of white South African gold

miners, determined that a miner who had worked in high dust for 20 years had a greater

chance of getting emphysema than a miner who had never worked in high dust. A

reanalysis of this data, including added back cases and controls (because of possible

selection bias in the original study), still found an increase risk for emphysema, although

the odds ratio had decreased (de Beer et al., 1992). Begin et al. (1995), in a study of the

prevalence of emphysema in silica-exposed workers with and without silicosis, found that

silica-exposed smokers without silicosis had a higher prevalence of emphysema than a

group of asbestos-exposed workers with similar smoking history. In non-smokers, the

prevalence of emphysema was much higher in those with silicosis than in those without

silicosis. A study of black underground gold miners found that the presence and grade of

emphysema were statistically significantly associated with the presence of silicosis but

not with years of mining (Cowie et al., 1993).

Several of the above studies (Becklake et al., 1987; Begin et al., 1995; Hnizdo et

al., 1994) found that emphysema can occur in silica-exposed workers who do not have

silicosis and suggest that a causal relationship may exist between exposure to silica and

emphysema. The findings of experimental (animal) studies that emphysema occurs at

lower silica doses than does fibrosis in the airways or the appearance of early silicotic
187

nodules (e.g., Wright et al., 1988) tend to support the findings in human studies that

silica-induced emphysema can occur absent signs of silicosis.

Others have concluded that there is a relationship between emphysema and

exposure to crystalline silica. Green and Vallyathan (1996) reviewed several studies of

emphysema in workers exposed to silica. The authors stated that these studies show an

association between cumulative dust exposure and death from emphysema. IARC (1997)

has also briefly reviewed studies on emphysema in its monograph on crystalline silica

carcinogenicity and concluded that exposure to crystalline silica causes emphysema. In

their 2002 Hazard Review, NIOSH concluded that occupational exposure to respirable

crystalline silica is associated with emphysema but that some epidemiologic studies

suggested that this effect may be less frequent or absent in non-smokers.

Hnizdo and Vallyathan (2003) also conducted a review of studies addressing

COPD due to occupational silica exposure and concluded that chronic exposure to silica

dust at levels that do not cause silicosis may cause emphysema.

Based on these findings, OSHA preliminarily concludes that exposure to

respirable crystalline silica or silica-containing dust can increase the risk of emphysema,

regardless of whether silicosis is present. This appears to be clearly the case for smokers.

It is less clear whether nonsmokers exposed to silica would also be at higher risk and if

so, at what levels of exposure. It is also possible that smoking potentiates the effect of

silica dust in increasing emphysema risk.

I.D.2. Chronic Bronchitis.

There were no longitudinal studies identified by OSHA that have examined the

relationship between silica exposure and chronic bronchitis. However, a number of

cross-sectional studies have reported finding a qualitative or semi-quantitative

relationship between silica exposure and development of chronic bronchitis.

Sluis-Cremer et al. (1967) conducted a community-based study of 827 male

residents of a South African gold-mining town. Occupational dust-exposed and nonexposed smokers and non-smokers were compared for prevalence of chronic bronchitis

(as ascertained by questionnaire). There was a significant difference (p < 0.01) between

the prevalence of chronic bronchitis in dust-exposed and non-exposed men among

smokers only. The authors suggested that the increased prevalence of bronchitis in

miners who smoke was the result of synergism between smoking and dust inhalation

rather than just the dust inhalation alone.

Wiles and Faure (1977) conducted a cross-sectional study of 2,209 South African

gold miners. The miners were 45 to 54 years of age and had 10 or more years of

employment. There were 653 who had been ex-miners for one year or more. The gold

mine dust was said to contain about 75-percent crystalline silica. Information was

available on mean dust counts (expressed as respirable surface area) for each occupation

and the number of shifts each miner had worked in an occupation. The prevalence of
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chronic bronchitis (as assessed by questionnaire) increased with increasing mean dust

concentration (p < 0.001) and with cumulative dust exposure in nonsmokers (p < 0.05),

ex-smokers (p < 0.05), and smokers (p < 0.001). Holman et al. (1987) conducted a

prevalence study of bronchitis in 1,363 gold miners in Western Australia in 1985. The

overall prevalence of bronchitis in the cohort was 14 percent. Years of underground

mining experience was used as a surrogate for dust exposure and the prevalence of

bronchitis was compared to lifetime non-miners. After controlling for age and smoking

the odds ratio for chronic bronchitis was 1.8 (95% CI, 1.0-3.3) for 1 to 9 years of

underground mining, 2.5 (95% CI, 1.2-5.2) for 10 to 19 years of mining, and 5.1 (95%

CI, 2.4-10.9) for more than 20 years of mining. The latter figure included miners with or

without functional obstruction; for those miners having both chronic bronchitis and a

restrictive disorder, the odds ratio was 8.2 (95% CI, 1.0-68.9).

Cowie and Mabena (1991) conducted a cross-sectional study of 1,197 black,

male South African gold miners. They found that “chronic bronchitic symptom

complex” reflected the intensity of dust exposure in the workplace. Chronic sputum

production (a symptom of bronchitis) was common and most prevalent in those with the

dustiest jobs (qualitative assessment). Chronic bronchitis was present in 62 percent of the

workers and in 45 percent of those who had never smoked.

A prevalence study of chronic bronchitis among 239 granite quarry workers in

Singapore was conducted by Ng et al. (1992b). Workers exposed to “high” levels of dust

(rock drilling and crushing) were compared to those exposed to “low” levels

(maintenance and transport) and both groups were compared to an external control group

(postal delivery workers). A respiratory questionnaire found a significantly higher

prevalence of symptoms of chronic bronchitis in the high exposure as compared to the

low and control groups. These results were independent of smoking and age and were

similar after excluding those with silicosis. The authors noted that in this prevalence

study, the “survivor” effect would have tended to underestimate the effects of dust

exposure. According to the authors, because of the strenuous and hazardous nature of

quarry work, those who seek employment in the industry were likely to be a highly

selected group in terms of physical fitness; this includes possibly a “superior” lung

function (relative to the average lung function in the general population) to begin with.

The authors further noted that, it is also likely that workers whose lung function were

impaired as a result of their work will select themselves out of the work force, leaving the

“survivors” in the work force.

A number of other cross-sectional studies failed to find an association between

exposure to crystalline silica and chronic bronchitis. Symptoms of chronic bronchitis

were not found to be statistically significantly more prevalent in a group of silicotic South

African gold miners compared to non-silicotic miners, although the prevalence was

slightly higher (Irwig and Rocks, 1978).

Samet et al. (1984) conducted a prevalence study of respiratory abnormalities in a

population of 192 current underground uranium miners. Of the 192 current workers, 64

were less than 40 years of age, 116 were 40 to 50 years of age, and 12 were 60 years of
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age or more. Duration of underground experience for these age groups is as follows:

Less than 40 years of age—33 miners with less than 10 years underground, 31 miners

with 10 to 19 years, no miners with 20 years or more; 40 to 59 years of age - 14 miners

with less than 10 years, 35 miners with 10 to 19 years, 67 miners with 20 or more years;

60 or more years of age - no miners with less than 10 years, 4 miners with 10 to 19 years,

8 miners with 20 years or more. Since production was from sandstone deposits, silica

exposure was anticipated. The authors reviewed available measurements taken by the

State Mine Inspector during the years of the study (1969 to 1981). The authors reported

that these measurements had shown that the crystalline silica content ranged from

approximately 10 to 70 percent and dust concentrations were “on occasion above the

Threshold Limit Value [of 0.1 mg/m3respirable quartz].” However, data were not

available to adequately assess exposures for each individual. The cigarette smokingstandardized prevalence of the symptoms of chronic bronchitis (chronic cough and

chronic phlegm) was not found to be associated with the number or years of mining.

However, the authors commented that, because this was a prevalence study, they had no

way to assess the potential bias that may have occurred if miners had left the workforce

because they had respiratory diseases, potentially making the remaining study population

unrepresentative.

A study of 281 hard-rock (molybdenum) miners and 108 non-miner residents of

Leadville, Colorado also showed no association between the prevalence of chronic

bronchitis and work in the mining industry (Kreiss et al., 1989). The mine had been

temporarily closed for 5 months when the study began, so miners were not exposed at the

time of the study. Personal silica samples had been taken during the period 1977 to 1981.

At that time, 27 percent and 49 percent of the samples were greater than 100 μg/m3and

50 μg/m3respirable silica, respectively. In discussing the negative finding, the authors

suggested that there may have been a differential out-migration of symptomatic miners

and retired miners from the industry and Leadville, resulting in a survivor effect.

No increase in the prevalence of chronic bronchitis was detected in a study of a

random sample of 342 workers in India whose job it was to chip and grind agate stones

(Rastogi et al., 1991). The grinding process was a mechanical process that produced a lot

of dust containing a high percentage of crystalline silica (70.4 percent). The chipping

process involved the breakage and removal of cracked stones and produced a respirable

dust concentration that was 6-fold less than that produced by the grinding process. There

were 240 men and 102 women in the group. There were 158 grinders and 82 chippers

among the men, while almost all the women were grinders. The controls (n = 149) were

shopkeepers, washermen, rickshaw pullers, and hospital staff such as messengers,

sweepers, and ward boys. They were matched with the study group for socioeconomic

status, age, and smoking, and were considered never to have been exposed to silica. A

large number (48.5 percent) of the agate workers had been exposed for less than 5 years,

while a small number (17.5 percent) had been exposed for greater than 11 years. The

mean exposure time was 10 ± 2.9 years for men and 8.9 ± 2.3 years for women. In

contrast to the finding for chronic bronchitis, the prevalence of pneumoconiosis was

significantly higher in agate workers as compared to controls (p < 0.001) and showed a

significantly increasing trend with duration of exposure (p < 0.01). Also, although
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neither gender was found as having an increased prevalence of chronic bronchitis, there

was a statistically significantly higher prevalence of acute bronchitis in the female agate

workers compared to controls (p < 0.05). NIOSH (2002) has commented that an

association between silica dust exposure and chronic bronchitis may not have been

detected because the workers in the control group (e.g. rickshaw pullers and sweepers)

may have been occupationally-exposed to silica and the high prevalence of tuberculosis

in both agate workers and controls may have masked an association for chronic

bronchitis.

I.D.2.a Summary and conclusions for bronchitis.

There were no longitudinal studies available designed to investigate the

relationship between silica exposure and bronchitis. However, several cross-sectional

studies provide useful information. Studies are about equally divided between those that

have reported a relationship between silica exposure and bronchitis and those that have

not. Several studies demonstrated a qualitative or semiquantitative relationship between

silica exposure and chronic bronchitis. Sluis-Cremer et al. (1967) found a significant

difference between the prevalence of chronic bronchitis in dust-exposed and non-dust

exposed male residents of a South African gold mining town who smoked, but found no

increased prevalence among non-smokers. In contrast, a different study of South African

gold miners found that the prevalence of chronic bronchitis increased significantly with

increasing dust concentration and cumulative dust exposure in smokers, nonsmokers, and

ex-smokers (Wiles and Faure, 1977). Similarly, a study of Western Australia gold miners

found that the prevalence of chronic bronchitis, as indicated by odds ratios (controlled for

age and smoking), was significantly increased in those that had worked in the mines for 1

to 9 years, 10 to 19 years, and more than 20 years, as compared to lifetime non-miners

(Holman et al., 1987). Chronic bronchitis was present in 62 percent of black South

African gold miners and 45 percent of those who had never smoked in a study by Cowie

and Mabena (1991). The prevalence of what the researchers called “chronic bronchitic

symptom complex” reflected the intensity of dust exposure. A higher prevalence of

respiratory symptoms, independent of smoking and age, was also found for granite quarry

workers in Singapore in a high exposure group as compared to low exposure and control

groups, even after excluding those with silicosis from the analysis (Ng et al., 1992b).

Other studies found no relationship between silica exposure and the prevalence of

chronic bronchitis. Irwig and Rocks (1978) compared silicotic and non-silicotic South

African gold miners and found no significant difference in symptoms of chronic

bronchitis. The prevalence of symptoms of chronic bronchitis were also not found to be

associated with years of mining, after adjusting for smoking, in a population of current

underground uranium miners (Samet et al., 1984). Silica exposure was described in the

study to be “on occasion” above the TLV. It was not possible to determine, however,

whether miners with respiratory diseases had left the workforce, making the remaining

population unrepresentative. Hard-rock (molybdenum) miners, with 27 and 49 percent of

personal silica samples greater than 100 and 55 μg/m3, respectively, also showed no

increase in prevalence of chronic bronchitis in association with work in that industry.

However, the authors (Kreiss et al., 1989) thought that differential out-migration of
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symptomatic miners and retired miners from the industry and town might explain that

finding. Finally, grinders of agate stones (with resulting dust containing 70.4 percent

silica) in India also had no increase in the prevalence of chronic bronchitis compared to

controls matched by socioeconomic status, age and smoking, although there was a

significantly higher prevalence of acute bronchitis in female grinders. A significantly

higher prevalence and increasing trend with exposure duration for pneumoconiosis in the

agate workers indicated that had an increased prevalence in chronic bronchitis been

present, it would have been detected (Rastogi et al., 1991). However, control workers in

this study may also have been exposed to silica and the study and control workers both

had high tuberculosis prevalence, possibly masking an association of exposure with

bronchitis (NIOSH, 2002). Furthermore, exposure durations were very short.

Thus, some prevalence studies supported a finding of increased bronchitis in

workers exposed to silica-containing dust, while other studies did not support such a

finding. However, OSHA believes that many of the studies that did not find such a

relationship were likely to be biased towards the null. For example, some of the

molybdenum miners studied by Kreiss et al. (1989), particularly retired and symptomatic

miners, may have left the town and the industry before the time that the cross-sectional

study was conducted, resulting in a survivor effect that could have interfered with

detection of a possible association between silica exposure and bronchitis. This survivor

effect may also have been operating in the study of uranium miners in New Mexico

(Samet et al., 1984). Some of the controls used in the Indian agate worker study (Rastogi

et al., 1991) may also have had occupational silica exposure. Additionally, tuberculosis

in both study and controls may have masked an effect (NIOSH, 2002), and the exposure

durations were very short. Several of the positive studies demonstrated a qualitative or

semiquantitative relationship between silica exposure and chronic bronchitis.

Others have reviewed relevant studies and also concluded that there is a

relationship between exposure to crystalline silica and the development of bronchitis.

The American Thoracic Society (ATS) (1997) published an official statement on the

adverse effects of crystalline silica exposure that included a section that discussed studies

on chronic bronchitis (defined by chronic sputum production). According to the ATS

review, chronic bronchitis was found to be common among worker groups exposed to

dusty environments contaminated with silica. In support of this conclusion, ATS cited

studies with what they viewed as positive findings of South African (Hnizdo et al., 1990)

and Australian (Holman et al., 1987) gold miners, Indonesian granite workers (Ng et al.,

1992b), and Indian agate workers (Rastogi et al., 1991). ATS did not mention studies

with negative findings.

A review published by NIOSH in 2002 discussed studies related to silica exposure

and development of chronic bronchitis. NIOSH concluded, based on the same studies

reviewed by OSHA, that occupational exposure to respirable crystalline silica is

associated with bronchitis, but that some epidemiologic studies suggested that this effect

may be less frequent or absent in non-smokers.
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Hnizdo and Vallyathan (2003) also reviewed studies addressing COPD due to

occupational silica exposure and concluded that chronic exposure to silica dust at levels

that do not cause silicosis may cause chronic bronchitis. They based this conclusion on

studies that they cited as showing that the prevalence of chronic bronchitis increases with

intensity of exposure. The cited studies were also reviewed by OSHA (Cowie and

Mabena, 1991; Holman et al., 1987; Kreiss et al., 1989; Sluis-Cremer et., 1967; Wiles

and Faure, 1977).

OSHA preliminarily concludes that exposure to respirable crystalline silica may

cause chronic bronchitis and an exposure-response relationship may exist. Smokers may

be at increased risk as compared to non-smokers. Chronic bronchitis may occur in silicaexposed workers who do not have silicosis.

I.D.3. Pulmonary Function Impairment.

In this section, OSHA reviews studies designed to evaluate relationships between

exposure to crystalline silica and pulmonary function loss. Since it has been wellestablished that silicosis progression leads to reduced pulmonary function (see Section

V.B.), this analysis focuses on studies of workers who did not exhibit progressive

silicosis to evaluate whether exposure to silica has an effect on pulmonary function in the

absence of silicosis.

Pulmonary function in workers exposed to silica has been examined in

longitudinal studies of Vermont granite workers (Eisen et al., 1983, 1995; Graham et al.,

1981, 1994), Swedish granite crushers (Malmberg et al., 1993), South African gold

miners (Cowie, 1998; Hnizdo, 1992), and U.S. automotive foundry workers (Hertzberg et

al., 2002).

Graham et al. (1981) conducted a longitudinal study of pulmonary function in

currently employed and retired Vermont granite stone shed workers. Three groups of

current workers were examined. One group was workers whose lung function had been

tested in 1974 to 1975 and again in 1979. Another group included workers additionally

tested in 1970 to 1971. The third group had worked for more than 20 years and had been

tested in 1974 to 1975 and 1979. A group of retired workers whose lung function had

been tested at all three times was also examined. In the group of all current workers who

had been tested in 1974 and 1979, surprisingly to the authors, an increase was found in

mean FVC and FEV1 between 1974 and 1979. There were also increases in mean FVC

in retired workers and those working more than 20 years. Mean FEV1 in retired workers

and those working more than 20 years either slightly increased or minimally decreased.

Based on previous studies, pulmonary function losses had been predicted. The authors

believed that there were technical deficiencies in the earlier studies, such as improper

instructions to the workers during the test and perhaps a leaky spirometer, that accounted

for inaccurate findings.

A follow-up study of Vermont granite workers was also conducted by Graham et

al. (1994). Starting with the last test date in the previous study (1979), pulmonary
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function tests were administered every two years up to 1987. In this study, quarry and

office workers (presumably lower or negligible exposure, although no measurements

were made) were included in addition to the stone shed workers. Estimated silica

exposure for the shed workers was between 50 and 100 μg/m3based on 413 personal

breathing zone measurements of total respirable dust taken in 1983 and 1984 and

previous estimates of the quartz percentage of the dust. The average quartz dust exposure

level was 60 μg/m3, and only 10.5 percent of the samples were over 100 μg/m3. The

analysis of the longitudinal loss of pulmonary function was based on 711 workers who

had been tested at least three times out of the five opportunities possible over the study

period. According to the authors, loss of FVC and FEV1 were not correlated with

number of years employed in the granite industry, did not differ between shed, quarry, or

office workers, and were similar to other blue collar workers not exposed to occupational

dust.

Vermont granite workers have also been studied by Eisen et al. (1983, 1995). The

main purpose of the study was to assess the chronic effects of long-term, low level

exposure to granite dust and shorter-term effects of current exposure on pulmonary

function. Another purpose of the study was to assess potential bias due to a healthy

worker effect. This longitudinal study followed 618 white male granite workers hired

after 1940 (when exposure controls were being implemented to reduce exposures), aged

25 to 65, employed a mean of 14.7 years, and who had annual pulmonary function testing

during the period 1970 to 1974 (five years). The authors noted that granite used in the

manufacture of monuments in the Vermont granite sheds is composed of approximately

11 percent quartz. The association between respirable granite dust exposure and FEV1

was assessed in two sub-groups: “survivors” (353) who were in the study for the entire

period and had all five annual exams, and “dropouts” (265) who did not participate in the

final survey.

There was a significant exposure-response (p < 0.05) observed in the “dropout”

group but not in the “survivor” group or in the total cohort. The dropout group lost 4

ml/year FEV1 per mg/m3-year of cumulative respirable granite dust exposure. The

dropout group also had a steeper FEV1 loss (69 ml/year vs. 44 ml/year) over the study

period compared to the survivor group. Similar trends were reported for workers divided

by smoking category. In fact, in the never-smoked category, the survivors had no excess

pulmonary function loss while the non-smoking dropouts lost lung function just as

rapidly as did their smoking counterparts. An examination of the effect of current

exposure on annual FEV1 loss showed that the dropouts had an additional annual loss of

100 ml (in addition to that due to smoking or age) for each additional mg/m3of current

respirable granite dust exposure. This finding was of “borderline” statistical significance

(p = 0.086). There was little evidence of such an association in the survivor group. The

authors concluded that exposures of approximately half the current U.S. permissible

exposure limit for silica-containing dusts are associated with measurable effects on lung

function with a four ml/year excess loss among the dropout group. The authors also

concluded that their study demonstrated the presence of a healthy worker effect in that no

statistically significant decline in pulmonary function was found for “survivors.”
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Changes in lung function over a 12-year follow-up period (1976 to 1988) in 45

granite crushers and 45 age- and smoking-matched referents in Sweden were studied by

Malmberg et al. (1993). Each granite crusher had an individual assessment of total and

average dust exposure. In 1988 the granite crushers had worked an average of 22 years

and had inhaled an average cumulative amount of 7 mg of respirable silica dust. Average

exposure concentration over the follow-up period was 0.16 mg/m3of respirable silica

dust. At the end of the follow-up period, granite crushers had significantly lower

FEV1/VC (p < 0.01) and FEF50 (p < 0.05) than referents (p < 0.01). There were 5

smoking granite crushers who had an FEV1 < 80 percent of that predicted. Over the

follow-up period, granite crushers had statistically significantly greater decreases in

FEV1, FEV1/VC, maximum expiratory flow, and FEF50 than the referents. However, the

change in lung function was not statistically significantly correlated with the inhaled dose

of respirable quartz.

The authors reported that two of the most heavily exposed workers showed

evidence of silicosis, but the others had changes in pulmonary function that did not

suggest silicosis. The authors believed that these findings were consistent with other

findings implying that airway obstructive changes may occur independently and precede

silicosis. They also hypothesized that obstructive changes may occur at lower exposures

than required for the development of silicosis and that tobacco smoke may aggravate the

changes, since four of the cases with a clinically significant reduction in FEV1 had a

“fairly low” exposure to silica and all five were tobacco smokers or ex-smokers.

However, the authors cautioned that the study group was too small to confirm the

hypothesis.

Another finding of the study was that the decrease in lung function over the 12-

year time period of the study seemed to be more pronounced in the group who had not

been exposed to silica dust for the entire period. Some in this group had retired for

reasons of age and some had left to take other jobs. The authors thought that the changes

in lung function in retired workers may have been due to retained silica and that changes

may continue for a long time after exposure to silica ends. The authors concluded that

“exposure to silica at concentrations of about twice the present TLV [0.1 mg/m3] was

thus associated with airway obstruction and loss of elastic recoil rather than fibrosis and a

restrictive function loss as seen in silicosis.”

A study providing quantitative estimates of increased risk for clinically significant

loss of lung function among South African gold miners was conducted by Hnizdo (1992).

The 1,625 miners included in the study had been tested during the period 1968 to 1971

and were retested five years later. There were 232 never smokers and 1,393 current

smokers. The average duration of exposure was 24 years and the average concentration

of respirable dust for the cohort was 0.30 mg/m3(30 percent crystalline silica). (The

authors measured respirable dust but presented their results in terms of silica dust and did

not refer to or separately address the effect of the mixed dust). The cumulative exposure

to dust up to the 1968 to 1971 examination was a significant predictor of most indices of

lung function, including FEV1 and FVC. A multiple linear regression analysis showed

that the effects of silica exposure and smoking were additive. For a 50-year old miner,
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the loss of lung function attributable to dust exposure was estimated to be 236 ml of

FEV1 (95% CI 135-338) and 217 ml of FVC (95% CI 110-324) for an average

cumulative respirable dust exposure of 14.4 ghm-3, and 364 (95% CI 207-501) of FEV1

and 335 (95% CI 170-500) of FVC for those in the highest dust quartile of 22.2 gh/m3.

The loss in lung function for smoking alone (30 pack-years) for a 50-year old was

estimated to be 552 ml (95% CI 461-644). Therefore, the authors estimated that loss in

FEV1 for a 50-year old smoking miner (30 pack-years) with an average cumulative dust

exposure of 22.2 gh/m3 would be 916 ml (95% CI 784-1042) based on the exam results

from 1968 to1971. Cumulative dust exposure was not associated with loss of FEV1 or

FVC between the 1968 to 1971 and the 5-year follow-up exams, after adjusting for the

initial (1968 to 1971) values. The variables, in order of significance, that were related to

this loss were the initial (1968 to 1971) pulmonary function value, cigarette equivalent

pack-years, the current smoking state in 1968 to 1971, and the years of follow-up.

Nonetheless, when miners were compared to non-miners, the predicted FEV1 values for

55 year-olds at the five-year follow-up showed that the miners experienced a steeper

decline in pulmonary function. The authors concluded that exposure to silica dust among

South African gold miners was associated with significant loss of lung function and that

even though the contribution of smoking was substantially higher than that of exposure to

dust, the combined effect had the potential to cause serious pulmonary disability. They

attributed a 10 ml per year loss of FEV1 to continued dust exposure.

A similar estimated loss of 13 ml per year was reported by Cowie (1998) after

adjusting for age among South African gold miners without silicosis. Cowie (1998)

studied lung function in 242 gold miners in a follow-up of a case-control study. He

compared baseline chest x-rays and pulmonary function studies of an initial cohort to

those obtained five years later. Before adjustment for age, annual loss of FEV1 was 37

ml. in those without silicosis. A similar loss was noted for FVC. Results of an earlier

study (Cowie et al., 1993) suggested that a loss of approximately 8 ml of FEV1 per year

would be expected due to continued exposure to the dusty mine environment, which

when added to the expected loss of 24 ml/yr due to aging, would be equivalent to

approximately 32 ml/yr. The findings of the second Cowie (1998) study approximate this

expectation with the finding of an average of 37 ml/yr. loss of FEV1 in the men who did

not have silicosis on entry to the study. This loss is equivalent to a 0.35 percent loss of

predicted FEV1 annually. Cowie (1998) noted that this was “remarkably” similar to the

loss of 0.38 percent per year attributed to silica dust exposure that was reported by

Malmberg et al. (1993) for Swedish granite workers.

Hertzberg et al. (2002), in a study of U.S. automotive foundry workers, found a

consistent association between increased pulmonary function abnormalities and estimated

measures of cumulative silica exposure. The cohort consisted of 563 current employees

and 473 retirees of a Midwest foundry who had been employed before January 1, 1986.

Eight individuals whose race was listed as other than white or African American were

excluded from the analysis of PFT results due to lack of accuracy from small numbers,

bringing the study cohort to 1,028 individuals. None of these workers had evidence of

parenchymal changes from exposure to asbestos or silica. Data collected from plant

walk-through surveys, company and union industrial hygiene files, and employee
196

interviews were used to estimate silica exposures. Estimated levels of exposure by date,

department, and job function were merged with personnel records to calculate the

cumulative exposure level for each employee. Exposure measurements were found for

26 of the 30 years covered by the study. Cumulative exposure categories were

established such that, over a 40-year working lifetime, for 286 workdays per year, the

four average daily exposure groups were: 0.006, 0.04, 0.12, and 0.28 mg/m3. Existing

company medical records were reviewed and abstracted for all annual PFT results since

the start of testing in 1978 as well as cigarette smoking histories.

Although there was no association among nonsmokers, there was a statisticallysignificant trend among smokers of an increasing percentage of individuals with a

decreased FVC and a statistically significant relationship of decreasing percent-predicted

FVC with increasing cumulative exposure (p = 0.042 and 0.0013, respectively).

Similarly, there was a suggestion of a trend in the relationship between abnormal FEV1

and a statistically significant pattern of decreasing percent-predicted FEV1 with

increasing cumulative silica exposure in smokers (p = 0.062 and 0.011, respectively).

There was also a statistically significant pattern of decreasing FEV1/FVC at the highest

cumulative silica exposure (p = 0.0013). A multiple linear regression analysis

demonstrated that, for each PFT endpoint, there was a statistically significant relationship

between decreasing PFT results and increasing cumulative silica exposure.

Hertzberg et al. (2002) also calculated odds ratios for the incidence of an

abnormal PFT for 20 and 40 years of exposure at a variety of time-weighted average

exposure levels. For example, for 20 years exposure at 0.1 mg/m3, the risk of developing

an abnormal FEV1 increased by 1.3 and an abnormal FVC by 1.19. At 40 years, the risk

of an abnormal FEV1 was 1.68 and an abnormal FVC was 1.42. At an exposure level of

0.05 mg/m3, the risk was reduced to 1.14 for FEV1 and 1.09 for FVC for 20 years and 1.3

for FEV1 and 1.19 for FVC for 40 years. In addition, longitudinal data analysis of FEV1

and FVC results over time showed a 1.1 and 1.6 mL/yr statistically significant decline,

respectively, for each mg/m3of silica exposure (p = 0.001 and 0.0108, respectively).

Finally, Hertzberg et al. (2002) used multivariate analyses to calculate that there would

be a loss of 104.4 mL of FEV1, 137.7 mL of FVC, and 1.49% of FEV1/FVC for 40 years

exposure at 0.1 mg/m3. For exposure at 0.05 mg/m3, the losses were 52.2 mL, 68.8 mL,

and 0.75%, respectively.

There are also a number of prevalence studies that have examined relationships

between lung function loss and silica exposure. Theriault et al. (1974a) studied 792

granite shed workers in Vermont in a c ross-sectional study correlating lung function

changes with changes in chest x-rays. In this series of studies, the authors attempted to

discern whether a quantifiable relationship existed between decrements in pulmonary

function and occupational exposure to respirable granite dust, and respirable quartz dust.

In this study (Theriault et al., 1974a), 784 full-shift, breathing-zone samples were

obtained from workers in 113 different occupations in 49 granite sheds; total dust

concentrations for all and respirable quartz for 483 of the samples were reported in

micrograms per cubic meter. One dust-year was defined as exposure to 523 micrograms
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per cubic meter for a 40-hour work week over a one-year period. One quartz-year was

defined as exposure to 50 micrograms per cubic meter respirable quartz for a 40-hour

work week for a one-year period. These concentrations were related to the occupational

history of each worker, and total lifetime dust and quartz exposure for each worker was

estimated.

The workers filled out questionnaires regarding exposures and smoking history at

the time of their annual chest x-ray and pulmonary function test. The study population

included exposed workers, non-exposed workers, smokers, and non-smokers. The

authors controlled for age and smoking. The decrease in FVC due to dust exposure was

estimated at 1.6 ml per dust-year; or 1.4 ml per quartz-year.

The same authors compared lung function with radiographic results for some of

these same granite shed workers (Theriault et al., 1974b). On average, changes in

pulmonary function testing could be detected after 32.5 dust-years of exposure. With

chest x-rays, opacities were not seen until after 46 dust-years of exposure had

accumulated. A similar analysis using quartz-years as the exposure metric was not

presented. The authors concluded that early detection of silica dust effects was more

proficiently accomplished by pulmonary function studies than by radiographs. These

results suggest that airflow in silica-exposed workers is significantly reduced by the time

disease is detectable on simple chest x-ray.

Irwig and Rocks (1978) studied 1973 white South African gold miners. Silicotic

(n = 134) and nonsilicotic miners were compared. Mean FVC was the same. Those with

silicosis (defined as pqr nodulation of 1/0 or greater profusion on chest radiograph, rated

according to the ILO U/C International Classification of Radiographs of 1971) had

significantly lower (p < 0.01) mean FEV1 (5 percent lower) and mean FEF25-75% (14

percent lower) than those without silicosis. An analysis of the effect of variables such as

height, age, smoking history, and exposure to mining dust demonstrated that the

difference in lung function was almost entirely accounted for by exposure. The authors

concluded that silicosis, per se, seemed to have little effect on lung function but that there

was a significant exposure-response relationship between exposure to dust in gold mines

and both symptoms and lung function tests indicative of COPD.

In a study of airflow obstruction in South African gold miners (Hnizdo et al.,

1990), the etiologic fractions for marked obstruction were 48 percent for dust, 82 percent

for smoking, and 90 percent for the combined effects of smoking and dust. The

preventable fractions were estimated as 8 percent for the elimination of silica dust alone,

42 percent for smoking, and 40 percent for the elimination of either silica dust or

smoking. The joint effect of dust and tobacco smoking on lung function impairment was

therefore found to be synergistic in this study. The authors concluded that smoking was

found to “potentiate” the effect of dust on pulmonary impairment.

Cowie and Mabena (1991), in a cross-sectional study discussed in the section

above on chronic bronchitis and in Section V.B., examined pulmonary function in a

working population of 1,197 black South African gold miners. Statistically significant
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reductions in FEV1, FEV1/FVC%, and MMEF were found to be associated with the

duration of exposure to the underground environment, after controlling for silicosis and

smoking. The reductions found attributable to 25 years of exposure were:

 FEV1 200ml (p = 0.006);

 MMEF 0.55 L/s (p = 0.0009); and

 FEV1/ FVC% 3.6% (p = 0.0001).

The average annual loss of FEV1 attributable to the underground environment was

calculated to be 8 ml. In contrast to the finding for duration of exposure, there was no

reduction in lung function attributed to high intensity dust exposure. Rather, workers in

the highest intensity of exposure had modest increases in some parameters. This finding

was attributed to the healthy worker effect, with the strongest (and healthiest) workers

tending to work in the hardest (and also the dustiest jobs). Other limitations of the study

were the lack of good, specific exposure information and that the design of the study was

intended to provide a strong contrast in silicosis as a determinant and, in the process,

produced a poor contrast in duration of exposure with most of the men close to the study

mean and few at the extremes. In the opinion of the authors, this aspect of the design

would have resulted in a significant under-estimation of the influence of exposure.

Several other prevalence studies of pulmonary function have examined granite

workers. Ng et al. (1992b), in a study also discussed above in the chronic bronchitis

section, compared workers in rock drilling and crushing with workers in maintenance and

transport in Singapore granite quarries and also compared those groups with postal

delivery workers as an unexposed control group. The highly exposed rock drilling and

crushing workers had a mean reduction of five percent in FEV1, FVC, and percent

FEV1/FVC that was independent of other factors such as age and smoking, as compared

to the low exposure or unexposed groups. This reduction was comparable in magnitude

(e.g., for FEV1) to that for a person smoking approximately 20 cigarettes a day for 45

years. The study also found an age- and smoking-adjusted two- to four-fold increase in

the prevalence of obstructive impairment related to high dust exposure. Another crosssectional study of quarry workers was conducted by Montes et al. (2004b). These

investigators studied 378 aggregate workers from 27 companies in Spain. The workers

were exposed to respirable concentrations of dust between 0.1 and 17.6 mg/m3.

Percentages of crystalline silica in this dust ranged between 0.1 and 75.8. Cumulative

exposure was calculated for each worker. In a bivariate analysis, FEV1 decreased

significantly in relation to the cumulative exposure to respirable dust (gh/m3) and tobacco

use. Loss of FVC was only statistically significantly related to dust. In a multivariate

analysis, FEV1 was inversely related to the product of dust exposure times pack-years (p

= 0.005), but not with each variable independently, controlling for age and the presence

of radiological opacities. The authors concluded that there was evidence of dust-tobacco

interactions for FEV1.
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Ng et al. (1987) studied respiratory symptoms, radiographic changes and lung

function in a cross-sectional survey of 218 male gemstone workers in Hong Kong.

Cutters and carvers had average respirable quartz concentrations of 60 and 30 μg/m3,

respectively. The high-exposure group had average respirable quartz exposures of 100

and 160 μg/m3. Silica flour with quartz content often exceeding 90% was commonly

used as an abrasive. The FEV1 and FVC values were not associated with radiographic

category after adjustment for years of employment. The authors concluded that there was

an independent effect of respirable dust exposure on FVC, but silicosis graded as less

than category 2 had no effect on lung function after dust exposure was accounted for.

Loss of lung function in concrete workers exposed to respirable silica was studied

in a cross-sectional study by Meijer et al. (2001). There were 144 concrete workers from

two factories in The Netherlands included in the study. The workers did not have

radiographic evidence of silicosis. Exposure to respirable dust and silica was measured

using personal samplers. Results were compared to a control group of 103 non-exposed

workers from an office-equipment factory in the same geographic area. In both concrete

factories, the average respirable dust and silica concentrations were 0.8 and 0.06 mg/m3,

respectively. The cumulative respirable dust and silica exposures were 7.0 and 0.6

mg/m3, respectively. Statistically significant losses in lung function (p = 0.02) (as

indicated by decreased FEV1/FVC ratio) were observed overall for concrete workers

compared to controls. These losses were independent of current smoking status and

allergy history. However, there was no exposure-response relationship found between

lung function loss and either current or cumulative dust exposure. The authors concluded

that their study had demonstrated a small lung function loss in workers exposed to

concrete dust at levels below 1 mg/m3respirable dust with a respirable crystalline silica

content of 10% (TWA, 8 hr).

Lung function loss in the absence of radiological silicosis was also observed in

Chinese refractory brick manufacturing workers in an iron-steel plant studied by Wang et

al. (1997). FVC, FEV1, and DLCO decreased significantly or close to significantly in both

smokers and non-smokers without the radiological presence of silicosis. The advent and

progression of silicosis was also associated with a decrease in FEV1/FVC in both

smokers and nonsmokers. Pulmonary function was decreased more in workers with

category I silicosis than in those without silicosis and decreased further as silicosis

progressed to categories II and III. The authors concluded that functional abnormalities

precede radiographic changes in silicosis.

Two studies examined the prevalence of pulmonary impairment in workers in the

hard rock mining industry. Manfreda et al. (1982) studied 95 underground miners from

two mining companies in Manitoba, Canada and 382 controls from the general

population. Most of the workers were smokers or ex-smokers. Only one miner had a

radiographic appearance consistent with silicosis. Although no historical exposure

records were available, exposure measurements made shortly after the lung function

testing indicated minimal, median, and maximal respirable dust exposure levels of 0.2,

0.5, and 4.8 mg/m3, respectively, with 6 to 9 percent being silica. Changes in FVC,

FEV1, FEF25-75, all Vmax rates except Vmax25, and the slope of phase III were
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significantly related to duration of employment (p < 0.05 for all except Vpeak which was

0.05 < p < 0.10). Kreiss et al. (1989), in a study that has been described above in the

bronchitis section, also examined the prevalence of pulmonary function impairments in a

hard-rock mining community in Colorado. Cumulative dust exposure was associated

with decreases in maximal expiratory flow rate when controlled for smoking, age, and

height. The results suggested to the authors that exposures resulted in irreversible

pulmonary function changes that appeared in smokers (not clear if this includes exsmokers) as airflow limitation (obstructive impairment) and in never-smokers as

restrictive impairment. Multiple regression analysis found an exposure-response

relationship for airflow limitations.

Chronic airflow limitation in pottery workers in France was observed in a crosssectional study by Neukirch et al. (1994). The pottery plant studied made bathroom

fixtures. Two categories of workers were established. One was considered directly

exposed and included 172 males and 42 females with the following jobs: maintenance

and cleaning, assembly line, checking goods, laboratory, casting, in front of the oven,

manufacturing, and stoneware, enameling, grinding, and glazing workshops. The other

category was considered indirectly exposed and included workers in offices, warehouses,

dispatching, and plaster, molding, and palletization workshops. This categorization

represented a qualitative base for silica dust levels since quantitative information was not

available. The controls worked in a pipeline-making factory with no exposure to silica

dust or other lung hazards. Workers with silicosis were not included in the analysis. All

the pottery workers, even the indirectly exposed, had significantly lower pulmonary

function values (FVC, FEV1, and most of the flows) than the controls. For directly

exposed men there were statistically significant reductions in FEF25-75 (p = .05) and V50

(p = .04). For indirectly exposed men there were statistically significant reductions in

FVC (p < .001) and FEV1 (.0001 < p < .004). For women there were statistically

significant reductions for those indirectly exposed in FVC (p =.01) and FEV1 (p = .03),

and, for those directly exposed, in FVC (p = .001), FEV1 (p = .0001), FEF25-75 (p = .004),

V50 (p = .02), and V75 (p = .001). The authors thought that the finding that pulmonary

function values were significantly lower than in controls, even in those not directly

exposed, could be either the result of the presence of vulnerable workers (e.g.,

asthmatics) choosing to work in areas with less exposure or the possibility that

environmental silica dust levels were high enough in the areas of indirect exposure to still

cause disease. An additional finding of the study was that there were no significant

correlations found between the mean values for pulmonary function and the duration of

exposure.

Potato sorters exposed to diatomaceous earth containing crystalline silica were the

subject of a cross-sectional study by Jorna et al. (1994). The workers were from five

potato sorting plants of the same agricultural cooperative in the Netherlands. The lung

function of currently exposed (n = 72) and retired exposed (n = 16) was compared to that

of 55 controls (office staff). Workers were exposed to dust mainly generated from clay

adhering to the incoming potatoes. In the year of the study, extensive measurements (at

least four (8-hour) personal samples per job) found that the geometric mean exposures for

total inspirable dust exposure, respirable dust exposure, and respirable silica exposure in
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were 9.9 mg/m3(range: 2.4 to 21.6), 2.21 mg/m3(range: 0.5 to 6.7), and 0.27 mg/m3

(range: 0.09 to 0.84), respectively. Cumulative exposure to respirable dust and silica was

estimated based on measurements for each job and each worker’s job history. Chest

radiographs found no silicosis in the study population. All spirometric parameters except

FVC were significantly lower in the currently exposed workers as compared to controls,

and this difference was even greater for retired exposed workers compared to controls.

Cumulative dust exposure in workers with FEV1 ≤ 80 percent of that predicted

(indicative of airflow limitation) was significantly higher than in those without airflow

limitation (223.4 vs. 112.5 gh/m3; p ≤ 0.001). A multiple linear regression analysis of

currently exposed workers, controlling for smoking, height, and age, revealed a

significant difference in FEV1 from controls, and FEV1 was statistically significantly

related to cumulative respirable dust exposure. The decrease in FEV1 was found to be

10.5 ml/year of employment for currently exposed workers. The authors noted that their

results do not allow for discrimination between the effects of exposure to total dust and

exposure to respirable silica, or possible exposure to diatomaceous earth, organic dust,

growth inhibiting agents, and herbicides.

Begin et al. (1995, also discussed in the emphysema section above and in Section

V.B.) studied the possible associations of age, work experience and industry, and

smoking habits with pulmonary function test results in a study population consisting of

207 workers exposed to silica and evaluated for pneumoconiosis at the Quebec Workman

Compensation Board and who had a radiographic reading of pneumoconiosis in the

category 0 or 1 of the ILO scale, as well as 5 control subjects. The subjects were 58 to 60

years of age and were exposed to mineral dusts for 25 to 27 years; 31 were lifetime nonsmokers and the others were either ex- or current smokers. Regression analyses

documented that age, smoking, and exposure to silica were significant predictors of

reduced pulmonary function in workers without pneumoconiosis.

A cross-sectional community study of 26,106 Norwegian men aged 30 to 46 who

had normal radiographs (i.e., were not silicotic) and had undergone spirometric testing

was conducted by Humerfelt et al. (1998). Thirteen percent of the men had occupational

quartz exposure with a mean duration of exposure of seven years. Among this exposed

group, significant inverse linear relationships were observed between years of exposure

and the level of FEV1 and the FEV1/FVC ratio. A decline of 4.3 ml (95% CI -1.1 to -7.5

ml; p < 0.01) was associated with each year of quartz exposure. In one analysis,

exclusion of those who worked in foundries did not change the relationships between

exposure and FEV1 or FVC levels. However, the effect of duration of exposure on FEV1

was reduced by 48 percent when those who worked as rock drillers were excluded. Rock

drillers had significantly lower FEV1 levels than foundry workers (p < 0.05).

Silica-exposed slate workers in Norway were studied by Suhr et al. (2003). The

cross-sectional study compared the occurrence of chronic obstructive pulmonary disease

(defined as the presence of coughing for greater than three months during a year, phlegm

when coughing, breathlessness walking uphill, or wheezing, and FEV1 less than 70

percent of FVC), lung function changes, and the prevalence of respiratory symptoms

among slate workers exposed to silica for at least one year and a control group with no
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present or previous dust exposure. An earlier study by the authors had measured quartz

exposure in different parts of the slate industry. The average concentration of total quartz

in the slate factory was 0.27 mg/m3and the average concentration of respirable quartz

was 0.12 mg/m3. Outside in the quarries the average levels of quartz were 0.58 and 0.13

mg/m3for total and respirable quartz, respectively. The authors noted that in the

preceding ten years most of the quarry-workers had built “quarry halls” to protect

themselves against a cold winter climate. Inside in these quarry halls the average levels

were 1.74 mg/m3total quartz and 0.46 mg/m3respirable quartz. Assessment of historical

exposure showed that 32 of the 45 quarry workers with available exposure history had a

lifetime inhaled quartz dose of more than 10 g (Bang and Suhr, 1998). The present study

did not state in which part of the industry each worker had been employed. Chest x-rays,

lung function tests and self-administered questionnaires were used to determine

respiratory health. The slate workers had a statistically significantly higher occurrence of

most respiratory symptoms (adjusted for smoking) and peak expiratory flow was

significantly lower (p < 0.01), but there were no other significant alterations in lung

function. Significantly more of the slate workers were smokers compared to controls (χ

2

,

p = 0.04). COPD prevalence was not increased among slate workers.

Respiratory disease in a cohort of 2579 coal miners in Spain has been examined in

a longitudinal study by Montes et al. (2004a). The workers were followed for 20 years,

during which they received an initial and subsequent respiratory exams. According to the

authors, some of the miners had to do a “great deal of rock work” to get to the coal and

thus would have experienced relatively high silica exposure compared to the direct coal

extractors. Average respirable dust levels (and silica fraction) for the rock workers and

coal extractors were 2.5 mg/m3(17.5 percent silica) and 3.4 mg/m3(8 percent silica),

respectively. A Cox model multivariate analysis found that accelerated FEV1 decreases

were statistically significantly related to rock work (p = 0.044) and tobacco use (p =

0.001).

I.D.3.a. Summary and conclusions for pulmonary function impairment.

OSHA has reviewed numerous studies on the relationship of silica exposure to

pulmonary function impairment as measured by spirometry. There were several

longitudinal studies available. Two groups of researchers conducted longitudinal studies

of lung function impairment in Vermont granite workers and reached opposite

conclusions. Graham et al. (1981, 1994) examined stone shed workers, who had the

highest silica exposure (between 50 and 100 μg/m3), along with quarry workers

(presumed to have lower exposure) and office workers (expected to have negligible

exposure). The longitudinal losses of FVC and FEV1 were not correlated with years

employed, did not differ among shed, quarry, and office workers, and were similar,

according to the authors, to other blue collar workers not exposed to occupational dust.

Eisen et al. (1983, 1995) found the opposite. They looked at lung function in two

groups of granite workers: “survivors” who were in the study the entire period (had all

five annual exams) and “dropouts” who did not participate in the final exam. There was

a significant exposure-response for silica exposure and FEV1 decline in the dropouts but
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not the survivors. The dropout group had a steeper FEV1 loss, and this was true for each

smoking category. The authors concluded that exposures of 50 ug/m3produced a

measurable effect in the dropouts. Eisen et al. (1995) felt that the “healthy worker effect”

was apparent in this study and that studies that only looked at “survivors” would be less

likely to see any effect of silica on pulmonary function.

A 12-year follow-up of age and smoking-matched granite crushers and referents

in Sweden found that over the follow-up period, the granite crushers had significantly

greater decreases in FEV1, FEV1/VC, maximum expiratory flow, and FEF50 than the

referents (Malmberg et al., 1993). A longitudinal study of South African gold miners

conducted by Hnizdo (1992) found that cumulative dust exposure was a significant

predictor of most indices of decreases in lung function, including FEV1 and FVC. A

multiple linear regression analysis showed that the effects of silica exposure and smoking

were additive. Finally, another study of South African gold miners (Cowie, 1998) also

found a loss of FEV1 in those without silicosis. Finally, a study of U.S. automotive

foundry workers (Hertzberg et al., 2002) found a consistent association with increased

pulmonary function abnormalities and estimated measures of cumulative silica exposure

within 0.1 mg/m3. The Hnizdo (1992), Cowie et al. (1993), and Cowie (1998) studies of

South African gold miners and the Malmberg et al. (1993) study of Swedish granite

workers found very similar reductions in FEV1 attributable to silica dust exposure.

A number of prevalence studies have described relationships between lung

function loss and silica exposure or exposure measurement surrogates (e.g., duration of

exposure). These findings support those of the longitudinal studies. Such results have

been found in studies of white South African gold miners (Hnizdo et al., 1990; Irwig and

Rocks, 1978), black South African gold miners (Cowie and Mabena, 1991), Quebec

silica-exposed workers (Begin, et al, 1995), Singapore rock drilling and crushing workers

(Ng et al., 1992b), Vermont granite shed workers (Theriault et al., 1974a, 1974b),

aggregate quarry workers and coal miners in Spain (Montes et al., 2004a, 2004b),

concrete workers in The Netherlands (Meijer et al., 2001), Chinese refractory brick

manufacturing workers in an iron-steel plant (Wang et al., 1997), Chinese gemstone

workers (Ng et al., 1987), hard-rock miners in Manitoba, Canada (Manfreda et al., 1982)

and Colorado (Kreiss et al., 1989), pottery workers in France (Neukirch et al., 1994),

potato sorters exposed to diatomaceous earth containing crystalline silica in The

Netherlands (Jorna et al., 1994), slate workers in Norway (Suhr et al., 2003), and men in

a Norwegian community (Humerfelt et al., 1998). Two of these prevalence studies also

addressed the role of smoking in lung function impairment associated with silica

exposure. In contrast to the longitudinal study of South African gold miners discussed

above (Hnizdo, 1992), another study of South African gold miners (Hnizdo et al., 1990)

found that the joint effect of dust and tobacco smoking on lung function impairment was

synergistic, rather than additive. Also, Montes et al. (2004b) found that the criteria for

dust-tobacco interactions were satisfied for FEV1 decline in a study of Spanish aggregate

quarry workers.

One of the longitudinal studies and many of the prevalence studies discussed

above directly addressed the question of whether silica-exposed workers can develop
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pulmonary function impairment in the absence of silicosis. These studies found that

pulmonary function impairment: (1) can occur in silica-exposed workers in the absence

of silicosis, (2) was still evident when silicosis was controlled for in the analysis, and (3)

was related to silica exposure rather than to the presence or severity of silicosis. Other

studies did not directly address this question but did not attribute lung function loss to

silicosis.

Many researchers have concluded that a relationship exists between exposure to

silica and lung function impairment. IARC (1997) has briefly reviewed studies on

airways disease (i.e., chronic airflow limitation and obstructive impairment of lung

function) in its monograph on crystalline silica carcinogenicity and concluded that

exposure to crystalline silica causes these effects. In its official statement on the adverse

effects of crystalline silica exposure, the American Thoracic Society (ATS) (1997)

included a section on airflow obstruction. The ATS noted that, in most of the studies

reviewed, airflow limitation was associated with chronic bronchitis. The review of

Hnizdo and Vallyathan (2003) also addressed COPD due to occupational silica exposure.

They examined the epidemiological evidence for an exposure-response relationship for

airflow obstruction in studies where silicosis was present or absent. Hnizdo and

Vallyathan (2003) concluded that chronic exposure to silica dust at levels that do not

cause silicosis may cause airflow obstruction.

Based on the evidence discussed above from a number of longitudinal studies and

numerous cross-sectional studies, OSHA preliminarily concludes that there is an

exposure-response relationship between exposure to respirable crystalline silica and the

development of impaired lung function. The effect of tobacco smoking on this

relationship may be additive or synergistic. Also, pulmonary function impairment can

occur in silica-exposed workers who do not show signs of silicosis.

I.D.4. Nonmalignant Respiratory Disease Mortality.

In this section, OSHA reviews two studies of gold miners, a study of

diatomaceous earth workers, and a death certificate case-control analysis that provide

information on the relationships between exposure to crystalline silica and NMRD

mortality other than that related to silicosis. A number of researchers have examined

nonmalignant respiratory disease (NMRD) mortality in workers exposed to silica. In

many studies, silicosis or pneumoconiosis mortality was included in the definition of

NMRD and made up a substantial portion of the excess mortality observed. These

studies have not been included here; instead, the question being addressed in this review

relates to the role of crystalline silica in producing excess mortality from NMRD other

than silicosis.

A cohort of 3,971 currently-working white South African gold miners was studied

by Wyndham et al. (1986). The cohort was followed for nine years. Two types of

analysis were conducted. The first was an analysis of SMRs in the miners compared to

the total white male population of the Republic of South Africa. This analysis found that

there was a statistically significant excess mortality for chronic respiratory diseases
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(SMR 165.2, 108.2-242.7). This category grouped together bronchitis, emphysema,

asthma, pneumoconiosis due to silica and silicates, other pneumoconiosis and other

related diseases, and pulmonary heart disease, because in comparing the cause of death

certified on the death certificate with the best available information from medical

examination records and other data from the Medical Bureau for Occupational Diseases,

the authors found evidence demonstrating that none of the miners certified on the death

certificate as dying from pneumoconiosis actually died from that disease. They found,

instead, that when pneumoconiosis was found in the miners, it was always an incidental

finding in those dying from some other cause, the most common of which was chronic

obstructive lung disease. Similarly, chronic obstructive lung disease was always the

primary cause of pulmonary heart disease. The second analysis was a case-referent study

in which each case of chronic respiratory disease was matched with four referents

selected at random from miners born the same year as the case and who survived the

case. The analysis found that the major risk factor for chronic respiratory disease was

smoking. However, cumulative dust exposure had a statistically significant additional

effect on the risk of disease, with the relative risk estimated as 2.48 per ten units of 1,000

particle-years of exposure (p = 0.03).

Mortality from “chronic obstructive lung disease” (“COLD”) (bronchitis,

emphysema, or chronic airways obstruction) in white South African gold miners was

studied by Hnizdo (1990). In the cohort were 2,209 miners who were aged 45 to 54

during the time period between 1968 and 1971, who started mining between 1936 and

1943, and who had received an annual medical exam between 1968 and 1971. They were

followed up through December 30, 1986. Retired miners were included if they had

sought a medical examination for compensation. A nested age-matched case-referent

study design was used. The study examined whether silica dust exposure was related to

COLD mortality and if so, sought to elucidate the shape of the exposure-response curve

and evaluate whether the combined effects of smoking and silica exposure were additive

or synergistic.

The odds ratios (ORs) showed a statistically significant increasing trend for dust

particle years (p = 0.003) and for cigarette years of smoking (p < 0.0001). The analysis

estimated that those with exposures of 10,000, 17,500, or 20,000 particle-years of

exposure had a 2.5, 5.06, or 6.4 times higher risk of dying from COLD, respectively, than

those with the lowest dust exposure (less than 5,000 particle-years). Analysis of various

combinations of dust exposure and smoking variables found that the multiplicative model

fit the data significantly better than the additive model, suggesting a synergistic effect.

Attributable risks estimated for dust exposure, smoking, and dust and smoking combined

were 64, 93, and 98 percent, respectively. Therefore, it follows that the relative

contribution of dust, smoking, or the combination of the two in causing COLD mortality

is 5 (98-93), 34 (98-64), and 59 (98-34-5) percent, respectively. The authors concluded

that dust exposure alone did not result in COLD mortality but that either smoking alone

or the combination of dust exposure and smoking were the main risk factors for COLD

mortality. The authors also concluded that smoking was more dangerous for miners

exposed to silica dust than for others because of this synergistic effect.
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Park et al. (2002) studied a cohort of 2,342 workers in a diatomaceous earth plant

(mining and processing). The cohort comprised all employees with at least one year of

employment and active anytime during the period 1942 to 1994. The cohort was exposed

to a mean concentration of respirable crystalline silica (mostly cristobalite) averaged over

the years of employment of 0.29 mg/m3. Cumulative exposures to respirable crystalline

silica were estimated for each worker. The mean final cumulative exposure to respirable

crystalline silica dust was 2.12 mg/m3-years (62.52 mg/m3-years maximum).

There were 67 deaths in the cohort with an underlying cause of death of lung

diseases other than cancer (LDOC). Ten of those deaths were from silicosis. Two of the

deaths were from asbestosis. Observation times with cumulative exposures over 10

mg/m3-years (16 percent of the deaths from LDOC) were excluded from the Poisson

regression analysis because a decline in exposure-response with increasing exposure had

resulted, in the opinion of the authors, from “some form of survivor selection.” The

authors found a statistically significant exposure-response trend for LDOC mortality,

from which they estimated lifetime risks. This analysis is further discussed in Section II

(Preliminary Quantitative Risk Assessment).

Calvert et al. (2003) conducted a case-control analysis from death certificate data

of mortality from various diseases and occupational silica exposure. Death certificates

were obtained from 27 US states. A qualitative silica exposure category (super-high,

high, medium, low/no) was determined for each individual based on industry/occupation

found on their death certificate. A statistically significantly increased risk for COPD

(ICD 490-492) mortality was observed for those in the super-high, high, and medium

exposure categories combined (OR = 1.12 , 95% CI 1.10 to1.14), as well as for those in

the high (OR = 1.29, 95% CI 1.25 to 1.33) and super-high (OR = 1.47, 95% CI 1.30 to

1.66) categories. There was also a statistically significant trend of increased risk for

COPD mortality with increasing silica exposures (p < 0.001). In addition, when silicotics

were compared to those without silicosis, the odds ratio for COPD mortality showed a

statistically significantly increased risk (4.38, 95% CI 3.39 to 5.67). The authors

concluded that there was an association between crystalline silica exposure and COPD

mortality, based on the consistently increased odds ratios among those in the medium and

higher crystalline silica exposure categories and the significant trend across those

categories.

I.D.4.a. Summary and conclusions for NMRD mortality.

In this section, OSHA reviewed studies on NMRD mortality that focused on

causes of death other than from silicosis. Two studies of gold miners, a study of

diatomaceous earth workers, and a case-control analysis of death certificate data provide

useful information.

Wyndham et al. (1986) found a significant excess mortality for chronic

respiratory diseases in a cohort of white South African gold miners. Although these data

did include silicosis mortality, the authors found evidence demonstrating that none of the

miners certified on the death certificate as dying from silicosis actually died from that
207

disease. Instead, pneumoconiosis was always an incidental finding in those dying from

some other cause, the most common of which was chronic obstructive lung disease. A

case-referent analysis found that while the major risk factor for chronic respiratory

disease was smoking, there was a statistically significant additional effect of cumulative

dust exposure, with the relative risk estimated as 2.48 per ten units of 1,000 particle years

of exposure.

A synergistic effect of smoking and cumulative dust exposure on mortality from

“chronic obstructive lung disease” (COLD) was found in another study of white South

African gold miners (Hnizdo, 1990). Analysis of various combinations of dust and

smoking found a trend in OR that indicated this synergism. There was a statistically

significant increasing trend for dust particle years and for cigarette years of smoking. For

cumulative dust exposure, an exposure-response relationship was found, with the analysis

estimating that those with exposures of 10,000, 17,500, or 20,000 particle-years exposure

had a 2.5, 5.06, or 6.4 times higher mortality risk for COLD, respectively, than those with

the lowest dust exposure of less than 5000 particle-years. The authors concluded that

dust alone would not lead to increased COLD mortality but that dust and smoking act

synergistically to cause COLD and were thus the main risk factor for death from COLD

in their study.

In a study of diatomaceous earth workers, Park et al. (2002) described positive

exposure-response relationships between exposure to crystalline silica and excess risk for

mortality from lung disease other than cancer. In a case-control analysis of death

certificate data drawn from 27 U.S. states, Calvert et al. (2003) found increased mortality

odds ratios among those in the medium and higher crystalline silica exposure categories,

a significant trend of increased risk for COPD mortality with increasing silica exposures,

and a significantly increased odds ratio for COPD mortality in silicotics as compared to

those without silicosis.

Green and Vallyathan (1996) also reviewed several studies of NMRD mortality

in workers exposed to silica. The authors stated that these studies showed an association

between cumulative dust exposure and death from the chronic respiratory diseases.

Based on the evidence presented in the studies above, OSHA preliminarily

concludes that respirable crystalline silica increases the risk for mortality from

nonmalignant respiratory disease (not including silicosis) in an exposure-related manner.

However, it appears that the risk is strongly influenced by smoking, and the effects of

smoking and silica exposure may be synergistic.

I.D.5. Preliminary Conclusions for Other Nonmalignant Respiratory Disease.

Based on the findings of studies of the relationship of silica exposure to morbidity

from emphysema, bronchitis, and lung function impairment (as measured by spirometry),

and mortality from NMRD (other than silicosis), OSHA preliminarily concludes that an

exposure-response relationship exists for exposure to respirable crystalline silica and the

risk of these conditions and that these conditions can occur in the absence of silicosis.
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However, except for NMRD mortality, data are insufficient for quantitative risk

assessment. For emphysema, silica exposure may not increase risk in non-smokers. For

all conditions, the effect of smoking may be additive (except for NMRD mortality) or

synergistic.

I.E. Renal and Autoimmune Effects.

In recent years, evidence has accumulated that suggests an association between

exposure to crystalline silica and an increased risk of renal disease. Over the past 10

years, epidemiologic studies have been conducted that provide evidence of exposureresponse trends to support this association. There is also suggestive evidence that silica

can increase the risk of rheumatoid arthritis and other autoimmune diseases (Steenland,

2005b). In fact, an autoimmune mechanism has been postulated for some silicaassociated renal disease (Calvert et al., 1997). This section will discuss the evidence

supporting an association of silica exposure with renal and autoimmune diseases. Several

review articles (IARC, 1997; Lancet, 1978; NIOSH, 2002; Parks et al, 1999; SSDC,

1988; Steenland, 2005b) that cite evidence for effects on both systems were used by

OSHA to identify key studies. These review articles and their conclusions are

summarized briefly, after which OSHA presents its evaluation of the primary literature.

An editorial in the Lancet (1978) noted a number of case reports that suggested a

role for silica exposure in the development of renal effects, including proteinuria, acute

renal failure, and the appearance of excessive amounts of silicon in the kidney. The

editorial concluded that inhaled silica dust should be considered as a rare cause of renal

disease. The editorial also stated that it was apparent that the inhalation of crystalline

silica can cause renal disease with no evidence of a wide-spread connective-tissue

disorder. With regard to autoimmune disease, the editorial cited a report stating that 10

percent of workers with acute silicosis also showed evidence of connective tissue

disorders such as scleroderma, systemic lupus erythematosus, and rheumatoid arthritis.

In addition, the editorial noted that other immunological changes have been described in

persons with silicosis.

Ten years later, the subject was reviewed again by the Silicosis and Silicate

Disease Committee (SSDC), a committee of pathologists appointed by NIOSH to assess

the understanding of the diseases resulting from the inhalation of a variety of nonfibrous

crystalline mineral particulates (SSDC, 1988). The SSDC cited additional reports of

glomerulonephritis and tubular lesions found in some patients with accelerated silicosis

as well as those with no pulmonary disease but with a history of silica exposure.

However, they pointed out that glomerular lesions and other renal changes found in

Vermont granite workers with silicosis were similar to those found in control subjects

with a variety of other diseases. Thus, they thought that the changes were nonspecific

and their association with silicosis uncertain. Of the finding of excessive silica in the

kidneys of the workers discussed in the Lancet editorial above, the SSDC noted that the

levels of crystalline silica in the kidneys of workers with silicosis or normal individuals

were not known. Finally, the SSDC believed that the limited number of animal

experiments conducted up to that point failed to provide an experimental basis for silica-
209

related renal disease. However, they also commented that it was difficult to ignore the

numerous case reports of acute glomerulonephritis occurring in persons with accelerated

silicosis.

The SSDC also addressed the role of crystalline silica in producing autoimmune

disorders. While commenting that the unique association between exposure to silica and

autoimmune diseases had long been recognized, they believed that the significance of the

observation remains a matter of debate. They reported on several studies and case reports

describing scleroderma among silica-exposed workers, including stone masons, coal and

gold miners (absent an increased prevalence of radiological silicosis and with intensity of

silica exposure seeming to be more important than duration), potters, and foundry

workers. However, the personal experience of one of the committee members failed to

support these findings. Finally, the SSDC discussed a study that demonstrated that the

rate of progression of silicosis and the likelihood of relatively large nodular pulmonary

lesions in patients with rheumatoid arthritis was greater than in control subjects.

However, silica dust exposure did not appear to predispose to rheumatoid arthritis.

The “extrapulmonary” effects of silica were addressed again by IARC in 1997.

Its review focused primarily on those studies published since the 1988 SSDC review.

With regard to renal effects, IARC (1997) discussed several studies. Findings of these

studies include the following: an increased prevalence of abnormal renal function among

silica-exposed individuals, both with and without silicosis; a positive relationship

between length of exposure to silica and severity of renal dysfunction; a contradictory

study in which silicosis was associated with renal alterations but there was no

relationship between loss of renal function and length of exposure or severity of silicosis;

persistence of renal effects after cessation of silica exposure; a relationship between

rapidly progressive glomerulonephritis and silica exposure; an elevated odds ratio for

end-stage renal disease among silica-exposed men; and a finding of crystalline silica

within the renal tubules in a case study of silica-related glomerulonephritis.

Several studies of autoimmune effects of silica were also cited by IARC (1997),

including reports of systemic sclerosis-like (scleroderma-like) disorders following

exposure to silica, evidence of an increased incidence of rheumatoid arthritis among

Finnish granite workers, and granulomas mimicking cutaneous sarcoidosis or

granulomatous cheilitis believed to be associated with cutaneous silica exposure.

Parks et al. (1999) have reviewed the human evidence for the association of silica

exposure with autoimmune diseases as well as studies describing possible mechanisms

that explain the role of crystalline silica in the development of these diseases. They

concluded that several studies of different designs conducted in a variety of exposed

occupational groups suggest an association between exposure to silica and increased risk

of systemic autoimmune disease. Based on an assessment of clinic-based case-series,

occupational cohort studies, registry linkage studies, and case-control studies, many

published after 1995, Parks et al. (1999) reported that the most common diseases

associated with silica exposure included scleroderma, rheumatoid arthritis, SLE, and

some of the small vessel vasculitidies with renal involvement.
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The question of whether silica exposure is a risk factor for renal disease was also

addressed in a review by Stratta et al. (2001). This review covered individual case

reports, case series, and occupational population-based epidemiological evidence.

Studies were divided into those looking for evidence of renal disease in workers exposed

to silica and those looking at the occupational exposures of persons with renal disease.

Based on their review of these studies, the authors drew several conclusions: 1) “The

evidence for the nephrotoxicity of silica continues to mount”; 2) Nephrotoxicity induced

by silica may develop in the absence of silicosis; and 3) “Silica toxicity may cooperate in

progression of renal damage due to any cause.”

An updated review of studies of silica-related renal and autoimmune disorders

was provided by NIOSH in their 2002 Hazard Review of silica. NIOSH (2002) cited

over 30 case reports published between 1914 and 1998 that describe various autoimmune

disorders in workers or patients who were occupationally exposed to crystalline silica.

The most frequently reported autoimmune diseases were scleroderma, systemic lupus

erythematosus (SLE), rheumatoid arthritis, autoimmune hemolytic anemia, and

dermatomyositis or dermatopolymyositis.

NIOSH (2002) also cited over 20 additional case reports describing health effects

that may be related to the immunologic abnormalities in patients with silicosis. These

health effects included chronic renal disease, ataxic sensory neuropathy, chronic

thyroiditis, hyperthyroidism (Grave’s disease), monoclonal gammopathy, and

polyarteritis nodosa. NIOSH (2002) also provided details on 13 post-1985 epidemiologic

studies of silica-exposed workers that reported statistically significant excess numbers of

cases or deaths from known autoimmune diseases or immunological disorders

(scleroderma, rheumatoid arthritis, and sarcoidosis), chronic renal disease, and

subclinical renal changes. Furthermore, NIOSH (2002) reported that epidemiologic

studies had found statistically significant associations between occupational exposure to

silica dust and several specific renal diseases or effects, including end-stage renal disease

morbidity (including that caused by glomerular nephritis), chronic renal disease

mortality, and Wegener’s granulomatosis (systemic vasculitis often accompanied by

glomerulonephritis). NIOSH (2002) also cited several studies that addressed the

pathogenesis of glomerulonephritis and other renal effects in silica-exposed workers as

well as possible cellular mechanisms of silica-related autoimmume diseases.

Most recently, Steenland (2005b) cited five occupational cohort studies and one

proportional mortality study that have consistently shown two- to three-fold excesses of

renal disease among silica-exposed populations (although he noted that this was based on

relatively small numbers), two population-based case-control studies of renal disease that

had shown odds ratios of two or more for silica exposure, and his own analysis of renal

disease mortality in three combined occupational cohorts that showed a strong exposureresponse trend for both underlying and multiple cause mortality. Steenland (2005b)

determined that the evidence overall was still too sparse to be summarized as conclusive,

but that it seemed very probable that silica causes kidney disease. In comparing the risks

of various diseases from silica exposure, Steenland (2005b) expressed the opinion that,
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surprisingly, kidney disease appears to be perhaps the most common serious health effect

of silica exposure after small opacities found on lung X-rays, although the kidney data is

based on fewer studies than for X-ray opacities. However, he also believed that silicosis

would represent the largest risk if X-ray opacities progress frequently to symptomatic

silicosis. Steenland (2005b) also cited supportive studies that have pointed to plausible

mechanisms by which crystalline silica may induce renal disease, which include a direct

toxic effect of silica on the kidneys, deposition in the kidney of immune complexes (IgA)

following silica-related pulmonary inflammation, or an autoimmune mechanism. Citing

Parks et al. (1999), Steenland (2005b) also noted that there is increasing evidence that

silica can cause other autoimmune diseases as well, particularly rheumatoid arthritis,

SLE, and scleroderma. He suggested that it is possible that the strong immune response

in the lung can trigger an autoimmune reaction.

In the discussion below, OSHA presents its evaluation of studies concerning the

relationship of silica exposure to renal disease and the autoimmune diseases scleroderma,

rheumatoid arthritis, systemic lupus erythematosus, and small vessel vasculitides.

I.E.1. Renal Disease.

A number of longitudinal and mortality studies have observed relationships

between exposure to silica and an increased risk of renal disease. A proportionate

mortality study of renal disease in granite cutters was conducted by Steenland et al.

(1992). Death certificates of the granite cutters were examined for any mention of renal

disease, whether it was as the underlying cause of death, contributory cause, or other

significant condition. The authors developed a data base of U.S. mortality rates (age, sex,

race, and calendar-time specific) and proportions, using multiple cause-of-death data for

the years 1960 to 1989. These rates and proportions were then used to calculate the

expected occurrence of renal disease in the cohort of granite cutters. The authors noted

that multiple cause data reflect the prevalence of specific diseases at death. The diseases

that are the best candidates for multiple cause analysis have a long course and are often

not the cause of death, but are serious enough to be noted by the physician on the death

certificate. Proportionate mortality ratios (PMR, the ratio of observed to expected) for

underlying cause and for multiple causes were calculated for acute and chronic renal

disease categories. For acute renal disease, neither PMR’s for multiple cause of death nor

underlying cause of death was statistically significantly elevated. For chronic renal

disease, the PMR was statistically significantly elevated using multiple cause (PMR 2.18,

26 deaths, 95% CI 1.43-3.20) but not underlying cause data. The authors concluded that

this finding confirmed an association between exposure to crystalline silica and renal

disease as seen in case reports and a case-control study (Steenland et al., 1990).

A cohort of 3,971 currently-working white South African gold miners was studied

by Wyndham et al. (1986). The authors stated that these miners were exposed to “low

levels of dust containing a moderate amount of silica.” The cohort was followed for nine

years. An analysis of SMRs in the miners compared to the total white male population of

the Republic of South Africa (based on causes of death given on the death certificates)
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found that there was statistically significant excess mortality for acute and chronic

nephritis (ICD 580-584) (SMR 381.0, 95% CI 164.4-750.9, 8 observed, 2.1 expected).

The incidence of end-stage renal disease (ESRD) was examined in a retrospective

cohort study of a subcohort of 2,412 men drawn from a cohort of South Dakota gold

miners (Calvert et al., 1997). The members of the Calvert et al. (1997) cohort with ESRD

were identified through the ESRD Program Management and Medical Information

System (a database maintained by the Health Care Financing Administration). The

incidence rate in the miners was compared to the expected incidence of ESRD in the U.S.

to obtain the standardized incidence ratio (SIR). The mean duration of employment was

eight years, the average year of first employment was 1946, and 94 percent had twenty

years since first employment. The mean, median, and range of cumulative silica

exposure were 0.18, 0.39, and 0.008 to 4.32 mg/m3-years, respectively. The median and

mean intensity of exposure were 0.04 and 0.05 mg/m3, respectively. The ESRD SIR for

the entire cohort was not statistically significantly elevated. There were a total of eleven

members of the cohort with ESRD. However, there was a statistically significantly

increased incidence of the type of ESRD known as non-systemic ESRD, which is caused

by glomerulonephritis and interstitial nephritis (SIR 4.22, 95% CI 1.54-9.18, 6 observed).

Most of this increase appeared to be due to ESRD caused by glomerulonephritis (SIR

4.28, 95% CI 1.38-10.00). The SIRs for non-systemic ESRD with duration of

underground employment and cumulative dust exposure were also determined. Miners

with the highest duration of employment (10 or more years) had a statistically

significantly increased SIR (7.70, 95% CI 1.59-22.48). The SIR for miners exposed to

cumulative exposures of from 0.22 to less than 0.55 mg/m3-year was statistically

significantly increased at 11.05 (95% CI 3.01-28.30). The SIR for those miners exposed

to 0.55 mg/m3-year or more, however, was not statistically significantly increased.

The authors suggested that this finding may be explained by a limitation in the

study. Since the database was only complete after 1977, cohort members who died

before 1977 were excluded from the analysis, thus excluding those with a higher mean

duration of employment and higher mean cumulative dust exposure. This reduced the

power of the study to detect elevated risks in those with high cumulative dust exposures.

To address this issue, the tertiles of exposure were redefined so that each had a similar

number of expected cases of non-systemic ESRD. The tertile with the highest cumulative

silica dust exposure (0.30 mg/m3-years or more, with a median intensity of exposure of

0.04 mg/m3) had the highest risk of non-systemic ESRD (SIR 8.11, 95% CI 2.20-20.77, 4

cases). An additional analysis examined a subgroup of workers first employed

underground after 1950 when silica exposures had been reduced to a median of 0.02

mg/m3. The risk for ESRD remained statistically significantly elevated (SIR 5.00, 95%

CI 1.03-14.61) in this subgroup. The authors concluded that their study findings provide

evidence that occupational exposure to silica is associated with an increased risk for

ESRD, especially that caused by glomerulonephritis. Because the median level of

exposure of the cohort was below the current OSHA PEL (0.09 mg/m3for this

workplace), the authors also concluded that the PEL might not be adequately protective.

However, the authors felt that they could not make strong conclusions about this due to

the small numbers and wide confidence intervals in their study.
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A similar study of ESRD was conducted on a cohort of 2,820 Italian ceramic

workers (Rapiti et al., 1999). All workers were enrolled in a health surveillance program

during the period 1974 to 1991 and were alive as of 1994. Data on employment history,

smoking status, and silicosis status were available. As in the Calvert et al. study, each

worker was matched to see whether they were in the regional ESRD registry as of 1994.

Data in the regional registry was also used to compute expected rates of ESRD for the

region. The total cohort of ceramic workers had a statistically significantly increased

prevalence of ESRD with an O/E ratio of 3.21 (6 observed, 95% CI 1.17-6.98). Also, the

prevalence of ESRD was statistically significantly increased for those with latency since

first exposure of 10 to 19 years (4 observed, O/E 4.65, 95% CI 1.26-11.9), but not for

those with latencies of less than 10 years, 20 to 29 years, or 30 years or greater. The six

observed cases had cumulative respirable silica exposures ranging from 0.2 to 3.8 mg/m3

-years. The authors concluded that their data confirmed the findings of Calvert et al.

(1997) that exposure to silica is associated with an increased risk for end stage renal

disease.

A study of North American industrial sand workers examined mortality from

nephritis/nephrosis (McDonald et al., 2001). This study has been described in detail in

Section C above [Carcinogenic Effects of Silica (Cancer of the Lung and Other Sites)].

Briefly, the cohort consisted of 2,670 men employed before 1980 for three years or more

in one of nine North American sand plants and a large associated office complex. They

were traced through 1994. The SMR for mortality from nephritis or nephrosis, calculated

using state/provincial rates, was 212 (16 vs 7.56, p = 0.002). The excess was present

only in workers employed for at least 10 years. The authors concluded that this finding

of excess mortality from non-malignant renal disease was important because the evidence

was fairly clear and consistent but that the scope of their study did not allow for further

examination of this finding.

McDonald et al. (2005) updated this cohort mortality study of North American

industrial sand workers by extending the follow-up to 2000. Mortality rates for the

cohort were compared to state and national rates. A cause of death was available for each

person who died. A nested case-referent analysis was conducted using quantitative

estimates of silica exposure. The SMR at 20 or more years since hire as compared to the

US rate for nephritis/nephrosis was still statistically significantly increased for the

extended follow-up period (SMR 280, p < 0.001, 18 deaths). Also, the SMR for kidney

cancer for the 20 or more years latency group, which was not statistically significantly

increased in the previous study, was statistically significantly increased for both the 1995

to 2000 period (SMR 342, p = 0.03, 4 deaths) and the entire follow-up period (SMR 202,

p = 0.03, 10 deaths). The comparison using the state cancer rates yielded lower but still

statistically significantly elevated rates for nephritis/nephrosis (SMR 222, p value not

provided) and kidney cancer (SMR 197, p value not provided) for the entire follow-up

period. An analysis by year of hire found a generally decreasing trend over time for

kidney cancer and nephritis/nephrosis, with the highest rates reported among pre-1950

hires. Looking at individual plants, an excess risk of mortality from nephritis/nephrosis

was observed among workers in most plants, while excess kidney cancer mortality was
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seen among workers mainly from plants in Pennsylvania and West Virginia. Casereferent analysis failed to demonstrate a relationship between either disease and

cumulative exposure or average exposure intensity (as was consistently seen for silicosis

and lung cancer). The authors suggested that biopersistent agents or those causing

immune effects may show a different pattern of exposure-response relationships. They

also commented that the size of their cohort did not allow for a more detailed analysis for

duration and intensity of exposure. The authors concluded that their findings do not

support a causal relationship between silica exposure and chronic renal disease or renal

cancer but fail to explain the excess mortality observed.

Steenland et al. (2002a) combined three silica-exposed cohorts for a pooled

analysis of renal disease mortality. The three cohorts were industrial sand workers, gold

miners, and granite workers. For each cohort, underlying and multiple cause mortality

data and a job-exposure matrix were available. The original gold miner (Steenland and

Brown, 1995a) and industrial sand (Steenland et al., 2001b) studies will be discussed in

turn, followed by a discussion of the pooled analysis. Results for renal disease mortality

in the granite worker cohort (Costello and Graham, 1988) had not been published

previously to Steenland et al. (2002a). This granite worker cohort is more fully described

in Section C [Carcinogenic Effects of Silica (Cancer of the Lung and Other Sites)] and

will be summarized below.

Steenland and Brown (1995a) conducted a mortality study of South Dakota gold

miners exposed to silica. This study has been extensively described above in Section C

[Carcinogenic Effects of Silica (Cancer of the Lung and Other Sites)]. Briefly, the cohort

consisted of 3,328 gold miners who had worked underground for at least one year

between 1940 and 1965. Status was followed up to 1990. A job exposure matrix was

used to estimate dust exposure for each job over time and was based on dust

measurements that were available for the years 1937 to 1975. For the entire cohort, there

was no statistically significant increase in mortality from chronic renal disease.

However, there was a statistically significant increase in mortality from chronic renal

disease in those miners with a cumulative dust exposure of 48,000 dust days (one dust

day is one day with exposure to a concentration of one mppcf dust) or greater (SMR 2.77,

significant at the 0.05 level, 8 observed). Moreover, a chi square trend test indicated a

statistically significant positive trend for chronic renal disease mortality with increasing

cumulative exposure category (significant at the 0.05 level). In an analysis by year of

hire, chronic renal disease mortality was statistically significantly elevated only for those

hired prior to 1930 (SMR 2.39, 95% CI not reported, only that it excluded 1.00, 7

observed). Additionally, excesses of chronic renal disease mortality in a review of

multiple cause mortality stratified by time of hire were shown to be concentrated in those

hired prior to 1930 (SMR 2.14, 95% CI 1.05-4.04, 10 observed). The authors noted that

exposures were known to be higher in earlier years. More than half (58 percent) of the

cohort had been first employed before 1950, a period during which the authors stated that

the exposures were “particularly high.” Follow-up of this cohort was extended six years

to the end of 1996 for this pooled analysis.
215

Steenland et al. (2001b) also studied kidney disease morbidity and mortality in a

cohort of industrial sand workers in the U.S. The cohort and study methods have been

described in detail in Section C above (Lung and Other Cancers). The cohort consisted

of 4,626 silica-exposed workers whose mortality experience was compared with that of

the U.S. population. The workers were employed in 18 plants from the 1940s to the

1980s, most producing silica flour, a nearly 100 percent pure and finely ground quartz.

Follow-up was until the end of 1996. As in the Steenland et al. (1992) study described

above, underlying and multiple-cause mortality data were used (i.e., any mention of the

disease on the death certificate). An exposure-response analysis was also conducted

using a job-exposure matrix based on more than 4,000 industrial hygiene samples. The

authors thought that their job-exposure matrix was probably reasonably accurate because

silicosis and other unspecified pneumoconiosis as underlying causes of death showed an

increasing trend in standardized rate ratios (SRRs) with cumulative exposure. Mortality

from acute renal disease was statistically significantly increased using multiple-cause

data (SMR 2.61, 95% CI 1.49-4.24, 16 observed deaths) but not using underlying cause

data. Mortality from chronic renal disease, on the other hand, was statistically

significantly increased using either underlying (SMR 2.22, 95% CI 1.06-4.08, 10

observed deaths) or multiple-cause (SMR 1.61, 95% CI 1.13-2.22, 36 observed deaths)

data. An analysis was also done for multiple-cause mortality with cumulative exposure.

Quartiles of exposure were >0 to 0.10, 0.10 to 0.51, 0.51 to 1.28, and 1.28+ mg/m3-years.

For both acute and chronic renal disease, standardized rate ratios increased with

increasing quartile of cumulative exposure.

Steenland et al. (2001b) also matched their cohort to the national registry of

treated end-stage renal disease (ESRD) (use of this data was described in Calvert et al.,

1997, as detailed above) to determine incidence rate ratios. The SIR for ESRD was

statistically significantly elevated at 1.97 (95% CI 1.25-2.96, 23 cases) as was the SIR for

glomerulonephritis (3.85, 95% CI 1.55-7.93, 7 cases). Exposure-response analyses were

also conducted for ESRD based on the same exposure quartiles used for the renal

mortality analysis. The authors reported finding a “pronounced” trend of increasing

ESRD risk by increasing cumulative exposure. In addition, case-control analyses by

conditional logistic regression found rate ratios by quartile of cumulative exposure of

1.00, 2.68, 4.00, and 4.38. Use of the log of cumulative exposure provided the best fit to

the data (coefficient = 0.84, 95% CI -0.04 to 0.66). The authors concluded that the

exposure-response trends observed supported the finding of a causal relation between

silica exposure and subsequent renal disease. They estimated that the excess lifetime risk

of ESRD through age 75 for males exposed at 0.05 mg/m3respirable silica was 14

percent (95% CI -1% to 70%), based on the coefficient for log cumulative exposure from

the nested case-control analysis restricted to ESRD cases. The authors noted that the

background lifetime risk for a non-exposed male for ESRD is 2 percent.

The 5,408 Vermont granite workers (Costello and Graham, 1988) were exposed

to silica in quarries or in sheds during the period 1950 to 1982. Follow-up for the cohort

continued to the end of 1994. The combined cohort for the pooled analysis (Steenland et

al., 2002a) consisted of 13,382 workers with exposure information available for 12,783.

Exposure matrices for the three cohorts (gold miners, industrial sand workers, and granite
216

workers) had been previously validated by exposure-response data analysis for silicosis

morbidity or mortality. The exposure estimates were validated by the monotonically

increasing exposure-response trends seen in these silicosis analyses, since cumulative

silica levels are known to predict silicosis. The mean duration of exposure, cumulative

exposure, and concentration of respirable silica for the cohort were 13.6 years, 1.2

mg/m3- years, and 0.07 mg/m3, respectively. SMRs (compared to the U.S population) for

renal disease (acute and chronic glomerulonephritis, nephrotic syndrome, acute and

chronic renal failure, renal sclerosis, and nephritis/nephropathy) were statistically

significantly elevated using multiple cause data (SMR 1.29, 95% CI 1.10-1.47, 193

deaths) and underlying cause data (SMR 1.41, 95% CI 1.05-1.85, 51 observed deaths).

Renal disease mortality was also evaluated for the following quartiles of cumulative

exposure: >0 to 0.15, 0.15 to 0.55, 0.55 to 1.67, and 1.67+ mg/m3-years. There were

highly statistically significant trends for increasing SMR with increasing cumulative

exposure for both multiple cause (p < 0.000001) and underlying cause (p = 0.0007).

Exposure-response analysis was also conducted as part of a nested case-control study

with odds ratios determined for the same cumulative exposure quartiles noted above. The

referent was the group of workers in the lowest exposure quartile. Statistically significant

monotonic trends of increasing OR with increasing exposure were seen for multiple cause

(p = 0.004 linear trend, 0.0002 log trend) and underlying cause (p = 0.21 linear trend,

0.03 log trend) analysis. The exposure-response trend was homogeneous across the three

cohorts; addition of interaction terms did not increase the log likelihood of the model

(e.g., the rate ratios by quartile of cumulative exposure using the multiple cause data were

1.00, 1.20, 1.36 and 3.31 for granite workers, 1.00, 1.15, 2.01 and 2.69 for gold miners,

and 1.00, 1.56, 1.87 and 1.88 for industrial sand workers). Within the individual

quartiles, statistically significantly increased odds ratios for multiple cause renal

mortality were observed in the two highest cumulative exposure quartiles (for 0.55-1.67

mg/m3-years OR = 1.77, 95% CI 1.10-2.85; for 1.67+ mg/m3-years OR = 2.86, 95% CI

1.73-4.72). For underlying cause renal mortality, statistically significantly increased odds

ratios were observed only for the highest exposure quartile (OR = 3.93, 95% CI 1.31-

11.76). The authors used the exposure-response coefficient for the model with the log of

cumulative exposure to calculate that the lifetime excess risk of death (underlying cause)

from renal disease by age 75 for an exposure of 0.10 mg/m3over a working lifetime (age

20 to 65) was 1.8 percent (95% CI 0.8-9.7%) above a background risk of 0.3 percent.

The authors concluded that their study added to the evidence that renal disease is

associated with exposure to crystalline silica. Noting that statistically significantly

increased odds ratios and SMRs were seen primarily for cumulative exposures of >0.5

mg/m3-years, the authors pointed out that this would come from working for five years at

an exposure level of 0.1 mg/m3or 10 years at 0.05 mg/m3. OSHA believes that the

findings of this pooled analysis seem credible because the analysis involved a large

number of workers from three cohorts with well-documented, validated job-exposure

matrices and found a positive and monotonic increase in renal disease risk with

increasing exposure for both underlying and multiple cause data.

Several mortality studies have not observed relationships between exposure to

silica and renal disease mortality. Two studies of granite workers, one in the U.S. and
217

one in Finland, did not report finding a relationship. Davis et al. (1983) examined

proportionate mortality during the period 1952 to 1978 for a cohort of 1,023 white male

Vermont granite quarry and shed workers. In contrast to the studies of Steenland et al.

(1992; 2001b; 2002a), only underlying cause of death was used. Comparisons were to

mortality rates for U.S. white males. Estimates of lifetime exposure to silica were made

and workers were grouped into four cumulative exposure categories. As has been noted

above, dust controls were installed in the sheds between 1937 and 1940 and in the

quarries by 1950. For the cohort as a whole, the observed-to-expected ratio (after

excluding deaths from tuberculosis or silicosis) was not statistically significantly

increased for “diseases of genitourinary system” (ICD 580-629) (O/E = 1.3, 95% CI 0.0-

2.1, 15 deaths). Another analysis that used time of entry into the industry, either before

or after implementation of controls, as a proxy for silica exposure resulted in an O/E of

1.4 (13 deaths, 9.0 expected) for diseases of genitourinary system, but the confidence

interval was not reported. The authors noted that the post-exposure control group worked

an average of 14 years and only nine had more than 25 years experience in the industry.

The relative risk of mortality from genitourinary diseases was increased for those in the

high (399-800 mppcf-years) and medium (199-400 mppcf-years) cumulative exposure

categories (RR = 1.2 and 2.0, respectively) but not for the very high or low-exposure

categories. Thus, no clear exposure-response relationship was seen (no information was

provided on the statistical significance of the relative risk measures). Finally, an analysis

by jobs ever worked found 5 deaths (1.8 expected) from genitourinary disease in “other

quarry workers” (statistical significance not reported). The authors concluded that their

findings do not provide consistent evidence of association between exposures in the

granite industry and mortality.

Finnish granite workers were studied in a mortality study by Koskela et al.

(1987). The cohort consisted of 1,026 workers hired between 1940 and 1971 and

followed until the end of 1981. Mortality rates were compared to the general male

population of Finland. There were 4 deaths (1.8 expected) where the main cause of death

was “diseases of the urinary tract.” Three of these deaths were from chronic

pyelonephritis (0.6 expected) and one was from chronic nephritis. Renal disease was also

reported in five other cases where it was not the primary cause of death. Three cases of

urinary tract disease were associated with rheumatoid arthritis on the death certificates.

The authors commented that a definite conclusion regarding an association of exposure to

granite dust with glomerulonephritis was not possible because of the small number of

cases.

Calvert et al. (2003) also did not find an increased mortality odds ratio for renal

diseases with presumed silica exposure in a death certificate, matched case-control

analysis of risks of mortality from various diseases and occupational silica exposure.

Death certificates were obtained from 27 U.S. states. A qualitative silica exposure

category (super high, high, medium, low/no) was determined for each individual based

on industry/occupation found on their death certificate. Further details of this study can

be found in Section C [Carcinogenic Effects of Silica (Cancer of the Lung and Other

Sites)]. Calvert et al. (2003) found no significant association between crystalline silica

exposure and several renal diseases, including acute and chronic renal failure and chronic
218

and membranous glomerulonephritis. In noting the contrast in their findings with other

recent studies, Calvert et al. (2003) commented that death certificates can be an

incomplete source of information (i.e., missing information may result in false negative

findings). However, they pointed out that, if their study missed a true increase in risk,

one would have to assume that renal diseases and/or silica exposed jobs are much more

likely to be missing from death certificates of those with increased silica exposure

compared to the general population.

Two mortality studies of lead and zinc mine workers in Sardinia, Italy, also failed

to find an increased mortality for urinary tract diseases. Carta et al. (1994) studied

cohorts (n = 906 and 835) from two mines, one with a higher silica content of the dust (n

= 835), over the period 1973 to 1988. Mortality from urinary diseases was not increased

for the combined cohort from the two mines. Data for cohorts from individual mines

were not provided.

No statistically significant increase in mortality from urinary diseases was

observed for silica-exposed women in a study of a cohort of women who appeared to

have worked in the same two mines described above and were followed from 1951 to

1988 (Cocco et al., 1994). Cocco et al. (1994) noted that the average respirable quartz

exposure in the two mines were 0.007 and 0.09 mg/m3, respectively. No increase in

mortality from urinary disease was found for the combined cohort or for cohorts from the

individual mines. There was only one case observed among the cohort from the lowerexposure mine and two cases in the cohort from the higher-exposure mine. The authors

noted that their study had low statistical power.

Several other studies, such as case series, case-control studies, cohort studies

comparing exposed and non-exposed populations, and prevalence studies also support the

finding of an effect of silica exposure on kidney disease. An early case series report

studied morphologic alterations in the kidneys of silicotics. Kolev et al. (1970)

conducted pathological examinations of the kidneys of 45 patients who had died of

advanced silicosis at ages between 45 and 58. These were compared to 40 control

patients who had died of obstructive emphysema and unspecific pneumosclerosis with

cor pulmonale. The kidneys of about 51 percent of the patients who had died of silicosis

displayed glomerular and interstitial lesions that the authors defined as a nonspecific

glomerulonephrosis. None of the kidneys of the controls had these lesions. A lack of

silica particles in the kidneys led the authors to suggest that a direct toxic effect was not

involved. Since chronic lung diseases or conditions cause prolonged hypoxia, which

leads to pulmonary hypertension resulting in cor pulmonale, the lack of effect in the

controls with cor pulmonale argued against a pathological association of the kidney

lesions with the hypoxia existing in advanced cases of silicosis. The authors believed

that autoantibodies against altered tissue components and macrophages might be formed

in the course of silicosis. They thought that the corresponding antigen-antibody

complexes, when reaching the glomeruli, might bring about the described renal lesions.

Osorio et al. (1987) reported on a case of glomerulonephritis in a worker exposed

to silica and seven other case reports from the literature. Their case was a foundry
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coremaker with extensive silica exposure (up to 2.5 times the OSHA PEL was measured

for the coremaker’s job description) but no pulmonary disease, who developed nephrotic

syndrome and renal failure over a three-month period and whose biopsy showed a

proliferative glomerulonephritis. The seven other cases with glomerulonephritis and high

silica exposure included a sandblaster, bricklayer, ceramic painter, ceramic glazer,

foundry worker, tile factory worker, and coal mine driller. Three of the eight cases did

not have clinical silicosis. Chest x-rays were normal and there were no pulmonary

symptoms. For the authors, this suggested that some silica-exposed workers might get

renal disease before chest x-ray changes or pulmonary symptoms were observed, and for

some individuals, renal disease might be the dominant effect.

OSHA reviewed three case-control studies of renal disease. Steenland et al.

(1990) conducted a study of 325 cases of ESRD selected from the Michigan Kidney

Registry. Controls were selected by random-digit dialing in the four urban areas of the

study and pair-matched to cases for age, race, and area of residence. Considered were

history of having ever been exposed to silica and cumulative exposure. Odds ratios were

statistically significantly elevated for exposure to silica overall (OR = 1.67, 95% CI 1.02-

2.74), silica in brick and foundry work (OR = 1.92, 95% CI 1.06-3.46), and silica in

sandblasting (OR = 3.83, 95% CI 0.97-15.19).

According to the authors, the only strongly positive trend of increasing risk with

increased duration of exposure was for silica in sandblasting. The authors reported that

the odds ratio for silica in sandblasting for 2.5 years for 40 hours a week was 2.74 (95%

CI .69-9.97). When the five years preceding the date of diagnosis were excluded, the

odds ratio for exposure to silica increased slightly from 1.67 to 1.81 (95% CI 1.09-3.02)

and the coefficient for cumulative duration of exposure changed from -0.0039 to -0.0004.

The authors concluded that their findings of an elevated risk of ESRD that was associated

with self-reported exposure to silica in foundries, brick manufacturing, and sandblasting

was consistent with other reports of renal disease resulting from acute exposure to silica.

A hospital-based case-control study found an association between silica exposure

and rapidly progressive glomerulonephritis (RPGN) that was positive for antineutrophil

cytoplasmic autoantibodies (ANCA, a marker for the small vessel vasculitides, an

autoimmune disease) (Gregorini et al., 1993). The authors studied 16 patients with

ANCA-positive RPGN who had been admitted to the hospital nephrology department.

The 32 controls were taken from male patients admitted to the department and affected

by nephropathies other than ANCA-positive RPGN. Interviews elicited information on

occupational histories, and silica exposure was assessed by identifying those jobs known

to be associated with silica exposure and by collecting and analyzing data related to “the

sources of silica dust, protection equipment and department features.” A total duration

for silica exposure was estimated for each case and control. Seven of the 16 cases and 1

of the 32 controls were considered definitely exposed to silica dust. The mean duration

of exposure for those considered definitely exposed was 26.3±8.8 years (range 10 to 34

years). For the cases with occupational history of silica exposure, the time to disease

from first exposure ranged from 30 to 39 years (mean 32). Four of the seven cases

definitely exposed to silica had pulmonary silicosis. For the cases and matched controls,
220

the conditional maximum likelihood point estimate of the OR for silica exposure was

14.0 (95% CI 1.7-113.8, p < 0.001). Renal biopsies available in six of the exposed cases

showed a severe crescentic and necrotizing glomerulonephritis not different from those in

unexposed patients. However, histological examination also showed, in three of the six

exposed patients but none of the unexposed, a distinctive glomerular lesion consisting in

peripheral nodular areas of glomerular sclerosis, in addition to the crescentic and

necrotizing glomerulonephritis. The authors concluded that their study shows a strong

relationship between silica exposure and ANCA-positive RPGN and that silica exposure,

therefore, should be considered a risk factor for ANCA-positive RPGN.

Another case-control study demonstrated an association of occupational exposure

to silicon compounds with Wegener granulomatosis with renal involvement. Nuyts et al.

(1995) selected 16 patients from six Belgian renal units. For each patient, two age-, sex-,

and region-matched controls were selected from the general population using lists of

voters (all Belgians 18 years and older). Occupational histories were reconstructed from

interviews and quantitatively scored by an industrial hygienist. Five of the cases had

been employed as bricklayer, stone cutter, in a brickyard, or sandblaster. Two had

worked on metal-turning tables, two as shoemakers and two in animal feed factories.

Exposures of seven cases were to silica or silica-containing dusts such as cement, quartz,

and grain dust. (The authors noted that rice husks may contain up to 20% crystalline

silica.) Statistically significantly increased odds ratios were observed for exposure to

silica (OR = 5, 95% CI 1.4-11.6) or silicon-containing compounds such as grain dust (OR

= 6.5, 95% CI 1.3-13.5). The authors stated that exposure to grain dust resulted in an

almost sevenfold increased risk of developing Wegener granulomatosis.

Two studies examined renal function as measured by excretion of specific highand low-molecular weight proteins and enzymes in silica-exposed workers compared to

workers not exposed to silica. These proteins and markers are used as markers of early

glomerular and tubular disturbances. Ng et al. (1992c) measured urinary excretion of

albumin, α-1-microglobulin (AMG), and β-N-acetyl-glucosaminidase (NAG) in 26 nonsilicotic and one silicotic crushers and grinders currently working in one of three granite

quarries in Singapore and six silicotic workers who had ceased exposure from three to 17

years before the study. The mean duration of exposure of the 33 was 16 years (range 1-

33). Five of the silicotics had silicosis profusion category 1 and the others category 2.

The non-exposed controls were 19 age-matched male hospital ancillary workers and

community volunteers.

Excretion of albumin was statistically significantly increased (p = 0.03, t test) in

the exposed as compared to non-exposed group with geometric means (SD, range) of 9.3

(2.6, 1.6-71.6) and 5.5 (2.0, 1.0-13.0) mg/g creatinine, respectively. Albumin excretion

was raised above the 95th percentile of the non-exposed subjects in 13 (39 percent) of the

exposed workers, compared with 1 (5 percent) of the non-exposed group (p < 0.001 by χ

2

test). Excretion of AMG was also statistically significantly increased (p = 0.002, t test) in

the exposed as compared to non-exposed group with arithmetic means (SD, range) of 7.5

(3.2, 1.6-17.1) and 4.6 (2.7, 1.7-12.0) mg/g creatinine, respectively. Increases for NAG
221

excretion in the exposed as compared to the non-exposed group were not statistically

significant.

In an additional analysis, silicotics were compared to nonsilicotic exposed

workers and non-exposed workers. Statistically significant increased excretion in

silicotics was observed for albumin (p = 0.05), AMG (p = 0.002), and NAG (p = 0.02).

An analysis restricted to workers 40 years and older found similar results (albumin, p =

0.06) (AMG, p = 0.002) (NAG, p = 0.04). These finding on silicotics suggested to the

authors that these functional changes are not reversible upon removal from exposure

given that all but one of the silicotics had not been exposed for many years (from 3 to 17

years before the study). The authors concluded that some degree of irreversible renal

functional disturbance related to lesions in the glomeruli and proximal tubules, likely

arising from prolonged exposure to silica, was demonstrated in seemingly healthy silicaexposed workers. However, the authors felt that further studies were needed to ascertain

whether the urinary alterations observed are of clinical significance in reflecting early and

asymptomatic glomerular or tubular disease in silica-exposed workers.

A similar study was conducted in quarry workers in Spain (Hotz et al., 1995).

The differences were that none of the 86 silica-exposed workers had silicosis, and they

were only exposed for an average of 15.2 months (range 11-20). The 86 controls were

matched for age, smoking status, and body mass index. The workers were also younger

by about fifteen years than those in the Singapore study. The rock in the quarry was

made of quartzite with 90 percent silicon dioxide (SiO2) and some aluminum oxide

(Al2O3) and ferric oxide (Fe2O3). Twenty-five to thirty percent of the silica dust particles

were less than six μm in diameter. The mean silica concentration ranged from 4 to 300

mg/m3.

Urinary excretion of albumin, transferrin, retinol-binding protein (RBP), and

NAG were all statistically significantly increased in exposed as compared to control

workers. The prevalence of values above the reference range followed a similar pattern

but only was statistically significantly elevated for RBP. Urinary silicon (mg/g

creatinine) was also statistically significantly increased in exposed as compared to control

workers (p = 0.0001). However, the authors noted that urinary silicon is only useful as an

indicator of recent exposure and confirmed that exposure was occurring despite the use of

personal protective equipment. The authors concluded that they had observed subclinical

renal effects in nonsilicotic workers after less than two years of exposure to silica. The

authors also concluded that the effects seen in their study may represent the start of a

cascade of degenerative changes, ultimately leading to overt nephropathy and renal

failure.

Boujemaa et al. (1994) conducted a cross-sectional study to examine these early

indicators of renal dysfunction in silicotic workers. The study group consisted of 116

male underground mine workers who had silicosis compensated by the Belgian

Occupational Disease Fund and who had been exposed to silica but whose exposure had

stopped several years earlier. The mean duration of exposure was 14.9 years (range 2 to
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35) and the average time since last exposure was 23.2 years (range 0 to 30). There were

61 age-matched referents from the general population.

The silicotic workers had statistically significantly higher excretion of several

markers, including albumin, RBP, and NAG, than the age-matched controls. However,

the prevalences of subjects with abnormally elevated values did not differ between the

two groups. The markers were also not correlated with duration of exposure or severity

of silicosis. The authors commented that markers of proximal tubule dysfunction

measured in their study (RBP) and by Ng et al. (1992c) (AMG) were comparable, so the

pattern of effects seen in the two studies were identical. Another similarity was seen in

the study of workers who were not currently exposed, confirming the suggestion that

renal alterations associated with silica exposure may be irreversible. Boujemaa et al.

(1994) concluded from their findings that silicosis is associated with infraclinical renal

alterations but also determined that a conclusion that silica caused these alterations could

not be drawn at the present time in the absence of an identified relationship with length of

exposure or severity of silicosis.

The prevalence of kidney disease was studied in a cohort of individuals with

silicosis by Rosenman et al. (2000). Silicotic patients were identified from a mandatory

reporting system in Michigan. Reports came from hospitals, physicians, the state

workers’ compensation bureau, and from death certificates. Each report was followed up

with a telephone interview questionnaire to the case or next of kin, gathering historical

information on lifetime work, cigarette smoking, medical care, medication, and

symptoms limited to respiratory conditions. Creatinine records were abstracted from all

medical records with a mention of kidney disease. By the time the reports were received,

most of the individuals were no longer exposed to silica. The study reviewed 583

confirmed cases of silicosis reported from 1985 to 1995. Seventy-nine percent had had

their exposure to silica in a foundry. Progressive massive fibrosis was reported for

twenty-nine percent. Seventy-four percent had had more than twenty years of exposure

to silica. Only 283 of the reports had medical records with creatinine levels.

Silicotics were statistically significantly more likely to have a serum creatinine

level greater than 1.5 mg/dl (considered elevated) within age and race strata than results

in the general population, based on the third National Health and Nutrition Examination

Survey data. Age-adjusted relative risks were 2.49 (95% CI 1.72-361) for whites and

1.68 (95% CI 1.18-2.40) for African-Americans. Presence of kidney disease or elevated

creatinine levels were not associated with increased profusion of silicosis or increased

duration of exposure to silica either in the overall group or by age- and race-specific

strata. The authors concluded that their findings confirmed an association between

kidney disease and exposure to silica and that chronic kidney disease should be

considered a potential complication in patients with silicosis.

Steenland et al. (2002b) conducted a study to determine the incidence of endstage renal disease (ESRD) among workers with silicosis. The study population of 1,328

workers with silicosis and adequate work history information was drawn from the

silicosis surveillance systems of Michigan (discussed above) and two other states (New
223

Jersey and Ohio). The cohort was then linked with the ESRD register as discussed by

Calvert et al. (1997). The workplaces or jobs of the cases were distributed as follows: in

Michigan, foundries (79 percent) and sandblasting (26 percent); in New Jersey, vitreous

plumbing fixtures (30 percent), foundries (21 percent), ceramic tile (11 percent), sand and

gravel mining (11 percent), iron ore mining (10 percent), and porcelain electrical supplies

(10 percent); and in Ohio, foundries (45 percent), production of stone/clay/concrete (23

percent), and sandblasting (22 percent). Data describing severity of silicosis were

available only for Michigan, where 69 percent of cases had simple silicosis, 25 percent

exhibited progressive massive fibrosis, and 3 percent had normal chest x-ray films but

were identified as silicotics from autopsy evidence. Exposure measurements were

available in 48 workplaces in Michigan where exposures exceeded 0.05 mg/m3in 63

percent of the workplaces, and in 29 workplaces in Ohio where exposures exceeded 0.05

mg/m3in 69 percent. The overall cohort had an average of 27 years of exposure.

However, there were relatively few person-years at risk (23,945) because person-years

could only be accumulated from the ESRD registry beginning in 1977. None of the

analyses performed yielded an increased SIR for ESRD among the silicotics, including an

analysis of glomerular nephropathy incidence, an analysis of trends by duration of

exposure, and analyses that varied the start date for accumulating person-years at risk

(e.g., using the date of entry into the silicosis register vs. the date of first exposure to

silica).

The authors concluded that, while their results did not show that silicotic patients

have an excess of ESRD, the results did suggest an excess of glomerular ESRD (a twofold excess was found but it was not statistically significant). The authors did allow that

their analyses were limited by the small numbers and possible selection biases. For

example, some subjects with silicosis may have died due to their renal disease before

being entered into silicosis registers.

I.E.2. Autoimmune Effects.

Several cases of autoimmune diseases have been reported in employees engaged

in occupations known to have high silica exposures. The most commonly reported

autoimmune diseases are scleroderma and rheumatoid arthritis. In 1914, Bramwell

described scleroderma in five masons, one coppersmith, and one coalminer (Bramwell,

1914). Although he attributed the scleroderma to use of hand tools in cold weather, it is

interesting that these cases manifested in workers of occupations with known silica

exposure. Erasmus (1957) described 17 cases of scleroderma in European underground

miners who were applying for financial benefits due to the onset of silicosis. All cases

exhibited skin lesions and pulmonary symptoms due to scleroderma.

Cutaneous silica granuloma was reported in a 57-year-old stonemason (Mowry et

al., 1991). The patient had reported that he used a rock saw and often returned home at

the end of each workday with lacerated, stinging, and bleeding forearms. A biopsy

specimen from one of his lesions showed fibrosis and innumerable crystalline structures.

Mulloy (2003) reported a case of systemic vasculitis in a former Department of Energy

employee. The employee was assigned to two jobs in which silica exposure was likely.
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However, throughout his career, he held many other positions which exposed him to

other hazardous chemicals such as solvents, heavy metals, beryllium, depleted uranium,

and ionizing radiation.

Twenty-four cases of scleroderma were reported among South African gold

miners between 1981 and 1988 (Cowie and Dansey, 1990). The incidence of

scleroderma was 25 times higher among silica-exposed miners than in the general

population.

Rodnan et al. (1967) described 60 cases of scleroderma in men of various

occupations, of which, 26 were in occupations known to have high silica exposures.

Onset of symptoms among these cases ranged from 5 years to 41 years. This study also

matched these cases with controls and found the frequency of silica exposure was higher

among cases than controls (p < 0.01). However, actual exposures were not reported in

this study. Finally, this study also estimated the prevalence of scleroderma to be

17/100,000 among coal miner hospital discharges compared to 6/100,000 in non-miner

hospital discharges among males.

Klockars et al. (1987) conducted a retrospective study examining the incidence

and prevalence of subjects awarded pensions and benefits due to rheumatoid arthritis

among Finnish granite workers. The study group comprised 1,026 Finnish granite

workers hired in quarries for at least three months between 1940 and 1971 and followed

until 1981. New disability pensions awarded between 1969 and 1981 were studied and

prevalence calculated at the end of 1981. Lifetime occupational histories were obtained

for surviving participants or next of kin (for deceased participants) via questionnaire.

Representative silica exposures were used from a separate study of Finnish quarries

completed in 1970 to 1972 by the Finnish Institute of Occupational Health. Using data

from the Institute of Occupational Health from 1970 to 1972, exposures to silica,

vibration, and noise were determined. Exposures to silica ranged from 0.2 to 4.9 mg/m3

with a geometric mean of 0.82 mg/m3.

The results showed that 10 subjects received compensation for rheumatoid

arthritis, compared to an expected 1.6 (p < 0.001). The number receiving free medicines

was 19, compared to an expected 7.5 (p < 0.001). The study concludes that there is an

association between silica exposure and rheumatoid arthritis.

Brown et al. (1997) examined the mortality of persons hospitalized for silicosis in

Sweden from 1965 through 1983 and in Denmark from 1977 through 1989. Subjects

with incomplete medical records or confirmed cases of asbestosis were excluded from the

study. Subjects were followed, beginning with the first hospitalization for silicosis and

ending either with the subject’s death, emigration, or the end of the study (1983 for

Sweden and 1989 for Denmark).

During the follow-up, six deaths due to autoimmune diseases were recorded:

three with rheumatoid arthritis, two with systemic lupus erythematosus, and one with

Sjogren’s syndrome. The SMR for these causes of death combined compared to the
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general population was reported as 5.9 (95% CI 2.2 - 2.9). Although the temporal

relationship between the diagnosis of silicosis and onset of autoimmune diseases cannot

be determined from this study, it nevertheless demonstrates an increased mortality rate

from autoimmune disease among silicotic men compared to the general public.

Another mortality study (Calvert et al., 2003) showed that those with silicosis

were more likely to have rheumatoid arthritis than those without silicosis (mortality odds

ratio 3.75, 95% CI 1.92-7.32). This study also showed an association between

rheumatoid arthritis and silica exposure (mortality odds ratio 1.19, 95% CI 1.12-1.25).

However, when exposures were stratified into medium, high, and super high exposures,

no trend or dose-response was observed. The study design is discussed in more detail in

Section C (Lung and Other Cancers).

A recent preliminary study provides evidence suggesting a mechanistic

association between silica exposure and autoimmune disease. Carlsten et al. (2007)

conducted a cross-sectional study of 16 mason apprentices and 26 electrician apprentices.

Although self-reported, the mason apprentices had significantly higher silica exposures (p

< 0.05) than the electrician apprentices. This study focused on differences in key

cytokines and lymphocyte cell surface makers and found statistically significantly (p <

0.05) higher levels of key cytokines, and lower CD25+ and CD69+ lymphocyte cell

surface markers in the masons than in the electricians. The author concluded that since

increased levels of key cytokines and lower lymphocyte cell surface markers can lead to

autoimmune diseases, those exposed to silica may be at risk for such diseases. The one

major limitation of this study was the inability to fully characterize silica exposures.

In an earlier study, Haustein et al. (1990) reviewed scleroderma in 120 patients in

East Germany between 1981 and 1988. The study revealed the presence of silica

particles between 1 and 20μm in diameter lodged in the skin of heavily exposed areas.

(The authors noted that silica is chemically inert, cannot be digested, and remains in the

tissue.) The authors explained that because silica is toxic to macrophages, the

macrophages die and silica is again exposed for ingestion and the phagocytotic process.

Fibroblasts are permanently stimulated by lymphokines and monokines, increasing

immune activity. This is believed to be the mechanism for development of silica-induced

scleroderma.

The majority of studies conducted that have examined the association between

silica exposure and autoimmune diseases are retrospective in nature. Major limitations of

these studies include the lack of detailed exposure characterization and the lack of a

demonstrated temporal relationship between silica exposure or silicosis and the onset of

autoimmune diseases. However, most studies do provide evidence of an association

between the presence of silicosis and autoimmune diseases. This suggests an association

between exposure to silica and autoimmune disease.

A recent case-control study was conducted to examine the association between

silica exposure and rheumatoid arthritis in Sweden (Stolt et al., 2005). From hospitalbased and private rheumatology units, 276 male cases of rheumatoid arthritis diagnosed
226

between 1996 and 2001 were identified that meet the diagnostic criteria set by the

American College of Rheumatology. Cases were selected from a larger study population

in a specific geographical area. Matching for age, sex, and residential area, 276 controls

were selected from the larger study population. Silica exposure was assigned via

questionnaire for both cases and controls.

Upon analysis, the study showed that the odds of having rheumatoid arthritis were

2.2 times higher (95% CI 1.2-3.9) for those exposed to silica (adjusting for age and

smoking). This odds ratio increased to 2.7 (95% CI = 1.2-5.8) when analyzing subjects

from 50 to 70 years-old separately. No statistically significant increase in risk was seen

in 18 to 49 year-old men. Based on job categories, the odds ratio for rock drilling and

stone crushing was reported to be 3.0 (95% CI = 1.2-7.6). The authors conceded that

misclassification of silica exposure could have occurred since exposures were ascertained

via questionnaire. In addition, since vibration is also a hazard associated with rock

drilling and stone crushing, it is unclear what effect, if any, vibration exposure had on

developing rheumatoid arthritis.

Haustein and Anderegg (1998) sent questionnaires to 298 dermatology clinics

between 1980 and 1981 in the former East Germany, requesting occupational information

for all cases of scleroderma and exposures to silica of greater than six months duration.

A total of 454 females and 137 males were registered for the study and the assessment

period ran from 1980 to 1997.

The reported incidence and prevalence of scleroderma in the general population

were 11.7 per million and 53.7 per million respectively (population of 1.4 million).

Although no information was given regarding the determination of silica exposures, the

study reported that relative risk for developing scleroderma was increased 12-fold for

silicosis patients and 5.7-fold for silica-exposed persons compared to the “healthy”

population over 40 years of age. The study also found the average latency period

between the beginning of exposure and onset of scleroderma to be 24.3 years in those

cases that did not have silicosis. The majority of cases with both silicosis and

scleroderma found that silicosis preceded the onset of scleroderma.

Rosenman and Zhu (1995) examined the association between pneumoconiosis

and connective tissue disease among men and women using Michigan hospital discharge

data between 1990 and 1991. From the discharge data, 155 cases of silicosis in men and

5 cases of silicosis in women were identified for review and analysis. Anyone under the

age of 20 and diagnosed with cystic fibrosis was excluded from the study. A

standardized incidence ratio (SIR) was calculated comparing actual cases to expected

cases.

The study yielded a significant SIR of 3.2 (95% CI 1.1-9.4) for rheumatoid

arthritis in silicotic men. The association was not statistically significant among women.

This study does not account for smoking nor does it specify if silicosis or rheumatoid

arthritis was first diagnosed among the cases. However, these data do suggest a higher

incidence of rheumatoid arthritis among silicotic men.
227

In a later study, Rosenman et al. (1999) showed an association between silicosis

and rheumatoid arthritis in men. This retrospective cohort study reviewed medical

records and questionnaires from 583 confirmed silicosis cases reported to the Michigan

state surveillance system between 1987 and 1995. Rheumatoid arthritis was self-reported

via questionnaire and was verified by medical records when available.

The results showed a relative risk of 2.73 (95% CI 1.75-4.06) for rheumatoid

arthritis prevalence among silicotics as compared to the general population. Although

not statistically significant, the study reported a relative risk of 15.65 (95% CI = 0.21-

87.03) for scleroderma prevalence in silicotics compared to the general population and a

relative risk of 11.37 (95% CI = 0.15-63.23) for systemic lupus erythematosus. Although

the onset of either silicosis or the autoimmune disease with respect to each other was not

discussed, the study highlights the importance of considering connective tissue disease as

an additional complication when evaluating patients for silicosis.

Sluis-Cremer et al. (1985, 1986) conducted two case-control studies examining

the association between silica exposure, silicosis, rheumatoid arthritis and systemic

sclerosis in South African gold miners. In the first study (Sluis-Cremer et al., 1985), 79

cases of systemic sclerosis were selected from the Medical Bureau for Occupational

Diseases (MBOD), South Africa through 1984. Controls were matched and selected

from miners attending MBOD examinations between 1970 and 1971. To estimate the

silica exposures, the authors reviewed occupational records, multiplied the number of

shifts worked by a weighting factor proportional to the silica dust concentration of that

occupation. Weighting factors were highest for underground high dust exposure,

followed by underground low-dust exposure, and finally, all dusty surface operations.

No other information on exposure characterization was available.

Results showed no statistical significance in the number of silicosis cases among

cases of systemic sclerosis and controls when controlled for cumulative silica exposure.

Although no odds ratios were reported, the study did report that cases of systemic

sclerosis had significantly higher life time exposures to crystalline silica. The authors

also reported that the difference in cumulative silica dust exposures was due to intensity

of exposure rather than duration of exposure. The authors believed that intensity of

exposure may have been a more important risk factor than duration of exposure.

In a second study (Sluis-Cremer et al., 1986), the association between silicosis

and rheumatoid arthritis was examined. From the same database of patients, 91 definite

and 66 probable cases of rheumatoid arthritis were identified. Cases were selected and

matched by year of birth with controls not having rheumatoid arthritis. Medical records

were reviewed to identify all subjects with silicosis. Silica exposures were calculated in

the same way as in the previous study (Sluis-Cremer et al., 1985). Definite and probable

cases of rheumatoid arthritis combined were found to be more likely to also have silicosis

(OR = 2.84, 95% CI 1.36-4.32). When definite and probable cases were analyzed

separately, only definite cases of rheumatoid arthritis were more likely to also have

silicosis (OR = 3.79, 95% CI = 1.72-8.36). The authors concluded that miners with
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rheumatoid arthritis and exposed to silica were more likely to develop silicosis than

miners without rheumatoid arthritis. This study found no significant differences in silica

exposures between cases and controls, but the authors believe that if an association

between exposure to silica and the development of rheumatoid arthritis exists, it is

unlikely to be a strong one.

Walsh (1997) evaluated scleroderma mortality rates among the general population

and those exposed to silica between 1985 and 1992. The results indicated that the

number of observed deaths (128) due to scleroderma among men exposed to silica was no

different than that expected in the general population (ratio = 1.0, 95% CI = 0.6-1.2). No

other information was provided in the abstract from this study.

In 1995, Bovenzi et al. conducted a case-referent study examining the association

between chemical exposures and scleroderma. Five hundred twenty seven cases of

musculoskeletal disorders or connective tissue disease were selected from hospitals from

1976 to 1991. Clinical records were verified for diagnoses. Two age- and gendermatched controls were selected from patients who were discharged from the same

hospital the same day as the cases but who were not affected with either disease.

Interviews were conducted to determine exposure to various chemicals, including

solvents and silica. Those indicating exposure durations of less than six months were

excluded from the study.

Although not statistically significant, the odds ratio of 5.2 (95% CI 0.48-74.1)

indicated that men with scleroderma were more likely to have been exposed to silica.

One possible explanation for this data is the small sample size; of the original 527 cases,

only 21 cases of scleroderma (16 women and 5 men) were selected for analysis with 42

matched controls.

I.E.3. Preliminary Conclusions for Renal and Autoimmune Effects.

Overall, there is substantial evidence suggesting an association between exposure

to crystalline silica and increased risks of renal and autoimmune diseases. In addition to

a number of case reports, epidemiologic studies have found statistically significant

associations between occupational exposure to silica dust and chronic renal disease (e.g.,

Calvert et al., 1997), subclinical renal changes (e.g., Ng et al., 1992c), end-stage renal

disease morbidity (e.g., Steenland et al., 1990), chronic renal disease mortality (Steenland

et al., 2001b, 2002a), and Wegener’s granulomatosis (Nuyts et al., 1995). In other

findings, silica-exposed individuals, both with and without silicosis, had an increased

prevalence of abnormal renal function (Hotz et al., 1995), and renal effects have been

reported to persist after cessation of silica exposure (Ng et al., 1992c). Possible

mechanisms suggested for silica-induced renal disease include a direct toxic effect on the

kidney, deposition in the kidney of immune complexes (IgA) following silica-related

pulmonary inflammation, or an autoimmune mechanism (Calvert et al., 1997; Gregorini

et al., 1993).
229

An analysis of renal disease mortality and silica exposure showed strong

exposure-response trends for both underlying and multiple cause mortality (Steenland et

al., 2002a). Steenland (2005b) estimated excess lifetime risks (age 75) after 45 years

exposure to 0.1 mg/m3respirable crystalline silica to be 5.1 percent (3.3-7.3) for endstage renal disease incidence, based on 23 cases (Steenland et al., 2001b), and 1.8 percent

(0.8-9.7) for kidney disease mortality (underlying), based on 51 deaths (Steenland et al.,

2002a). OSHA believes that these findings are credible, as they are based on large

numbers of workers and the exposure information has been validated. However, there

are considerably less data, and thus the findings based on them are less robust, than what

is available for silicosis mortality or lung cancer mortality. Nevertheless, OSHA

preliminarily concludes that the underlying data are sufficient to provide useful estimates

of risk and has included the Steenland et al. (2002a) analysis in its Preliminary

Quantitative Risk Assessment.

Several studies of different designs, including case series, cohort, registry linkage

and case-control, conducted in a variety of exposed groups suggest an association

between silica exposure and increased risk of systemic autoimmune disease (Parks et al.,

1999). Studies have found that the most common autoimmune diseases associated with

silica exposure are scleroderma (e.g., Sluis-Cremer et al., 1985); rheumatoid arthritis (e.g.

Klockars et al., 1987; Rosenman and Zhu, 1995); and systemic lupus erythematosus (e.g.,

Brown et al., 1997). Mechanisms suggested for silica-related autoimmune disease

include an adjuvant effect of silica (Parks et al., 1999), activation of the immune system

by the fibrogenic proteins and growth factors released as a result of the interaction of

silica particles with macrophages (e.g., Haustein and Anderegg, 1998), and a direct local

effect of non-respirable silica particles penetrating the skin and producing scleroderma

(Green and Vallyathan, 1996). However, there are no quantitative exposure-response

data for the association between exposure to silica and autoimmune diseases, making

quantitative risks assessments for these diseases not possible at this time.

Therefore, OSHA preliminarily concludes that there is substantial evidence that

silica exposure increases the risks of renal and autoimmune disease. The positive and

monotonic exposure-response trends demonstrated for silica exposure and renal disease

risk more strongly suggest a causal link. There are two studies of renal disease that

provide quantitative exposure-response data. There are no quantitative exposureresponse data with regard to autoimmune diseases. OSHA preliminarily concludes that

the available exposure-response data on silica exposure and renal disease is sufficient to

allow for quantitative estimates of risk.

I.F. Physical Factors That May Influence Toxicity of Crystalline Silica.

OSHA has preliminarily concluded that epidemiologic studies provide ample

evidence that exposure to respirable crystalline silica increases the risk of lung cancer

among workers (see Section V.C. above). OSHA has also preliminarily concluded that it

is established that exposure to respirable crystalline silica causes silicosis. IARC (1997)

has also determined that “crystalline silica inhaled in the form of quartz or cristobalite

from occupational sources is carcinogenic to humans.” In making this determination, the
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IARC Working Group noted that “carcinogenicity was not detected in all industrial

circumstances studied.” The Working Group also stated that “carcinogenicity may be

dependent on inherent characteristics of the crystalline silica or on external factors

affecting its biological activity or distribution of its polymorphs.” Thus, while IARC has

determined that cristobalite and quartz are both carcinogenic to humans, there has been

considerable discussion among researchers as to whether the toxicologic potency of

crystalline silica might vary depending on crystalline structure or surface chemistry of the

particles.

Much research has been conducted to investigate the influence of various physical

factors on the toxicologic potency of crystalline silica. Such factors include crystal

polymorphism, the age of fractured surfaces of the crystal particle, the presence of

impurities on particle surfaces, and coating of the particle. These factors may vary

among different workplace settings suggesting that the health risk to workers exposed to

a given level of respirable crystalline silica may not be equivalent in different work

environments. These findings are discussed in this section.

I.F.1. Mechanism of Action.

Physical characteristics relevant to the toxicity of crystalline silica primarily relate

to the surface of silica particles, which researchers believe play an important role in the

mechanism by which silica causes lung damage. Thus, any factor that influences or

modifies these surface characteristics may alter the toxicity of silica by affecting the

mechanistic process. There have been many studies that have examined possible

mechanisms of action for silica, and these studies are discussed in this section. First, the

overall proposed basic mechanism of action will be described. This will be followed by a

discussion of studies which have examined in further detail, and at the cellular and

molecular level, specific parts of the process by which silica is proposed to cause silicosis

and cancer.

Before a discussion of the possible mechanisms by which a silica particle entering

the lungs could cause lung damage, a brief review of the pharmacokinetics of silica

deposition and clearance will be presented. IARC (1997) reviewed studies on the

pharmacokinetics of crystalline silica in humans and animals. However, at the time of

the IARC review there were only a few studies that had investigated retention of

crystalline silica particles in the human lung. Although these studies described finding

quartz particles in the bronchoalveolar macrophages and sputum of silicotic patients,

there was generally no correlation between lung quartz content and severity of

pathological changes in the lung. For example, one study of hard-rock miners with 14-36

years of exposure reported lung silica burdens of 25-264 mg per single lung (Verma et

al., 1982). The miners had variable amounts of pathological response that was not

correlated with lung burden.

These early studies also found that the dissolution of quartz did not appear to

contribute substantially to its clearance or to changes in its biological activity. In fact, the

quartz component of dust residing in the lung was generally found to be greater than that
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of the dust in the air, suggesting that crystalline silica was not cleared as well as the other

components of the dust (IARC, 1997). A study in which silica particles were counted in

the bronchoalveolar fluid of people occupationally exposed to silica (Pairon et al., 1994),

further confirmed that silica is one of the most persistent mineral particles in the lung.

It is difficult to rely on animal studies to describe the pharmacokinetics of

crystalline silica in humans because rodents are obligate nasal breathers and have a

different pattern (cycle period and tidal volume) of breathing. Also, there are differences

between species in terms of quartz clearance rates with the clearance rates of humans

being slower than that of rats and hamsters. Nonetheless, animal studies reviewed by

IARC (1997) have demonstrated that clearance from the lung periphery is slow and

incomplete, resulting in a captured fraction of silica that is never cleared. In rats, it was

observed that quartz particles that had deposited on the terminal bronchiolar and alveolar

duct surfaces had moved into epithelial cells and to the interstitium. The quartz then

moved to the lymph nodes, where accumulation continued up to 150 days after exposure

has stopped. Particle removal via macrophages was found to be severely inhibited due to

a direct toxic effect of silica on macrophages.

Since the IARC review, Kuempel et al. (2001) have developed a

toxicokinetic/dynamic model to predict the relationship between occupational quartz

exposure and lung burden. The researchers used the toxicokinetic/dynamic model fit to

lung burden and pulmonary response data from a subchronic inhalation study in rats to

estimate the minimum critical quartz burden associated with reduced pulmonary

clearance and increased neutrophilic inflammation in humans. The minimum critical

quartz lung burden estimated by the model that would be associated with reduced

pulmonary clearance and increased neutrophil inflammation in humans was 0.39 mg/g

lung tissue. Although the model was originally developed for respirable coal mine dust

(with approximately five percent respirable quartz), it was extended to describe quartz

clearance and retention in the lungs. In the study to evaluate the model, lung burden of

quartz was measured at autopsy of the coal miners. The model predicted a lung burden

1.7 times greater than the observed quartz lung burden, but this was within the confidence

interval. Thus, the model was used to predict the human internal dose (lung and lymph

node quartz burdens, at age 75 years, following a 45-year working lifetime, beginning at

age 20 years, plus 10 years retirement) associated with exposure to a given airborne

concentration of respirable silica. The model was also used to predict the average quartz

concentration associated with a given internal dose. The average exposure concentration

over a 45-year working lifetime, predicted from the model to be associated with the

critical quartz lung burden (0.39 mg/g) associated with reduced pulmonary clearance and

increased neutrophilic inflammation was 0.036 mg/m3. The lung burdens associated with

exposure concentrations of 0.05 and 0.1 mg/m3 were 0.54 and 1.08 mg/g, respectively.

This lung dosimetry model was also used by the authors to estimate quartz lung

burdens in a study of early pulmonary inflammatory responses in coal miners (Kuempel

et al., 2003). The miners were exposed to a mean respirable crystalline silica (quartz)

concentration of 0.046 (± 0.029) mg/m3. The mean years working in mining was 16.7 (±

4.8). The model predictions of quartz lung burden were evaluated using data available on
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quartz mass recovered from the lungs of two individuals who volunteered for whole lung

lavage (WLL). The observed lung quartz burdens of the two were consistent with the

predictions of the lung dosimetry model (0.46 observed vs 0.66 predicted). The authors

suggested that, since quartz may be sequestered in the lung (e.g. in granulomatous lesions

in the alveolar lumen or in the interstitium), the total lung burden is likely to be higher

than that lavageable by WLL and that this was consistent with the somewhat higher

predictions of the model. They also noted that the dosimetry model assumes very slow

alveolar clearance, such that nearly all the quartz deposited in the deep lung is predicted

to be retained in the alveoli, or in the interstitium, or transferred to the lung-associated

lymph nodes. The actual and predicted lung burdens could also differ because particle

deposition and clearance could differ among individuals and thus differ from the average

values assumed in the models. Also, uncertainties in exposure estimates could account

for the differences from predicted to actual lung burdens. The authors concluded that,

given these issues, the lung dosimetry model seemed to provide adequate predictions of

lung burdens associated with exposure concentrations. Cumulative exposure to or

estimated lung burden of respirable quartz was a highly statistically significant predictor

of an inflammatory response, as measured by increased polymorphonuclear leukocyte

(PMN) count in bronchoalveolar lavage fluid. Estimated quartz lung burden was a highly

statistically significant predictor of radiographic category of small opacities (p < 0.0001).

Both PMN count and estimated quartz lung burden were statistically significantly

predictive of radiographic category in a model with both covariates (p-values < 0.04).

The statistically significant relationship between estimated quartz lung-burden and early

radiographic categories (including 0/1 and 1/0) suggested to the authors that these

changes represent early stages of pneumonconiosis. The authors pointed out that these

miners had relatively low working lifetime dust exposures, having worked on average 17

years and almost entirely under U.S exposure limits for coal and quartz. Even under

these conditions, some showed evidence of early pulmonary response to the inhaled

particles, including inflammation and radiographic small opacities.

It has been proposed that silicosis results from a cycle of cell damage, oxidant

generation, inflammation, scarring, and fibrosis (Brown and Donaldson, 1996;

Castranova, 2004; Fubini et al., 2004; Nolan et al., 1981; Shi et al., 1989, 1998). A silica

particle entering the lung could cause lung damage by three major mechanisms. One

mechanism is that silica could cause direct damage to lung cells due to its unique surface

properties. Silanol groups are present on the surface of silica particles. Hydrogen from

silanol groups forms bonds with oxygen and nitrogen groups in biological membranes,

resulting in the loss of membrane integrity, lysosomal enzyme leakage, tissue injury, and

lung scarring. Silica also has reactive sites on its surface consisting of silicon-based free

radicals. When a silica particle is fractured, siloxyl radicals form on the fracture plane.

These free radicals react with aqueous (water-based) constituents in the lung, generating

reactive oxygen species, or ROS, that can react with and damage cellular constituents

such as DNA, proteins, lipids, and carbohydrates. It is hypothesized that cellular

response, and particularly macrophage activation and death, is mediated by strong

interactions between reactive sites on the particle surface and cell membrane components

(Brown and Donaldson, 1996; Castranova, 2004; Fubini et al., 2004; Nolan et al., 1981;

Shi et al., 1989, 1998).
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The second basic mechanism for silica-induced lung damage is the activation or

stimulation, by silica particles, of alveolar macrophages (after phagocytosis) and/or

alveolar epithelial cells leading to (1) release of cytotoxic enzymes, ROS, reactive

nitrogen species (RNS), inflammatory cytokines, and chemokines, (2) eventual cell death

with the release of the silica particle, and (3) the recruitment and activation of

polymorphonuclear leukocytes (PMN) and additional alveolar macrophages. The

elevated production of ROS/RNS would result in oxidative stress and lung injury that

stimulates alveolar macrophages and/or alveolar epithelial cells to produce growth factors

and fibrogenic mediators, resulting in fibroblast activation and pulmonary fibrosis.

Basically, a continuous ingestion-reingestion cycle, with cell activation and death, is

established. The prolonged recruitment of macrophages and PMN causes a persistent

inflammation, regarded as the primary step in the development of silicosis. ROS

generated from silica particles directly or by stimulated cells that may damage the lung

epithelia may also play a role in silica-induced DNA damage or cell proliferation

contributing to carcinogenesis. The third basic mechanism involves negative surface

charge as a significant contributor to the cytotoxicity of silica. At pH 7.4, 1 in 30 of the

silanol (SiOH) groups on the silica surface exist as SiO-. Contact with the negative

surface charge on the silica surface has been proposed to cause lysis of cell membranes.

Binding of some metal ions (Al+3, Fe+3, Zn+3) to ionized silanol groups on the quartz

surface has been shown to neutralize this surface charge and decrease toxicity by

interfering with the interaction between quartz particles and components of the cell

membranes (Brown and Donaldson, 1996; Castranova, 2004; Fubini et al., 2004; Nolan et

al., 1981; Shi et al., 1989, 1998).

Additional proposed mechanisms involved in silica-induced carcinogenesis

include direct DNA damage, inhibition of tumor suppressor gene p53, loss of cell cycle

regulation, stimulation of growth factors, and production of oncogenes. In rat models of

particle-induced lung cancer, hyperplasia of alveolar type II epithelial cells has been

viewed as a precursor to metaplasia and tumor formation (Brown and Donaldson, 1996;

Castranova, 2004; Fubini et al., 2004; Nolan et al., 1981; Shi et al., 1989, 1998).

Castranova (2004) has reviewed the studies examining components of the

proposed mechanisms by which silica exposure leads to silicosis and cancer and has

summarized the findings to arrive at a description of the proposed mechanistic process.

The discussion that follows is derived from this review, unless otherwise noted.

As described above, the first step in the process involves the action of the ROS

that either occur on the surface of silica or that are generated by the activation of

macrophages upon phagocytosis of the silica particle. These ROS cause the activation of

nuclear factor κB (NF-κB), a transcription factor that controls the gene expression of

chemokines, cytokines, adhesion molecules, and growth factors. Before it is activated,

NF-κB is in the cytoplasm as an inactive form bound to an inhibitory protein (IκB). NFκB is activated when IκB is phosphorylated. Silica has been shown to induce the

phosphorylation of IκB and thus the activation of NF-κB. Both the phosphorylation and

activation are blocked by antioxidants, suggesting that silica-induced oxidants activate
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phosphorylation of IκB. It has also been demonstrated that IκB is phosphorylated by

protein tyrosine kinase (PTK), and that PTK inhibitors block the silica-induced

phosphorylation of IκB and the activation of NF-κB. Thus, silica-induced oxidants

activate phosphorylation of IκB by PTK, which results in NF-κB activation.

Silica also induces the activity of phosphoinositide 3-kinase (PI3-kinase) in

macrophages. This activation was inhibited by antioxidants, suggesting to the authors

that ROS are involved. Also, the inhibition of PI3-kinase partially inhibited the silicainduced activation of NF-κB, suggesting that PI3-kinase is involved. Thus, crystalline

silica particles can activate NF-κB by two routes: (1) by inducing phosphorylation of IκB,

which then activates NF-κB; and (2) by inducing P13 kinase, which appears to have a

role in NF-κB activation. After activation, NF-κB translocates to the nucleus where it

binds to gene promoters on DNA. This binding activates transcription of mRNA, which

induces translational production of chemokines, cytokines, and growth factors.

Tumor necrosis factor-α (TNF-α) is a cytokine that is thought to be a key

mediator in the pathogenesis of silicosis, in particular in silica-induced inflammation and

fibrosis. A direct relationship has been demonstrated between silica-induced production

of TNF-α by alveolar macrophages and infiltration of inflammatory cells into the lungs

(Driscoll and Guthrie, 1997). Also, mice that have been immunized with antibody to

TNF-α have an attenuated increase in lung chemokine mRNA expression and a markedly

reduced inflammatory response to silica exposure (Driscoll and Guthrie, 1997). The

translational production of TNF-α is activated by NF-κB. It has been shown that an

inhibitor of NF-κB translocation to the nucleus can decrease NF-κB binding to DNA,

NF-κB activation of the TNF-α gene promoter, and TNF-α production. Nitric oxide,

produced by macrophages upon stimulation by silica, may also play a role in the

activation of NF-κB, and thus TNF-α. In silica-exposed mice lacking the gene for nitric

oxide production, there was a decrease in the amount of TNF-α produced as well as a

decrease in histological evidence of silica-induced lung damage and inflammation

(Srivastava et al, 2002; Zeidler et al., 2004). The release of TNF-α appears to occur at

non-cytotoxic doses of silica. This suggests that the activation of cells to produce these

factors is as important as, or possibly more important than, direct cytotoxicity in the

response to silica (Driscoll and Guthrie, 1997).

TNF-α itself does not act directly to attract inflammatory cells. Inflammatory

cells are attracted by chemotactic cytokines called chemokines. The infiltration of

inflammatory cells that results from TNF-α production appears to be related to the

production of macrophage inflammatory protein (MIP-2), which is a chemokine for

neutrophils. Silica exposure of rats has been shown to increase lung expression of MIP-2

as well as MIP-1α, which is a chemokine for neutrophils, macrophages, and lymphocytes

(Driscoll and Guthrie, 1997). Treatment with an antibody to TNF-α has been shown to

decrease MIP-2 production, inflammation, and the resulting pulmonary fibrosis. An

experiment in which rats were exposed to silica by intratracheal instillation demonstrated

an association between silica-induced induction of NF-κB, neutrophil recruitment, and

MIP-2 production. According to Driscoll and Guthrie (1997), TNF-α (in general, not

necessarily when it is a result of silica exposure) induces a number of processes that
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contribute to inflammatory and immune responses including expression of adhesion

molecules on endothelial cells, production of other chemokines such as interleukin-8 (IL8) and monocyte chemotactic protein-1 (MCP-1), production of ROS by phagocytic cells,

arachidonic acid metabolism (i.e., prostaglandin E2, prostacyclin), and hepatic acute

phase response.

The activation of NF-κB has also been associated with an exposure-dependent

increase in production of the cytokine interleukin-1 (IL-1) by the bronchoalveolar cells of

rats exposed by inhalation to silica. IL-1 appears to also play an important role in the

pathogenesis of silicosis. IL-1 has been demonstrated to affect inflammation in the lung

by stimulating the production of chemokines and adhesion molecules (which allow for

adhesion of neutrophils to vascular endothelial cells). Also, an experiment was

conducted in which mice that did not have functional IL-1 (IL-1 knockout) were exposed

to silica. At 1, 6, and 12 weeks post-exposure, the number and size of granulomas were

dramatically decreased compared to normal mice (Srivastava et al., 2002).

Other chemotactic or inflammatory factors are also thought to influence

inflammatory cell recruitment in response to silica exposure. These factors are as

follows, with the cellular target in parentheses: leukotriene B4 (neutrophils), platelet

activating factor (neutrophils, monocytes), complement C5a (neutrophils, monocytes)

and transforming growth factor-β (monocytes) (Driscoll and Guthrie, 1997).

As discussed in Section V.B. above, epidemiological studies have shown that

silicosis can develop or progress even after exposure to silica dust has ended. Porter et al.

(2004, 2006) and Scabilloni et al. (2005) have examined the progression of lung

inflammation and damage in rats after the cessation of silica exposure. Rats were

exposed to silica by inhalation for 20, 40, or 60 days, and a portion of each group was

examined for 36 days post-exposure. Inflammation, as indicated by bronchoalveolar

lavage polymorphonuclear leukocytes (PMNs), increased in all groups during exposure,

but remained increased in the 36-day post-exposure period in rats exposed for 40 or 60

but not 20 days. The authors concluded that in the two higher-exposure groups,

recruitment of PMNs into the lung continued without further silica exposure. Fibrosis, on

the other hand, was present in all exposure groups over the 36-day post-exposure period

but appeared earlier in the 40- and 60-day exposure groups than in the 20-day exposure

group. The observation that the PMN influx did not progress in the rats exposed for 20

days, while fibrosis did, suggested to the authors that lavagable PMNs do not predict

fibrogenicity. The authors also pointed to the consistency of this finding with the lack of

PMN influx seen in human chronic silicosis cases despite the progressive nature of the

disease.

Porter et al. (2006) found that the severity of oxidative stress and the magnitude

of the increase in lung nitric oxide, which may participate in silica-induced pulmonary

inflammation, damage, and fibrosis production, also increased during the post-exposure

period. Future research to determine whether the levels of the other mediators discussed

above (e.g., IL-1 and/or TNF-α) also increase after cessation of silica exposure in parallel

to inflammation and fibrosis was proposed (Porter et al. 2004).
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As noted above, it has been proposed that ROS, either directly from silica or from

activated cells, may also play a role in the carcinogenic process. Shi et al. (1998) have

described general mechanisms of carcinogenesis thought to involve ROS and reviewed

evidence suggesting that silica-induced carcinogenesis may also follow this pattern.

According to the investigators, the general mechanisms of carcinogenesis that may result

from ROS include: direct DNA damage leading to mutation (e.g. strand breaks);

excessive cell proliferation involving oncogenes, cytokines such as IL-1 and TNF-α as

mediators of growth and differentiation, and transcription factors such as NF-κB and

activator protein 1 (AP-1,); loss of growth regulation via loss of tumor suppressor

function by mutation of tumor suppressor genes, such as p53; and division of damaged

cells with injury caused by lipid peroxidation products and a rise in intracellular calcium.

Shi et al. (1998) reviewed the evidence suggesting that DNA damage can be

induced by silica. Silica has been shown to cause DNA strand breaks in vitro. This

action is blocked by hydroxyl radical scavenging agents, indicating a role for ROS.

Studies have demonstrated that silica binds to DNA by the formation of hydrogen bonds

between the DNA phosphate backbone and silanol groups on the silica surface, thus

bringing the DNA strand close to the sites of ROS production on the silica surface. It has

also been demonstrated that silica, via interaction with hydroxyl radical, produces 8-

hydroxydeoxyguanine—a modified DNA base important in mutagenesis and

carcinogenesis.

Driscoll et al. (1997) examined mutation in rat alveolar epithelial cells. Rats were

exposed to saline or saline suspensions of silica by intratracheal instillation. Fifteen

months later alveolar epithelial cells were isolated from bronchoalveolar lavage (BAL)

cells and cultured in 6 thioguanine-containing media to select for mutations in the hprt

gene. Mutations were increased in alveolar epithelial cells taken from rats exposed to

silica as compared to cells taken from rats exposed to saline only. In addition, to examine

the role of inflammatory cells in inducing mutations, a cultured line of rat alveolar

epithelial cells were exposed in vitro to BAL cells (macrophages and neutrophils) taken

from rats exposed to silica. Mutations were caused in the cultured alveolar cells by the

silica-exposed BAL cells. BAL cells enriched to have more neutrophils were more

mutagenic then those enriched to have more macrophages, although both were

mutagenic. When these cultured cells exposed to BAL were also treated with the

antioxidant enzyme catalase, which promotes the conversion of hydrogen peroxide to

water and molecular oxygen, mutation was inhibited. The authors suggested that these

study results supported a role for these inflammatory cells and their cell-derived oxidants

in the in vivo mutagenic effects of silica exposure. However, in a further study, these

authors determined that there were other key factors in silica-induced alveolar epithelial

cell mutagenesis in addition to the inflammatory response.

Johnston et al. (2000) exposed rats to crystalline or amorphous silica by inhalation

for 13 weeks. Lung burdens for both forms of silica were similar. At the end of the 13-

week exposure period, neutrophils were increased in BAL following exposure to both

crystalline and amorphous silica but more so for amorphous silica. Cytotoxicity was
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twice as high for amorphous as for crystalline silica. MIP-2 was also increased in both

exposure groups. After a post-exposure recovery period of eight months, however, these

measures remained increased in rats exposed to crystalline but not for those exposed to

amorphous silica. Mutation frequency at the end of the exposure period, on the other

hand, was significantly increased only with crystalline silica. Thus, genotoxic effects in

alveolar epithelial cells occurred only in response to crystalline silica, despite the

presence of an inflammatory response to both forms of silica. This result suggested to the

authors that, in addition to an inflammatory response, particle biopersistence, solubility,

and direct or indirect epithelial cell cytotoxicity may be key factors for mutation induced

by crystalline silica. It should be noted that Castranova (2006, personal communication)

has expressed the opinion that solubility is not critical and that, rather, amorphous silica

is less toxic to alveolar macrophages and can be more readily cleared.

As noted above, Shi et al. (1998) discussed factors involved in possible

mechanisms of carcinogenesis. Shi et al. (1998) identified various cytokines, such as IL1 and TNF-α, as important mediators of growth and differentiation and transcription

factors, such as NF-κB and activator protein-1 (AP-1) as being involved in the expression

of and response to growth factors and oncogenes. TNF-α has been shown to act as a

tumor promoter in BALB/3T3 cell transformation.

Castranova (2004) discussed AP-1 activation as controlling the production of

inflammatory mediators, growth factors, and oncogenes. Activation of AP-1 has been

reported to be involved in neoplastic transformation, tumor progression, and metastasis.

AP-1 is composed of dimers of the protein products of individual member within the Jun

and Fos immediate-early response gene families. AP-1 can bind to the TPA response

elements in the promoter or 5' flanking regions of a number of target genes, such as those

encoding collagenase and transforming growth factor-β, and a number of other genes

involved in both inflammation and carcinogenesis. Silica-induced activation of AP-1 has

been reported in rat lung type II epithelial cells, mouse epidermal cells, and macrophages.

As for other activations induced by silica, oxidants also appear to play a role in

activation of AP-1. The signaling pathway appears to begin with the ROS-induction of

the translocation of protein kinase C (PKC) from the cytosol to the cell membrane (Ding

et al., 2006). The subsequent phosphorylation of mitogen-activated protein kinase

(MAPK) family members is PKC-dependent. The MAPK family members undergoing

phosphorylation are p38 and extracellular signal-related protein kinases (ERKs).

Inhibition of PKC has been shown to decrease silica-induced phosphorylation of ERKs

and p38 as well as inhibit silica-induced AP-1 activation. Direct inhibition of ERKs and

p38 also directly inhibits silica-induced AP-1 activation.

The p53 tumor suppressor gene is believed to act by preventing the passage of

genetic lesions in cells with DNA damage to a new generation of cells (Shi et al., 1998).

It does this by upregulating the expression of several genes that control growth inhibitory

and apoptotic (controlled cell death) pathways. Mutational inactivation of p53 is a

frequent alteration seen in human cancers. Studies have shown that ROS can also

damage p53. Liu et al. (2000) have studied p53 and K-ras genes in lung cancer patients
238

with silicosis to evaluate whether p53 and K-ras mutations were correlated with

occupational silica dust exposure. Ras gene products are proteins that bind guanine

nucleotides with high affinity and are involved in signal transduction pathways in many

cell types. K-ras is a commonly activated oncogene in human lung cancer with

predominant structure alterations of the 12th codon. The study examined p53 and K-ras

mutations in primary lung cancers in 36 workers occupationally exposed to crystalline

silica and who had silicosis. It was observed that the majority of p53 gene mutations

clustered on exon 8—a pattern distinct from that for non-occupational lung cancer. Also,

the p53 mutation incidence distributions among histological lung cancer types (small cell

vs. adenocarcinoma) differed from that for non-occupational lung cancer. For K-ras, it

was noted that in common lung adenocarcinoma, such as is seen in smokers, K-ras

mutations are detected in 30 percent of cases. Mutational activation occurs primarily in

codon 12 of the K-ras gene (in 70-100 percent of total mutations). This is true for both

Europeans and Chinese. In contrast, in the workers studied, no mutations were detected

in codon 12. Instead mutations were found in codons 7, 15, 20, and 21 and were

clustered in 15. Also, the spectrum of base substitutions was G to C in these workers as

opposed to G to T in non-occupational lung cancer. The authors noted that mutations

with lung cancer caused by smoking differ from those that develop in response to defined

chemicals (e.g., as seen in uranium miners). The authors concluded that the unusual

pattern of p53 and K-ras mutations may serve as molecular evidence of silica as a

“special” human carcinogen. They also concluded that their findings support a

carcinogenic effect of silica at the DNA molecular level.

I.F.1.a. Relationship between silicosis and lung cancer.

As described above, the early steps in the proposed pathways that lead to silicosis

and lung cancer seem to share some common features. This, among other things, has led

some researchers to suggest that silicosis is a necessary prerequisite to developing lung

cancer in silica-exposed individuals. According to Castranova (2004), ROS generated

directly from the silica surface and/or during phagocytosis of those particles seem to

trigger critical signaling events for both NF-κB and AP-1 activation. Therefore,

oxidative stress has been proposed to play a key role in the pathogenesis of silicosis and

silica-induced lung cancer. Driscoll and Guthrie (1997) pointed out that there is limited

evidence for a direct genotoxic effect of silica. They suggested that any increased lung

cancer risk associated with silica may be a consequence of the inflammation and

increased epithelial cell proliferation associated with the development of silicosis.

According to these authors, ROS released from inflammatory cells could damage

DNA, representing a potential indirect mechanism by which silica exposure could result

in damage to DNA. The increased epithelial cell proliferation associated with silica

exposure was also noted as a possible contributor to increased lung cancer risk. This is

because increased cell proliferation may increase the probability that a spontaneous

genetic error or a genotoxic effect from ROS would be fixed in a proliferating cell and be

clonally expanded. However, as discussed above, Driscoll and Guthrie (1997) completed

a further study and determined that there were other key factors in silica-induced alveolar
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epithelial cell mutagenesis in addition to the inflammatory response (Johnston et al.,

2000).

A review of epidemiologic studies has also attempted to answer the question of

whether silicosis is a necessary precursor of lung cancer in silica-exposed individuals.

(See also Section I.C.4) Checkoway and Franzblau (2000) reviewed 17 studies of lung

cancer mortality among silicotics. Although they found that the association between

silica exposure and lung cancer was generally stronger among silicotics than nonsilicotics, there were a number of issues that they believed complicated the analysis. One

issue was the relative insensitivity of chest radiographs that might have resulted in

underascertainment of silicosis cases. Also, for most studies, researchers did not have

access to serial radiographs over a worker’s lifetime, thus making it difficult to determine

the temporal relationship between silicosis and lung cancer. One of the studies

(Checkoway et al., 1999) appeared to show evidence of an exposure-response

relationship for lung cancer with cumulative silica exposure among workers without

radiographic evidence of silicosis. However, in that study, there was a shorter interval

between date of hire and date of final radiograph in non-silicotics compared to silicotics,

providing another occasion for underascertainment of cases.

Perhaps the biggest issue is the strong correlation between exposure and silicosis,

suggesting that silicosis may be functioning as a marker for silica exposure, which is, in

turn, also correlated with lung cancer risk. Checkoway and Franzblau (2000) believed

that the best information on this question would be derived from well-designed animal

studies. They concluded that the question of whether silicosis is required for elevated

lung cancer risk in silica-exposed individuals is “virtually unanswerable” from currently

available epidemiologic literature, and is unlikely to be addressable in future

epidemiologic studies. Finally, the authors concluded that risk assessments should

consider silicosis and lung cancer in silica-exposed individuals as separate entities whose

cause/effect relations are not necessarily linked.

I.F.2. Toxicity of Crystalline Polymorphs.

Most studies of crystalline silica toxicity concern quartz, which is the

predominant crystalline form involved in occupational settings. Other major polymorphs

of crystalline silica occur less frequently and include cristobalite and tridymite. Early

animal studies appeared to suggest that the crystalline polymorphs cristobalite and

tridymite were more toxic to the lung than quartz. The earliest animal study (Gardner,

1938) showed that experimental animals injected with cristobalite showed a more severe

response than that produced by quartz and that the resulting fibrosis that followed was

diffuse rather than nodular. King et al. (1953), who exposed rats by single intratracheal

injection to quartz, cristobalite, or tridymite, confirmed the earlier study and described

the action of cristobalite as “perhaps slightly faster than quartz,” and tridymite as having

a “spectacular” fibrotic effect.

Another study with rats also demonstrated significantly more tumors in rats

treated with tridymite as compared with those treated with cristobalite or quartz (Wagner
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et al., 1980). In this study, groups of 32 rats were treated by single intrapleural injection

with tridymite, cristobalite, or one of four different types of quartz. The rats were then

allowed to live until natural death, at which time they were examined for the occurrence

of malignant lymphomas of histiocytic type (MLHT). The numbers of tumors in each

group of 32 rats were as follows: tridymite, 16; Min-U-Sil (quartz), 11; D&D (quartz), 8;

Snowit (quartz), 8; DQ12 (quartz), 5; cristobalite, 4; and saline control, 0. These

differences were statistically significant (p < 0.01). These results were in contrast to a

previous similar experiment (Wagner, 1976) in which cristobalite was found to be the

most carcinogenic. However, a further analysis (Wagner et al. 1980) showed that the

discrepancy did not reflect a difference between the two experiments in the

carcinogenicity of cristobalite, but rather that Min-U-Sil and Snowit proved more

carcinogenic in Wagner et al. (1980). In vitro cytotoxicity to mouse peritoneal

macrophages was also examined with the polymorphs and quartz samples (Wagner et al.,

1980). There was a correlation between this cytotoxicity and the rat tumor potency,

except for DQ12. The authors suggested that cristobalite may have shown little in vitro

cytotoxicity because it is relatively unstable. They also thought that since tridymite is a

“denser” particle and thus of smaller particle size and greater surface area than

cristobalite, differences in surface area and perhaps surface charge might have accounted

for its higher toxicity.

Hemenway et al. (1990) examined the comparative clearance, from rat lungs, of

quartz from two sources and pure cristobalite. Clearance kinetics and biological response

were determined after short-term exposure. The clearance of cristobalite was much less

than either of the quartz samples. There was little or no clearance of cristobalite after the

first 30-day post-exposure period. Cristobalite also exhibited the greatest cellular

biological response. The response was early and sustained as evidenced by elevated

numbers of macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage

through 180 days post-exposure. One quartz sample showed a response of about 30

percent that of cristobalite, while the response of the other quartz sample was no different

from control.

Jakab and Hemenway (1992) examined the interaction of quartz or cristobalite

with influenza virus infection (also known to cause pulmonary fibrosis) in mice. Mice

were intratracheally instilled with quartz or cristobalite followed three days later by

infection with influenza by aerosol inhalation. Several parameters indicative of

pulmonary reaction were examined at 30, 60, and 90 days after infection. In mice that

were not infected with influenza virus, cristobalite caused more of a fibrotic reaction than

quartz. The influenza infection increased the fibrogenic response to both forms of silica

suggesting that the response was additive.

Fubini et al. (1995) explored altered surface physicochemical properties of several

polymorphs in an effort to examine their implications for biological responses. Building

on the observation that freshly ground silicas have shown a higher degree of toxicity than

aged particles and that this phenomenon has been attributed to the presence of reactive

radicals on the newly cut surfaces (see section below for further discussion of this issue),

the authors compared the amount of surface radicals for several silica polymorphs after a
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very mild grinding in a ball mill. The overall number of surface radicals after grinding

was higher for cristobalite than for quartz.

Warheit et al. (1995) compared pulmonary responses in rats after short-term (3

days) inhalation exposure to cristobalite or quartz. Indices studied were measures of

pulmonary inflammation and cytotoxicity. Inflammation was increased over controls in

animals exposed to both cristobalite and quartz (p < 0.05). The inflammatory reaction at

30 days post-exposure appeared greater for exposure to cristobalite than quartz. At 90

days, this difference was much smaller and not statistically significant. Indices of

cytotoxicity were much greater for cristobalite than for quartz at both time periods. For

example, bronchoalveolar lavage levels of lactate dehydrogenase at 90 days postexposure were elevated 12-fold for cristobalite and 4-fold for quartz. The authors also

cited a previous study (Hemenway et al., 1986) in which rats were exposed for 8 days to

aerosols of cristobalite, quartz, or amorphous silica. Cristobalite caused the most lung

injury, causing substantial inflammation and fibrosis. Quartz produced intermediate

effects and amorphous silica produced minimal effects.

DNA strand breakage, production of thymine glycol (a DNA damage product of

oxidative mutagens) and hydroxyl radical generation induced in vitro by cristobalite,

tridymite, or several different quartz samples was studied by Daniel et al. (1995). The

relative order of the different polymorphs and quartz samples in assays for oxygen

consumption and hydroxyl radical production differed from the order in which they

caused DNA strand breakage or altered thymine glycol production. Cristobalite,

tridymite, and some of the quartz samples showed stronger activity in some assays but

less activity in others. The cristobalite sample exhibited rapid molecular oxygen

consumption and was the most active sample when hydrogen peroxide was used in the

assay but was less active than some quartz samples when hydrogen peroxide was omitted.

Cristobalite showed less ability to generate hydroxyl radicals from hydrogen peroxide

compared to the quartz samples. This suggested to the authors that the different

polymorphs may vary with respect to the mechanisms by which they generate oxygen

radicals and thereby damage DNA. However, the authors drew no conclusions

concerning relative potency of the polymorphs, but rather concluded that the mechanisms

of crystalline silica carcinogenesis needed to be further investigated in relation to the

underlying physicochemical characteristics.

In contrast to the studies discussed above, several authors have concluded that

cristobalite and tridymite are not more potent than quartz in their toxicities. Guthrie and

Heaney (1995) reviewed studies examining mineralogical characteristics of silica

polymorphs in relation to their pathogenic effects. In their opinion, tridymite and

cristobalite generally appeared to have pathogenic effects comparable to quartz. Bolsaitis

and Wallace (1996) reviewed studies showing the effect of different polymorphs on

hemolytic activity and on inflammation and fibrosis in mouse lungs induced by quartz,

cristobalite, or tridymite. The results showed that hemolytic activities were within the

range of experimental error and development of lung fibrosis was essentially the same

among the three polymorphs. In noting that the mechanisms of action and particle

characteristics that cause silicosis and other silica-related diseases have not been
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precisely defined, NIOSH (2002) determined that additional research was needed,

including further in vivo and in vitro studies on the pathogenicity and toxicity of quartz

compared to its polymorphs.

A difference in toxicity between cristobalite and quartz has not been observed in

epidemiologic studies. (Exposure to tridymite has not been the subject of epidemiologic

study.) In some workplaces, such as ceramics, pottery, or brick manufacture, exposure

may involve more than one polymorph. In such cases, epidemiologic studies have not

usually identified specific exposure to quartz or cristobalite. Therefore, excess lung

cancer mortality observed in these studies cannot be attributed to a specific polymorph

but only to crystalline silica in general (NIOSH, 2002).

IARC (1997) also addressed whether there were possible differences in

carcinogenic potential among polymorphs. Among the studies considered by IARC (and

reviewed in Section V.C above), most studies were of populations principally exposed to

quartz. Only the study of U.S. diatomaceous earth workers (Checkoway et al., 1997)

examined workers exposed predominantly to cristobalite. The IARC Working Group

concluded that although there were some indications that cancer risks varied by type of

industry and process in a manner suggestive of polymorph-specific hazards, available

data did not permit differentiation of the cancer hazard between quartz and cristobalite.

In their study of diatomaceous earth workers, whose predominant exposure was to

cristobalite, Rice et al. (2001) reiterated that differential polymorph toxicity had not been

confirmed by results of epidemiological studies. However, citing results from studies of

pottery workers, they also believed that there may be some evidence of increased

mortality from lung cancer among workers in industries with high-temperature processes.

These authors concluded that differences in the carcinogenic potential of various

crystalline silica polymorphs have not been established and therefore cancer risks from

workplace exposure to crystalline silica cannot yet be attributed or limited to a particular

polymorph. Steenland et al. (2001a) further addressed this issue and found that the

exposure-response trends observed within the diatomaceous earth cohort did not differ

notably from those derived from other studies involving exposure to quartz.

OSHA preliminarily concludes, based on epidemiologic and experimental

evidence, that the crystalline silica polymorphs quartz, cristobalite, and tridymite have

similar toxicity and carcinogenic potency.

I.F.3. Freshly Fractured vs. Aged Silica.

When crystalline silica is subjected to high energy forces, as occurs in work

processes such as abrasive blasting, rock drilling, tunneling, stone carving and the

production of silica flour, it is said to be “freshly fractured.” Silica that is not fractured

by the work process is said to be “aged.” For example, workers in the glass industry and

those who work with paint fillers do not work in processes that fracture silica particles.

A number of studies have examined the question of whether freshly fractured silica is

more toxic than aged silica. It has been noted that acute silicosis is typically associated
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with the generation of freshly fractured silica dust in these occupations (Castranova et al.,

1996). Studies addressing these issues are described in this section.

I.F.3.a. In vitro studies.

The surfaces of freshly fractured silica particles have a greater number of silicon

(Si) and siloxyl (SiO) radicals than do those of aged silica. After four weeks, silica

stored in air will still have 20 percent of the surface-free radicals that were present

immediately after grinding. These free radicals can react with water to form hydroxyl

radicals through the production of hydrogen peroxide (H2O2) (Shi et al., 1989).

Early in vitro studies demonstrated that freshly fractured silica caused more

cytotoxicity in cells than did aged silica. The significantly increased cytotoxicity of

freshly fractured silica over aged was evidenced by a decrease in cell membrane integrity

as measured by induction of lipid peroxidation (three-fold), an increase in release of

lactate dehydrogenase from macrophages (1.5-fold), and an increase in hemolytic activity

(36-fold) (Vallyathan et al., 1988).

Studies have also demonstrated that freshly fractured silica has an increased

ability to activate respiratory bursts in alveolar macrophages. During the respiratory

burst, the macrophage produces superoxide anion (O2

-

), which is then converted to

hydrogen peroxide (H2O2). Respiratory bursts in macrophages after in vitro exposure

were monitored by measuring superoxide anion, hydrogen peroxide secretion and nitro

blue tetrazolium (NBT) reduction to formazan. Superoxide secretion decreased by 16

percent and 27 percent after storage of ground silica for 24 and 96 hours, respectively.

Hydrogen peroxide secretion decreased by 65 percent after 24 hours of storage. After 48

hours, NBT reduction was 39 percent as compared to 69 percent immediately after

grinding (Shi et al., 1989).

Vallyathan et al. (1988) noted that silica aged for years still retained the ability to

stimulate alveolar macrophages, decrease membrane integrity, and cause lipid

peroxidation, suggesting that silicon-based ROS on the crystalline surfaces can only

partly explain the biologic reactivity of silica. They found that substances, such as

superoxide dismutase, that blocked the activity of ROS were only partially effective in

decreasing lysis. In contrast, there was a significant or complete inhibition of H2O2

release and lipid peroxidation by several hydroxyl scavengers. The authors suggested

that the ability of these scavengers to inhibit the freshly fractured silica-induced lipid

peroxidation and H2O2 release provided evidence of a direct correlation between hydroxyl

radical generation and cellular injury. These authors suggested that freshly fractured

silica is more potent due to surface formation of newly generated silicon-based radicals

as well as the propagation of other oxygenated radicals in aqueous environments. They

suggested that these radicals plus the ones generated by macrophages may overwhelm the

cell’s defense mechanisms. They also proposed that these mechanisms should be viewed

as particularly relevant to the pathogenesis of acute silicosis.
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In a further study of the increased activity of freshly fractured silica, Vallyathan et

al. (1992) demonstrated that the biological reactivity of silica was reduced when it was

coated with an organosilane material. In this study, the cytotoxicity of freshly fractured

and aged silica to macrophages was determined by measuring membrane integrity.

Freshly fractured silica was 4.2-fold more potent in decreasing membrane integrity than

aged silica. The ability of silica to activate macrophages was measured by the secretion

of hydrogen peroxide or the generation of chemiluminescence (reactive species react with

a light-emitting probe and the light is detected with a luminometer). Freshly fractured

silica was 50 percent more potent than aged silica in inducing hydrogen peroxide

secretion and 4.6-fold more potent in stimulating chemiluminescence. When freshly

fractured silica was coated with the organosilane, its cytoxicity to macrophages was

decreased by 53 percent for a one-hour exposure and 73 percent for a five-hour exposure.

Also, chemiluminescence generated from silica-exposed macrophages was decreased by

58 percent when the silica particles were coated. The authors concluded that these

findings suggest that surface radicals may be an important factor in the induction of

disease by silica.

The generation of free radicals from macrophages and polymorphonuclear

leukocytes (PMN) upon induction of the respiratory burst by silica has also been directly

measured by electron spin resonance (Vallyathan et al., 1992). Freshly fractured silica

induced an enhanced radical generation with an increased dose of silica. Silica aged for

14 days induced a weaker radical generation response.

Elias et al. (2000) studied the cytotoxic and transforming potencies of various

silica samples on Syrian hamster embryo cells. Upon grinding in a wet atmosphere, the

cytotoxic and transforming potencies of quartz particles were greatly reduced compared

to those of the quartz that was dry-ground. The authors concluded that wet grinding

resulted in the amorphization of the external layers of the quartz particles. Thus, the

surface functionalities (such as silanol patches and iron sites active in ROS generation)

involved in the induction of cytotoxicity were deactivated.

I.F.3.b. In vivo studies.

Several in vivo studies have also been done to compare the effects of freshly

fractured and aged silica. Vallyathan et al. (1995) (also reported in Shoemaker et al.,

1995) exposed rats to an average of 20 mg/m3freshly fractured or aged silica for 2 weeks

by inhalation. Biochemical and pathological changes in the lavagate (fluid used to wash

out the lungs) and lungs were examined.

In exposed rats, there were increases in the total number of cells, red blood cells

(indicative of damage at the alveolar blood-air barrier level) and lymphocytes and

neutrophils (indicative of an inflammatory response) found in the lavagate. These

increases were significantly greater (p < 0.05) in the rats exposed to freshly fractured as

compared to aged silica. Histopathology done on the lungs confirmed the findings of

inflammation. As with the lavagate, the changes found were significantly increased (p <

0.05) in those exposed to freshly fractured as compared to aged silica. Similarly, lipid
245

peroxidation was significantly increased (p < 0.05) (indicative of damage at the

membrane level). The fluid of the lavagate from rats exposed to freshly fractured silica

also had significantly more albumin and protein (indicative of damage at the alveolar

blood-air barrier) and β-N-acetyl glucosaminidase (indicative of damage at the cell level)

than that from those exposed to aged silica (p < 0.05). Cells in the lavagate showed

significantly greater biochemical changes (due to membrane injury, disruption of the

integrity of lysosomes and increased production of ROS) in the rats that had been

exposed to freshly fractured as compared to aged silica (p < 0.05), which, in turn,

produced a significantly greater response as compared to controls (p < 0.05). The authors

suggested that this was probably because quartz causes persistent acute biologic toxicity

in the lung by repeated cycles of phagocytosis and macrophage injury.

This study also demonstrated that there was a decrease in antioxidant defense

indices in animals exposed to freshly fractured, as compared to aged silica. The authors

suggested that their study results indicated that the pulmonary reactions of rats to shortduration exposure to freshly fractured silica mimic those seen in acute silicosis in

humans. These reactions in the rat include inflammation, blood-air barrier damage,

activation and generation of ROS by pulmonary phagocytes, and increased lipid

peroxidation. The authors cited studies of human acute silicosis which have

demonstrated increases of phospholipid and inflammatory cells in lavage fluid, damage to

the blood-alveolar air barrier, and activation of oxidant production by pulmonary

phagocytes (Goodman et al., 1992).

In a follow-up to this study, the investigators altered the level of iron

contamination of the freshly fractured silica (Castranova et al., 1997). As discussed

above, surface radicals on freshly fractured silica are thought to generate hydroxyl

radicals upon contact with water. Since iron chelation reduces the number of hydroxyl

radicals on the particle surface, it was thought that trace contamination of silica with

ferrous iron could enhance hydroxyl radical generation via a Fenton-like reaction. The

finding that both the production of hydroxyl radicals and silica-induced biological

reactions decrease in a similar fashion with time after fracturing suggested that a

relationship exists between hydroxyl radical generation and toxicity. Thus, the

investigators believed that trace contamination with iron would increase the pulmonary

responses to inhaled silica.

In this study, animals were exposed as in the previous study but low- and highiron contamination of the silica was accomplished by altering the length of the

polyethylene delivery tube of the stainless steel screw feeder. The iron contamination

was correlated with length of contact time of the silica with the stainless steel before

going into the mill. The study found that silica with high-iron contamination produced

more reactive species than did silica with low-iron contamination. Pulmonary responses

were also increased with the high- vs low-iron silica. Silica with high-iron contamination

produced significantly more damage to the alveolar air-blood barrier, more inflammation,

increased macrophage activity, and a greater level of lipid peroxidation in the lung

tissues. The authors concluded that the results support the hypothesis that trace iron

contamination can augment the generation of oxidants by silica and enhance its
246

inflammatory and cytotoxic potency in the lung. They suggested that trace contamination

of silica with iron may occur in occupational circumstances such as rock drilling and

sandblasting, leading to increased lung damage and inflammation in workers in these

occupations.

Interestingly, Vallyathan and Shi (1997) have noted that chemical etching of silica

particles with hydrochloric acid to remove metal ion impurities and reactive centers that

were created by fracturing the particle surface resulted in markedly diminished ability to

cause DNA double strand breakage in vitro. They also noted that these in vivo studies

agree with the in vitro studies that confirm the presence of reactive sites on the surface of

freshly fractured silica and the significant role they may play in the pathogenesis of acute

silicosis.

In a recent study, Porter et al. (2002) compared low doses of aged and freshly

fractured silica on pulmonary inflammation and damage in rats. In this study rats were

treated by intratracheal instillation with either vehicle, aged, or freshly fractured silica, at

a dose of either 5 or 20 g once a week for 12 weeks (for a total of 60 and 240 μg silica).

These doses were chosen to approximate human exposures of between 270 and 1,000

g/m3, 8 hr/day, 6 days/week for 10 years, which are in the range of mean 8-hour timeweighted-average levels of respirable quartz (340 to 490 g/m3

) reported for high wall

drillers, bulldozer operators and back fillers in U.S. surface mines. These estimates of

equivalent human exposures were made with the following assumptions: (1) total

ventilation in a person performing light work is approximately 10 m3/8-hour work day,

(2) alveolar deposition in humans of inspired particles 1 μm in aerodynamic diameter is

approximately 20 percent, (3) the ratio of alveolar surface area in humans versus rats is

approximately 255, and (4) adjusted for lifespan, 12 weeks in the rat is approximately

equivalent to 10 years for humans. Exposure to 60 g silica caused the same

inflammatory response and alveolar macrophage activation whether the silica was aged

or freshly fractured. However, at the 240 g dose, freshly fractured silica was

significantly more potent (p ≤ 0.05) than aged silica in stimulating the activation of

alveolar macrophages, but the amount of pulmonary damage did not differ between aged

and freshly fractured silica. These results showed that silica induced pulmonary

inflammation in rats at levels much lower than had previously been demonstrated. The

authors suggested that the difference in potency between aged and freshly fractured silica

is apparent only after a threshold lung burden of silica is reached.

I.F.3.c. Human studies.

A few human studies with workers presumed to be exposed to freshly fractured

silica have demonstrated similar effects to those seen in animal studies. Goodman et al.

(1992) studied a worker with acute silicosis who had worked as a rock driller at a quarry

and also at surface coal mines. Although much of his work in the past had been done

with a wet process in which water was applied to reduce dust generation, in the period

just prior to getting acute silicosis, he had worked primarily as a driller at a surface coal

mine using a dry process. The worker had described the dust during this dry drilling as

being so dense that he “couldn’t see anything.” Similar to results seen in animals
247

exposed to silica, bronchoalveolar cells from this worker exhibited an increased level of

activity (as measured by resting and stimulated chemiluminescence) as compared to those

observed in individuals without histories of occupational dust exposure.

Castranova et al. (1998) demonstrated that in rats, exposure to silica by

intratracheal instillation or by inhalation results in an increase in levels of mRNA for

inducible nitric oxide synthase in bronchoalveolar lavage cells, elevated nitric oxide

production by bronchoalveolar lavage cells, and an increase in nitric oxide-dependent

chemiluminescence from alveolar macrophages. Freshly fractured silica was a more

potent stimulant of nitric oxide-dependent chemiluminescence than aged silica. These

authors also compared similar endpoints in a healthy volunteer, a silica-exposed coal

miner with a normal chest x-ray, and a silica-exposed miner with an abnormal chest x-ray

with an ILO reading of 1/0. There was some mRNA for inducible nitric oxide synthase

in the bronchoalveolar lavage cells of the miner with the normal chest x-ray. However,

there was much more in the cells of the miner with the abnormal chest x-ray. There was

also more nitric oxide-dependent chemiluminescence seen in cells from the miner with

the abnormal chest x-ray compared to the miner with the normal x-ray. For the miner

with the normal x-ray, both of these endpoints were increased above control.

I.F.3.d. Discussion and conclusions.

Many animal and in vitro studies have demonstrated that crystalline silica that is

freshly fractured in the laboratory shows greater biological activity than aged silica. A

few studies have demonstrated similar inflammatory and cellular effects in workers

whose jobs result in exposure to freshly fractured silica and experimental animals

exposed to freshly fractured silica.

In the studies described above, silica was fractured by several different methods,

such as crushing or grinding in an agate mortar and pestle or generating in an air jet mill

fitted with a polyurethane liner and stainless steel jets. However, it has been reported that

the toxicity of silica can be changed according to the method of preparation. Shi et al.

(1989) found that the toxicity of quartz particles increased when the sample was ground

in a mill rather than in a press and suggested that after crushing in a press, the particle has

a smooth surface, while the milled particle has sharp edges and a larger surface area.

Thus, it appears that the methods used to generate fractured surfaces can affect toxicity

by alteration of surface characteristics. Occupational exposure to freshly fractured silica

can occur in many different work processes. However, there is insufficient information

available at this time on the surface characteristics of the freshly fractured silica

generated in these varied work processes to enable a process-specific characterization of

the potential toxicity of the silica to which workers are exposed.

I.F.4. Metal Impurities/Clay Encapsulation.

Metal impurities can also modify the surface reactivity of silica (IARC, 1997).

Iron, depending on the quantity and ionic state, has been shown to either enhance or

decrease the toxicity of crystalline silica. Aluminum has been shown to reduce the
248

toxicity of silica in several studies. Another physical factor relevant to the toxicologic

potency of silica is the presence of a mineral coating, or “occlusion” of the silica surface,

which may affect the biological availability of the quartz component of the dust.

Research has suggested that contaminants on the surface, such as aluminosilicate clay,

may diminish the biological availability of surface active sites affecting toxicity by gross

occlusion of the silica surface. It is thought that contamination by this clay may leave

aluminum ions at the abraded quartz surface and that this may be the mechanism of

action for inhibition of silica toxicity. There have also been a number of studies of the

effect on toxicity of coating silica with non-naturally occurring materials, such as

polyvinylpyridine-N-oxide (e.g., Albrecht et al., 2004; Knaapen et al., 2002; Schins et al.,

2002). This topic will not be discussed here. Studies of the effect on silica toxicity of

iron, aluminum, other metal contaminants, and occlusion with aluminosilicate clay will

be discussed below.

There have been a number of studies in which the presence of iron was shown to

enhance the toxicity of crystalline silica. For example, as described above, Castranova et

al. (1997) altered the level of iron contamination of freshly-fractured silica and

demonstrated that trace iron contamination augmented the generation of oxidants by

silica and enhanced its inflammatory and cytotoxic potency in the lung. This finding led

the authors to suggest that trace contamination of silica with iron may occur in

occupational circumstances, such as rock drilling and sandblasting, leading to increased

lung damage and inflammation in workers in these occupations.

Donaldson and Borm (1998) and Fubini (1998) reviewed studies on the effect of

iron on the toxicity of silica (quartz). They reported that in contrast to the findings

described above, other studies have shown that iron can reduce the toxicity of quartz.

Iron salts have been shown to protect against quartz-mediated damage to erythrocyte

membranes. One study found that metallic iron diminished the ability of quartz to cause

inflammation in the lungs of rats, measured as the mean number of neutrophils in the

bronchoalveolar lavage (BAL) 7 days following instillation. Donaldson and Borm (1998)

pointed out, however, that the ionic state of iron may be important. Contamination with

ferrous or ferric iron, as opposed to metallic iron, was involved in the Castranova et al.

(1997) study showing increased toxicity. This may be due to the generation by ferrous or

ferric iron of Fenton-derived hydroxyl radicals on the silica particle surfaces, which

would increase oxidative stress. The quantity of iron may also be important, with trace

amounts increasing toxicity by assisting ROS generation, and large excesses decreasing

toxicity by detoxifying the surface of silica particles. The authors concluded that further

research would be needed to fully understand the phenomenon.

Fubini (1998) discussed the possible role of physicochemical factors in the

sequence of events leading to silicosis and silicosis-induced cancer. Trace amounts of

iron, which are very common in mineral samples, are thought to lead to the prolonged

generation of Fenton chemistry-derived hydroxyl radicals which can cause DNA damage

and induce transformation in epithelial cells, resulting in cancer. Fubini (1998) stressed

that this effect does not usually relate to the actual amount of iron but to small fractions

with particular redox and coordination states.
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In reviewing other studies of the effects of iron, Fubini (1998) noted that ironcontamination is probably responsible for the pathogenic effects of crystalline silica of

biogenic origin such as diatomaceous earth that becomes cristobalite upon heating. Iron

is always present in these kinds of materials formed from living matter. Fubini (1998)

cited other studies as demonstrating iron enhanced toxicity. For example, Saffiotti and

Ahmed (1995) found that iron ions increased silica-induced cell-free damage as well as

DNA damage and cell transformation. On the other hand, Nolan et al. (1981)

demonstrated that iron reduced silica-induced cytotoxicity and membranolysis in vitro,

probably by surface modification of silanols. Other studies cited by Fubini (1998) on the

protective effects of iron include decreased silica-induced in vitro cytotoxicity and

membranolysis and DNA damage and transformation in cells by a bulk iron oxide

(hematite) mixed with quartz (Saffiotti and Ahmed, 1995) as well as reduced in vivo

inflammation and fibrosis by metallic iron (Cullen et al., 1997). Fubini (1998) suggested

that the latter result (Cullen et al., 1997) may be due to reduction of surface sites or the

annealing of radicals.

As an additional point of information, Fubini (1998) noted that, among

epidemiologic studies not finding increased cancer mortality (as reported in IARC, 1997),

the sources of quartz are all from metal mines—gold, zinc, and tungsten. Fubini (1998)

suggested that contact of the quartz with metals that are reducing agents could have

modified the nature of the silica surface sites that otherwise are involved in the

carcinogenic mechanism. A possible explanation is that such metals assist the annealing

of surface radicals, thus eliminating particle-generated ROS, reducing the oxidative

stress, and thus reducing damage to epithelial cells. Another possibility suggested is that

metal-ion binding to silanols reduces membranolysis and cytotoxicity, which would favor

clearance of silica particles.

Elias et al. (2000) examined the cytotoxic and transforming effects of silica

particles with regard to various surface properties. The assay used was the Syrian

hamster embryo (SHE) cell transformation assay, which is used as an appropriate in vitro

model for screening for tumorigenic potential. Several different silica samples were

used, including two quartz and three cristobalite samples. Cytotoxic and transforming

potencies of the various silica samples were related to the composition and structure of

surface functionalities. Specifically, the cytotoxic effects were related to the distribution

and number of silanol groups and to the presence of trace amounts of iron on the surface.

SHE cell transformation was induced by silica particles with iron-active sites that were

able to generate ROS. Furthermore, it was determined that redox activity of the surface

iron sites was different among the silica samples, likely dependent on the organization of

the surface silanols and whether the surface silanols were isolated or in pairs. The

different transforming potencies of trace iron-contaminated silica samples could be

partially explained by the different potentials of surface iron to play a role in ROS

generation.

The investigators then continued and expanded this line of research using the SHE

cell transformation assay. Fubini et al. (2001) compared the cytotoxicity and
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transforming potency of a series of different silica samples, all derived from the same

original batch of Min-U-Sil. Each original sample was treated differently in order to

generate a collection of samples, each of which differed in one physicochemical property

that was being evaluated for its ability to inhibit or enhance the cytotoxic and

transforming potency. Modification of surface iron content was accomplished by either

treating the sample with deferoxamine, which extracts free iron, or enriching the sample

with iron. The sample treated with deferoxamine showed a large decrease in, but not the

elimination of, hydroxyl radicals and cytoxicity. Cellular transforming potency was

decreased in a dose-related fashion as compared to the original quartz at the same doses.

This result suggested to Fubini et al. (2001) that intrinsic iron was involved in the

induction of cell transformation. It has also been suggested that this effect could be due

to neutralization of surface charge (Castranova, personal communication, 2006). The

sample enriched with iron also greatly decreased hydroxyl radical yield and the celltransforming potency compared to the unmodified quartz. These results suggested to the

authors that not all iron at the silica surface is active in free radical release but that only

some isolated iron ions that are bound to the crystal lattice in a particular redox and

coordination state are active. Also, a silica surface fully covered with iron exhibits an

opposite effect of a silica surface with only trace amounts of iron.

The roles of iron and free radical generation in silica toxicity were further

explored by Fenoglio et al. (2001). Three different samples of quartz were tested. One

was Min-U-Sil, which contained trace levels of iron. Another was a sample of pure

quartz dust, obtained from quartz chips that were purified by melting and ground in an

agate mortar. The last sample was the Min-U-Sil treated with deferroxamine to remove

iron. Two radical generating mechanisms, hydroxyl radical from hydrogen peroxide and

cleavage of a C-H bond, were studied. The untreated Min-U-Sil was the most active,

because it contained traces of iron, followed by the Min-U-Sil sample treated with

deferroxamine and then the pure quartz. These results suggested to the authors that there

were active sites other than iron but that at the active iron sites, the iron speciates at the

surface giving rise to two kinds of surface centers where ROS is produced. The authors

believed that iron speciation was one of the possible causes of the variability seen in the

toxicities of silica samples of different origin. It has also been suggested that the

temperature used in producing the quartz chips for this study could have deformed the

crystalline surface, thus decreasing toxicity (Castranova, personal communication, 2006).

In another investigation (Clouter et al., 2001; Donaldson et al., 2001), actual

workplace quartz samples were compared to a standard research quartz sample (DQ12)

for their ability to damage erythrocyte membranes in vitro (as a measure of the direct

reactivity of the quartz surface), cause inflammation following instillation into rat lung

(as measured by total cells, PMN, protein, and LDH in the BAL fluid), and generate

hydroxyl radicals. One workplace sample labeled OM, as described by Clouter et al.

(2001), represented sand that was produced from medium-hard sandstone, crushed,

processed, and then milled in a rotary ball mill to produce silica flour. Another

workplace sample, labeled RH1, was from a similar site location although the feedstock

to the plant was a soft, loosely consolidated sand where no crushing was required to

produce the sand product and the only grain breakage was due to the milling circuit.
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Although iron was present at a concentration of less than 0.5% in the samples, RH1

released 10 times more iron than either the other workplace sample or the DQ12 in both

acid and neutral pH environments. The authors hypothesized that workplace sample RH1

would cause the most damage in the toxicity assays if iron played a role in mediating the

toxicity of quartz. However, that did not turn out to be the case. Only the DQ12 sample

caused significant erythrocyte membrane damage and lung inflammation in rats. There

was also no relationship between the ability to release iron and the ability to generate free

radicals. In fact, both workplace samples showed a greater ability to generate hydroxyl

radicals than DQ12. Also, the ability of any sample to generate hydroxyl radicals was

not predictive of the ability to cause hemolysis or lung inflammation. The authors

concluded that workplace quartz species can be substantially less biologically active than

standard quartz (DQ12) and that releasable iron was not a factor in this activity.

Fenoglio et al. (2003) examined the role of cysteine (CYS) and glutathione (GSH)

in silica toxicity. GSH is essential for the protection of cells against oxidative stress.

When it is depleted by a toxic substance such as quartz, nearby cells may be damaged.

The quartz-induced depletion of GSH as well as the depletion of CYS are due to the

oxidation of their thiol groups by a radical mechanism triggered by Fe(III) ions trapped

on the silica particle surface. All quartz contains some iron in traces and this will cause

the above-described reaction. Fenoglio et al. (2003) looked at the activity in a system of

silica samples that were either native or that had been treated by grinding or by other

mechanisms that altered the amount or state of the iron at the particle surface. The results

demonstrated that the presence and quantity of iron and its state in various silica samples

was correlated with GSH and CYS depletion.

There have been a number of studies in which aluminum has been shown to

decrease the toxicity of silica. For example, Brown et al. (1989) assessed the

inflammatory and fibrogenic potential in rats of silica as modified by pretreatment with

aluminum lactate. The mode of action of the aluminum in reducing quartz toxicity was

also investigated. The effect on inflammation was assessed by measuring the total

number of leukocytes and the percentage of polymorphonuclear leukocytes (PMN) in the

bronchoalveolar lavage (BAL). Silica was administered by intratracheal instillation into

the lung. One week after administration of silica, the total number of leukocytes had

increased 7-fold. This increase peaked at 4 weeks post-administration and was then

sustained for 12 weeks. In the rats treated with silica plus aluminum lactate, there was

only a small, nonsignificant increase in the total number of leukocytes at one week postadministration and then the number returned to the control level. In control rats there

were no PMN in the BAL. In rats administered silica, PMN made up 45 to 55 percent of

the BAL leukocytes, while in rats administered aluminum lactate along with silica, this

was reduced to 10 to 20 percent. Functional status of the silica-exposed BAL leukocytes,

as measured by their ability to degrade fibronectin, was also reduced by co-treatment

with aluminum lactate. When administration of aluminum lactate was delayed until one

month after silica administration, total leukocytes and percentage of PMN were

significantly reduced at one month post-aluminum treatment, but not at one week.

Functional status of leukocytes was not affected. Co-administration of silica and

aluminum lactate also minimized areas of alveolar lipoproteinosis with septal hyperplasia
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seen at one month. At 4 months, co-administration lessened the severity and reduced the

percent of tissue involved from 80 to 5 percent. An inflammatory response to treatment

with bacteria was not attenuated by co-administration of aluminum lactate. This finding

suggests that in the case of co-administration with silica, aluminum lactate affects the

silica particle itself rather than the inflammatory cell. If aluminum lactate were acting

directly on the inflammatory cell, it would have affected the inflammatory cell upon coadministration with bacteria, resulting in an attenuation of the inflammatory response to

the bacteria.

Brown et al. (1989) also cited several earlier studies demonstrating that coadministration of aluminum and crystalline silica attenuated the inflammogenicity and

fibrogenicity of silica, markedly reducing the pathogenicity of silica in rats, guinea pigs,

mice, sheep, and rabbits. Additionally, research was cited that demonstrated that a clay

mineral, a potential source of aluminum in mixed dusts, co-administered with silica,

reduced the biological activity of silica.

Donaldson and Borm (1998) and Fubini (1998) reviewed studies on the effect of

aluminum on the toxicity of silica (quartz). They reported on a study that demonstrated

that aluminum is better at neutralizing silica’s negative surface charge than iron (Brown

and Donaldson, 1996). Donaldson and Borm (1998) also reported that several studies

have shown that aluminum salts, which are commonly found in minerals that are

associated with quartz, lower the toxicity of quartz. In one study (Daniel et al., 1970),

rats were exposed to 300 mg/m3quartz by inhalation for 12 months. During that period,

a group of the rats were also exposed, by inhalation, to aluminum hydroxide or aluminum

chlorohydroxyallatoinate for 30 minutes per day. The fibrogenic response to quartz was

decreased in the rats that were also treated with aluminum. The accumulation of quartz

was similar in all treatment groups.

In another study (Bégin et al., 1987b), sheep were instilled with quartz, aluminum

lactate, or quartz together with aluminum lactate. Co-treatment with aluminum lactate

decreased pathology scores and inflammation, as indicated by reduced cellular activity in

BAL fluid. Donaldson and Borm (1998) proposed that the biological effects of quartz,

such as silicosis and cancer, could be understood in terms of surface reactivity and noted

that a range of substances, including minerals, could modify the ability of quartz to

generate free radicals and cause oxidative stress. They proposed that the hazard posed by

quartz is not constant but may vary depending on the origin of the silica sample and its

contact with other chemicals and minerals.

Fubini (1998), in discussing the possible role of physicochemical factors in the

sequence of events leading to silicosis and silica-induced cancer, reported that aluminum

and other metal ions are thought to modify silanol groups on the silica surface. This

decreases the membranolytic and cytotoxic potency and allows greater particle clearance

from the lung before damage can occur. Fubini (1998) noted that the protective effect of

aluminum is demonstrated by studies in which aluminum ions or kaolin reduced in vitro

cytotoxicity and membranolysis and in vivo inflammation and fibrosis. Fubini (1998)
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suggested that the aluminum ions acted by replacing the hydrogen in SiOH and the kaolin

acted by the release of aluminum ions.

More recent studies continue to demonstrate the protective effect of aluminum

on silica-induced toxicity. Duffin et al. (2001) (also reported in Donaldson et al., 2001)

instilled rats with 250 μg quartz or the same amount of quartz treated with aluminum

lactate. Bronchoalveolar lavage was performed 18 hours later. The degree of

inflammation was measured by counting the number of PMN in BAL fluid. Instillation

with quartz caused a large inflammatory reaction, whereas instillation with aluminum

lactate caused almost no inflammatory reaction. Similarly, the levels of macrophage

inflammatory protein-2 (MIP-2) tracked with the inflammatory reaction. There was

much less MIP-2 mRNA and protein in the BAL of rats instilled with aluminum lactate

than those instilled with untreated quartz. BAL protein and gamma glutamyl

transpeptidase, both indicators of epithelial cell (Type II and Clara) damage, were

increased with quartz but not with aluminum lactate. Additionally, BAL cells from rats

instilled with aluminum lactate showed minimal change in DNA binding of NF-κB, in

contrast to the marked increase in binding induced by quartz. As discussed earlier, NFκB is believed to be involved in the regulation of proinflammatory gene expression and

plays a role in the mechanism of action of silica toxicity. Duffin et al. (2001)

demonstrated that aluminum lactate had a greatly decreased ability to signal via the NFκB pathway for transcription of the key proinflammatory cytokine, MIP-2. Additionally,

it was demonstrated in vitro that aluminum lactate had a reduced surface activity as

indicated by a 60 percent decrease in the ability to generate hydroxyl radicals as well as a

reduced hemolytic potential.

Schins et al. (2002) examined the effect of coating silica with aluminum lactate on

silica toxicity, uptake, and silica-induced DNA damage in the human lung cell epithelial

cell line, A549. These cells have structural and biochemical characteristics of human

type II cells and are known to ingest particles. Two assays determined cytoxicity: the

MTT assay as an indicator of metabolic competence and the LDH assay a measure of

plasma membrane leakage. Measurements of DNA damage were DNA strand breakage

and the hydroxyl radical-specific DNA lesion 8-hydroxydeoxyguanosine (8-OHdG).

Coating with aluminum lactate significantly inhibited the cytotoxicity of quartz in

the MTT assay. Only uncoated quartz caused a significant increase in LDH at 4 hours.

However, at 24 hours LDH was significantly increased with both coated and uncoated

quartz, although this effect was less pronounced with aluminum lactate coating. The

formation of DNA strand breaks was also significantly reduced (χ

2

, p < 0.01) for the

coated quartz compared to uncoated quartz. Oxidative DNA damage was increased only

by the non-coated quartz. Lastly, cellular uptake of quartz particles coated with

aluminum lactate was markedly less than that seen with uncoated particles.

The authors concluded that the aluminum coating, which could easily occur

naturally, was shown to eliminate the ability of quartz both to generate hydroxyl radicals

and exert critical genotoxic effects that very likely play a role in quartz carcinogenesis.

The authors also believed that these data, along with previous data obtained in their
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laboratory, provided further support for a role of surface-mediated ROS-formation and

intracellular oxidant generation in the genotoxicity of quartz. The authors also noted that

the coating appeared to affect the acidity and the solubility of the quartz, perhaps

explaining its membranolytic potential. The coating was reported to hinder the formation

of surface radicals and block surface charge formation caused by grinding.

Knaapen et al. (2002) also examined the effect of aluminum treatment on the

DNA-damaging potential of silica in rat lung epithelial cells in vivo. Rats were exposed

to quartz or quartz treated with aluminum lactate by intratracheal instillation. After three

days, DNA strand breakage was measured in lung epithelial cells. In order to assess the

role of inflammatory cells in DNA strand breakage, the DNA damage was measured in

relation to the presence and activation of macrophages and neutrophils. BAL fluid was

used to determine macrophage and neutrophil influx. Neutrophil activation was

measured by myeloperoxidae (MPO), and total antioxidant capacity of the BAL fluid was

measured by the TEAC (trolox equivalent antioxidant capacity) assay. The authors

hypothesized that coating the silica surface with aluminum would prevent DNA damage

in the epithelial cells by inhibiting inflammatory cell influx into the lung. Uncoated silica

was shown to cause acute induction of DNA strand breaks. This effect was completely

inhibited by treatment of the silica with aluminum. Treatment with aluminum reduced

neutrophil influx and completely inhibited macrophage influx. MPO, the marker of

neutrophil activation, was increased only by uncoated silica. TEAC assay results showed

that both Al-treated and untreated silica resulted in an increased total antioxidant

capacity, but to a lesser extent with aluminum-treated silica. These results suggested to

the authors that the reactive particle surface plays an important role in silica-induced

DNA damage in vivo. The data also provided support for the possible role of

inflammatory cells in silica-induced genotoxicity.

The time course of silica-induced inflammation and the impact of coating with

aluminum were also investigated by Albrecht et al. (2004). These researchers

intratracheally treated rats with quartz or quartz coated with aluminum. Markers of lung

toxicity, inflammation, and oxidative stress (total protein, LDH, and alkaline phosphatase

in the BAL; total number of cells, macrophages and neutrophils, PMN percentage, βglucuronidase, and MIP-2 levels in the BAL; MPO and TEAC activities, respectively)

were determined at 3, 7, 21, and 90 days after quartz instillation. The authors

hypothesized that the inhibition of subacute inflammation by the coating of silica with

aluminum might reduce the onset and extent of epithelial hyperplasia (as preneoplastic

lesion) as well as fibrosis. Thus, the purpose of their study was to evaluate the

inflammatory response elicited by aluminum-coated quartz up to 90 days after

instillation. Quartz induced both an acute and subchronic inflammatory and oxidative

stress response. Quartz increased the total number of cells (alveolar macrophages,

neutrophils, PMN) in the BAL fluid and total number of macrophages and neutrophils

over time up to the 90-day point. The neutrophilic inflammation induced by quartz was

inhibited at various time points by aluminum coating (by 48 to 86 percent) but the PMN

percentage was significantly reduced (p < 0.01) only at 7 days. Aluminum coating also

reduced the quartz-induced increase in total protein in the BAL fluid seen at 28 and 90

days from 64 to 53 percent. The increase in LDH level in the BAL was also reduced by
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aluminum between 42 and 83 percent, although this level of LDH was still significantly

increased (p < 0.05) as compared to controls. Alkaline phosphatase (an indicator of

cytotoxicity) showed a significant increase only at 7 days after quartz instillation and this

was reduced by aluminum coating by 31 percent. Aluminum coating significantly

reduced the quartz-induced β-glucuronidase increase at all time periods (reduction

between 74 and 83 percent). However, at 90 days, the level of β-glucuronidase induced

by aluminum-coated quartz was still significantly increased over controls. The quartzrelated increase in MIP-2 levels, which continued throughout the 90-day period, was

reduced by aluminum coating until day 28 (by 32 to 43 percent). MPO and TEAC

activity was increased at all time periods by quartz and this increase was inhibited by

aluminum coating (MPO by 78 to 100 percent; TEAC by 43-57 percent). However, as

with β-glucuronidase, even with aluminum-coated quartz, a significant increase in TEAC

(p < 0.05) was still seen at the 90 day time point.

Albrecht et al. (2004) also measured activation of NF-κB in rat lung by quartz and

quartz coated with aluminum, using the indicators of degradation of the inhibitor protein

IκBα and immunohistochemistry for the p65 subunit of NF-κB. Treatment with

aluminum-treated quartz resulted in less degradation of IκBα and lesser amounts of p65

subunit of NF-κB than untreated-quartz at both 3 and 90 days after administration. Both

indicators, however, were still significantly different from controls after administration of

aluminum-coated silica. Aluminum coating also completely inhibited the translocation to

the nucleus of NF-κB upon treatment of RLE cells in vitro with BAL fluid taken at 3

days from rats treated with quartz. From their results, the authors concluded that

aluminum coating reduced the acute inflammatory and toxic effects of quartz but did not

inhibit the persistent inflammation.

It has been noted that treatment of silica with aluminum lactate has been used as a

model to study the protective effects of aluminum silicate clays on the quartz surface

(Clouter et al., 2001). There are several studies on the protective effect of occlusion with

aluminum silicate clays. The research group of Fubini et al. (along with the research

group that conducted the studies just discussed above) has published a series of studies

relating the state of the surface of quartz to biological activity in vitro and in vivo (Bruch

et al., 2004; Cakmak et al., 2004; Fubini et al., 2004). They examined the surface

properties of four commercial quartz flours. Two of the samples had been shown to

cause inflammation in vivo and to activate macrophages in vitro. The two active samples

were also genotoxic in vivo. The other two samples, which were mostly inert, contained

a higher content of impurities, including aluminum, potassium, carbon, and iron. The

authors suggested that their results were consistent with a model in which the difference

in behavior of the four dusts are mainly caused by different levels and dispersion of

contaminants on the silica surfaces (mainly aluminum and potassium, but possibly also

iron), which changed the silanol patches that correlate with cell damage. They proposed

that the aluminum may have originated from kaolinite that might either remain as intact

grains on the quartz surfaces or be spread on the harder quartz surface during grinding,

thus providing reactive aluminum ions located in prominent positions. The more

extended the aluminum dispersion, the less ordered the silanol patches would be. They

suggested that the presence of aluminum may favor the clearance of the quartz before it
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could damage cells. The two toxic quartzes, having ordered silanol patches, would

initiate the macrophage ingestion-reingestion cycle. According to the authors, several

differences found between the two low- and two high- toxicity quartzes may be explained

on the basis of the low-toxicity samples having a high level of poorly coordinated

aluminum ions at the surface. The authors cited the Duffin et al. (2001) study discussed

above, suggesting that the aluminum ions on their samples may act similarly to those

deposited from aluminum lactate in that study. Finally, the authors, citing studies that

have demonstrated that kaolin contamination reduces quartz toxicity, suggested that

kaolin contamination may leave aluminum ions at the abraded quartz surface during

grinding.

Wallace et al. (1990) have examined the issue of aluminosilicate clay occlusion of

quartz and its effect on toxicity. They noted that in mining and some other dusty

workplaces, the measurements of quartz content are not always accurate predictors of the

prevalence of silica-related disease. The authors suggested that the biologically available

quartz surface may not be equivalent to the conventionally-measured quartz content of

the respirable dust in such settings. Wallace et al. (1990) devised an analytical method

and examined samples of settled and airborne dust from a clay mine and mill. They

determined that some of the respirable quartz particles were occluded with

aluminosilicate. The question arose as to whether clay would remain attached to a

respirable quartz particle after deposition in the lung. To simulate this situation, quartz

samples were mixed with lecithin surfactant for 3 hours. The particles retained the clay

occlusion on their surfaces, suggesting that after deposition in the lung, and before

phagocytosis by pulmonary macrophages, some quartz particles would present

themselves as clay-surfaced. The authors suggested that the longer-term fate of such

coatings during phagolysosomal events and clearance or sequestration would determine if

and when unoccluded quartz surfaces of the particle became biologically available to

tissue.

Wallace et al. (1996) cited research that has indicated that clay-occluded silica

particles show comparable in vitro cytotoxicity to the same amount (size and surface area

comparable) of pure quartz. They noted that comparisons of pathologic potential and

silica exposure must, therefore, be made on the basis of worker population

epidemiological data, for which surface properties of dust exposures typically are not

investigated, or on the basis of in vivo animal model studies. Commenting on the results

of the earlier 1990 study, the authors expressed the opinion that relatively soluble clay

occlusion would be expected to persist at least until phagocytosis but that longer-term

persistence under conditions of residence in interstitial tissue or the lymphatics was an

open question. The authors, therefore, called for additional research to detail the nature

of such occluded particle surfaces, the geological and processing factors which affect

such occlusion, and the durability of such particles in tissue.

Stone et al. (2004) have studied whether water soluble extracts of standard clay

samples also block the reactivity of pure quartz samples both in vivo and in vitro. DQ12

samples were treated with water soluble extract of high aluminum clays (kaolin and

attapulgite) or low aluminum clays (hectorite and montmorillonite). The effect of these
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treatments on DQ12-induced hemolysis of sheep erythrocytes in vitro and inflammation

in vivo as indicated by increases in the total cell numbers, neutrophil cell numbers, MIP-2

protein, and albumin content of the BAL fluid was examined. Treatment with the

extracts of either of the high aluminum clays completely inhibited DQ12-induced

hemolysis. Addition of a cation chelator to the kaolin extracts significantly prevented the

inhibition. Extracts of the low aluminum clays had no inhibitory effect. Treatment of the

DQ12 with either a high aluminum clay extract (kaolin) or the low aluminum clay

(hectorite) significantly inhibited the increases in total inflammatory cell number,

neutrophil cell number, and protein in the BAL. The authors suggested that, since

hectorite did not prevent hemolysis but did prevent inflammation, either there was a

difference in sensitivity of the two assays to the silica surface or a difference in the

mechanism by which hectorite inhibits silica activity compared to the other sample

extracts. According to the authors, the kaolin extract inhibition of inflammation supports

the hypothesis that aluminum salts within aluminum-rich silicate clays may dampen the

potency of the silica surface. However, the observation that hectorite was also inhibitory

suggested that substances other than aluminum can reduce the reactivity of the silica

surface. Hectorite had relatively high levels of MgO and CaO.

Several studies have examined the role of surface-modified silica in human silicarelated disease or in workplaces where silica occurs. For instance, Tourmann and

Kauffman (1994) studied the contents of dusts recovered from lungs of coal miners with

silicosis. They used an analytical technique that could distinguish between pure quartz

particles and an admixture of quartz and clay particles. Citing other studies showing that

the fibrogenicity of some quartz-rich samples of coal mine dusts correlated better with

the incidence of pure quartz particles than with the gross quartz content, they

hypothesized that there would be a positive correlation of silicosis grade with the pure

quartz content of recovered lung dusts. However, no such correlation was observed. In

fact, even for one sample that had a high gross quartz content, only a minute fraction of

pure quartz particles could be detected. Most of the quartz of the dusts recovered from

silicotic lungs was still contaminated with clay minerals. The authors concluded that the

aluminosilicate layers on quartz do not dissolve completely and thus do not reveal new

quartz particles with free surfaces. Furthermore, protective layers persist, even during

long-term contact with human lung tissues (up to 40 to 50 years). The preliminary

results suggested that the fibrosis caused by these coal mine dusts may be correlated with

the release of iron from iron-containing mineral particles.

Several epidemiologic studies have examined the risks of silicosis and other

respiratory diseases in industries where the workers would be presumed to be exposed to

silica subject to aluminosilicate clay occlusion. Love et al. (1999) conducted a crosssectional study of the risk of silicosis and other respiratory diseases in the heavy clay

industry in the United Kingdom. Although ninety-seven percent of all quartz

concentrations were less than 0.4 mg/m3respirable quartz, 10 percent were higher than

this among the groups of workers exposed to the most dust. The profusion of small

opacities in the chest radiographs classified as ≥ ILO category 1/0 was 1.4% (25 workers)

and 7 of those workers had radiographs rated ≥ category 2/1. A logistic regression of risk

of median profusion of small opacities category ≥ 0/1 for a 25 year old non-smoker with
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a cumulative respirable quartz exposure of 1 mg/m3-year found that a doubling of

cumulative quartz exposure increased the risk by a factor of 1.33 (95% CI 1.05 to 1.68)

The prevalence of chronic bronchitis and breathlessness were 14.2 and 4.4 percent,

respectively and both were significantly related to dust exposure with ORs of 1.5 (95%

CI 1.1 to 2.0) and 1.5 (95% CI 1.1 to 2.2), respectively. The authors called the

prevalence figure for silicosis “relatively low” and suggested that the accompanying clay

minerals, and specifically the release of aluminum, had modified (reduced) the toxicity of

the quartz.

A retrospective cohort epidemiologic study has examined the risk of silicosis in

Chinese tin and tungsten miners and pottery workers with regard to the clay occlusion of

the silica in those workplaces (Chen et al. 2005; Harrison et al., 2005). This study is

reviewed in detail in Section VI, Preliminary Quantitative Risk Assessment, and is briefly

described here. The cohorts included 4,028 tin miners, 14,427 tungsten miners, and

4,547 pottery workers selected from 20 Chinese mines and potteries. Respirable silica

particles from these three types of workplaces were analyzed for occlusion of the silica

particle surfaces. According to the authors, the cumulative risk of silicosis for a given

level of cumulative respirable silica exposure was significantly lower for the pottery

workers compared to tin and tungsten miners. Analysis of the silica surfaces showed that

55 percent of surfaces of the silica particles from the potteries were not occluded,

compared to 82 percent from the tin mines, and 87 percent from the tungsten mines.

When cumulative exposure was adjusted for silica surface availability, much of the

difference in the exposure-response relationships between the pottery cohort and the

miner cohorts was resolved. The authors concluded that differences in clay occlusion of

silica particles was a factor in the differences in silicosis risk observed between the

pottery workers and miners. They suggested that silica particle surface occlusion by

aluminosilicate clay may have partially but substantially diminished fibrogenic activity of

pottery workplace silica dusts.

I.F.5. Preliminary Conclusions on Factors Affecting the Toxicity of Crystalline

Silica.

OSHA has reviewed evidence concerning potential effects on silica-related

toxicity of physical factors such as crystal polymorphism; the age of fractured surfaces of

the crystal particle; the presence of impurities, particularly metals, on particle surfaces;

and clay occlusion of the particle. These factors likely vary among different workplace

settings suggesting that the risk to workers exposed to a given level of respirable

crystalline silica may not be equivalent in different work environments.

The modification of surface characteristics by the physical factors noted above

may alter the toxicity of silica by affecting the physical and biochemical pathways of the

mechanistic process. Thus, OSHA has reviewed the proposed mechanisms by which

silica exposure leads to silicosis and lung cancer. It has been proposed that silicosis

results from a cycle of cell damage, oxidant generation, inflammation, scarring and

fibrosis. A silica particle entering the lung can cause lung damage by two major

mechanisms: direct damage to lung cells due to the silica particle’s unique surface
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properties or by the activation or stimulation of alveolar macrophages (after

phagocytosis) and/or alveolar epithelial cells. In either case, an elevated production of

ROS/RNS results in oxidant damage to lung cells. The oxidative stress and lung injury

stimulates alveolar macrophages and/or alveolar epithelial cells to produce growth factors

and fibrogenic mediators, resulting in fibroblast activation and pulmonary fibrosis. A

continuous ingestion-reingestion cycle, with cell activation and death, is established. The

mechanism of silica-induced carcinogenesis may also involve the generation of ROS that

may damage the lung epithelia and play a role in DNA damage and cell proliferation

(Castranova, 2004; Fubini et al., 2004; Shi et al., 1989, 1998).

Thus, the early steps in the proposed pathways that lead to silicosis and lung

cancer seem to share some common features, leading some researchers to suggest that

silicosis is a prerequisite to lung cancer in silica-exposed individuals. Oxidative stress

has been proposed to play a key role in the pathogenesis of silicosis and silica-induced

lung cancer (Castranova 2004). Driscoll and Guthrie (1997) believed that any increased

lung cancer risk associated with silica may be a consequence of the inflammation and

increased epithelial cell proliferation associated with the development of silicosis.

However, these authors completed a further study and determined that there were other

key factors in silica-induced alveolar epithelial cell mutagenesis in addition to the

inflammatory response (Johnston et al., 2000). Additional proposed mechanisms

involved in silica-induced carcinogenesis include direct DNA damage, inhibition of p53,

loss of cell cycle regulation, stimulation of growth factors, and production of oncogenes

(Castranova, 2004; Fubini et al., 2004; Shi et al., 1989, 1998). Thus, it appears that lung

cancer could arise from either inflammatory reactions responsible for silicosis or from

other mechanisms not involving fibrogenesis. OSHA preliminarily concludes that

available animal and in vitro studies have not conclusively demonstrated that silicosis is a

prerequisite for lung cancer in silica-exposed individuals.

A number of epidemiologic studies have also examined the relationship between

silicosis and lung cancer (Checkoway and Franzblau, 2000; see also Section V.C.4).

Checkoway and Franzblau (2000) concluded, and OSHA agrees, that the question of

whether silicosis is required for elevated lung cancer risk in silica-exposed individuals is

virtually unanswerable from currently available epidemiologic literature, and is unlikely

to be addressable in future epidemiologic studies.

OSHA has examined evidence on the comparative toxicity of the silica

polymorphs (quartz, cristobalite, and tridymite). A number of animal studies appear to

suggest that cristobalite and tridymite are more toxic to the lung than quartz and more

tumorigenic (e.g., King et al., 1953; Wagner et al., 1980). However, in contrast to these

findings, several authors have reviewed the studies done in this area and concluded that

cristobalite and tridymite are not more toxic than quartz (e.g., Bolsaitis and Wallace,

1996; Guthrie and Heaney, 1995). Furthermore, a difference in toxicity between

cristobalite and quartz has not been observed in epidemiologic studies (tridymite has not

been studied) (NIOSH, 2002). In an analysis of exposure-response for lung cancer,

Steenland et al. (2001a) found similar exposure-response trends between cristobaliteexposed workers and other cohorts exposed to quartz.
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A number of studies have compared the toxicity of freshly fractured versus aged

silica. Although animal studies have demonstrated that freshly fractured silica is more

toxic than aged silica, aged silica still retains significant toxicity (Porter et al., 2002;

Shoemaker et al., 1995; Vallyathan et al., 1995). Studies of workers exposed to freshly

fractured silica have demonstrated that these workers exhibit the same cellular effects as

seen in animals exposed to freshly fractured silica (Castranova et al., 1998; Goodman et

al., 1992). There have been no studies, however, comparing workers exposed to freshly

fractured silica to those exposed to aged silica. Animal studies also suggest that

pulmonary reactions of rats to short-duration exposure to freshly fractured silica mimic

those seen in acute silicosis in humans (Vallyathan et al., 1995).

Surface impurities, particularly metals, have been shown to alter silica toxicity.

Iron, depending on its state and quantity, has been shown to either increase or decrease

toxicity. Aluminum has been shown to decrease toxicity (Castranova et al., 1997;

Donaldson and Borm, 1998; Fubini, 1998). Silica coated with aluminosilicate clay

exhibits lower toxicity possibly due to reduced bioavailability of the silica particle

surface (Donaldson and Borm, 1998; Fubini, 1998). This may be due to aluminum ions

left on the silica surface by the clay (Bruch et al., 2004; Cakmak et al., 2004; Fubini et

al., 2004). Aluminum and other metal ions are thought to modify silanol groups on the

silica surface, thus decreasing the membranolytic and cytotoxic potency and resulting in

enhanced particle clearance from the lung before damage can take place (Fubini, 1998).

An epidemiologic study found that the risk of silicosis was less in pottery workers than in

tin and tungsten miners (Chen et al., 2005; Harrison et al., 2005), possibly reflecting that

pottery workers were exposed to silica particles having less biologically available, nonclay-occluded surface area than was the case for miners. The authors concluded that clay

occlusion of silica particles can be a factor in reducing disease risk.

Although it is evident that a number of factors can act to mediate the toxicological

potency of crystalline silica, it is not clear how such considerations should be taken into

account to evaluate lung cancer and silicosis risks to exposed workers. After evaluating

many in vitro studies that had been conducted to investigate the surface characteristics of

crystalline silica particles and their influence on fibrogenic activity, NIOSH (2002)

concluded that further research is needed to associate specific surface characteristics that

can affect toxicity with specific occupational exposure situations and consequent health

risks to workers. According to NIOSH (2002), such exposures may include work

processes that produce freshly fractured silica surfaces or that involve quartz

contaminated with trace elements such as iron. NIOSH called for further in vitro and in

vivo studies of the toxicity and pathogenicity of alpha quartz compared with its

polymorphs, quartz contaminated with trace elements, and further research on the

association of surface properties with specific work practices and health effects.

In discussing the “considerable” heterogeneity shown across the 10 studies used

in the pooled lung cancer risk analysis, Steenland et al. (2001a) pointed to hypotheses

that physical differences in silica exposure (e.g., freshness of particle cleavage) between

cohorts may be a partial explanation of observed differences in exposure-response
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coefficients derived from those cohort studies. However, the authors did not have

specific information on whether or how these factors might have actually influenced the

observed differences. Similarly, in the pooled analysis and risk assessments for silicosis

mortality conducted by Mannetje et al. (2002b), differences in biological activity of

different types of silica dust could not be specifically taken into account. Mannetje et al.

(2002b) determined that the exposure-response relationship between silicosis and logtransformed cumulative exposure to crystalline silica was comparable between studies

and no significant heterogeneity was found. The authors therefore concluded that their

findings were relevant for different circumstances of occupational exposure to crystalline

silica. Both the Steenland et al. (2001a) and Mannetje et al. (2002b) studies are discussed

in detail in Section II, Preliminary Quantitative Risk Assessment.

OSHA preliminarily concludes that there is considerable evidence to support the

hypothesis that surface activity of crystalline silica particles plays an important role in

producing disease, and that several environmental influences can modify surface activity

to either enhance or diminish the toxicity of silica. However, OSHA believes that the

available information is insufficient to determine how these influences may affect disease

risk to workers in any particular workplace setting.

I.G. Overall Conclusions.

Silicosis is a disabling, non-reversible, and progressive lung disease caused by

inhaling dust containing crystalline silica. In its later stages, it is associated with

significant loss of lung capacity and gas exchange function, and increased airflow

obstruction. The person with silicosis experiences dyspnea (difficulty breathing), perhaps

while attempting to complete the most simple activities of daily living. On average, those

with silicosis have a life span approximately 11 years shorter than those without silicosis

(NIOSH, 2008c; NORMS database).

Silicosis can be detected using chest radiography and computed tomography,

though both techniques are relatively insensitive and will not detect the presence of

silicosis in a large proportion of affected individuals, particularly in its early stages.

Although many cases of silicosis may be missed using these imaging techniques, those

cases that are identified are very likely to be not only true, but well-established silicosis

cases. However, several recent studies and reviews have suggested that a newer type of

computed tomography known as high resolution computed tomography may be superior

to chest x-ray in the early detection of silicosis and the identification of progressive

massive fibrosis (Blum et al., 2008; Sun et al., 2008; Lopes et al., 2008).

Progression of silicosis is typically defined in terms of increasing profusion of

fibrotic tissue, which appears as opacities on x-ray; however decrements in lung function,

as measured by spirometry or PFT, also characterize the progression of the disease. Lung

function deterioration has been documented to occur more rapidly in workers exposed to

crystalline silica, especially those with silicosis, than is expected from the normal aging

process.
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OSHA reviewed studies that evaluated the course of progression, as observed on

x-ray and as measured by spirometry, and was particularly interested in studies that

attempted to correlate x-ray progression with functional decrements over time. No

studies were found that were designed to elicit information on the temporal relationship

(i.e., which occurred first) between x-ray progression and changes in pulmonary function.

Two studies attempted to evaluate progression by comparing both chest x-rays and PFTs

for the same workers for at least two distinct points in time (Cowie, 1998; Ng and Chan,

1992;). Ng and Chan (1992) found statistically significant lung function decrements that

exceeded the expected values for those men with chest x-rays consistent with ILO

categories 2 and 3. In the literature and medical texts, silicosis graded on the ILO scale

as Category 3 (3/2, 3/3, 3/+), due to either the size or the extent of opacities viewed on xray or due to the presence of complications such as pulmonary massive fibrosis (PMF) or

tuberculosis (TB), has been widely associated with significant pulmonary impairment.

For ILO Category 2, the extent of pulmonary impairment has been less definitive.

For the earlier stages of silicosis (0/1 or 1/0 to 1/1), the literature reported, in

general, that associated impairment may be relatively mild, and few studies included

examination and testing of workers whose silicosis was categorized as less than ILO

Category 2. One exception, however, was Cowie (1998), who reported that lung function

deteriorated across all categories and that the deterioration increased in proportion to the

degree of silicosis. Other studies have reported finding measurable decrements in

pulmonary function that exceed those related to age, with no radiographic evidence of

silicosis, and have raised the question of whether functional decrements precede the

detection of silicosis on chest x-rays.

Based on the evidence in these studies, OSHA preliminarily concludes that there

is a positive association between pulmonary function decrements and radiographic

silicosis graded at least category 2 (i.e., for categories 2 and 3) on the ILO scale. For ILO

category 1, OSHA believes that the evidence is insufficient to make a preliminary finding

that pulmonary function decrements can occur among those with early radiologic

evidence of silicosis (ILO Category 1), or even absent such evidence. While a few

investigators found evidence of reduced lung function prior to radiological initiation of

silicosis (ILO category 0/1 or 1/0), OSHA preliminarily determines that those decrements

have not been substantial or reported consistently enough for a finding of an association

between lung function decrements and a radiograph consistent with ILO category 0/1 or

1/0. It is important to note that this finding is based on insufficient evidence found in the

research, and not sufficient evidence of a lack of an association.

Silicosis is known to be a progressive disease, both with and without further

exposure to crystalline silica (Hessel et al., 1988; Ng et al., 1987a; Ogawa et al., 2003;

Yang et al., 2006). Progression rates, i.e., the increase in the number of sub-categories on

the ILO profusion scale exhibited by persons with silicosis, have been the subject of

several studies. OSHA is particularly interested in studies that attempted to quantify

progression in workers exposed to levels of silica near OSHA’s current PEL (0.1 mg/m3).

Unfortunately, few studies have included reliable measurements of historical exposures,

and when reconstructions of past exposures were attempted, they are generally
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considerably higher than the current PEL. One study (Ng et al., 1987a), reported mean

respirable silica exposure of 0.48 mg/m3for the workers identified as “simple silicotics,”

and found that 45% of the 53 patients progressed at least one sub-category on the ILO

system over a mean of 7.2 years. In the cohort of South African miners followed

longitudinally by Cowie (1998), silicosis progressed an average of one subcategory of

nodule profusion during the 4.5 years. Unfortunately, no exposure data were provided.

Based on its review of the literature, OSHA preliminarily concludes that the

exposure variables that are positively related to the progression of silicosis (i.e., those for

which higher exposure correlates with higher risk) are average concentration of

crystalline silica (Hughes et al., 1982; Ng et al., 1987a), cumulative respirable quartz (or

silica) exposure, and duration of exposure (usually determined by duration of

employment or length of service in a particular job). These are the same exposure factors

that have been shown to play a role in the initiation of silicosis. Once silicosis has been

detected, the likelihood of progression continues, even in the absence of additional

exposure to silica (Hessel et al., 1988; Miller et al., 1998; Ogawa, et al., 2003; Yang et

al., 2006), although those with silicosis exposed after onset of disease are more likely to

progress than those who are not further exposed (Hessel et al., 1988).

Some authors have suggested that the decline in pulmonary function observed in

occupational cohorts exposed to crystalline silica may not be directly due to the silicarelated fibrosis, but may be due to an alternate process that occurs prior to the

development of silicosis, for example, mixed dust fibrosis. Though this may account for

some of the inconsistency in the findings in the studies that attempted to measure and

correlate x-ray findings and PFT measures, differences in study design, exposure

misclassification, and errors in exposure measurements, x-ray findings, and PFT

measurements could also account for the observed inconsistencies.

Nonmalignant respiratory diseases (NMRD) other than silicosis have been linked

to silica exposure, which may also explain some of the inconsistencies in findings

attempting to correlate lung function with early radiographic evidence of silicosis. Based

on the findings of studies of the relationship of silica exposure to morbidity from

emphysema, bronchitis, and lung function impairment (as measured by spirometry), and

mortality from NMRD (other than silicosis), OSHA preliminarily concludes that an

exposure-response relationship exists for exposure to respirable crystalline silica and the

risk of these conditions and that these conditions can occur in the absence of silicosis.

However, except for NMRD mortality, data are insufficient for quantitative risk

assessment. For emphysema, silica exposure may not increase risk among non-smokers.

For all conditions, the effect of smoking may be additive (except for NMRD mortality,

e.g., see Hnizdo, 1990) or synergistic.

OSHA conducted an independent review of the epidemiological literature on

exposure to respirable crystalline silica and lung cancer, covering more than 30

occupational groups in over a dozen industrial sectors. In addition, OSHA reviewed a

pooled case-control study, a large national death certificate study, two cancer registry

studies, and six meta-analyses. Based on this review, OSHA preliminarily concludes that
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the human data summarized in this section provides ample evidence that exposure to

respirable crystalline silica increases the risk of lung cancer among exposed workers.

The strongest evidence for the carcinogenicity of respirable crystalline silica

comes from the worldwide cohort and case-control studies reporting excess lung cancer

mortality among workers exposed to silica dust as quartz in various industrial sectors,

including granite/stone quarrying and processing, industrial sand, pottery and ceramic,

and coal mining industries, as well as to cristobalite in diatomaceous earth and refractory

brick industries. In addition, several studies of metal ore mining cohorts have found

excess lung cancer risks to be associated with exposure to respirable crystalline silica,

although exposures to other co-carcinogens were also present, complicating interpretation

of the findings. The 10-cohort pooled case-control analysis by Steenland et al. (2001a)

confirms these findings. A more recent, clinic-based pooled case-control analysis of

seven European countries by Cassidy et al. (2007) as well as two national death

certificate registry studies (by Pukkala et al., 2005 in Finland and by Calvert et al., 2003

in the United States) support the findings of the cohort and case-control analysis.

Among studies conducted on cohorts in three industry sectors (foundry, silicon

carbide, and construction), OSHA found that silica exposures were profoundly

confounded by the presence of exposures to other carcinogens. However, with respect to

the construction industry, Cassidy et al. (2007) reported finding a statistically significant

elevated odds ratio of 1.27 for lung cancer. This study was a very large multi-national

European case-control study, which had detailed analysis of exposure to silica and many

other occupational exposures, as well as smoking histories obtained principally from

interviews of cases and controls.

OSHA reviewed the literature regarding concomitant exposure to crystalline silica

and tobacco smoke. Given the findings of investigators who have accounted for the

impact of smoking, OSHA believes that there is sufficient evidence to identify respirable

crystalline silica as an independent risk factor for lung cancer mortality. This finding is

also supported by animal studies demonstrating that exposure to silica alone can cause

lung cancer (e.g., Muhle et al., 1995).

In general, studies of workers with silicosis, as well as meta-analyses that include

these studies, have shown that silicotics have higher lung cancer risk than non-silicotics

or mixed cohorts. Three meta-analyses attempted to look at the association of increasing

ILO radiographic categories of silicosis with increasing lung cancer mortality; two

showed no association with increasing lung cancer mortality, while Lacasse et al. (2005)

demonstrated a positive dose-response for lung cancer with increasing ILO radiographic

category. Animal and in vitro studies have demonstrated that the early steps in the

proposed mechanistic pathways that lead to silicosis and lung cancer seem to share some

common features. This has led some of these researchers to suggest that silicosis is a

prerequisite to lung cancer in silica-exposed individuals. However, other studies have

suggested alternative mechanisms such as direct DNA damage, inhibition of p53, loss of

cell cycle regulation, stimulation of growth factors, and production of oncogenes. After

reviewing all available evidence, OSHA preliminarily concludes that epidemiologic,
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animal, and in vitro studies do not convincingly show that silicosis (as defined by chest xray findings) is a necessary precursor to lung cancer induction in silica-exposed

individuals.

Respirable crystalline silica exposure has also been investigated as a potential risk

factor for cancer at other sites including cancer of the larynx and nasopharynx and

cancers of the digestive system including the esophagus or stomach. Although many of

these studies suggest an association between exposure to crystalline silica and an excess

risk of cancer mortality, most are too limited in terms of size, study design, or potential

confounding to be conclusive. Other than for lung cancer, cancer mortality studies

demonstrating a dose-response relationship are quite limited. In 2002, NIOSH concluded

that, exclusive of the lung, an association has not been established between silica

exposure and excess mortality from cancer at other sites. At this point in time, OSHA

concurs with this finding.

Epidemiologic studies have demonstrated an association between exposure to

crystalline silica and increased risk of renal and autoimmune disease. Studies have found

statistically significant associations between occupational exposure to silica dust and

chronic renal disease, sub-clinical renal changes, end-stage renal disease morbidity,

chronic renal disease mortality, and Wegener’s granulomatosis. A strong exposureresponse association for renal disease mortality and silica exposure has also been

demonstrated (Steenland et al., 2002a). A number of epidemiologic studies have found

an association between silica exposure and increased risk of systemic autoimmune

diseases, such as scleroderma, rheumatoid arthritis; and systemic lupus erythematosus.

There are no quantitative exposure-response data with regard to autoimmune diseases.

OSHA preliminarily concludes that there is substantial evidence that silica

exposure increases the risks of renal and autoimmune disease. The positive and

monotonic exposure-response trends demonstrated for silica exposure and renal disease

risk more strongly suggest a causal link. OSHA preliminarily concludes that the

underlying data are sufficient to provide estimates of risk for renal disease. OSHA also

preliminarily concludes that at the present time insufficient evidence exists for a

quantitative estimate of risk of systemic autoimmune diseases associated with

occupational exposure to silica.

A number of physical factors appear to influence the toxicity of silica. Freshly

fractured silica has been shown to be more toxic than aged. Aluminum, by itself or as

part of an aluminosilicate clay coating, appears to decrease toxicity. Iron can decrease or

increase toxicity, depending on its valence state and amount. However, OSHA

preliminarily concludes that available information on these factors is not specific enough

at this time to predict how risks might vary among exposed employees in different

industry sectors. OSHA also preliminarily concludes, based on epidemiologic and

experimental evidence, that the crystalline silica polymorphs quartz, cristobalite, and

tridymite have similar toxicity and carcinogenic potency.
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II. Preliminary Quantitative Risk Assessment.

II.A. Introduction.

The Occupational Safety and Health Act (OSH Act or Act) and some landmark

court cases have led OSHA to rely on quantitative risk assessment, where possible, to

support the risk determinations required to set a permissible exposure limit (PEL) for a

toxic substance in standards under the OSH Act. Section 6(b)(5) of the Act states that:

“The Secretary [of Labor], in promulgating standards dealing with toxic materials or

harmful physical agents under this subsection, shall set the standard which most

adequately assures, to the extent feasible, on the basis of the best available evidence, that

no employee will suffer material impairment of health or functional capacity even if such

employee has regular exposure to the hazard dealt with by such standard for the period of

his working life” (29 U.S.C. 655).

In a further interpretation of the risk requirements for OSHA standard setting, the

United States Supreme Court in the 1980 “Benzene” decision, (Industrial Union

Department, AFL-CIO v. American Petroleum Institute, 448 U.S. 607, 639 (1980)), ruled

that the OSH Act requires that, prior to the issuance of a new standard, a determination

must be made that there is a significant risk of material impairment of health at the

existing PEL and that issuance of a new standard will significantly reduce or eliminate

that risk. The Court stated that “before he can promulgate any permanent health or safety

standard, the Secretary is required to make a threshold finding that a place of

employment is unsafe in the sense that significant risks are present and can be eliminated

or lessened by a change in practices” (448 U.S. 642). While the Court indicated that the

use of quantitative risk analysis was an appropriate means to establish significant risk, it

made clear that “OSHA is not required to support its finding that a significant risk exists

with anything approaching scientific certainty” (448 U.S. 656).

A determining factor in the decision to perform a quantitative risk assessment is

the availability of suitable data for such an assessment. In the case of crystalline silica,

there has been extensive research on its health effects and several quantitative risk

assessments have been published in the peer-reviewed scientific literature that describe

the risk to exposed workers of lung cancer mortality, silicosis and non-malignant

respiratory disease mortality, renal disease mortality, and silicosis morbidity. These

assessments were based on several studies of occupational cohorts in a variety of industry

sectors, the underlying studies of which are described in the Health Effects section of this

preamble.

Quantitative risk assessments for lung cancer and silicosis mortality were

published after 1997, when the International Agency for Research on Cancer (IARC)

determined that there was sufficient evidence to regard crystalline silica as a human

carcinogen (IARC, 1997). This finding was based on several studies of worker cohorts

demonstrating associations between exposure to crystalline silica and an increased risk of

lung cancer. Although IARC judged the overall evidence as being sufficient to support

this conclusion, IARC also noted that some studies of crystalline silica-exposed workers

did not demonstrate an excess risk of lung cancer and that exposure-response trends were
267

not always consistent among studies that were able to describe such trends. These

findings led Steenland et al. (2001a) and Mannetje et al. (2002b) to conduct

comprehensive exposure-response analyses of the risk of lung cancer and silicosis

mortality associated with exposure to crystalline silica. These studies, referred to as the

IARC multi-center studies of lung cancer and silicosis mortality, relied on all available

cohort data from previously published epidemiological studies for which there were

adequate quantitative data on worker exposures to crystalline silica to derive pooled

estimates of disease risk. In addition, OSHA identified four single-cohort studies of lung

cancer mortality that it judged suitable for quantitative risk assessment; two of these

cohorts (Attfield and Costello, 2004; Rice et al., 2001) were included among the 10 used

in the IARC multi-center study and studies of two other cohorts appeared later (Hughes et

al., 2001; Miller and MacCalman, 2009). For non-malignant respiratory disease

mortality, in addition to the silicosis mortality study by Mannetje et al. (2002b), Park et

al. (2002) conducted an exposure-response analysis of non-malignant respiratory disease

mortality (including silicosis and other chronic obstructive pulmonary diseases) among

diatomaceous earth workers. Exposure-response analyses for silicosis morbidity have

been published in several single-cohort studies (Chen et al., 2005; Hnizdo and SluisCremer, 1993; Steenland and Brown, 1995b; Miller et al., 1998; Buchanan et al., 2003).

In addition to these published studies, OSHA’s contractor, Toxichemica, Inc.,

commissioned Drs. Kyle Steenland and Scott Bartell of Emory University to perform an

uncertainty analysis to examine the effect on lung cancer and silicosis mortality risk

estimates of uncertainties that exist in the exposure assessments underlying the two IARC

multi-center analyses (Toxichemica, Inc., 2004). In the sections below, OSHA describes

the published risk assessments for lung cancer mortality, silicosis mortality, and silicosis

morbidity and the results of the uncertainty analysis. This is followed by discussions of

the appropriateness of using cumulative exposure as the exposure metric in the risk

assessments, factors that have been reported to attenuate or enhance the toxicological

potency of crystalline silica, and OSHA’s overall preliminary conclusions.

In quantitative risk assessments presented in past rulemakings, OSHA typically

has estimated lifetime risks associated with exposure to the current permissible exposure

limit (PEL) and the proposed exposure limit(s) over a full working life (i.e., 45 years). In

the case of respirable silica, OSHA’s PELs for general industry, shipyard employment,

and construction are variable entities since the PELs are expressed as formulas that

impose a limit on exposure to respirable dust, with the limit decreasing with increasing

crystalline silica content. OSHA’s current general industry PEL for respirable quartz is

expressed both in terms of a particle count formula and a gravimetric concentration

formula, while the current construction and shipyard employment PELs for respirable

quartz are only expressed in terms of a particle count formula. OSHA’s current

gravimetric formula PEL for quartz in general industry is

10 mg/m3/(%quartz + 2),

expressed as the 8-hour time-weighted average (TWA) concentration of respirable dust.

As an example, if a respirable dust sample contained 18 percent quartz, the PEL would be

0.5 mg/m3(or 10/(18+2)) of respirable dust, which would be equivalent to a respirable
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quartz concentration of 0.09 mg/m3(0.5 mg/m3 X 18%). For quartz concentrations

exceeding 5 percent, the PEL expressed as the concentration of respirable quartz exceeds

0.07 mg/m3and approaches 0.1 mg/m3as the quartz content increases. For the purposes

of the risk assessment, the general industry PEL formula is considered approximately

equal to 0.1 mg/m3respirable quartz. OSHA’s general industry PEL for cristobalite and

tridymite is half that of the PEL for quartz (i.e., approximately 0.05 mg/m3).

OSHA’s construction and shipyard PELs are based on particle count according to

the formula

250 mppcf/(%quartz + 5),

where mppcf is million particles per cubic foot. The relationship between the particlecount PEL and gravimetric PEL will vary with the density of the particles and particle

size distribution of airborne dust generated during an operation and thus is not expected

to be constant across all construction and shipyard operations. However, a number of

investigators have used concurrent particle count and mass dust sampling data from a

variety of industrial settings to develop conversion factors that can be used to estimate

mass-based exposures from particle count exposure measurements; these factors have

been reported to range from 0.07 to 0.2 mg/m3respirable dust per mppcf, with most

estimates clustering around 0.1 mg/m3per mppcf (Ayer et al., 1968; Ayer et al. 1973;

Jacobson and Tomb, 1967; Sheehy and McJilton, 1987; Steenland et al., 2001a; Sutton

and Reno, 1968). As described in Table I-1 of the health effects review, investigators

have used similar values as a basis for estimating exposures of cohorts in epidemiological

studies, although Rando et al. (2001) used higher conversion factors in their study of U.S.

industrial sand workers (ranging from 0.206 to .364). Applying a conversion factor of

0.1 mg/m3respirable dust per mppcf to OSHA’s construction and shipyard PELs for

quartz, and assuming a quartz content of 5, 10, 50 or 100 percent in respirable dust, yields

equivalent gravimetric PELs of 0.125, 0.167, 0.227, and 0.238 mg/m3of respirable

quartz. Using a higher conversion factor of 0.2 mg/m3respirable dust per mppcf yields

equivalent gravimetric PELs of 0.250, 0.333, 0.455, and 0.476 mg/m3respirable quartz

for 5, 10, 50, and 100 percent quartz content of respirable dust, respectively. Thus, for

the purpose of evaluating health risks associated with exposure to the current construction

and shipyard industry PEL, OSHA assumes that the equivalent gravimetric PEL for

respirable quartz would lie in the range of 0.25 to 0.5 mg/m3.

OSHA is proposing a PEL of 0.05 mg/m3 measured as respirable crystalline silica

(i.e., quartz, cristobalite, and tridymite) for general industry, construction, and shipyards;

this is equal to the NIOSH Recommended Exposure Limit (REL). To capture the range

of exposures represented by OSHA’s current and proposed PELs, this section provides

estimates of mortality and morbidity risks corresponding to 45 years of exposure to 0.05,

0.1, 0.25, and 0.5 mg/m3respirable silica (i.e., cumulative exposures of 2.25, 4.5, 11.25,

and 22.5 mg/m3-years). In addition, OSHA is proposing an action level of 0.025 mg/m3

for respirable crystalline silica; consequently, the preliminary risk assessment presents

risk estimates associated with 45 years of exposure to the action level, which corresponds

to a cumulative exposure of 1.125 mg/m3-years.
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Throughout this assessment, reference is made to a variety of model forms and

different treatments of the exposure metric within the models. For clarity, OSHA uses

the following terms in describing the models used most often by various investigators:

 A “linear model” is one where relative risk is linearly related to exposure, i.e.,

has the form RR = 1 + βx, where RR is relative risk, x is the measure of

exposure, and β is the parameter to be estimated;

 A “log-linear” model is one where the log of relative risk is linearly related to

exposure, i.e., log RR = βx, or alternatively, RR = exp(βx); and

 “Log cumulative exposure” or “log-transformed cumulative exposure” means

that the model uses the log of cumulative exposure plus 1 as the exposure

metric (1 is added to avoid taking the log of zero). Typically, cumulative

exposure is expressed in units of mg/m3-years, and log-transformed

cumulative exposure in mg/m3-days.

Both linear and log-linear models may make use of cumulative exposure (i.e.,

untransformed cumulative exposure) or log-transformed cumulative exposure. Other

model forms will be defined as they occur throughout the document.

II.B. Lung Cancer Risk Estimates.

Based on its review of studies presented in Section I, OSHA identified a number

of published studies that analyzed exposure-response relationships for crystalline silica

and lung cancer and provided estimates of risk associated with exposure to the PEL.

These include the quantitative analysis by Steenland et al. (2001a) of worker cohort data

pooled from ten studies; a dose-response analysis by Rice et al. (2001) of a cohort of

diatomaceous earth workers primarily exposed to cristobalite; an analysis by Attfield and

Costello (2004) of U.S. granite workers; a risk assessment by Kuempel et al. (2001), who

employed a kinetic lung model, derived from rat studies, to describe the relationship

between quartz lung burden and cancer risk based on the diatomaceous earth worker and

granite worker cohort mortality data; a study of North American industrial sand workers

(Hughes et al., 2001; McDonald et al., 2001; McDonald et al., 2005); and a study of

British coalminers (Miller et al., 2007; Miller and MacCalman, 2009). Each of these

studies are described below, along with the estimates of silica-related lung cancer risk

derived from them by OSHA and, where available, by the investigators themselves.

To estimate lifetime risks at the exposure levels of interest to OSHA (0.025, 0.05,

0.1, 0.25, and 0.5 mg/m3respirable crystalline silica), the Agency implemented each of

the risk models in a life table analysis that accounted for competing causes of death due

to background causes and cumulating risk through age 85. For these analyses, OSHA

used lung cancer and all-cause mortality rates to account for background lung cancer and

competing risks (U.S. 2006 data for all males, obtained from cause-specific death rate

tables published by the National Center for Health Statistics (2009)). Like the risk

estimates reported by the authors of some of the original studies, OSHA calculated these

risk estimates assuming occupational exposure from age 20 to age 65. In calculating
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each risk estimate, OSHA used the same lag period selected by the original investigators.

The life table method used by OSHA appears in an Appendix to this preliminary

quantitative risk assessment. For all analyses, OSHA used the life table method to

estimate excess risk, i.e., Px – P0, where Px is the lifetime probability of dying from lung

cancer given exposure to respirable silica and P0 is the background lifetime probability

given no exposure.

II.B.1. Steenland et al. (2001a) Pooled Cohort Analysis.

The lung cancer analysis conducted by Steenland et al. (2001a) as part of the

IARC multi-centric study consisted of a pooled exposure-response analysis and risk

assessment based on raw data obtained for ten cohorts of silica-exposed workers (65,980

workers, 1,072 lung cancer deaths). The ten cohort studies were selected from 13 that

were identified at the time as containing exposure information sufficient to develop a

quantitative exposure assessment. Three cohort studies were excluded for reasons of data

unavailability or incompatibility. In addition, studies of coal workers and foundry

workers were not considered because (1) studies of coal workers were not included in the

IARC evaluation of silica carcinogenicity, and (2) because of the likely confounding of

foundry worker studies due to potential exposure to carcinogenic polycyclic aromatic

hydrocarbons. The cohorts in the pooled analysis included U.S. gold miners (Steenland

and Brown, 1995a), U.S. diatomaceous earth workers (Checkoway et al., 1997),

Australian gold miners (de Klerk and Musk, 1998), Finnish granite workers (Koskela et

al., 1994), U.S. industrial sand employees (Steenland et al., 2001b), Vermont granite

workers (Costello and Graham, 1988), South African gold miners (Hnizdo and SluisCremer, 1991; Hnizdo et al., 1997), and Chinese pottery workers, tin miners, and

tungsten miners (Chen et al., 1992).

The exposure assessments developed for the pooled analysis are described by

Mannetje et al. (2002a). The exposure information available from each of the 10 cohort

studies varied and included dust measurements representing particle counts, mass of total

dust, and respirable dust mass. Measurement methods also changed over time for each of

the cohort studies investigated, generally with impinger sampling performed in earlier

decades and gravimetric sampling performed later. Exposure data based on analysis for

respirable crystalline silica by x-ray diffraction (the current method of choice) were

available only from the study of U.S. industrial sand workers. In order to develop

cumulative exposure estimates for all cohort members and pool the cohort data, all

exposure information was converted to units of mg/m3respirable crystalline silica by

generating cohort-specific conversion factors based on the silica content of the dust to

which workers were exposed and, in some instances, results of side-by-side comparison

sampling. Within each cohort, available job- or process-specific information on the silica

composition or nature of the dust was used to reconstruct silica exposures of cohort

members. Most of the studies did not have exposure measurement data prior to the

1950s; exposures occurring prior to that time were estimated either by assuming such

exposures were the same as the earliest recorded for the cohort, or by modeling that

accounted for documented changes in dust control measures.
271

To evaluate the reasonableness of the exposure assessment for the lung cancer

pooled study, Mannetje et al. (2002a) investigated the relationship between silicosis

mortality and cumulative exposure by performing a nested case-control analysis for

silicosis or unspecified pneumoconiosis using conditional logistic regression. Since

exposure to crystalline silica is the sole cause of silicosis, a finding that cumulative

exposure was unrelated to silicosis mortality risk would suggest that serious

misclassification of the exposures assigned to cohort members had taken place. Cases

and controls were matched for race, sex, age (within 5 years) and study; 100 controls

were matched to each case. Each cohort was stratified into quartiles by cumulative

exposure, and standardized rate ratios (SRR) were calculated using the lowest-exposure

quartile as the baseline. Odds ratios (OR) were also calculated for the pooled data set

overall, which was stratified into quintiles based on cumulative exposure. For the pooled

data set, the relationship between odds ratio for silicosis mortality and cumulative

exposure were as follows:

--4.45 mg/m3-years, OR = 3.1 (95% CI, 2.5-4.0);

--9.08 mg/m3-years, OR = 4.6 (95% CI, 3.6-5.9);

--16.26 mg/m3-years, OR = 4.5 (95% CI, 3.5-5.8); and

--42.33 mg/m3-years, OR = 4.8 (95% CI, 3.7-6.2).

In addition, in seven of the cohorts, there was a statistically significant trend between

silicosis mortality (SRR) and cumulative exposure. For two of the cohorts (U.S. granite

workers and U.S. gold miners), the trend test was not statistically significant (p = 0.10).

An analysis could not be performed on the South African gold miner cohort because

silicosis was never coded as an underlying cause of death, apparently due to coding

practices in that country. Based on this analysis, Mannetje et al. (2002a) concluded that

the exposure-response relationship for the pooled data set was “positive and reasonably

monotonic” (that is, the response was reasonably consistently increasing with exposure)

and indicated that the exposure assessments yielded reasonable estimates of cumulative

exposures. In addition, despite some large differences in the range of cumulative

exposures between cohorts, a clear exposure-related trend was evident in seven of the

cohorts. Furthermore, in their pooled analysis of silicosis mortality for six of the cohorts,

Mannetje et al. (2002b) found a clear and consistent positive response with increasing

decile of cumulative exposure, although there is an anomaly in the 9th decile (the pooled

silicosis mortality study by Mannetje et al (2002b) is discussed in detail below in section

II.C.1). Overall, these data support a monotonic exposure-response for silicosis. Thus,

although some exposure misclassification almost certainly exists in the pooled data set,

the authors concluded that exposure estimates did not appear to have been sufficiently

misclassified so as to obscure an exposure-response relationship.

As part of an uncertainty analysis conducted for OSHA, Drs. Steenland and

Bartell examined the quality of the original data set and analysis to identify and correct

any data entry, programming, or reporting errors (Toxichemica, Inc., 2004). This quality

assurance process revealed a small number of errors in exposure calculation for the
272

originally reported results, primarily resulting from rounding of job class exposures when

converting the original data file for use with a different statistical program. Although the

corrections affected some of the exposure-response models for individual cohorts (see

discussion of results below), Steenland and Bartell (Toxichemica, Inc., 2004) reported

that models based on the pooled dataset were not impacted by the correction of these

errors.

For the pooled lung cancer mortality analysis, Steenland et al. (2001a) conducted

a nested case-control analysis via Cox regression, in which there were 100 controls

chosen for each case randomly selected from among cohort members who survived past

the age at which the case died, and matched on age (the time variable in Cox regression),

study, race/ethnicity, sex, and date of birth within 5 years (which, in effect, matched on

calendar time given the matching on age). Exposures were truncated for controls when

they attained the age at which their index case died. The principal exposure metrics of

interest were cumulative exposure, the log of cumulative exposure plus 1, and average

exposure. After testing models based on unlagged exposure and exposure lags of 5, 10,

15, and 20 years to account for disease latency, the authors selected an exposure lag of 15

years for most analyses. Exposure-response models included only a term for exposure

since other variables of interest were matched between cases and controls.

Categorical analysis of the pooled data set showed that the risk of lung cancer

increased in a monotonic fashion using categories of cumulative exposure (quintiles

based on the cases’ exposures), with odds ratios of 1.0, 1.0, 1.3, 1.5, and 1.6. Findings

for categorical analyses using average exposure were similar (odds ratios 1.0, 1.4, 1.6,

1.6, 1.7). Duration of exposure alone did not show a monotonic relationship with lung

cancer in categorical analysis (odds ratios 1.0, 1.3, 1.8, 1.4, 1.2). Using alternative

continuous exposure variables in a log-linear relative risk model (log RR = βx, where x

represents the exposure variable and β the coefficient to be estimated), Steenland et al.

(2001a) found that the use of either 1) cumulative exposure with a 15-year lag, 2) the log

of cumulative exposure with a 15-year lag, or 3) average exposure resulted in positive

statistically significant (p ≤ 0.05) exposure-response coefficients.

Steenland et al. (2001a) also employed a spline function using the log of

cumulative exposure (15-year lag), which is largely unconstrained and allows any cubic

function to be fit between two adjacent exposure points, or knots. Five knots were

selected across the exposure range of the pooled data set. Because of its increased

flexibility, the spline model provided a statistically significantly improved fit over the

log-linear model; however, the resulting model was not monotonic over the entire range

of exposure, particularly in the region corresponding to 45-year exposures below about

0.002 mg/m3(less than 3 log mg/m3-days) and between 0.1 and 0.25 mg/m3(less than 7

to 8 log mg/m3-days). OSHA believes that the lack of a consistently monotonic

exposure-response curve from the spline model lessens its credibility since there is no

reason to believe that the biological response to increasing silica exposure should not be

monotonic throughout the observed range of exposure.

The models that provided the best fit to the data were those that used cumulative

exposure and log-transformed cumulative exposure. Steenland et al. (2001a) reported
273

roughly similar fits for all log-linear relative risk models based on cumulative or logcumulative exposure, with model likelihoods ranging from 17.3 (1 d.f., unlagged

cumulative exposure) to 21.4 (1 d.f., 15-year lagged cumulative exposure) and logtransformed cumulative exposure models in between (model likelihoods of 18.8, 1 d.f.,

15-year lagged and 19.2, 1 d.f., unlagged) (Steenland, 2001a). The average exposure

metric was clearly inferior to the cumulative and log-cumulative metrics, with a model

likelihood of 4.4 (1 d.f.). Table II-1 summarizes the exposure-response coefficients

determined from each of the ten cohorts as well as a weighted average coefficient for the

pooled analysis, based on using the log-linear model with cumulative exposure and the

log of cumulative exposure (15-year lag, taken from Steenland et al., 2001a). Table II-1

also presents coefficients calculated after Dr. Steenland examined the quality of the

original data set to identify and correct any data entry, programming, or reporting errors

(Toxichemica, Inc., 2004). Although the corrections affected some of the regression

coefficients for individual cohorts (e.g., the Finnish granite workers’ cohort 15-year

lagged log-cumulative exposure coefficient changed from 0.049 (se = 0.07) to -0.015 (se

= 0.063)), Steenland reported that the pooled coefficients are virtually unchanged. The

coefficient for 15-year lagged log cumulative exposure was 0.062 (se 0.015) in the

original analysis and 0.060 (se 0.015) in the revised analysis

There was significant heterogeneity among studies (cohorts) using either

cumulative exposure or average exposure. The authors suggested a number of possible

reasons for such heterogeneity, including errors in measurement of high exposures

(which tends to have strong influence on the exposure-response curve when

untransformed exposure measures are used), the differential toxicity of silica depending

on the crystalline polymorph, the presence of coatings or trace minerals that alter the

reactivity of the crystal surfaces, and the age of the fractured surfaces. (See section I.F

for a discussion of factors that may modify the toxicity of crystalline silica). Models that

used the log transform of cumulative exposure showed no statistically significant

heterogeneity among cohorts (p = 0.36), possibly because they are less influenced by

very high exposures than models using untransformed cumulative exposure. For this

reason, as well as the good fit of the model using log-cumulative exposure, Steenland et

al. (2001a) conducted much of their analysis and calculated their risk estimates using logtransformed cumulative exposure.

Among the 10 cohort studies included in the pooled data set, the South African

gold miner study provided the largest exposure-response coefficient regardless of the

exposure metric used. Steenland et al. (2001a) found that excluding this cohort from the

data set and re-fitting the model using log-cumulative exposure yielded almost no change

in the exposure-response coefficient for the pooled data set (β = 0.062, se = 0.015 with

the South African data vs. β = 0.060, se = 0.015 without) (Steenland et al., 2001a).

Furthermore, exclusion of the three Chinese studies from the pooled data set, where there

was potential confounding by exposures to radon, arsenic, and polycyclic hydrocarbons,

resulted in a small but statistically significant increase in the exposure-response

coefficient (β = 0.075, se 0.025, p = 0.003). Based on these analyses, there is no

evidence to indicate that data from any particular cohort unduly influenced the results of

the pooled analysis.
274

Table II-1. Descriptive data and log-linear exposure-response coefficients for 10 studies and for pooled data, using 15-year

lagged log cumulative exposure

Study

Median

respirable

crystalline silica

exposure

(mg/m3)

a

Median cumulative

silica exposure

(mg/m3-years)

Number

of lung

cancer

deathsb,c

Original

exposureresponse

coefficient

(SE)d,e

Revised

exposureresponse

coefficient

(SE)d,f

US Diatomaceous earth (Checkoway et al., 1997) 0.18 1.05 77 0.089 (0.054) 0.086 (0.054)

S Africa gold (Hnizdo and Sluis-Cremer, 1991; Hnizdo et al., 1997) 0.19 4.23 77 0.666 (0.336) 0.582 (0.329)

US gold (Steenland and Brown, 1995a) 0.05 0.23 156 -0.039 (0.078) -0.041 (0.078)

Australian gold (de Klerk and Musk, 1998) 0.43 11.37 135 0.194 (0.115) 0.172 (0.111)

US granite (Costello and Graham, 1988) 0.05 0.71 124 0.112 (0.050) 0.118 (0.048)

Finnish granite (Koskela et al., 1994) 0.59 4.63 38 0.049 (0.070) -0.015 (0.063)

US industrial sand (Steenland et al., 2001b) 0.04 0.13 85 0.031 (0.057) 0.045 (0.057)

Ch. Tungsten (Chen et al., 1992) 0.32 8.56 174 0.030 (0.026) 0.039 (0.027)

Ch. Pottery (Chen et al., 1992) 0.22 6.07 81 0.076 (0.036) 0.086 (0.039)

Ch. Tin (Chen et al., 1992) 0.19 5.27 119 0.078 (0.034) 0.054 (0.033)

Pooled 1066 0.062 (0.015) 0.060 (0.015)

Footnotes for Table II-1

a

From Mannetje et al. (2002b)

b Lung cancer deaths among exposed workers; about 32% of the lung cancer deaths among Chinese tungsten, pottery, and tin workers occurred among non-exposed workers.

c

6 lung cancer deaths were excluded due to problems with their demographic data or work history.

d Units are log odds per log(mg/m3

-days).

e Reported in Steenland et al. (2001a).

f Coefficient reflects corrections to data used in Steenland et al. (2001a); see Toxichemica, Inc. (2004).

Source: Toxichemica, Inc. (2004)
275

Steenland et al. (2001a) estimated excess lifetime risk of lung cancer based on rate ratios

from the spline and log-linear models (15-year lagged log-cumulative exposure for both), using

NIOSH data on U.S. males in the early 1990s in a life table formula to account for background

lung cancer and competing mortality (Gail, 1975). Results from the log-linear model indicated

that 45 years of exposure at 0.1 mg/m3 would result in a lifetime risk (through age 75) of 28

excess lung cancer deaths per 1,000 workers (95% CI, 13-46) (Steenland et al., 2001a), with U.S.-

specific results and confidence intervals reported in Toxichemica, Inc. (2004). The spline model

yielded a somewhat lower risk estimate of 17 per 1,000 (95% CI, 2-36) due to a shallower rise in

risk at low cumulative exposures compared to the log-linear model (Steenland et al., 2001a), with

U.S.-specific results and confidence intervals reported in Toxichemica, Inc. (2004).

Steenland and Deddens (2002) conducted further analyses of the data to determine whether

there was any empirical evidence of a threshold (e.g., a level of exposure below which there is no

excess risk of lung cancer). Threshold models using average exposure or untransformed

cumulative exposure did not show any statistically significant improvement in fit over models

without a threshold. They found that a threshold model based on the log of cumulative dose (15-

year lag) fit better than a no threshold model, with the best threshold at 4.8 log mg/m3-days

(representing an average exposure of 0.01 mg/m3over a 45-year working lifetime). This suggests

that, among the studies evaluated by Steenland et al. (2001a) in the pooled analysis, there is no

empirical evidence of a threshold for lung cancer in the exposure range represented by the current

and proposed PELs (i.e., at 0.05 mg/m3or higher).

During the external peer review, OSHA received comments questioning the

appropriateness of relying on non-linear models and log transformation of exposure over the more

preferred linear model for estimating cancer risks. In response, OSHA asked Drs. Steenland and

Bartell to conduct additional analyses with linear relative risk models on the pooled data set; this

approach favors the use of linear models over reducing heterogeneity between cohorts (Steenland,

personal communication, 2010). For this analysis, the following models were fit to the pooled data

set:

 Linear relative risk (RR = 1 + βx) with cumulative exposure in mg/m3-years;

 Log-linear (RR = exp(βx)) with cumulative exposure in mg/m3-years;

 A 2-piece linear spline model with cumulative exposure in mg/m3-years; and

 A linear relative risk model with log cumulative exposure (mg/m3-days + 1).

The 2-piece spline model is a 2-parameter model and has the form:

 RR = 1 + β1 x for x ≤ Xknot, and

 RR = 1 + β1 x + β2(x-Xknot) for x > Xknot

where Xknot, which defines the inflection point, is selected based on maximizing the likelihood (see

Figure II-1). For cumulative exposure with a 15-year lag, the knot is 2.19 mg/m3-years.
276

Figure II-1. Plot of Model Likelihood vs. Knot Location for the

Linear 2-Piece Spline Model

As was done in the original analysis by Steenland, et al. (2001a), a case-control design was

used, matching each case with 100 controls. Models were fit via SAS using the statistical methods

proposed by Langholz and Richardson (2009), which maximizes the Cox partial likelihood used in

conditional logistic regression, while allowing various functional forms to model relative risk.

Figure II-2 shows the results for the models incorporating a 15-year exposure lag, and

compares the models to a categorical analysis that shows the observed relative risk by quintile of

cumulative exposure. The results for models without an exposure lag were similar, fitting only

slightly worse than those with the lag. The linear relative risk models using cumulative exposure

(lagged or unlagged) fit somewhat worse than did the log-linear model with log cumulative

exposure that was used in the original analysis; this difference was not statistically significant.

However, the linear relative risk models using cumulative exposure fail to capture the initial

steeper slope of the exposure-response curve, as is evident from the categorical analysis (Figure II2). The shape of the exposure-response curve is better captured using either the linear model with

log-transformed cumulative exposure, or with the 2-piece linear spline.

The linear model with log cumulative exposure and the linear spline model yielded lifetime

risk estimates (to age 85) that were comparable to those reported by Steenland et al. (2001a) from

the log linear model using log cumulative exposure; the estimates reported by Steenland and
277

Bartell were 38 and 27 deaths, respectively, per 1,000 workers exposed for 45 years to 0.1 mg/m3

respirable crystalline silica (Steenland, personal communication, 2010). In contrast, the lifetime

risk estimated from the linear model using cumulative exposure was almost an order of magnitude

lower (4 deaths per 1,000 workers). Since the 2-piece linear spline model and linear relative risk

model with log cumulative exposure best reflect the shape of the underlying exposure-response

curve observed for the pooled cohort data set, OSHA believes that these models are more

appropriate than the linear model with untransformed cumulative exposure for estimating lung

cancer risk.

Therefore, OSHA is basing its lung cancer risk estimates from the pooled cohort on the

log-linear model with log cumulative exposure (i.e., the original model used by Steenland et al.,

2001a, with corrections to the data set as described by Toxichemica, Inc., 2004), as well as on the

linear model with log cumulative exposure and the 2-piece linear spline model. For the models

using log cumulative exposure, OSHA assumed 250 days of exposure per year (since the unit for

exposure in these cases is mg/m3-days). Based on these models, OSHA estimates the excess

lifetime lung cancer risk resulting from 45 years of exposure to the current general industry PEL

(0.1 mg/m3) to range from 22 to 29 deaths per 1,000 workers, and, for exposure to the current

construction/shipyard PEL (0.25 – 0.5 mg/m3), to range from 27 to 38 deaths per 1,000 workers.

For the proposed PEL of 0.05 mg/m3, OSHA estimates the excess lung cancer risk ranges from 18

to 26 deaths per 1,000 and, for the proposed action level of 0.025 mg/m3, to range from 9 to 23

deaths per 1,000.

In addition to the analyses conducted by Steenland (2010), OSHA also used the individual

exposure coefficients for the 10 cohort studies used in the pooled analysis to estimate the range of

risks reflected by the individual studies. The exposure coefficients used were reported in Table 3

of Steenland et al. (2001a) and are the coefficients for untransformed cumulative exposure with a

15-year lag. At the current general industry PEL, the range of risks derived from the 10 studies is

0.83-69 deaths per 1,000, and for exposure to the current construction/shipyard PEL, the range is

2.1-687 deaths per 1,000. For exposure at the proposed PEL over a working lifetime, the range is

from 0.41 to 28 deaths per 1,000. The low end of the range is derived from the Chinese pottery

cohort and the upper end of the range by the South African gold miner cohort. These ranges,

which span more than two orders of magnitude, reflect the heterogeneity that was addressed

originally in Steenland et al. (2001a) by relying on the log transformed cumulative exposure

metric.

II.B.2. Rice et al. (2001) Analysis of Diatomaceous Earth Workers.

Rice et al. (2001) applied a variety of exposure-response models to the same

California diatomaceous earth cohort data originally reported on by Checkoway et al. (1993, 1996,

1997) and included in the pooled analysis conducted by Steenland et al. (2001a) described above.

The cohort consisted of 2,342 white males employed for at least one year between 1942 and 1987

in a California diatomaceous earth mining and processing plant. The cohort was followed until

1994, and included 77 lung cancer deaths.
278

Figure II-2. Plot and Parameters of Relative Risk Models Fit to the Pooled Cohort Data

Originally Analyzed by Steenland et al. (2001a)

1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

2

0 5 10 15 20 25 30

Cumulative Exposure (mg/m3-years)

Relative Risk

Linear RR Cumul Exp Log RR Cumul Exp 2-Piece Spline Linear RR Log Cumul Exp Categorical

Model Dose Metric Parameters SE -2*Log-Likelihood

Linear Relative Risk Cumulative Exposure

(mg/m3-years)

β= 0.018388 SE = 0.0056557 9641.37

Log Relative Risk Cumulative Exposure

(mg/m3-years)

β = 0.010638 SE = 0.002063 9642.61

2-Piece Spline Cumulative Exposure

Knot=2.19 mg/m3-years

β1 = 0.16498

β2 = -0.149285

SE1=0.065335

SE2=0.0657

9634.58

Linear Relative Risk

Log Cumulative

Exposure

(mg/m3-days)

β = 0.074950 SE = 0.024121 9646.49

Categorical Analysis Cumulative Exposure

(mg/m3-years)

N/A N/A N/A
279

Rice et al. (2001) relied on the dust exposure assessment developed by Seixas et al. (1997)

from company records of over 6000 samples collected from 1948 to 1988; cristobalite was the

predominate form of crystalline silica to which the cohort was exposed. Each worker in the cohort

was assigned a cumulative silica dust exposure based on this exposure assessment and

employment records; the mean cumulative exposure for the cohort was 7.31 mg/m3-years for

respirable dust and 2.16 mg/m3-years for respirable crystalline silica dust. The mean concentration

of respirable crystalline silica over the employment period of the cohort was 0.29 mg/m3. Rice et

al. (2001) considered lag periods of 0, 2, 5, 8, 10, 12, and 15 years in the development of

cumulative exposure estimates, selecting 10 years for the risk analysis based on model fit

(statistics not reported).

The authors developed Poisson regression models to estimate the relationship between

silica exposure and lung cancer mortality rate, including both relative rate (λ = λ0 x f(E)) and

additive excess rate (λ = λ0 + f(E)) models, where λ is the predicted lung cancer incidence, f(E) is a

function of cumulative silica exposure in mg/m3-years, and λ0 is the background incidence. The

following model forms were evaluated:

 Log-linear: RR = exp(β1E);

 Log square root: RR = exp(β1E

0.5);

 Log quadratic: RR = exp(β1E + β2E

2

);

 Power: RR = (1+E)β

1;

 Linear relative rate: RR = 1 + β1E;

 Shape(α): RR = 1 + β1E

α

, and;

 Additive excess rate: AER = β1E,

where β1, β2, and α are parameters to be estimated, E is cumulative exposure, RR is relative rate,

and AER is additive excess rate. Background lung cancer mortality incidences were determined

both internally from the cohort, stratifying on three levels of time since first observation (< 10, 10-

19, and  20 years), calendar time, age, and ethnicity (Hispanic vs. non-Hispanic), and externally,

based on U.S. mortality rates from 1940 to 1994, adjusted for age and calendar time. Rice et al.

(2001) examined a variety of exposure groupings, including 5, 10, 20, and 50 exposure levels,

selecting 50 levels for the main analysis based on model fit (statistics not reported). The authors

also fit Cox’s proportional hazards models using the log linear, log square root, log quadratic, and

power model forms described above, stratifying as in the Poisson models on time since first

observation, calendar time, and ethnicity.

Rice et al. (2001) reported that exposure to crystalline silica was a significant predictor of

lung cancer mortality for nearly all of the models employed, with the linear relative risk model

providing the best fit to the data in the Poisson regression analysis. Results from Cox’s

proportional hazards models were similar to the Poisson regression when 50 exposure categories

were used in the latter, supporting Rice et al.’s (2001) use of that exposure categorization scheme.
280

The use of external cancer mortality rates to estimate background lung cancer incidence yielded

slope estimates that were similar to, but substantially more precise than, those based on internally

standardized models

Rice et al. (2001) estimated excess lung cancer risk based on the log linear, log square root,

power, and linear relative rate models with 10-year lagged cumulative exposure and using 1992

U.S. mortality data to adjust for competing mortality. Based on the linear relative rate model with

external standardization, the authors predicted an excess risk of lung cancer by age 85, for a

mixed-gender population, of 29 per 1,000 workers after 45 years of exposure at 0.1 mg/m3

respirable crystalline silica (95% CI, 8-68, calculated as part of the Toxichemica, Inc., 2004

analysis based on information provided in Rice et al., 2001). Excess risk estimates for male

workers were 36-37 per 1,000 (no CI reported). Note that the same exposure-response coefficients

were used by Rice et al. (2001) to estimate risk for all demographic groups; however, the higher

background lung cancer rates found among men than in the general population result in higher

excess risk estimates using a relative risk model. At an exposure level of 0.05 mg/m3(equal to the

proposed PEL and NIOSH REL), Rice et al. (2001) estimated a lifetime excess risk of 15 per 1,000

for the total U.S. population, or 19 per 1,000 for male workers (95% CI 5-46 reported for white

males). Excess risk estimates based on models other than the linear relative rate model were

reported to be, in general, higher than those based on the linear relative rate model. Sources of

uncertainty in the risk estimates based on the Rice et al. (2001) study include possible error in

exposure estimates and confounding of the exposure-response analysis due to smoking and

occupational co-exposures such as asbestos. These issues are addressed in the discussion on

uncertainty presented later in this section.

II.B.3. Attfield and Costello (2004) Analysis of Granite Workers.

Attfield and Costello (2004) analyzed the same U.S. granite cohort originally studied by

Costello and Graham (1988) and Davis et al. (1983) and included in the Steenland et al. (2001a)

pooled analysis, consisting of 5414 male granite workers who were employed in the Vermont

granite industry between 1950 and 1982 and who had received at least one chest x-ray from the

surveillance program of the Vermont Department of Industrial Hygiene. Attfield and Costello

(2004) extended follow-up from 1982 to 1994, increasing the number of lung cancer deaths from

124 in the original Costello and Graham (1988) study and the pooled analysis to 201. Workers’

cumulative exposures were estimated by Davis et al. (1983) based on historical exposure data

collected in six environmental surveys conducted between 1924 and 1977 and work history

information collected at the time that each worker was X-rayed, including start and stop year for

each job worked in the industry. Attfield and Costello (2004) did not update work histories

beyond the original 1982 follow-up.

Categorical analyses were performed using seven exposure groups, allocating

approximately equal numbers of deaths from all causes into each. Poisson regression models were

evaluated using unlagged exposure vs. a 15-year lag, untransformed vs. log transformed

cumulative exposure, and internal vs. external adjustment of baseline lung cancer rates. Attfield

and Costello (2004) evaluated the exposure-response both with and without the highest exposure

group, based on their belief that this group is marked by a stronger healthy worker effect than the

rest of the cohort. In addition, the authors believed that lung cancer may have been underreported

as a cause of death among the workers in the highest exposure group, most of whom worked for 20
281

years or more prior to institution of exposure controls, during a time when tuberculosis and

silicosis were the primary health concerns among granite workers.

The results of the categorical analysis showed a generally increasing trend of lung cancer

rate ratios with increasing cumulative exposure. However, the rate ratio for the highest exposure

group in the analysis (cumulative exposures of 6.0 mg/m3-years or higher) was substantially lower

than those for other exposure groups; for example, the lung cancer rate ratios for the categorical

analysis using 15-year lagged cumulative exposures were 1.00; 1.24; 2.14; 1.93; 1.68; 2.60; 1.90;

and 1.18. The highest exposure category appeared to have a strong effect on the overall exposure

response relationship observed in models using untransformed exposure metrics, which yielded

relatively weak, non-statistically significant exposure coefficients when the highest exposure

group was included in the analysis, and highly significant (p < 0.005) exposure coefficients when

the highest group was excluded. A significant exposure-response relationship (p < 0.01) was

observed in all models using a log transformation on exposure, which tends to decrease the

influence of very high exposures on the model.

Attfield and Costello (2004) reported that the best-fitting model was based on a 15-year

lag, use of untransformed cumulative exposure, and omission of the highest exposure group.

Based on this model, and using 1992 NIOSH data on white U.S. males in a life table formula to

account for background lung cancer and competing mortality (Gail, 1975), they estimated a

lifetime lung cancer mortality risk (through age 85) of 64 deaths per 1,000 workers (95% CI,

22/1000, 123/1000) exposed for 45 years to 0.1 mg/m3respirable quartz. At an exposure of 0.05

mg/m3, the estimated lifetime risk was 27 deaths per 1,000 (95% CI, 10/1000, 48/1000). The

authors argued that it was appropriate to base their risk estimates on a model that was fitted

without the highest exposure group for several reasons. They believed the underlying exposure

data for the high-exposure group was weaker than for the others, and that there was a greater

likelihood that competing causes of death and misdiagnoses of causes of death attenuated the lung

cancer death rate. Second, all of the remaining groups comprised 85 percent of the deaths in the

cohort and showed a strong linear increase in lung cancer mortality with increasing exposure.

Third, Attfield and Costello (2004) believed that the exposure-response relationship seen in the

lower exposure groups was more relevant given that the exposures of these groups were within the

range of current occupational standards. Finally, the authors stated that risk estimates derived

from the model after excluding the highest exposure group were more consistent with other

published risk estimates than was the case for estimates derived from the model using all exposure

groups. In a letter responding to criticism of these reasons for excluding the high-exposure group

(Graham, 2004), Attfield (2004) pointed out that attenuation of an observed response at high

exposures was often seen in epidemiological studies, and referred to Stayner et al. (2003), who

described several reasons that explain such observations, including survivor effects, a limit on the

relative risk that can be achieved for diseases with a high background rate (e.g. lung cancer), and

misclassification of exposure.

Graham et al. (2004) reported on the mortality experience of this cohort, extending the

follow-up period by two years, through 1996. The relationship between lung cancer mortality and

exposure to quartz dust was examined by comparing mortality rates of granite shed workers hired

before 1940 to those of workers hired after 1940 when dust control measures were introduced.

Prior to 1940, estimated respirable quartz levels in the sheds averaged 0.2 mg/m3, with workers

operating pneumatic chisels exposed to 0.6 mg/m3. After 1940, implementation of dust controls
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resulted in a gradual decline in exposures over several years until exposures were reduced by 80 to

90 percent by the 1950s. There were statistically significant increases in lung cancer mortality

among shed workers hired before and up to 1940 (SMR = 1.48) and among shed workers hired

after 1940 (SMR = 1.24); however, the difference in lung cancer mortality between these two

groups was not statistically significant. In addition, Graham et al. (2004) reported that smoking

histories were available for 80 percent of workers who died of lung cancer and that all of these

workers smoked. They also noted that radiographic evidence of silicosis was evident in 27 percent

of workers hired before 1940 compared to 5.7 percent of those hired after 1940, and that all but

one of the post-1940 workers with radiographic evidence of silicosis were hired between 1940 and

1955 when dust levels were being reduced. Graham et al. (2004) concluded that dust control

measures were shown to be effective in reducing lung disease and mortality among granite

workers and that their analysis did not support a causal relationship between exposure to quartz

and lung cancer.

However, OSHA believes that the finding by Attfield and Costello (2004) of a positive

exposure-response relationship for lung cancer among granite workers is more convincing than are

the results from the Graham et al. (2004) study. In particular, OSHA believes it likely that some of

the workers hired after 1940 continued to be exposed to dust levels that, although somewhat lower

than before 1940, were still appreciably higher than those that resulted after dust controls had been

fully implemented after 1950. For example, Attfield and Costello (2004) summarized respirable

quartz levels for several granite shed jobs and reported that, for cutter/marker/surfacer jobs,

respirable quartz exposures averaged 0.37 mg/m3prior to 1940, 0.22 mg/m3between 1940 and

1950, and 0.07 mg/m3after 1950. Similarly, crane operators, which included shed derrickmen,

were exposed to average quartz levels of 0.14 mg/m3before 1940, 0.09 mg/m3between 1940 and

1950, and 0.03 mg/m3after 1950. OSHA notes that about one-fourth of the lung cancer deaths

among post-1940 hires were associated with 40 or more years of latency, indicating that these

workers were, for the most part, hired between 1940 and 1950. Given these considerations, OSHA

believes that the finding by Attfield and Costello (2004) of a positive exposure-response

relationship among granite workers, which was based on a quantitative assessment of the exposure

of each cohort member, provides evidence of a causal relationship between exposure to crystalline

silica and lung cancer, and that it is reasonable to estimate lung cancer risk from their analysis.

II.B.4. Kuempel et al. (2001) Assessment Based on a Lung Dosimetry Model.

Kuempel et al. (2001) used kinetic lung models for both rat and human to relate lung

burden of crystalline silica to cancer risk based on studies of diatomaceous earth workers (Rice et

al., 2001) and U.S. granite workers (Attfield and Costello, 2001). The models were also used to

estimate a threshold lung burden of quartz above which macrophage-mediated particle clearance

begins to decline and neutrophilic inflammation begins to increase. The rat model used is a

compartmentalized model that was modified from a coal dust model to account for the uptake of

silica particles by alveolar macrophages (AM) and, once a critical silica burden within the

macrophages is reached, the initiation of the inflammatory response and subsequent impairment of

particle clearance (Tran et al., 2001). Parameters of the model, which included the critical AM

burden of silica particles and kinetics of neutrophil and alveolar macrophage recruitment, were

estimated by fitting the model to NIOSH data obtained by exposing rats to MIN-U-SIL 5 for up to

84 days and measuring various indicators of inflammation. From the model estimate of critical

AM silica burden, Kuempel et al. (2001) estimated the mean critical total quartz burden in the rat
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lung and lymph nodes (Mcrit) to be 0.39 mg/g lung; this represented the threshold for quartzinduced pulmonary inflammation and reduced particle clearance.

Kuempel et al. (2001) then used a previously developed human model describing respirable

particle clearance and retention in coal miners to estimate the external exposure of respirable

quartz necessary to accumulate a critical quartz burden in the lung. The human model was

developed from data describing dust lung burdens in U.S. coal miners and modified to describe

quartz clearance and retention based on quartz lung burden data from U.K. coal miners. The

model predicted a quartz burden of about 1.7 times greater than the mean burden reported from

autopsy data from U.S. coal workers, but the predicted value was within the confidence interval

reported from the autopsy study. From this model, Kuempel et al. (2001) estimated that a 45-year

exposure to 0.36 mg/m3respirable quartz was necessary to accumulate a total quartz burden (lung

and lymph node) equal to the mean Mcrit value of 0.39 mg/g. Since the critical quartz burden is a

mean value derived from the model, the authors also reported that a 45-year exposure to 0.005

mg/m3respirable quartz would result in a lung quartz burden equal to the 95% lower confidence

limit on Mcrit.

The rat and human models were then used to estimate lung cancer risk as a function of lung

burden in both rats and humans. Kuempel et al. (2001) found that the rat model yielded

reasonably close predictions of long-term lung burden when compared to lung burden data from a

2-year quartz inhalation study in rats (Bellmann et al., 1991; Muhle et al., 1991; Muhle et al.,

1995); overall, lung burden values predicted from the rat model were somewhat lower than those

seen in chronically exposed rats, with the predicted burden after 2 years of exposure being 86

percent of the values reported from the chronic rat study (Muhle et al., 1991; Muhle et al., 1995).

Using a linear multistage model, Kuempel et al. (2001) then used the rat lung model to predict

excess lung cancer risks in rats at lung burdens equal to Mcrit, and the quartz lung burden in

humans associated with 45 years of exposure to 0.05 or 0.1 mg/m3respirable quartz.

Finally, Kuempel et al. (2001) used the dose coefficients from the previously discussed

diatomaceous earth (Rice et al., 2001) and U.S. granite worker (Attfield and Costello, 2001)

studies (linear relative risk models with cumulative exposure lagged 10 and 15 years, respectively)

to estimate human lung cancer risk associated with 45 years of occupational exposure to respirable

quartz at 0.036 mg/m3, 0.05 mg/m3and 0.1 mg/m3. Lifetime risk from each of these exposure

levels, adjusted for competing mortality, was estimated through age 75 using a life table method

and 1992 U.S. vital statistics for age-specific rates for lung cancer and competing causes of death.

The excess lung cancer risk predicted at the critical quartz dose using the relative rate

coefficients from the diatomaceous earth and granite cohort studies were 8.7 deaths per 1,000

workers (95% upper confidence limit (UCL) of 18 per 1,000) and 9.7 per 1,000 (95% UCL of 15

per 1,000), respectively (lower confidence limits not reported). The predicted lung cancer risks for

workers exposed to 0.1 mg/m3for 45 years were 24 per 1,000 (95% UCL of 50 per 1,000) from the

diatomaceous earth study and 27 per 1,000 (95% UCL of 42 per 1,000) from the granite worker

study. For exposure to 0.05 mg/m3, predicted lung cancer risks were 12 per 1,000 (95% UCL of

26) and 13 per 1,000 (95% UCL of 21) for the diatomaceous earth and granite worker cohorts,

respectively. The risk estimates based on the Muhle et al. (1991, 1995) 2-year rat study were

about 3-fold higher for male rats, with a predicted excess risk at the critical dose of 28 per 1,000

(upper 95% confidence limit of 65 per 1,000). Kuempel et al. (2001) identified a number of
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factors that may have contributed to the observed difference between the risk estimates based on

epidemiological cohort studies and those based on animal data, including: (1) the risk estimates

derived from animal data were based on a single chronic study that investigated several types of

quartz using a single dose; (2) extrapolating from animals to humans involved an assumption that

the critical mass of quartz in the lung is the same in rats and humans, on a mg/g lung basis; (3) use

of mass as the dose metric assumes that the particle surface area, which may be a better predictor

of risk than particle mass, was the same in rats and humans; and (4) potential misclassification of

exposures in the human studies and possible confounding by smoking introduced uncertainties in

the human data. Nevertheless, Kuempel et al. (2001) concluded that the estimates of excess cancer

risk to rats and humans exposed to quartz are reasonably similar.

The work by Kuempel et al. (2001) suggests that lung burden may be a reasonable

exposure metric for predicting lung cancer risk. Toxichemica, Inc. (2004) investigated whether

use of the dosimetry model would substantially affect the results of the pooled lung cancer data

analysis initially conducted by Steenland et al. (2001a). They replicated the lung dosimetry model

using Kuempel et al.’s (2001) reported median fit parameter values, and compared the relationship

between log cumulative exposure and 15-year lagged lung burden at the age of death in case

subjects selected for the pooled case-control analysis. Although the two were found to be highly

correlated (r = 0.99), Toxichemica, Inc. (2004) reported finding some differences between the two

measures of exposure, particularly in individuals with sporadic exposures such as many workers in

the Australia cohort. Fitting the conditional logistic regression model with a 15-year exposure lag,

Toxichemica, Inc. (2004) found that log silica lung burden and log cumulative exposure were

similarly good predictors of lung cancer risk in the pooled analysis (similar log-likelihoods of –

4843.96 and –4843.996, respectively).

In summary, the Kuempel et al. (2001) study is a rat-based toxicokinetic/ toxicodynamic

modeling effort to predict human lung cancer risk based on lung burden concentrations necessary

to cause the precursor events that can lead to adverse physiological effects in the lung. These

adverse physiological effects can then lead to lung fibrosis and an indirect genotoxic cause of lung

cancer. The hypothesized first step, or earliest expected response, in these disease processes is

chronic lung inflammation, which the authors consider as a disease limiting step. Since the

threshold effect level of lung burden associated with this inflammation (Mcrit), based on the

authors’ rat-to-human lung model conversion, is the equivalent of exposure to 0.036 mg/m3for 45

years, exposures below this level would presumably not lead to an excess lung cancer risk (based

on an indirect genotoxic mechanism), at least in the “average individual.” If at least some of the

silica-related lung cancer risk is from a direct genotoxic mechanism, then this threshold value

doesn’t hold. Since silicosis also is inflammation mediated, this exposure could also be considered

to be an average threshold level for that disease as well.

OSHA believes that the Kuempel et al. (2001) analysis is a credible attempt to

quantitatively describe the retention and accumulation of quartz in the lung, and to relate the

external exposure and its associated lung burden to the inflammatory process. However, for the

purpose of quantitatively evaluating lung cancer risk in exposed workers, OSHA has chosen to

rely on the epidemiology studies themselves and the exposure metrics used in those studies. The

use by Kuempel et al. (2001) of the cumulative exposure coefficients from the two epidemiology

studies to estimate lung cancer risk as a function of lung quartz burden involved converting

cumulative exposure metrics to equivalent lung burdens after the epidemiology exposure-response
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analysis has already been done; in other words, the analysis did not involve estimating lung

burdens for individual cohort members (based on their exposure histories) in order to evaluate

dose-response based on lung burden and mortality experience of the cohort. Therefore, OSHA

believes that the dose-response analysis performed by Kuempel et al., adds little new information

about the dose-response relationships seen in these studies beyond that provided by the

epidemiological studies themselves. Although a risk assessment based on the estimated or

measured lung burden in humans whose mortality experience is known might provide an improved

basis for risk assessment, the Kuempel et al. (2001) analysis does not provide that kind of

information.

II.B.5. Hughes et al. (2001) Analysis of Industrial Sand Workers.

McDonald et al. (2001), Hughes et al. (2001), and McDonald et al. (2005) followed up on a

cohort study of North American industrial sand workers that overlapped with the industrial sand

cohort (18 plants, 4,626 workers) studied by Steenland and Sanderson (2001). The McDonald et

al. (2001) follow-up cohort included 2,670 men employed before 1980 for three years or more in

one of nine North American (8 U.S. and 1 Canadian) sand-producing plants, including 1 large

associated office complex. Information on cause of death was obtained, from 1960 through 1994,

for 99 percent of the deceased workers for a total 1,025 deaths representing 38 percent of the

cohort. A nested case-control analysis based on 90 lung cancer deaths from this cohort was also

conducted by Hughes et al. (2001). A later update, through 2000, of both the cohort and nested

case-control studies by McDonald et al. (2005), eliminated the Canadian plant, following 2,452

men from the 8 U.S. plants. For the lung cancer case-control part of the study, the update included

105 lung cancer deaths. Both the initial and update case control studies used up to two controls

per case. Both of these case-control analyses relied on an analysis of exposure information

published by Rando et al. (2001). Additional details on these studies are given in the Health

Effects literature review (section I.B).

The cohort study by McDonald et al. (2001) showed a statistically significantly elevated

SMR for trachea/lung/bronchus cancer (83 deaths, SMR = 150, p = 0.001, based on U.S. rates) for

deaths occurring 20 or more years from hire. The SMR for trachea/lung/bronchus cancer declined

slightly when regional cancer mortality rates were used (SMR = 139, p = 0.001). SMRs for

trachea/lung/bronchus cancer, using U.S. rates, increased with increasing time since hire (SMRs:

87, 127 and 162 for <20, 20-30 and ≥ 30 years, respectively), but not with duration of

employment. There was no consistent correlation between duration of employment and lung

cancer risk in this cohort. SMRs for NMRD and tuberculosis were statistically elevated for deaths

occurring 20 years or more from hire (SMR = 178 (97 deaths) and 393 (8 deaths) for <20 and ≥ 30

years, respectively; p < 0.01). McDonald et al. (2001) also noted a statistically significant

elevation in chronic renal disease (SMR = 212; 16 deaths; p < 0.002).

Although the cohort studies provided evidence of increased risk from lung cancer, the

nested case-control studies, Hughes et al. (2001) and McDonald et al. (2005), allowed for

individual job, exposure, and smoking histories to be taken into account, allowing for good

exposure-response analysis for lung cancer. The method of determining exposure and developing

a job exposure matrix was reported by Sanderson et al. (2000). Smoking data were collected from

medical records supplemented by information from next of kin or living subjects for over 90

percent of cases and controls. These case-control studies were analyzed by conditional logistic
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regression to evaluate the relationships between lung cancer mortality and cumulative exposure,

average exposure, duration, and peak exposure, all adjusted for smoking histories. Statistically

significant positive exposure-response trends for lung cancer were found for both cumulative

exposure (lagged 15 years) and average exposure concentration, but not for duration of

employment, after controlling for smoking. A monotonic increase was seen for both lagged and

unlagged cumulative exposure when the four upper exposure categories were collapsed into two.

With exposure lagged 15 years and after adjusting for smoking, increasing quartiles of cumulative

silica exposure were associated with lung cancer mortality odds ratios of 1.00, 0.84, 2.02 and 2.07

(p-value for trend = 0.04). There was no indication of an interaction effect of smoking and

cumulative silica exposure (Hughes et al., 2001).

OSHA considers this Hughes et al (2001) study and analysis to be of high enough quality

to provide risk estimates for excess lung cancer for silica exposure to industrial sand workers.

Using the median exposure levels of 0, 0.758, 2.229 and 6.183 mg-years/m3, respectively, for each

of the four categories described above, and using the model: ln OR = α + β x Cumulative

Exposure, the coefficient for the exposure estimate was β = 0.13 per (mg/m3-years), with a

standard error of β = 0.074 (calculated from the trend test p-value in the same paper). In this

model with background lung cancer risks of about 5 percent, the OR provides a suitable estimate

of the relative risk. Using this slope estimate from Hughes et al. (2001), OSHA has used the life

table program (see Appendix) to estimate excess lifetime lung cancer risks for these workers at

concentrations from 0.025 to 0.5 mg/m3for 45 years. At the proposed action level, the proposed

PEL, and the current general industry PEL, excess risk estimates from this study are 7, 15, and 34

deaths per 1,000 workers, respectively. For exposure at the higher construction/shipyard PEL, the

estimated risk ranges from 120 to 387 deaths per 1,000. The estimates at the lower exposure levels

of 0.025, 0.05 and 0.10 mg/m3levels very closely approximate those of the other studies for which

OSHA has estimated excess risk. Some divergence in the risk estimates seen at the higher

exposure levels is related to the risk models used.

The McDonald et al. (2005) update of the Hughes et al. (2001) study, extended the

observation period by six years, from 1995 to 2000. In the original cohort study, there were 990

deaths among a cohort of industrial sand workers employed in nine plants. The update was limited

to workers in eight U.S. plants, eliminating the Canadian plant. An additional 231 deaths were

identified, for a total of 1,205 deaths (49 percent of the cohort). Vital status and cause of death

was obtained and determined for 99 percent of the cohort. Exposure estimation and case-control

selection and analysis were similar to the original study. Differences in smoking were analyzed by

conditional multiple regression and exposure categories were the same as in the original study.

The findings of the follow-up study confirmed the findings of the original Hughes et al.

(2001) analysis. SMRs for all causes of death, based on U.S. male death rates, for workers who

died 20 or more years after hire were elevated in the follow-up (SMR = 142; p < 001) as compared

to the initial study (SMR = 118; p < 0.001). Elevated SMRs were also identified for lung cancer

(SMR = 147, p = 0.001, 102 deaths) for workers who died 20 or more years after hire. These

values were not significantly different than the initial study. Also, as was observed in the original

study, the follow-up study found that the risk of lung cancer was related to average silica

concentration but not to the length of employment. Smoking was independently and strongly

related to silicosis and lung cancer.
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For the updated nested case control analysis McDonald et al. (2005) found that, with

exposure lagged 15 years and after adjusting for smoking, increasing quartiles of cumulative silica

exposure were associated lung cancer odds ratios (deaths) of 1.00 (13), 0.94 (17), 2.24 (38), and

2.66 (37) (p-value for trend = 0.006). These OR’s were very similar to the original study. The

slope of this exposure-response from the update appeared to be slightly greater than the slope

given by Hughes et al. (2001), but could not be calculated with assurance, because, unlike Hughes

et al. (2001), the medians of the exposure categories were not provided in the update. Because of

the missing information in the McDonald et al. (2005) update, and because of otherwise very

similar results in the two papers, OSHA has chosen to base its lifetime excess lung cancer risk

estimate for these industrial sand workers on the Hughes et al. (2001) case-control study.

II.B.6. Miller and MacCalman (2009) Analysis of British Coal Workers.

Miller et al. (2007) and Miller and MacCalman (2009) conducted a follow-up study of

cohort mortality, begun in 1970. Their previous report on mortality presented a follow-up analysis

on 18,166 coalminers from 10 British coalmines followed through the end of 1992 (Miller et al.,

1997). The two recent reports analyzed the mortality experience of 17,800 of these miners (18,166

minus 346 men whose vital status could not be determined), and extended the analysis through the

end of 2005. By that time, there were 516,431 person years of observation, an average of 29 years

per miner, with 10,698 deaths from all causes. Causes of deaths of interest included

pneumoconiosis, other non-malignant respiratory diseases (NMRD), lung cancer, stomach cancer,

and tuberculosis. The authors noted that no additional exposure measurements were included in

the updated analysis, since all the mines had closed by the mid 1980’s. However, some of these

men might have had additional exposure at other mines or facilities, not reported in this study.

(One of these coalmines has already been discussed in section I.B.3.a, above for the relationship of

silica exposure and silicosis progression and morbidity among 547 miners exposed to high levels

of quartz during the early to mid 1970’s.)

For this cohort mortality study there were analyses using both external and internal

controls. The external controls used British administrative regional age-, time-, and cause-specific

mortality rates from which to calculate SMR’s. The internal controls from the mines used Cox’s

proportional hazards regression methods, which allowed for each individual miner’s age and

smoking status, as well as the individual’s detailed dust and quartz time-dependent exposure

measurements. Cox regression analyses were done in stages, with the initial analyses used to

establish what factors were required for baseline adjustment.

For the analysis using external mortality rates, the all-cause mortality SMR from 1959

through 2005 was 100.9 (95% C.I., 99.0-102.8), based on all 10,698 deaths. However, these

SMRs were not uniform over time. For the period from 1990-2005, the SMR was 109.6 (95% CI

106.5-112.8), while the ratios for previous periods were less than 100. This pattern of increasing

SMRs in the recent past was also seen for cause-specific deaths from chronic bronchitis, SMR =

330.0 (95% CI 268.1-406.2); tuberculosis, SMR = 193.4 (95% CI 86.9-430.5); cardiovascular

disease, SMR = 106.6 (95% CI 102.0-111.5); all cancers, SMR = 107.1 (95% CI 101.3-113.2); and

lung cancer, SMR = 115.7 (95% CI 104.8-127.7). The SMR for NMRD was 142.1 (95% CI

132.9-152.0) in this recent period, and remained highly statistically significant. In their previous

analysis on mortality from lung cancer, reflecting follow-up through 1995, Miller et al. (1997), had

not found any increase in lung cancer mortality risk.
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Three of the strengths of this study are the availability of detailed time-exposure

measurements of both quartz and total mine dust, detailed individual work histories, and individual

smoking histories. All these data were used in the internal analyses using Cox regression methods.

Using these analyses, Miller and MacCalman (2009) estimated relative risks for a lifetime

exposure of 5 gram-hours/m3(ghm-3) to respirable quartz (equivalent to approximately 0.055

mg/m3for 45 years, assuming 2,000 hours per year of exposure) and/or 100 ghm-3 total dust. They

presented (see their Table 4) estimated relative risks for various causes of death - pneumoconiosis,

COPD, ischemic heart disease, lung cancer, and stomach cancer - based on models with either

single (dust or quartz) exposures or to simultaneous exposures to both, either with or without 15-

year lag periods. Generally, the risk estimates were slightly greater using a 15-year lag period.

For the models using only quartz exposures with a 15-year lag, only pneumoconiosis, RR = 1.21

(95% CI 1.12-1.31); COPD, RR = 1.11 (95% CI 1.05-1.16); and lung cancer, RR = 1.07 (95% CI

1.01-1.13) showed statistically significant increased risks.

For lung cancer, analyses based on these Cox regression methods provide strong evidence

that, for these coal miners, quartz exposures were associated with increased lung cancer risk, but

simultaneous exposures to coal dust were not associated with increased lung cancer risk. The

relative risk estimate for lung cancer deaths using coal dust with a 15-year lag in the single

exposure model was 1.03 (95% CI 0.96 to 1.10). In the model using both quartz and coal mine

dust exposures, the relative risk based on coal dust decreased to 0.91, while that for quartz

exposure remained statistically significant, increasing to a RR = 1.14 (95% CI 1.04 to 1.25).

The RRs in the Miller and MacCalman (2009) report can be used to estimate excess lung

cancer risk for OSHA’s purposes, using the same life table analyses as was done for the other

studies above. Based on the relative risk of 1.14 (95% C.I. 1.04-1.25) for a cumulative exposure

of 5 ghm-3, the regression slope is recalculated as β = 0.0524 per mg/m3-years and used in the life

table program (see Appendix). Similarly, the 95-percent confidence interval on slope is 0.0157 –

0.08926. From this study, the lifetime (to age 85) risk estimates for 45 years of exposure to 0.05

mg/m3and 0.100 mg/m3crystalline silica are 6 and 13 excess lung cancer deaths per 1,000

workers, respectively. These lung cancer risk estimates are less by about 2- to 4-fold than those

estimated from the other cohort studies described above. However, three factors might explain

these differences. First, these estimates are adjusted for individual smoking histories so any

smoking-related lung cancer risk (or smoking – silica interaction) that might possibly be attributed

to silica exposure in the other studies will not be reflected in the risk estimates derived from the

study of these coalminers. Second, these coalminers had significantly increased risks of death

from other lung diseases, which could tend to decrease the lung-cancer-susceptible population. Of

note, for example, are the higher increased SMRs for NMRD during the years 1959-2005 for this

cohort (see Table 2, Miller and MacCalman, 2009). Third, the difference in risk seen in these

coalminers could be the result of differences in the toxicity of quartz present in the coal mines as

compared to the work environments of the other cohorts. One Scottish mine (Miller et al., 1998)

in this 10-mine study had been cited as having presented “unusually high exposures to [freshly

fractured] quartz.” However, this was also described as an atypical exposure among miners

working in the 10 mines. Miller and MacCalman (2009) stated that increased quartz-related lung

cancer risk in their cohort was not confined to that Scottish mine alone. They also stated that “the

general nature of some quartz exposures in later years ... may have been different from earlier

periods when coal extraction was largely manual ....”
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All of these factors in this British coalminer cohort mortality analysis could combine to

yield lung cancer risk estimates on the lower side of all the lung cancer risk estimates. However,

OSHA believes that these coalminer-derived estimates are quite credible because of the quality of

several study factors relating to both study design and conduct. In terms of design, the cohort was

based on union rolls with very good participation rates and good reporting. The study group was

also over 17,000 with an average of nearly 30 years of follow-up, and about 60 percent of the

cohort had died. Just as important was the high quality and detail of the exposure measurements,

both of total dust and quartz. However, one exposure factor that may have biased the estimates

upward was the lack of exposure information available for the cohort after the mines closed in the

mid 1980’s. Since the lung cancer death ratio was higher during this last study period, 1990 –

2005, this period of time contributed to the increased lung cancer risk. It is possible that any

quartz exposure experienced by the cohort after the mines had closed could have accelerated either

death or tumor growth. Not accounting for this exposure, if there were any, would bias the risk

estimates upwards. Although the 15-year lag period for quartz exposure used in the analyses

provided slightly higher risk estimates than use of no lag period, the better fit seen with the lag

may have been artificial, since there appear to have been no exposures during the recent period

when risks were seen to have increased.

II.B.7. Summary of OSHA’s Estimates of Lung Cancer Mortality Risk.

Table II-2 summarizes the excess risk estimates based on each of the lung cancer risk

assessments discussed in this section. OSHA’s estimates of lifetime lung cancer risk associated

with 45 years of exposure to crystalline silica at 0.1 mg/m3(approximately the current general

industry PEL) range from 13 to 60 deaths per 1,000 workers. For exposure to the proposed PEL of

0.05 mg/m3, the lifetime risk estimates calculated by OSHA are in the range of 6 to 26 deaths per

1,000. For a 45-year exposure at he proposed action level of 0.025 mg/m3, OSHA estimates the

risk to range from 3 to 23 deaths per 1,000 workers. The results from these assessments are

reasonably consistent despite the use of data from different cohorts and the reliance on different

analytical techniques for evaluating dose-response relationships. Furthermore, OSHA notes that in

this range of exposure there is statistical consistency between the risk estimates, as evidenced by

the considerable overlap in the 95-percent confidence intervals of the risk estimates presented in

Table II-2.

Estimating lung cancer risks over the range of cumulative exposures of interest to OSHA

required some degree of extrapolation above the range of exposures experienced by most of the

workers included in the occupational studies. Exposure to 0.25 or 0.5 mg/m3(the range

approximating the current construction/shipyard PEL) over 45 years represents cumulative

exposures of 11.25 and 22.5 mg/m3-years, respectively. This range of cumulative exposure is well

above the median cumulative exposure for the diatomaceous earth cohort, the U.S. granite cohort,

and each of the other cohorts included in the pooled risk analysis, the highest being 11.37 mg/m3-

years for the Australian gold miner cohort. In addition, third quartile cumulative exposures were

within or above this range for only three cohorts (Australian gold miners, Chinese tungsten miners,

and Finnish granite workers, see Table II of Mannetje et al., 2002a), although for 7 of the 10

cohorts, the maximum cumulative exposure of cohort members exceeded this range. As such, a

45-year occupational exposure to 0.25 or 0.5 mg/m3respirable silica reflects cumulative exposures

of the minority of workers who were the most highly exposed among the cohorts included in the
290

Table II-2. Estimates of Lifetimea Lung Cancer Mortality Risk Resulting from 45-Years of Exposure to Crystalline Silica

(Deaths per 1,000 Workers (95% Confidence Interval))

Footnotes for Table II-2

a

Risk to age 85 and based on 2006 background mortality rates for all males (see Appendix for life table method).

b Model with log cumulative exposure (mg/m3

-days + 1).

c Model with cumulative exposure (mg/m3

-years).

d

95% confidence interval calculated as follows (where CE = cumulative exposure in mg/m3-years and SE is standard error of the parameter estimate):

For CE ≤ 2.19: 1 + [(β1 ± (1.96*SE1)) *CE]

For CE > 2.19: 1 + [(β1 * CE) + (β2 * (CE-2.19))] ± 1.96 * SQRT[ (CE2* SE1

2

) + ((CE-2.19)2*SE2

2

) + (2*CE*(CE-3.29)*-0.00429) ]

e

Standard error not reported, upper and lower confidence limit on beta estimated from confidence interval of risk estimate reported in original article.

f

Standard error of the coefficient was estimated from the p-value for trend.

Cohort Model

Exposure

Lag

(years)

Model Parameters

(Standard Error)

Exposure Level (mg/m3)

0.025 0.05 0.10 0.25 0.50

Ten pooled cohorts

(see Table II-1)

Range from 10 cohorts

Log-linearb

Linearb

Linear Splinec,d

Log-linearc

15

15

15

15

β = 0.60 (0.015)

β = 0.074950 (0.024121)

β1 = 0.16498 (0.0653) and

β2 = -0.1493 (0.0657)

Various

22 (11-36)

23 (9-38)

9 (2-16)

0.21 – 13

26 (12-41)

26 (10-43)

18 (4-31)

0.41 – 28

29 (13-48)

29 (11-47)

22 (6-38)

0.83 – 69

34 (15-56)

33 (12-53)

27 (12-43)

2.1 – 298

38 (17-63)

36 (14-58)

36 (20-51)

4.2 - 687

Diatomaceous earth

workers

Linearc10 β = 0.1441e9 (2-21) 17 (5-41) 34 (10-79) 81 (24-180) 152 (46-312)

U.S.Granite workers Log-linearc15 β = 0.19e11 (4-18) 25 (9-42) 60 (19-111) 250 (59-502) 653 (167-760)

North American

industrial sand workers

Log-linearc15 β = 0.13 (0.074)f7 (0-16) 15 (0-37) 34 (0-93) 120 (0-425) 387 (0-750)

British coal miners Log-linearc15 Β = 0.0524 (0.0188) 3 (1-5) 6 (2-11) 13 (4-23) 37 (9-75) 95 (20-224)
291

pooled analysis and thus represents cumulative exposures that lie above the observed

range of exposures experienced by most of the workers included in the pooled cohort

study.

Thus, estimates of lung cancer risk at higher exposures approximating the current

construction/shipyard PEL (0.25 and 0.5 mg/m3) are more uncertain. The estimates

calculated by OSHA based on four individual cohort studies range from 37 to 250 deaths

per 1,000 at 0.25 mg/m3, and range from 95 to 653 deaths per 1,000 at 0.5 mg/m3.

Estimates based on the model from the pooled analysis yielded estimates approximately

1.3- to 18-fold lower (27 to 34 deaths per 1,000 at 0.25 mg/m3and 36-38 deaths per

1,000 at 0.5 mg/m3). This difference reflects the shape of the underlying exposureresponse model, which flattens out at higher exposures. It is unclear whether the

flattening out of the exposure-response curve fit by Steenland et al. (2001a) captures

some feature of the actual exposure-response (e.g., a decline in slope at high exposures

due to saturation or an increase in competing non-cancer risks associated with exposure

to silica), or whether attenuation of the observed exposure-response slope reflects

methodological limitations (such as the presence of a survivor effect, or exposure

misclassification). All of these were suggested by Steenland et al. (2001a) as reasons

why attenuation of the observed exposure-response curve is often observed in

epidemiological studies. OSHA notes that, in contrast, such attenuation of the exposureresponse curve was not seen in three of the four individual cohort studies evaluated in the

risk assessment (Rice et al., 2001; Hughes et al., 2001; Miller and MacCalman et al.,

2009), and, in the fourth study used by OSHA (Attfield and Costello, 2004), the

exposure-response trend was linear except for a decline in the lung cancer rate seen only

for the highest exposure group. This group had cumulative exposures of 6 mg/m3-years

or more with an average of about 10 mg/m3-years, which corresponds to 45 years of

exposure to 0.22 mg/m3. In contrast, no decline in lung cancer mortality rate was evident

among diatomaceous earth workers with similarly high exposures (13 mg/m3-years or

higher), based on a categorical analysis of the cohort (see Figure 1 in Rice et al., 2001).

In the industrial sand and coal miner studies, cumulative exposures of the more highly

exposed workers were comparable to the granite and diatomaceous earth studies, with the

75th-percentile exposure of industrial sand workers being about 5 mg/m3-years (Hughes et

al., 2001) and the upper quartile of cumulative exposure for the coal miners reported to

be about 9 ghm-3 (4.5 mg/m3-years), with a maximum exposure of 42 ghm-3 (21 mg/m3-

years) (Miller and MacCalman, 2009). There was no evidence of a decline in lung cancer

mortality among the more highly exposed workers in these two cohorts based on

information presented in the reports.

It should also be noted that, although the log transformation of cumulative

exposure reduced the heterogeneity observed by Steenland et al. among the 10 cohorts

used in the pooled analysis, there was no statistically significant difference in fit between

the models using log-transformed cumulative exposure vs. untransformed lagged

cumulative exposure. OSHA believes that use of log-transformed cumulative exposure

provides a highly credible basis for deriving a central tendency estimate of risk from the

10 cohorts used for the analysis, but these estimates of risk may understate the risk

presented to workers in some industry sectors, based on risk estimates derived from the

single-cohort studies.
292

The cohort studies included in the pooled analysis relied in part on particle count

data and the use of conversion factors to estimate exposures of workers to mass respirable

quartz. A few studies were able to include at least some respirable mass sampling data.

OSHA believes that uncertainty in the exposure assessments that underlie each of the 10

studies included in the pooled analysis is likely to represent one of the most important

sources of uncertainty in the risk estimates. To evaluate the potential impact of

uncertainties in the underlying exposure assessments on estimates of the risk, OSHA’s

contractor, Toxichemica, Inc. (2004), commissioned Drs. Kyle Steenland and Scott

Bartell of Emory University to conduct an uncertainty analysis using the raw data from

the pooled cancer risk assessment. The findings from their uncertainty analysis and other

sources of uncertainty in OSHA’s risk estimates, such as selection bias and confounding

by smoking and occupational co-exposures, are presented in section II-D following the

discussion of silicosis and non-malignant respiratory disease mortality risk below.

II.C. Silicosis and Non-Malignant Respiratory Disease Mortality Risk Estimates.

There are two published quantitative risk assessment studies of silicosis and nonmalignant respiratory disease (NMRD) mortality; a pooled analysis of silicosis mortality

by Mannetje et al. (2002b) of data from six epidemiological studies, and an exposureresponse analysis of NMRD mortality among diatomaceous earth workers (Park et al.,

2002). These studies are summarized below, with detailed discussion and analysis of

uncertainty in the studies and associated risk estimates.

II.C.1. Mannetje et al. (2002b) Pooled Analysis.

The pooled analysis conducted by Mannetje et al. (2002b) was based on six of the

ten cohorts that were part of the IARC multi-centric exposure-response study of lung

cancer (Steenland et al., 2001a) discussed in section II.B.1 above, including U.S.

diatomaceous earth (DE) workers (Checkoway et al., 1997); Finnish granite workers

studied by Koskela et al. (1994); U.S. granite workers assessed by Costello and Graham

(1988); U.S. industrial sand workers examined by Steenland et al. (2001b); U.S. gold

miners studied by Steenland and Brown (1995b); and Australian gold miners assessed by

de Klerk and Musk (1998). These six cohorts contained 18,634 subjects and 170 silicosis

deaths, where Mannetje et al. (2002b) defined silicosis mortality as death from silicosis

(ICD-9 502, n = 150) or from unspecified pneumoconiosis (ICD-9 505, n = 20). The

authors believed this definition to be conservative in that some cases of death from

silicosis in the cohorts were probably miscategorized as other causes (e.g., tuberculosis or

chronic obstructive pulmonary disease without mention of pneumoconiosis). Information

on these cohorts is provided in Table II-3, including size, time period studied, overall

number of deaths and number of deaths identified as silicosis for the pooled analysis.

Four cohorts were not included in the silicosis mortality study; the three Chinese studies

did not use the International Classification of Diseases (ICD) to code cause of death and,

in the South African gold miner study, silicosis was not generally recognized as an

underlying cause of death in South Africa and thus did not appear on death certificates.
293

Table II-3. Summary of Cohort Data Used in the Pooled

Analysis for Silicosis Mortality

Author Cohort Size of cohort Time period of

study

Number of

deaths

Number

of silicosis

deaths

Checkoway

et al., 1997 U.S. diatomaceous

earth

2,342 1942-1994 749

15 (“other”

NMRDa,

including

silicosis)

Koskela et

al., 1994 Finnish granite 1,026 1940-1993 418 14

Costello and

Graham,

1988

U.S. granite 5,408 1950-1982 1,762 43

Steenland et

al., 2001b U.S. industrial sand 4,027 1974-1996 860 15

Steenland

and Brown,

1995b U.S. gold miners 3,348 1940-1996 1925 39

de Klerk and

Musk, 1998

Australian surface and

underground gold

miners

2,213 1961-1993 1,351 44

Footnotes for Table II-3

a Non-malignant respiratory disease

Source: Adapted from Mannetje et al., 2002b

The exposure assessment used in the pooled silicosis mortality study is the same

as that used in the lung cancer study and is summarized in section II.B.1 (Mannetje et al.,

2002a). As also discussed in Section II.B.1, an analysis later conducted by Dr. Kyle
294

Steenland for OSHA corrected a small number of errors primarily related to rounding in

exposure calculations for the originally reported results. Correction of these errors did

not significantly impact the results of the exposure-response analysis (Toxichemica, Inc.,

2004).

Silicosis mortality was evaluated using standard life table analysis. Poisson

regression, using ten categories of cumulative exposure and adjusting for age, calendar

time, and cohort, was conducted to derive silicosis mortality rate ratios using the lowest

exposure group (0-1 mg/m3-year) as the referent group. More detailed exploration of the

exposure-response curve using a variety of exposure metrics, including cumulative

exposure, duration of exposure, average exposure (calculated as cumulative

exposure/duration), and the log transformations of these variables, was conducted via

nested case-control analyses (conditional logistic regression). Each case was matched to

100 controls selected from among those who had survived to at least the age of the case,

with additional matching on cohort, race, sex, and date of birth within five years. The

authors explored lags of 0, 5, 10, 15, and 20 years, noting that there is no a priori reason

to apply an exposure lag, as silicosis can develop within a short period after exposure, but

that a lag could potentially improve the model as there is often a considerable delay in the

development of silicosis following exposure. In addition to the parametric conditional

logistic regression models, the authors ran some analyses using a cubic spline model with

knots at 5%, 25%, 50%, 75%, and 95% of the distribution of exposure. Models with

cohort-exposure interaction terms were fit to assess heterogeneity between cohorts.

The categorical analysis found a nearly monotonic increase in silicosis rates with

cumulative exposure, from 4.7 per 100,000 person-years in the lowest exposure category

(0-0.99 mg/m3-years) to 299 per 100,000 person-years in the highest exposure category

(>28 mg/m3-years). Nested case-control analyses showed a significant association

between silicosis mortality and cumulative exposure, average exposure, and duration of

exposure. The best fitting conditional logistic regression model used log-transformed

cumulative exposure with no exposure lag, with a model 2

 of 73.2 vs. 2 values ranging

from 19.9 to 30.9 for average exposure, duration of exposure, and untransformed

cumulative exposure (1 d.f.). No significant heterogeneity was found between individual

cohorts for the model based on log-cumulative exposure. The cubic-spline model did not

improve upon the model fit for the parametric logistic regression model using the log of

cumulative exposure.

Mannetje et al. (2002b) developed estimates of silicosis mortality risk through age

65 for two levels of exposure (0.05 and 0.1 mg/m3 crystalline silica), assuming a working

lifetime of occupational exposure from age 20 to 65. Risk estimates were calculated

based on the silicosis mortality rate ratios derived from the categorical analysis described

above using the standard formula:

Risk = 1 – exp(-∑time*rate)

Here, the time period over which workers’ exposures and risk are calculated (age 20 to

65) is divided into one-year intervals, and the mortality rate used to calculate risk in any

given interval depends on the worker’s cumulative exposure at that time; the equation is:
295

Risk = 











   



65

20

exp1

i

ii

ratetime

where timei is equal to 1 for every age i, and ratei is the age-, calendar time-, and cohortadjusted silicosis mortality rate associated with the level of cumulative exposure acquired

at age i, as presented in Table 2 of Mannetje et al., 2002b). Absolute risks rather than

excess risks were calculated since there is no background rate of silicosis in the exposed

population. Mannetje et al. (2002b) estimated the lifetime risk of death from silicosis,

assuming 45 years of exposure to 0.1 mg/m3to be 13 deaths per 1,000 workers; at an

exposure of 0.05 mg/m3, the estimated lifetime risk was 6 per 1,000 (confidence intervals

not reported).

To estimate the risk of silicosis mortality at the current and proposed PELs,

OSHA used the model described by Mannetje et al. (2002b) but used rate ratios that were

estimated from a nested case-control design implemented as part of a sensitivity analysis

conducted by Toxichemica, Inc. (2004), rather than the Poisson regression originally

conducted by Mannetje et al. (2002b). The case-control design was selected because it

was expected to better control for age; in addition, the rate ratios derived from the casecontrol study were derived from a Monte Carlo analysis to reflect exposure measurement

uncertainty (see section II.D below). (The adjusted rate ratios appear in Table 7 of

Toxichemica, Inc. (2004) and in Table II-8 of this report). The rate ratio for each interval

of cumulative exposure was multiplied by the annual silicosis rate assumed to be

associated with the lowest exposure interval, 4.7 per 100,000 for exposures of 0-0.99

mg/m3-years, to estimate the silicosis rate for each interval of exposure. The lifetime

silicosis mortality risk is the sum of the silicosis rate for each year of life through age 85

and assuming exposure from age 20 to 65. From this analysis, OSHA estimates the

silicosis mortality risk for exposure to the current general industry and proposed PEL to

be 11 (95% CI 5-37) and 7 (95% CI 3-21) deaths per 1,000 workers. For exposure to

0.25 and 0.5 mg/m3, the range approximating the current construction/shipyard PEL,

OSHA estimates the risk to range from 17 (95% CI 5-66) to 22 (95% CI 6-85) deaths per

1,000.

II.C.2. Park et al. (2002) Study of Diatomaceous Earth Workers.

Park et al. (2002) analyzed the California diatomaceous earth cohort data

originally studied by Checkoway et al. (1997), consisting of 2,570 diatomaceous earth

workers employed for 12 months or more from 1942 to 1994, to quantify the relationship

between exposure to cristobalite and mortality from chronic lung disease other than

cancer (LDOC). Diseases in this category included pneumoconiosis (which included

silicosis), chronic bronchitis, and emphysema, but excluded pneumonia and other

infectious diseases. The investigators selected LDOC as the health endpoint for three

reasons. First, increased mortality from LDOC had been documented among crystalline

silica-exposed workers in several industry sectors, including gold mining, pottery,

granite, and foundry industries (see Section I.D. of the Health Effects literature review for

a discussion). In addition, they pointed to the likelihood that silicosis as a cause of death

is often misclassified as emphysema or chronic bronchitis. Finally, the number of deaths
296

from the diatomaceous earth worker cohort that were attributed to silicosis was too small

(10) for analysis. Industrial hygiene data for the cohort were available from the employer

for total dust, silica (mostly cristobalite), and asbestos. Smoking information was

available for about 50 percent of the cohort and for 22 of the 67 LDOC deaths available

for analysis, permitting Park et al. (2002) to at least partially adjust for smoking.

Park et al. (2002) used the exposure assessment previously reported by Seixas et

al. (1997) and used by Rice et al. (2001) to estimate cumulative crystalline silica

exposures for each worker in the cohort based on detailed work history files, as discussed

in Section I.C.2.r. of Health Effects. The mean silica concentration for the cohort overall

was 0.29 mg/m3over the period of employment (Seixas et al., 1997). The total respirable

dust concentration in the diatomaceous earth plant was 3.55 mg/m3before 1949, and

declined by more than 10-fold after 1973. The concentration of crystalline silica in the

dust ranged from 1 to 25 percent depending on location within the establishment; it was

lowest at the mine and greatest in the plant where the raw ore was calcined into final

product. The mean cumulative exposure values for total respirable dust and respirable

crystalline silica were 7.31 and 2.16 mg/m3-year, respectively. Similar cumulative

exposure estimates were made for asbestos.

Using both Poisson regression models and Cox’s proportional hazards models,

they fit the same series of relative rate exposure-response models that were evaluated by

Rice et al. (2001) for lung cancer (i.e., log-linear, log-square root, log-quadratic, linear

relative rate, a power function, and a shape function). In general form, the relative rate

model was:

Rate = exp (a0) x f(E),

where exp (a0) is the background rate and E is the cumulative exposure to silica. Park et

al. (2002) also employed an additive excess rate model of the form:

Rate = exp(a0) + exp (aE).

Relative or excess rates were modeled using internal controls and adjusting for age,

calendar time, ethnicity (Hispanic versus white), and time since first entry into the cohort.

In addition, relative rate models were evaluated using age- and calendar time-adjusted

external standardization to U.S population mortality rates for 1940 to 1994.

There were no LDOC deaths recorded among workers having cumulative

exposures above 32 mg/m3-years, causing the response to level off or decline in the

highest exposure range. The authors believed the most likely explanation for this

observation (which was also observed in their analysis of silicosis morbidity in this

cohort, see section II.F.2 below) was some form of survivor selection, possibly smokers

or others with compromised respiratory function leaving work involving extremely high

dust concentrations. Alternative explanations suggested by the investigators included a

greater depletion of susceptible populations in high dust areas, a higher degree of

misclassification of exposures in the earlier years where exposure data were lacking (and

when exposures were presumably the highest), and the nature of relative risk models for
297

which both background disease rates and cumulative exposures increase with age.

Therefore, Park et al. (2002) performed exposure-response analyses that restricted the

dataset to observations where cumulative exposures were below 10 mg/m3-years, a level

more than four times higher than that resulting from 45 years of exposure to the current

PEL for cristobalite (which is about 0.05 mg/m3), as well as analyses using the full

dataset.

Model fit was assessed by evaluating the decrease in deviance resulting from

addition of the exposure term, and cubic spline models were used to test for smooth

departures from each of the model forms described. Park et al. (2002) found that both

lagged and unlagged models fit well, but that unlagged models provided a better fit. In

addition, they believed that unlagged models were biologically plausible in that recent

exposure could contribute to LDOC mortality. The Cox’s proportional hazards models

yielded results that were similar to those from the Poisson analysis; consequently, only

the results from the Poisson analysis were reported. In general, the use of external

adjustment for age and calendar time yielded considerably improved fit over models

using internal adjustment. The additive excess rate model also proved to be clearly

inferior compared to the relative rate models. Use of cumulative exposure as the

exposure metric consistently provided better fits to the data than did intensity of exposure

(cumulative exposure divided by duration of exposure), with one exception: when the

highest-exposure cohort members were included in the analysis, the log linear model

produced a significantly improved fit with exposure intensity as the exposure metric, but

a poor fit with cumulative dose as the metric.

Among the models based on the restricted dataset (excluding observations with

cumulative exposures  10 mg/m3-years) the best-fitting model with a single exposure

term was the linear relative rate model using external adjustment. Most of the other

single-term models using external adjustment fit almost as well. Of the models with

more than one exposure term, the shape model provided no improvement in fit compared

with the linear relative rate model; the log-quadratic model fit slightly better than the

linear relative rate model, but Park et al. (2002) did not consider the gain in fit sufficient

to justify an additional exposure term in the model.

Based on its superior fit to the cohort data, Park et al. (2002) selected the linear

relative rate model with external adjustment and use of cumulative exposure as the basis

for estimating LDOC mortality risks among exposed workers. Competing mortality was

accounted for using U.S. background death rates published by the National Center for

Health Statistics (1996). The authors estimated the excess lifetime risk for white men

exposed to mainly respirable cristobalite dust for 45 years at 0.05 mg/m3to be 54 deaths

per 1000 workers (95% CI 17, 150) using the restricted dataset, and 50 deaths per 1000

using the full dataset (confidence interval not reported). For exposure to 0.1 mg/m3, they

estimated 100 deaths per 1000 using the restricted dataset, and 86 deaths per 1000 using

the full dataset (confidence intervals not reported).

Park et al.’s (2002) estimates, which are about 8 to 9 times higher than those

calculated for the pooled analysis of silicosis mortality (Mannetje et al., 2002b), are not

directly comparable to the Mannetje et al. risk estimates since the mortality endpoint for
298

the Park et al. (2002) analysis is death from all non-cancer lung diseases, including

pneumoconiosis, emphysema, and chronic bronchitis, whereas the pooled analysis by

Mannetje et al. (2002b) included only deaths coded as silicosis or other pneumoconiosis.

Less than 25% of the LDOC deaths in the Park et al. (2002) analysis were coded as

silicosis or other pneumoconiosis (15 of 67). As noted by Park et al. (2002), it is likely

that silicosis as a cause of death is often misclassified as emphysema or chronic

bronchitis; thus, Mannetje et al.’s selection of deaths may tend to underestimate the true

risk of silicosis mortality, and Park et al.’s (2002) analysis would more fairly capture the

total respiratory mortality risk from all non-malignant causes, including silicosis and

chronic obstructive pulmonary disease. Another difference between the analyses is the

use by Park et al. (2002) of untransformed cumulative exposure in a linear model

compared to the log-transformed cumulative exposure metric used by Mannetje et al.

(2002b), which causes the exposure-response to flatten out in the higher exposure ranges.

It is also possible that some of the difference between Mannetje et al.’s and Park et al.’s

risk estimates reflects factors specific to the nature of exposure among diatomaceous

earth workers (e.g., exposure to cristobalite vs. quartz). However, neither the cancer risk

assessments nor assessments of silicosis morbidity (discussed in sections II.B and II.F,

respectively) support the hypothesis that cristobalite is more hazardous than quartz.

Based on the available risk assessments for silicosis mortality, OSHA believes

that the estimates from the pooled study represent the most conservative estimates of

mortality risk (i.e., unlikely to overstate risks) from silicosis given that the estimates

reflect only those deaths where silicosis was specifically identified on death certificates,

and is therefore most likely an underestimate of the true silicosis mortality risk. In

contrast, the risk estimates provided by Park et al. (2002) for the diatomaceous earth

cohort would capture some of this misclassification and include risks from other lung

diseases (emphysema, chronic bronchitis) that have been associated with exposure to

crystalline silica. Therefore, OSHA believes that the Park et al. study provides a better

basis for estimating the silica-related risk of NMRD mortality, including that from

silicosis. Based on Park et al.’s linear relative rate model (RR = 1 + βx, β = 0.5469 (no

standard error reported) and x = cumulative exposure), OSHA used a life table analysis

(see Appendix to this section) to estimate the lifetime excess NMRD mortality through

age 85. For this analysis, OSHA used all-cause and cause-specific background mortality

rates for for all males (National Center for Health Statistics, 2009). Background rates for

NMRD mortality were based on rates for ICD-10 codes J40-J47 (chronic lower

respiratory disease) and J60-J66 (pneumoconioses and chemical effects), which OSHA

believes correspond closely to the ICD-9 disease classes (ICD 490-519) used by the

original investigators; according to CDC (2001), background rates for chronic lower

respiratory diseases were increased by less than 5 percent as a result of the reclassification to ICD-10. From the life table analysis, OSHA estimates that the excess

NMRD risk due to exposure to the current general industry and the proposed PEL for 45

years are 83 and 43 deaths per 1,000, respectively. For exposure at the the current

construction/shipyard PEL, OSHA estimates that the excess NMRD risk ranges from 188

to 321 deaths per 1,000.
299

II.D. Uncertainty in Lung Cancer and Silicosis Mortality Risk Estimates.

The risk estimates for lung cancer and silicosis presented in the previous sections

are inherently uncertain, as they depend on a variety of assumptions and inputs. In this

section, sources of uncertainty in OSHA’s risk assessment are identified and evaluated,

and potentially significant sources of uncertainty are quantitatively analyzed where it is

reasonable to do so given the significance of the uncertainty and the availability of

methods and data for use in a quantitative uncertainty analysis. This treatment of

uncertainty contributes to the development of reasonable risk estimates, provides for

informed decision-making, and is consistent with the Department of Labor’s Information

Quality Guidelines.

Uncertainty that results from estimating risk from these studies is reflected in the

confidence limits for the risk estimates presented in Table II-2 and in the earlier

discussions of this section. These confidence limits depend on the study design, the study

sample sizes, the number of deaths, and the goodness of fit of the models to the data.

They do not explicitly reflect other important sources of uncertainty. Sources of nonrandom or “systematic” error that frequently affect epidemiological risk assessments

include confounding, selection bias, and measurement error. These types of error can

sometimes create bias in a risk assessment, leading to risk estimates that are substantially

higher or lower than the true risk. As discussed below, OSHA does not have reason to

believe that either selection bias or confounding has a substantial impact on the risk

estimates for lung cancer or silicosis mortality. It is more difficult to assess the

importance of exposure measurement error, but the quantitative analyses conducted by

Steenalnd and Bartell for Toxichemica, Inc. (2004) to explore uncertainty due to

measurement error do not suggest that such errors have a substantial impact on the

previously presented risk estimates.

II.D.1. Selection Bias.

Selection bias is error due to systematic differences in risk-related characteristics

between individuals who participate in a study and those who do not. The pooled risk

analyses for lung cancer and silicosis mortality are unlikely to have substantial selection

bias because all potentially eligible workers were typically included in the cohorts, and

because follow-up was generally quite complete. Furthermore, virtually all known cohort

studies for which quantitative exposure data were available at the time were included in

the Steenland et al. (2001a) pooled analysis for lung cancer. For the pooled analysis of

silicosis mortality, Mannetje et al. (2002b) included six of these same studies for which

ICD coding was available on death certificates; ICD coding was not available from the

three Chinese cohorts and the South African miner cohort. OSHA does not believe that

exclusion of these four cohorts was likely to contribute to any significant selection bias in

the silicosis mortality study since there is no evidence that indicates that the

characteristics of the excluded cohorts would be substantially different from the others.

With respect to the South African cohort, Mannetje et al. (2002b) reported that, although

silicosis was not typically coded as a cause of death in that country, the cohort did exhibit

an exposure-related increase in mortality from related causes of death, such as

tuberculosis and chronic obstructive pulmonary disease. Furthermore, exclusion of either
300

the South African cohort or the three Chinese cohorts did not appreciably change the

resulting coefficient or fit of the log-linear model in the pooled lung cancer analysis

(Steenland et al., 2001a).

II.D.2. Confounding.

Confounding occurs when the estimated effect of exposure on disease risk is

distorted due to an extraneous factor associated with both the exposure and the disease.

Cigarette smoking can act as a positive confounder in studies of occupational disease

when smoking rates are higher among the working-class study participants than in the

larger populations whose lung cancer rates often serve as the point of comparison or

“reference rates”; in this case, the observation that lung cancer is related to exposure

would be spurious since the observed effect could just as easily be attributed to smoking.

Positive confounding by smoking in lung cancer studies becomes less likely when (1)

comparison populations are drawn internally using subjects from the same work

environment as the exposed population because it is less likely that smoking histories will

be substantially different between controls and study subjects; (2) analyses are performed

to look for an exposure-response gradient, since smoking history would have to be

positively correlated with exposure to contribute to the observed exposure-response

gradient, again an unlikely outcome; and (3) data on smoking history are available to

permit including a smoking term in a quantitative exposure-response analysis. Smoking

can also act to bias a weak exposure-response trend towards the null when baseline

cancer risks are elevated due to smoking; this is not considered confounding per se, but

modifies the magnitude of the exposure-related effect relative to the baseline risk such

that the exposure-related effect becomes more difficult to detect (Axelson, 1989).

Smoking can act as a true negative confounder in cases where the referent population has

a greater proportion of smokers than does the exposed population.

Occupational co-exposures are another potential confounder, since workers may

be exposed to a variety of carcinogenic or toxic agents other than the exposure of interest.

Among the cohorts discussed here, radon and asbestos were potential occupational

confounders for the lung cancer risk analysis.

The Steenland et al. (2001a) pooled analysis compared lung cancer rates in

workers with higher exposures to workers with lower exposures rather than to the general

population, and, for this reason, is unlikely to be much affected by confounding due to

smoking. Furthermore, complete or partial smoking data were collected and considered

in the original exposure-response analyses for four of the ten cohorts in the pooled

analysis, with little or no effect on exposure-response coefficients (Steenland et al.,

2001a). Another potential source of confounding in the pooled lung cancer analysis is

radon exposure of the mining cohorts included. Serious confounding from radon

exposure seems unlikely in that, according to Steenland et al. (2001a), the mining cohorts

demonstrated exposure-response relationships of a magnitude similar to those for nonmining cohorts. In addition, removal of the South African mining cohort, which showed

the highest exposure-response and where radon exposure was most likely to confound the

results, did not have any appreciable effect on the magnitude of exposure-response for the

remainder of the pooled cohort.
301

Two studies relied on by OSHA to estimate excess lung cancer risks had

individual smoking status data and could thus include an adjustment for smoking in the

regression models (Hughes et al., 2001; Miller and MacCalman 2009). In both cases, the

exposure-response trend remained statistically significant and the risk estimates derived

from the exposure-response coefficients reflect estimates adjusted for smoking.

Because of the lack of smoking data on the cohort (69.4% of the lung cancer

deaths had unknown smoking habits), Rice et al. (2001) did not formally evaluate

potential confounding of the exposure-response from smoking. However, they referred

to the original analysis of the cohort in which Checkoway et al. (1997) employed an

indirect method to evaluate the impact of smoking. This approach entailed estimating

smoking-related lung cancer rates for the highest cumulative exposure group and for the

reference group, based on available data on smoking prevalence and a conservative

estimate of smoking-related relative risk. Using this method, Checkoway et al. (1997)

predicted a lung cancer mortality rate ratio of 1.67 for the high-exposure group, which

was smaller than the observed rate of 2.15. In addition, the smoking prevalences of the

two highest exposure groups were comparable (0.86 vs. 0.83) but there was a substantial

difference in observed lung cancer rate ratios (1.26 vs. 2.15), again indicating that

smoking was an unlikely confounder and that the observed increases in risk were

associated with exposure to crystalline silica. Rice et al. (2001) also argued that smoking

was not likely to be a serious confounder because the prevalence of smoking was

unrelated to cumulative exposure to crystalline silica in the cohort. In addition, internal

adjustment models that compare the mortality experience of exposed and non-exposed

workers in the same cohort reduce the likelihood that results are confounded by smoking.

In Rice et al.’s (2001) analysis, the use of internally standardized models yielded slope

estimates that were similar to those based on external mortality rates.

As described in the Health Effects section, Gibbs (1998) argued that the results of

the diatomaceous earth study were confounded by concurrent exposure to asbestos, in

particular among workers employed prior to 1930. In examining the influence of

potential asbestos exposure on the mortality experience of the cohort, Checkoway et al.

(1993) found that the risk ratio for the highest silica exposure group after excluding these

workers from the cohort (RR = 1.73) was almost identical to the risk ratio of the highexposure group after excluding workers hired prior to 1930 (RR = 1.74). In addition,

Checkoway et al.’s (1996) reanalysis of the original cohort study (Checkoway et al.,

1993) examined those members of the cohort for whom there was quantitative

information on asbestos exposure, based on a mixture of historical exposure monitoring

data, production records, and recorded quantities of asbestos included in mixed products

of the plant. Cohort members’ cumulative exposures to asbestos were calculated from

these estimates using the same methods as for the silica exposure assessment. The

authors found an increasing trend in lung cancer mortality with exposure to crystalline

silica after controlling for asbestos exposure, and found only minor changes in relative

risk estimates after adjusting for asbestos exposure. Finally, Checkoway et al. (1998)

reported that the prevalence of pleural plaques among workers hired before 1930 (4.2%)

was similar to that of workers hired after 1930 (4.9%) when asbestos was presumably no

longer used in the process. From these findings, Checkoway et al. (1998) concluded that

asbestos was not likely to significantly confound the exposure-response relationship
302

observed between lung cancer mortality and exposure to crystalline silica in

diatomaceous earth workers. Rice et al. (2001) also utilized Checkway et al.’s (1997)

data to test for confounding by asbestos in their Poisson and Cox’s proportaional hazards

models; finding no evidence of confounding, they did not include asbestos exposure as a

variable in the final models presented in their 2001 paper.

According to Mannetje et al. (2002b), it was not possible to adjust for smoking in

the pooled silicosis mortality analysis. Park et al. (2002) used what smoking data were

available for the cohort to adjust for smoking in their Poisson analyses of LDOC

mortality among diatomaceous earth workers. They reported that analyses that did not

control for smoking yielded slightly smaller risk estimates than did analyses that partially

controlled for smoking, suggesting that estimates of silicosis mortality risk based on this

cohort are not likely to be exaggerated due to cohort members’ smoking habits.

However, as discussed by Rice et al. (2001) in their analysis of this cohort for lung

cancer, their ability to control for smoking in this cohort is constrained by the limited

smoking data, which was available for only 50% of the overall cohort and 33% of the

workers who died of LDOC. As in the Rice et al. (2001) study, Park et al. (2002)

performed internally standardized analyses, which tend to be less susceptible to

confounding by smoking as they compare groups of workers in the cohort rather than

comparing workers with an unexposed population (which sometimes have lower smoking

rates than worker populations). The authors reported that internally standardized models

yielded only slightly lower exposure-response coefficients than externally adjusted

models (exact values not presented). Park et al. (2002) used externally standardized

models to produce excess risk estimates because they appeared to provide a considerably

better fit to the data than the internally standardized models. Finally, Park et al. (2002)

also cited the original Checkoway et al. (1997) study, which presented analyses

indicating that confounding by smoking was not likely to account for the observed

relationship between cumulative exposure to crystalline silica and LDOC mortality.

II.D.3. Exposure Measurement Error.

The lung cancer and silicosis risk estimates discussed in previous sections may be

affected by one or more sources of error in silica exposure measurements. First,

individual workers’ exposures were assigned based on exposure measurements for a

sample of workers in the same job (defined by facility, task, and work areas to the extent

permitted by the available data), or based on estimated exposure levels for specific jobs

in the past when no measurements were available, via a job-exposure matrix (JEM)

(Mannetje et al., 2002a). The observed or assigned job-specific mean exposure from the

matrix is assumed to equal the true mean exposure level for workers in a specific job, but

assignment of individual workers’ exposure levels using the mean level for specific jobs

necessarily results in an assigned exposure level different from the true exposure for each

individual. Second, error results from the conversion of historically available dust

measurements, typically particle count concentrations, to gravimetric respirable silica

measurements. The conversion factors used in the exposure assessment may not have

accounted for all of the differences in silica content of the dust at different worksites or in

different jobs within a worksite.
303

Errors resulting from the assignment of job-specific mean exposures to

individuals results in a type of error known as a Berkson error, in which the true exposure

level in a job is assumed to vary randomly around the assigned, or “observed” exposure

level for the job (Snedecor and Cochran, 1989). That is:

Exposuretrue = Exposureobserved + ε.

In this instance, measurement error is independent of the observed exposure and is

positively correlated with the true exposure level. This is in contrast to the classical error

model, where the error is independent of the true exposure and the observed exposure

varies randomly around the true value. When, as is the case for the pooled cohort

analysis, the exposure metric is a log transformed measure, the Berkson model becomes:

Log Exposuretrue = Log Exposureobserved + ε

which is a multiplicative error model in which both the mean and variance of the true

exposure is correlated with the observed exposure.

Berkson error can result in overestimation or underestimation of exposure-related

disease risk in log-linear models with dichotomous disease outcomes, such as the doseresponse models presented earlier (Armstrong, 1988, 1990; Deddens and Hornung, 1994;

Prentice, 1982). Bias has been shown to occur when 1) the disease is rare, 2) the true

exposure levels are distributed log-normally, and 3) the variance in the measurement

error increases with exposure level, all common conditions in occupational epidemiology

(Deddens and Hornung, 1994). For this reason, OSHA believed it important to assess

these errors and their potential effects on the lung cancer and silicosis risk estimates. To

accomplish this, OSHA’s contractor, Toxichemica, Inc., conducted an uncertainty

analysis using the raw data from the IARC multi-centric study to address the separate and

joint effects of errors resulting from exposure metric conversion and from assignment of

exposure values to individual members of the cohort. In addition, the analysis evaluated

the effect of a systematic bias in the exposure estimates. The methods and results are

summarized below and reported in detail in Toxichemica, Inc. (2004).

II.D.3.a. Lung cancer uncertainty analysis.

Monte Carlo analysis of error in the assignment of individual exposure values

A common approach to quantitatively assess uncertainty in a model is to test its

sensitivity to error in the values that were assigned to the model’s various inputs. In the

simplest type of sensitivity analysis, the analyst isolates a single model input and

calculates the model results for a range of values the selected input might have, while

holding all other inputs constant. Toxichemica, Inc.’s (2004) approach to account for

error caused by the assignment of mean exposures to individual workers is similar, except

that the input they test is the matrix of job-specific exposure estimates used to calculate

individual workers’ cumulative exposures used in the exposure-response analysis

previously described. Given the substantial difficulties of defining and testing a “range”

of possible values for an exposure matrix of this size, Toxichemica, Inc. randomly

sampled new values for workers’ job-specific exposure levels from a distribution that
304

they believed characterizes the variability in exposures of individual workers in each job.

The sampled exposure values were then used to repeat the risk analysis. The extent to

which altering the exposure values leads to changes in the results suggests how sensitive

the previously presented risk estimates may be to Berkson error in the exposure

estimates.

For each worker in the 10 cohorts included in the Steenland et al. (2001a) pooled

analysis, a possible value for every exposure concentration for every job worked was

sampled from a distribution of values constructed specifically for that worker and job.

To construct the estimated exposure distributions for each worker-job combination,

Toxichemica, Inc. (2004) assumed that the mean exposure value reported for each job in

the original analysis represents the mean μ of an underlying log normal distribution of

exposures experienced by workers in that job. The standard deviation σ of the

distribution was estimated based on respirable quartz measurements collected from one

of the industrial sand plants that was studied by Steenland et al. (2001b). A total of 37

observations were available, each representing a job-specific mean based on at least 10

respirable quartz measurements. From these exposure measurement data, Toxichemica,

Inc. assigned the distribution a standard deviation of σ = 0.8 * μ. This relationship was

then used to derive the mean (μlni) and standard deviation (σlni) of the distribution of the

log of exposure values, which was assumed to be normally distributed. μlni and σlni were

then used as parameters of a normal distribution to generate random values of log mean

exposure, which represented possible true mean exposure values for a given job and a

given worker. The sampled mean exposure values were then used to calculate a new

estimate of each worker’s cumulative exposure(s). When an entire set of cumulative

exposure values was assembled for all workers based on these randomly sampled values,

the set was used in a conditional logistic regression to fit a new exposure-response model.

Toxichemica, Inc. fit a set of ten new exposure-response models based on ten of these

exposure simulations. The mean of the resulting exposure-response coefficients for each

cohort and the standard deviation for the coefficients appear in Table II-4.

Toxichemica, Inc. (2004) reported that the presence of Berkson error in the

exposure estimates adds additional uncertainty to the fitted model coefficients, as

indicated by the standard deviations across 10 iterations. Among the individual cohorts,

most of the mean regression coefficients resulting from the simulation analysis were

similar to the coefficients from the exposure-response analyses reported in Steenland et

al. (2001) and Toxichemica, Inc. (2004) (following correction for minor data entry and

rounding errors), except for the mean of the simulation coefficients based on the South

Africa gold cohort (0.26), which was lower than the previously calculated exposure

coefficient (0.582). The simulations also resulted in somewhat lower coefficients for

Australia gold (0.156 vs. 0.172), U.S. granite (0.106 vs. 0.118), and China tungsten

(0.033 vs. 0.039) cohorts. The mean of the coefficients for the pooled analysis after

simulating random error in job-specific exposure assignments was very close to the

previously calculated coefficient (0.058 vs. 0.060; standard error not reported). Based on

the mean coefficient values after adjusting for Berkson error in the exposure estimates,

Toxichemica, Inc. (2004) concluded that this error source probably did not appreciably

change the estimated exposure-response coefficient for the pooled data set.
305

Table II-4. Conditional logistic regression coefficient for silica and lung cancer, 10

simulations adjusting for Berkson error in job-specific exposures for each worker,

due to assignment of job-specific mean to each worker

Study

Unadjusted

coefficient

(std error)a

Mean Adjusted

Coefficientb

Standard

Deviation

of

Adjusted

Coefficient

c

US Diatomaceous earth

(Checkoway et al., 1997) 0.086 (0.054) 0.086 0.014

S Africa gold (Hnizdo and Sluis-Cremer,

1991; Hnizdo et al., 1997)

0.582 (0.329) 0.260 0.147

US gold (Steenland and Brown, 1995a) -0.041 (0.078) -0.037 0.021

Australian gold (de Klerk and Musk, 1998) 0.172 (0.111) 0.156 0.038

US granite (Costello and Graham, 1988) 0.118 (0.048) 0.106 0.011

Finnish granite (Koskela et al., 1994) -0.015 (0.063) -0.013 0.012

US industrial sand (Steenland et al., 2001b) 0.045 (0.057) 0.047 0.010

Ch. Tungsten (Chen et al., 1992) 0.039 (0.027) 0.033 0.003

Ch. Pottery (Chen et al., 1992) 0.086 (0.039) 0.086 0.005

Ch. Tin (Chen et al., 1992) 0.054 (0.033) 0.059 0.005

Footnotes for Table II-4

a

Coefficients without adjustment for Berkson error , using corrected data, single run

b Mean of coefficients from 10 simulated data sets adjusting for Berkson error

c

Standard deviation of coefficients from 10 simulated data sets reflects only measurement error

Note: Coefficients are log odds per log (mg/m3-days) lagged 15 years

Source: Toxichemica, Inc. (2004)

Monte Carlo analysis of error in estimating exposures to silica from historical

dust concentration data

A second source of Berkson error in the pooled lung cancer and silicosis mortality

studies is the conversion of historical dust samples to equivalent measures of gravimetric

respirable crystalline silica. These adjustments involved converting particle count

measurements, total dust measurements, and respirable dust measurements to measures of

respirable crystalline silica based on available data on the silica content of dust present in
306

different work areas of the workplaces from which the cohorts were drawn. Uncertainties

exist in both the estimates of silica content and in the conversion factors used, which

were based in some cases on side-by-side comparison sampling but were estimated in

other cases absent such sampling. To consider this source of uncertainty, Toxichemica,

Inc. (2004) used a procedure similar to that used to assess uncertainties in individual

exposure value assignments. Toxichemica, Inc. assumed that, for each job in the dataset,

a specific conversion factor existed that related workers’ exposure measurements to

gravimetric respirable silica exposures, and that this conversion factor comes from a

normal distribution with a standard deviation σ = 1⁄2 its mean μ. This relationship was

derived from data reported by Kreiss and Zhen (1996), who found that silica content

among 80 samples taken from one region of a Colorado mine averaged 19 percent with a

standard deviation of 11 percent. For the sensitivity analysis, Toxichemica, Inc. sampled

a new conversion factor for each job from the appropriate distribution, then used the

complete set of sampled conversion factors to re-run the risk analysis. Since the

estimated silica exposure level for a particular job is a simple product of the job’s dust

exposure d and a scalar conversion factor, this amounts to selecting a new exposure level

for each job from a normal distribution with mean μ equal to the job’s reported silica

exposure level and standard error σ = 1⁄2 μ. To avoid extreme outliers, Toxichemica, Inc.

constrained the sampling such that each generated exposure level was between 10% and

190% of the original value.

Toxichemica, Inc. (2004) generated ten sets of sampled exposure levels for each

individual in the cohort, using each set to fit a study-specific coefficient and a pooled

coefficient, holding the original exposures fixed in all other cohorts. The mean of the 10

study-specific coefficients, the standard deviation of the 10 study-specific coefficients,

and the mean pooled coefficient are presented for each cohort in Table II-5. The results

are similar to the coefficients originally derived from each cohort; the only coefficient

much affected by the procedure was that for the South African cohort, with an average

value of 0.350 across ten runs compared to the original value of 0.582 (pooled

coefficients not reported for this analysis).

Monte Carlo analysis incorporating both types of measurement error

To explore the potential effects of both kinds of random uncertainty described

above, Toxichemica, Inc. (2004) used the distributions representing the error in jobspecific exposure assignment and the error in converting exposure metrics to generate 50

new exposure simulations for each cohort. A study-specific coefficient and a pooled

coefficient were fit for each new simulation, with the assumption that the two sources of

uncertainty are independent. The distribution describing error in converting to

gravimetric exposure measures was used first to generate randomly sampled job-specific

exposure levels, which represented a new estimate of the mean exposure for each job.

Randomly sampled exposure levels for each individual in each cohort were then

generated using the distribution representing error in individual exposure assignments

using the sampled mean job exposure values.
307

Table II-5. Study-specific coefficients for log cumulative exposure in relation to

lung cancer, after adjusting for measurement error in job-specific silica dust

fractions within each cohort. Last column is a sensitivity analysis based on 10

simulations for each cohort adjusting for Berkson error in job-specific silica dust

fractions in that cohort while holding exposures constant for all other cohorts.

Study

Unadjusted

coefficient

(std error)a

Mean

Adjusted

Coefficientb

Standard

Deviation of

Adjusted

Coefficientc

US Diatomaceous earth

(Checkoway et al., 1997) 0.086 (0.054) 0.086 0.011

S Africa gold (Hnizdo and Sluis-Cremer,

1991; Hnizdo et al., 1997)

0.582 (0.329) 0.350 0.170

US gold (Steenland and Brown, 1995a) -0.041 (0.078) -0.050 0.017

Australian gold (de Klerk and Musk, 1998) 0.172 (0.111) 0.157 0.030

US granite (Costello and Graham, 1988) 0.118 (0.048) 0.104 0.013

Finnish granite (Koskela et al., 1994) -0.015 (0.063) -0.016 0.010

US industrial sand (Steenland et al., 2001b) 0.045 (0.057) 0.041 0.007

Ch. Tungsten (Chen et al., 1992) 0.039 (0.027) 0.034 0.004

Ch. Pottery (Chen et al., 1992) 0.086 (0.039) 0.086 0.006

Ch. Tin (Chen et al., 1992) 0.054 (0.033) 0.058 0.005

Footnotes for Table 11-5

a Coefficient estimate without adjustment for Berkson error (single run)

b Mean of study-specific coefficients from 10 simulated data sets adjusting for Berkson error due to use of a single conversion factor

to convert dust to silica for all jobs in a cohort

c

Standard deviation of study-specific coefficients from 10 simulated data sets adjusting for Berkson error due to use of a single

conversion factor to convert dust to silica for all jobs in a cohort.

Source: Toxichemica, Inc. (2004)

The mean coefficients for these 50 simulations, and their observed standard

deviations, are shown in Table II-6 for the model using log cumulative dose (15-year

lag). Again, the only cohort for which the mean of the exposure coefficients derived

from the 50 simulations differed substantially from the previously calculated exposure

coefficient was the South African cohort (simulation mean of 0.181 vs. original

coefficient of 0.582). The mean exposure coefficient for the diatomaceous earth cohort

was almost identical to the previously calculated coefficient (0.086 vs. 0.088,

respectively) and that from the U.S. granite cohort was slightly lower (0.102 vs. 0.118).

For the pooled analysis, the mean coefficient estimate from the simulations is 0.057, just
308

slightly lower than the previous estimate of 0.060. Although simulating exposure mismeasurement contributed additional uncertainty to the coefficient estimate (standard

deviation of 0.004 across 50 iterations), the average standard error for the 50 simulated

coefficients is only slightly smaller than the standard error of the original coefficient

(0.014 versus 0.015). Adding the variance from the standard error due to sampling

(0.0142), and the Monte Carlo variance (0.0042) results in a new variance estimate that

incorporates both sampling uncertainty and measurement error uncertainty; the square

root of that estimate is about 0.015, equivalent to the original standard error estimate for

the pooled analysis. Based on the results of this uncertainty analysis, OSHA does not

have reason to believe that random error in the underlying exposure estimates in the

Steenland et al. (2001a) pooled cohort study of lung cancer is likely to have substantially

influenced the original findings, although a few individual cohorts (particularly the South

African and Australian gold miner cohorts) appeared to be sensitive to measurement

errors.

Sensitivity analyses of biased conversion factors

Toxichemica Inc.’s (2004) consideration of the uncertainty in conversion factors

in the discussion above assumed that the estimated conversion factors were unbiased.

However, it is also possible that conversion factors may have been systematically underestimated or over-estimated for a given cohort, if the “true” mean conversion factor was

lower or higher than the estimated mean conversion factor used. For example, with

respect to the South African gold miner cohort, Gibbs and Du Toit (2002) have argued

that the assumption by Hnizdo et al. (1997) of a 30-percent silica content of the dust was

in error, and that a value of 54 percent should have been used instead. Such an error

would have resulted in about a 2-fold underestimate of the exposure of the cohort with a

resulting 2-fold overestimate of disease risk. This issue is further discussed in OSHA’s

review of the Hnizdo and Sluis-Cremer (1993) study of silicosis morbidity among South

African miners (see section II.F.2.c below). In addition, as pointed out in the

Toxichemica, Inc. (2004) report, the exposure-response coefficients for lung cancer for

the South African gold miner cohort are the highest among the ten cohorts in the

Steenland et al. (2001a) pooled analysis, which could be a reflection of under-estimation

of exposure due to under-estimation of the conversion factor. There is also a higher

exposure-response seen for silicosis morbidity in the South African cohort compared to

other studies (see section II.F.2.c below). Whether this is due to biased underestimation

of exposure in the South African miner study, a reflection of an unusually high biological

activity of freshly cleaved quartz particles (Hnizdo, personal communication, see

Toxichemica, Inc., 2004), or a combination of these factors is not known. OSHA is

unaware of any general criticism that the conversion factors used to estimate exposures of

the other cohorts analyzed by Steenland et al. (2001a) resulted in a systematic bias;

nevertheless, it remains possible that some conversion factors may have been similarly

over or under-estimated, resulting in systematic over or under-estimation of exposure,

with the resulting systematic under or over-estimation of the exposure coefficient for a

given study.
309

Table II-6. Conditional logistic regression coefficient for silica and lung cancer, 50

simulations adjusting for Berkson error in both job-specific exposures for each

worker and job-specific silica dust fractions (single conversion factor)

Study

Unadjusted

coefficient

(std error)a

Mean

Adjusted

Coefficientb

Standard

Deviation of

Adjusted

Coefficientc

US Diatomaceous earth

(Checkoway et al., 1997) 0.086 (0.054) 0.088 0.014

S Africa gold (Hnizdo and Sluis-Cremer,

1991; Hnizdo et al., 1997)

0.582 (0.329) 0.181 0.150

US gold (Steenland and Brown, 1995a) -0.041 (0.078) -0.042 0.026

Australian gold (de Klerk and Musk, 1998) 0.172 (0.111) 0.137 0.031

US granite (Costello and Graham, 1988) 0.118 (0.048) 0.102 0.014

Finnish granite (Koskela et al., 1994) -0.015 (0.063) -0.015 0.017

US industrial sand (Steenland et al., 2001b) 0.045 (0.057) 0.045 0.013

Ch. Tungsten (Chen et al., 1992) 0.039 (0.027) 0.034 0.005

Ch. Pottery (Chen et al., 1992) 0.086 (0.039) 0.085 0.006

Ch. Tin (Chen et al., 1992) 0.054 (0.033) 0.060 0.007

Pooled 0.060 (0.015) 0.057 (0.014) 0.004

Footnotes for Table II-6

a Coefficients without adjustment for Berkson error, using corrected data (based on a single run); for pooled data, number in

parentheses is standard error of coefficient (reflects random error)

b Mean of coefficients from 50 simulated data sets adjusting for Berkson error; for pooled data, number in parentheses is average

standard error of coefficient over 50 runs (reflects random error)

c

Standard deviation of coefficients from 50 simulated data sets adjusting for Berkson error, reflects only measurement error

Source: Toxichemica, Inc. (2004)

Absent a priori reasons to suspect bias in a specific direction (with the possible

exception of the South African cohort), Toxichemica, Inc. (2004) considered possible

biases in either direction by assuming that exposure was under-estimated by 100% (i.e.,

the true exposure was twice the estimated) or over-estimated by 100% (i.e., the true

exposure was half the estimated) for any given cohort in the original pooled dataset. This

type of sensitivity analysis considered the possible influence of consistently biased
310

exposure estimation across an entire cohort by generating 20 new simulations of exposure

estimates for each of the workers in the pooled case-control data set. This exercise was

done without considering the two Berkson sources of uncertainty discussed above.

For the conditional logistic regression model using log cumulative exposure with

a 15-year lag, doubling or halving the exposure for a specific study resulted in virtually

no change in the exposure-response coefficient for that study or for the pooled analysis

overall. According to Toxichemica, Inc., (2004) the use of the log transformation (i.e.,

either the log-linear model with log cumulative exposure or the spline model using log

cumulative exposure) ensures that any constant multiplicative bias in exposure has

virtually no effect on conditional logistic regression coefficients, and would have no

effect at all using a pure log transformation (i.e., without adding 1 to allow for exposures

at 0 mg/m3-days). The maximum change in the pooled exposure-response coefficient

using the log of cumulative exposure was a 1.7-percent increase when exposure is halved

for Chinese tungsten miners. The maximum decrease in the coefficient for pooled

analysis was a decline of only 1.3 percent when exposure is doubled in China tungsten

miners.

II.D.3.b. Silicosis mortality.

Monte Carlo analyses incorporating two types of random measurement error

Following the procedures described above for the lung cancer analysis,

Toxichemica, Inc. (2004) combined both sources of random measurement error (error

due to assignment of a mean exposure for each job to each worker and error due to use of

converting exposure measurements to a single metric) in a Monte Carlo analysis of the

silicosis mortality data. Categorical analyses were done with a nested case control model

(in contrast to the Poisson model used previously by Mannetje et al., 2002b), which can

be expected to control more effectively for age in that it uses exact age matching rather

than matching by age categories as was done in the Poisson analysis. This yielded

categorical rate ratio results using the original data (prior to simulation of measurement

error) which were approximately 20-25% lower than those reported by Mannetje et al.

(2002b).

Table II-7 provides the original exposure coefficients (i.e., rate ratios for silicosis

death per unit increase in log mg/m3-day) reported by Mannetje et al. (2002b) for each

cohort and the pooled data set, which were based on a nested case control study selecting

100 controls per case and using the best fitting exposure-response model (i.e., a

conditional logistic regression model with the log of cumulative exposure and no

exposure lag). Table II-7 also provides the mean coefficients resulting from 50 iterations

(50 selections of 100 controls per case) after simulating both types of random

measurement error. The mean of the simulation coefficients was lower than the

previously calculated exposure-response coefficient for the pooled data set by about 25

percent (log 1.74/log 2.08=0.76), although the precision of the estimate was virtually

unchanged. Table II-8 provides the results for the categorical analyses for the original

pooled data set (single run), the corrected data set (after correcting minor coding errors
311

discovered in the original data set) (single run), and the corrected data with simulation of

both types of random measurement error (50 runs).

Table II-7. Rate ratios for silicosis from cohort-specific and combined data, using

conditional logistic regression with log cumulative exposure (nested case-control

analysis, 100 controls per case) -- Original data (single run), corrected data (single

run), corrected data were adjusted for two type of measurement error (average of

50 runs).

Cohort Original data

(95% CI.)a

Corrected data

(95% CI)b

Corrected data with

measurement error

(95% observed

interval)c

US diatomaceous earth 2.08 (1.23-3.53) 1.96 (1.20-3.19) 1.77 (1.12-2.79)

Finnish granite 2.76 (1.37-5.57) 2.73 (1.36-5.49) 2.63 (1.47-4.69)

US granite 1.76 (1.30-5.57) 1.74 (1.30-2.33) 1.97 (1.15-3.40)

US industrial sand 1.63 (1.03-2.57) 1.66 (1.03-2.67) 1.50 (1.12-2.01)

US gold miners 3.57 (1.90-6.69) 3.84 (2.03-7.27) 2.04 (1.17-3.55)

Australian gold miners 2.31 (1.34-3.97) 2.33 (1.35-4.02) 1.56 (1.00-2.44)

Combined 2.08 (1.71-2.53) 2.07 (1.71-2.51) 1.74 (1.45-2.08)

Footnotes for Table 11-7

a

Rate ratio for one unit increase in log mg/m3-day, no lag, model controls for age, date of birth within five years, and includes an

indicator variable for cohort (six cohorts); taken from Table 3 of Mannetje et al. (2002b)

b Based on a single run (single selection of 100 controls); multiple runs with re-selection of 100 controls per case showed very little

change in these coefficients

c Average coefficient across 50 selection of controls incorporating two sources of Berkson error, with the errors generated anew with

each control selection The 95% observed interval is based on a standard error, which was the square root of the sum of two

variances. The average variance of coefficient in 50 runs (random or sampling error) was 0.006 for the pooled data, and the observed

variance of the coefficient across the 50 runs (measurement error+variance in control selection), was 0.0022 for the pooled data.

Source: Toxichemica, Inc. (2004)

The categorical analysis simulating the two types of random measurement error

(third column, Table II-8) does not result in much change in the rate ratios for the first

four categories above the referent, but causes an approximate 20- to 25-percent reduction

in the log of the rate ratios for the uppermost five categories. Furthermore, the

confidence intervals for the rate ratios across all exposure categories after simulating

random measurement error are considerably wider than those from the original analysis.

For the first three categories above the referent, where the point estimates are scarcely

altered by simulating measurement error, the ratio of the upper to lower confidence limit

is approximately 11, while the ratio from the original result not simulating measurement

error is approximately 4-5. The silicosis mortality dataset thus appears to be more

sensitive to possible error in exposure measurement than the lung cancer dataset, for

which the mean of the simulation coefficients was virtually identical to the original.

According to the Toxichemica, Inc. (2004) report, the reason for this greater sensitivity is

not known. It is possible that the smaller size of the silicosis mortality data set (170

silicosis cases among 18,000 cohort members vs. 1,066 lung cancer cases among 66,000

cohort members) rendered it more sensitive to changes in underlying exposure data.
312

Table II-8. Rate ratios for silicosis by cumulative exposure category derived from

categorical analysis of the combined data set and using corrected data incorporating

two sources of measurement error.

Footnotes for Table 11-8

a

Single run (single selection of controls), model adjusts for age, date of birth within 5 years, and includes an indicator variable for

cohort (six cohorts included)

b Average across 50 runs (50 selection of controls). 95% observed confidence intervals derived using the standard deviation of the

exposure coefficient (sd) across the 50 Monte Carlo estimates (measurement error) and the average standard error (se) of these

estimates (sampling error), ie, 95% interval = average coefficient +/- 1.96*√(sd2+ se2)

Source: Toxichemica, Inc. (2004)

Exposure

Category

Original

data

(95% CI.)a

Corrected data,

Unadjusted for

measurement

error (95%

observed

interval)a

Corrected data,

adjusted for

measurement

error (95%

observed

interval)b

0-.99 mg/m3-

years

1.00 1.00 1.00

0.99-1.97 2.09 (1.05-

4.19)

2.14 (1.07-

4.27)

2.18 (0.64-

7.38)

1.97-2.87 3.14 (1.51-

6.53)

3.29 (1.59-

6.79)

3.35 (1.00-

11.27)

2.87-4.33 4.20 (1.95-

9.02)

4.26 (1.98-

9.19)

4.27 (1.26-

14.55)

4.33-7.12 6.07 (2.72-

13.55)

6.17 (2.73-

13.98)

5.35 (1.48-

19.39)

7.12-9.58 10.86

(4.69-

25.34)

12.30 (5.34-

28.36)

6.26 (1.48-

26.53)

9.58-13.21 10.85

(4.60-

25.13)

12.18 (5.17-

28.69)

7.42 (1.80-

30.65)

13.21-15.89 19.15

(7.97-

46.02)

18.17 (7.46-

44.25)

7.65 (1.47-

39.74)

15.89-28.10 12.60

(5.12-

30.97)

13.46 (5.52-

32.85)

9.20 (2.44-

34.77)

>28.10 29.56

(11.51-

75.91)

27.66 (10.75-

71.44)

12.83 (3.34-

49.82)
313

Potential effects of random measurement errors on silicosis mortality risk

estimates

Toxichemica, Inc. (2004) estimated the risk of death from silicosis to age 75,

assuming 45 years of exposure to crystalline silica beginning at age 20, based on

converting predicted silicosis mortality rates to risk (risk = 1-exp(-Σ(rate*time)), where

time is divided into intervals of one year). Predicted rates were derived either from the

categorical analysis of the corrected data after incorporating simulated measurement error

(ten categories, Table II-8), or the conditional logistic regression model using the mean of

the log cumulative exposure coefficients after incorporating simulated measurement error

(Table II-7). The log cumulative exposure model and the spline both fit the data well and

conformed to the categorical analysis (see Figure 5 of Toxichemica, Inc., 2004). In both

cases, the referent rate was taken to be that of the low exposure group of the cohort under

study (i.e., 4.7/100,000 for the group with 0 to 0.99 mg/m3years, based on 17 silicosis

deaths). The risk of silicosis mortality to age 75 was calculated for exposure levels of

0.05 and 0.10 mg/m3, resulting in cumulative exposures of 2.25 and 4.5 mg/m3-years

respectively. Two exposure categories in Table II-9 from the categorical model that

reflect this range of exposure are 1.97-2.87 and 4.33-7.12 mg/m3-years, which correspond

to 45 years of exposure to 0.05 and 0.10 mg/m3, respectively. The variance of the log

rate for each category was estimated by adding the variance of the log of referent group

rate (4.7/100,000) and the variance of the categorical log rate ratio taken from either the

categorical model or the linear model using log cumulative exposure. The variance of the

log of the referent group rate was derived via the delta method approximation assuming a

Poisson distribution for the observed number of silicosis deaths (n = 17) in the referent

group, resulting in an approximate variance of 1/17 or 0.06.

Table II-9 presents risk estimates for silicosis death by age 75 after a 45-year

working lifetime exposed to various levels of crystalline silica, based on either the

categorical model or the model with the log of cumulative exposure (no lag). Results of

the categorical model were slightly higher than those for the log cumulative exposure.

Estimated lifetime risks for age 65 are also presented for comparison with Mannetje et al.

(2002b), who estimated a risk of silicosis death of 13 deaths per 1000 for exposure to

0.10 mg/m3, and 6 per 1000 for exposure to 0.05 mg/m3. After simulating random

measurement error, Toxichemica, Inc. (2004) estimated corresponding risks of 7 (95% CI

2-23) and 4 (95% CI 2-12) per 1,000, respectively, based on the categorical model.

According to Toxichemica, Inc., the decrease in estimated risk partly reflects the use of a

nested case-control analysis here versus the Poisson regression originally performed by

Mannetje et al. (2002b). The control over age, which is tighter in the nested case-control

approach, is likely to be a factor that led to somewhat decreased rate ratios for the first

three exposure categories above the referent in the current analysis compared to the

analysis by Mannetje et al. (2002b). However, incorporation of uncertainty in the

exposure estimates had the effect of further reducing estimates of silicosis rate ratios in

the higher cumulative exposure categories.

To summarize, a quantitative examination of the potential effects of unbiased and

biased exposure uncertainty suggested little effect on the pooled exposure coefficient
314

Table II-9. Silicosis mortality. Absolute risk estimates (in deaths per 1,000

workers) and 95% CI assuming a 45-year working lifetime, by modela, by exposure

level, and by age, taking into account measurement error

Exposure level Age Categorical model

(95% CI)

Log-Linear modelb

(95% CI)

1.00 mg/m375 0.026 (0.007-0.094) 0.023 (0.010-0.054)

0.75 mg/m375 0.024 (0.006-0.087) 0.019 (0.009-0.045)

0.50 mg/m375 0.019 (0.005-0.069) 0.016 (0.007-0.034)

0.25 mg/m375 0.014 (0.004-0.053) 0.011 (0.006-0.021)

0.20 mg/m375 0.013 (0.004-0.047) 0.010 (0.005-0.019)

0.15 mg/m375 0.011 (0.003-0.040) 0.009 (0.005-0.016)

0.1 mg/m375 0.009 (0.003-0.033) 0.006 (0.004-0.011)

0.1 mg/m365 0.007 (0.002-0.023) 0.005 (0.003-0.008)

0.05 mg/m375 0.006 (0.002-0.018) 0.004 (0.003-0.007)

0.05 mg/m365 0.004 (0.002-0.012) 0.003 (0.002-0.005)

Foot notes for Table II-9.

a Both models use the lowest exposure group (<1.00 mg/m3

-year) from Mannetje et al. (2002b) as the referent category for rate ratios,

which in turn are used to calculate estimated rates for higher exposures (i.e., multiplying the rate in lowest exposure group

(0.000047/100,000) by the rate ratio)

b Uses 0.5 mg/m3

-years (the midpoint of lowest exposure category) as the exposure level for the referent group to calculate rate ratios

(and hence rates) for higher exposure levels

Source: Toxichemica, Inc. (2004)

(and the variance around that estimate) for the lung cancer risk model. For the silicosis

mortality risk model, consideration of exposure uncertainty had some effect on predicted

silicosis mortality rates, particularly for higher exposure categories, and resulted in an

overall decline in estimated risk from the pooled analysis. OSHA believes that it is

difficult to fully assess the uncertainty associated with error in exposure estimates on the

basis of Toxichemica, Inc.’s (2004) analysis, in part because the computational intensity

of their analysis limited the number of runs that could be performed. It is also unclear

whether the mean value of the exposure coefficients produced by this analysis may be

regarded as adjusted for Berkson error and meaningfully compared with the original

estimates. However, OSHA believes Toxichemica, Inc.’s analysis to be a reasonable

approach to quantitative evaluation of the uncertainty associated with error in exposure

estimates. Considering the information available to Toxichemica, Inc. and the limits on

the number of simulations that could reasonably be performed, the Agency regards their

analysis as best available treatment of exposure uncertainty and believes that their results,

overall, do not suggest that Berkson error in the exposure assessment is likely to have

introduced substantial error in risk estimates for lung cancer related to silica exposure.

II.E. Quantitative Assessment of Renal Disease Mortality.

OSHA believes that there is substantial epidemiological evidence that exposure to

respirable crystalline silica increases the risk of renal disease morbidity and mortality (see
315

section I.E). OSHA also reviewed a pooled cohort exposure-response analysis by

Steenland et al. (2002a) and believes that this study provides a suitable basis for

quantitatively estimating renal disease risks because the findings are based on a large

number of workers and sufficient exposure data were available to characterize exposures

of these cohorts. The three cohorts included U.S. gold miners (Steenland and Brown,

1995a), U.S. industrial sand workers (Steenland et al., 2001b), and Vermont granite

workers (Costello and Graham, 1998). These cohorts were chosen because data were

available for both underlying cause mortality and multiple cause mortality; this was

believed important because renal disease is often listed on death certificates without

being identified as an underlying cause of death.

Details of the pooled analysis were provided in the health effects literature review

(section II.E) and are summarized here. The combined cohort for the pooled analysis

(Steenland et al., 2002a) consisted of 13,382 workers with exposure information available

for 12,783 (95 percent). Exposure matrices for the three cohorts had been used in

previous studies (Steenland and Brown, 1995; Attfield and Costello, 2001; Steenland et

al., 2001b) that showed positive exposure-response trends for silicosis morbidity or

mortality, thus tending to validate the underlying exposure and work history data. The

mean duration of exposure, cumulative exposure, and concentration of respirable silica

for the pooled cohort were 13.6 years, 1.2 mg/m3- years, and 0.07 mg/m3, respectively.

SMRs (compared to the U.S. population) for renal disease (acute and chronic

glomerulonephritis, nephrotic syndrome, acute and chronic renal failure, renal sclerosis,

and nephritis/nephropathy) were statistically significantly elevated using multiple cause

data (SMR 1.29, 95% CI 1.10-1.47, 193 deaths) and underlying cause data (SMR 1.41,

95% CI 1.05-1.85, 51 observed deaths).

Exposure-response trends were examined in a categorical analysis where renal

disease mortality of the cohort divided by exposure quartile was compared to U.S. rates.

This analysis included 95 percent of the cohort for which there were adequate data on

work history and exposure to respirable quartz. In this analysis, highly statistically

significant exposure-response trends for SMRs were observed for both multiple-cause (p

< .000001) and underlying cause (p = .0007) mortality.

A nested case-control analysis was also performed which allowed for more

detailed examination of exposure-response. This analysis included either 50 cases

(underlying cause mortality) or 194 cases (multiple-cause mortality), each matched by

race, sex, and age within 5 years to 100 controls from the cohort. With the lowest

exposure quartile group serving as a referent, the case-control analysis showed monotonic

trends in mortality with increasing cumulative exposure. Conditional regression models

using log cumulative exposure fit the data better than cumulative exposure (with or

without a 15-year lag), or average exposure. For multiple-cause mortality, the exposureresponse trend was statistically significant for both cumulative exposure (p = .004) and

log cumulative exposure (p = .0002), whereas for underlying cause mortality, the trend

was statistically significant only for log cumulative exposure (p = .03). The exposureresponse trend was homogeneous across the three cohorts and interaction terms did not

improve model fit.
316

Based on the exposure-response coefficient for the model with the log of

cumulative exposure, the authors estimated the lifetime excess risk of death (underlying

cause) from renal disease by age 75 for an exposure of 0.10 mg/m3over a working

lifetime (age 20 to 65) to be 1.8 percent (95% CI 0.8-9.7%) above a background risk of

0.3 percent. The authors concluded that their study added to the evidence that renal

disease is associated with exposure to crystalline silica. Noting that statistically

significantly increased odds ratios and SMRs were seen primarily for cumulative

exposures of >0.5 mg/m3-years, the authors pointed out that this would come from

working for five years at an exposure level of 0.1 mg/m3or 10 years at 0.05 mg/m3.

OSHA believes that the findings of this pooled analysis are credible because the analysis

involved a large number of workers from three cohorts for which there were substantial

exposure and job history data that were previously used in analyses that found monotonic

increases in silicosis morbidity or mortality with increasing exposure, thus indicating that

the exposure and work history data were unlikely to have been seriously misclassified.

Consequently, OSHA is including the pooled cohort analysis of renal disease mortality

(underlying cause) in its preliminary risk assessment.

To estimate renal disease mortality risk from the pooled cohort analysis, OSHA

implemented the same life table approach as was done for the assessments on lung cancer

and non-malignant respiratory disease. However, for this life table analysis, OSHA used

1998 background all-cause and renal mortality rates for U.S. males, rather than the 2006

rates used for lung cancer and NMRD. The 1998 rates are based on the ICD-9

classification of diseases, which is the same as used by Steenland et al. (2002a) to

ascertain the cause of death of workers in their study. However, U.S. cause-of-death data

from 1999 to present are based on the ICD-10, in which there were significant changes in

the classification system for renal diseases. According to CDC (2001), the change in the

classification from ICD-9 to ICD-10 increased death rates for nephritis, nephritic

syndrome, and nephrosis by 23 percent, in large part due to reclassifying end-stage renal

disease (ESRD). The change from ICD-9 to ICD-10 did not materially affect background

rates for those diseases grouped as lung cancer or NMRD. Consequently, OSHA is

conducting its analysis of excess renal disease mortality associated with exposure to

crystalline silica using background mortality rates for 1998. As before, lifetime risk

estimates reflect excess risk through age 85.

To estimate renal mortality risks, OSHA used the log-linear model with log

cumulative exposure that Steenland et al. (2002a) found provided the best fit to the

pooled cohort data. The coefficient for this model is 0.269 (se = 0.120) (Steenland,

personal communication, 2010).

Based on the life table analysis, OSHA estimates that exposure to the current and

proposed general industry PEL over a working life would result in a lifetime excess renal

disease risk of 39 (95% CI 2-200) and 32 (95% CI 1.7-147) deaths per 1,000,

respectively. For exposure to the current construction/shipyard PEL, OSHA estimates

the excess lifetime risk to range from 52 (95% CI 2.2-289) to 63 (95% CI 2.5-368) deaths

per 1,000 workers.

II.F. Quantitative Assessment of Silicosis Morbidity Risk.
317

In this section, OSHA summarizes the principal cross-sectional and cohort studies

that have quantitatively characterized relationships between exposure to crystalline silica

and development of radiographic evidence of silicosis. These studies were identified

from reviews by Finkelstein (2000), NIOSH (2002), Toxichemica, Inc. (2004); literature

search; and contact with outside organizations. The studies reviewed in this section are

summarized in Table II-10. Each of these studies relied on estimates of cumulative

exposure to evaluate the relationship between exposure and silicosis prevalence in the

worker populations examined. The health endpoint of interest in these studies is the

appearance of opacities on chest roentgenograms indicative of pulmonary fibrosis.

The studies evaluated fall into three major types. Some are cross-sectional studies

in which radiographs taken at a point in time were examined to ascertain cases (Kreiss

and Zhen, 1996; Love et al., 1999; Ng and Chan, 1994; Rosenman et al., 1996;

Churchyard et al., 2003, 2004); these radiographs may have been taken as part of a health

survey conducted by the investigators or represent the most recent chest x-ray available

for study subjects. Other studies were designed to examine radiographs over time in an

effort to determine onset of disease. Some of these studies examined radiographs taken

primarily from active, or current, workers (Hughes et al., 1998; Muir et al., 1989a, 1989b;

Park et al., 2002), while others evaluated radiographs for both active and retired workers

(Chen et al., 2001, 2005; Hnizdo and Sluis-Cremer, 1993; Miller et al., 1995, 1998;

Buchannan et al., 2003; Steenland and Brown, 1995b).

In this section of the risk assessment, OSHA first describes the criteria used in

these studies to identify silicosis cases. This is followed by a discussion of each of the

studies identified by OSHA where estimates of silicosis morbidity risk could be

estimated.
318

Table II-10. Summary of Silicosis Morbidity Studies

Authors Industry Number in study Time period of study

Number of cases (ILO classification)

Rosenman et al. (1996) Grey iron foundry 1,072 Current: as of 6/91, started < 1/1/86

Retired: started < 1/1/86, pension as of

7/2/91

28 (≥ 1/0 rounded opacities)

Ng and Chan (1994) Hong Kong granite 338 Employed at least 1 yr between 1967

and 1985

(≥ 1/1 rounded or irregular opacities)

Kreiss and Zhen (1996) Hardrock mining 100 + 34 community controls

w/o occupational silica

exposure

40 years old in 1986, chest radiograph

then if not previous 2 yrs

32 (small opacities ≥ 1/0)

Churchyard et al. (2003,

2004)

South African miners 520 Current workers who participated in a

medical exam over a 5-month period in

2000-2001

94 from one reader, 102 from another

((≥ 1/1 rounded or irregular

opacities)

Love et al. (1999) Structural brick workers in

the U.K.

1,831 Exposure and medical surveys carried

out in 1990-1991

25 (≥ 1/0 rounded and irreegular

opacities)

67 (≥ 0/1 rounded and irregular

opacities)

Muir et al. (1989a,1989b) and

Verma et al. (1989)

Canadian gold and uranium

miners

2,109 Started and worked ≥ 5 yrs between

1940 and 1959; followed to 1982 or end

of exposure, whichever came first

32 (≥ 1/1 and small, rounded

opacities)

Hughes et al. (1998) U.S. Diatomaceous earth

mining and processing

1,809 Employed at least 1 yr between 1942

and 1987, radiograph taken more than 1

month after hire

81 (small opacities ≥ 1/0 and /or

large opacities)
319

Table II-10. Summary of Silicosis Morbidity Studies

Authors Industry Number in study Time period of study

Number of cases (ILO classification)

Park et al. (2002) U.S. Diatomaceous earth

mining and processing

2,342 Employed for at least 1 yr between

1942-1994, followed from the later of

date of 1yr employment or 1942 until

earlier of 12/31/94 or date of death

70 (≥ 1/0 or large opacities)

Hnizdo and Sluis-Cremer

(1993)

South African gold miners 2,235 Aged 45-54 at 1968-1971 medical

exam; started working after 1938,

worked ≥ 10 yrs., followed until 1991

313 (≥ 1/1 and rounded opacities)

Steenland and Brown (1995b) U.S. underground gold

miners

3,330 Employed ≥ 1 yr between 1940 and

1965; followed through 1990

170 total (≥ 1/1 [1976 radiographic

survey] of “small opacities” or “large

opacities”[1960 radiographic

survey]); 128 by death certificate

(any mention)

Miller et al. (1998) Coal 547 Had worked during the 1970s, chest

radiograph in 1990/91 compared to

most recent one in 1970, 1974, or 1978

203 showed progression from earlier

radiographs; 47 had profusion of

median small opacities of ≥ 2/1

Buchanan et al. (2003) Coal 371 Members of Miller et al. (1998) cohort

who were between the ages of 50 and

74 at the time of follow-up in 1990/91

35 with profusion of opacities

consistent with ILO 2/1+

Chen et al. (2001) Chinese tin miners 3,010 Employed for at least 1 yr between

1/1/60 and 12/31/65, followed from

first employment to end of 1994

1,015 (Chinese classification system

stages I, II, or III)

Chen et al. (2005) Tin and tungsten mining,

pottery workers

4,028 tin miners

14,427 tungsten miners

4,547 pottery workers

Males who worked at least one year

between 1960 and 1974. Follow-up at

end of 1994

855 tin miners

2,816 tungsten miners

785 pottery workers

(Chinese classification system stages
320

Table II-10. Summary of Silicosis Morbidity Studies

Authors Industry Number in study Time period of study

Number of cases (ILO classification)

I, II, or III)
321

II.F.1. Definition of Silicosis.

The International Labour Organization’s (ILO) 1980 International Classification

of Radiographs of the Pneumoconioses is now accepted as the standard against which

chest radiographs are measured in epidemiologic studies, for medical surveillance, and

for clinical evaluation. According to this standard, if radiographic findings are or may be

consistent with pneumoconiosis, then the size, shape, and extent of profusion of opacities

are characterized by comparing the radiograph to standard films. Classification by shape

(rounded vs. irregular) and size involves identifying primary and secondary types of

small opacities on the radiograph and classifying them into one of six size/shape

categories. The extent of profusion is judged by recording the lung zone in which the

small opacities are observed. The six zones correspond to the upper, middle, and lower

thirds of the right and left lungs, respectively. Profusion is an assessment of the

concentrations of opacities as compared with that on the standard radiographs and is

graded on a 12-point scale of four major categories, each with three subcategories:

MAJOR CATEGORY: SUBCATEGORY:

Category 0 0/- 0/0 0/1

Category 1 1/0 1/1 1/2

Category 2 2/1 2/2 2/3

Category 3 3/1 3/2 3/+

Categories 1, 2 and 3 and their subcategories are intended to model a continuum

of increasing concentration of opacities. Major category 0 is defined as no opacities or a

concentration of opacities less than the lowest subcategory of category 1. For each

subcategory, the top number indicates the major category that the profusion most closely

resembles, and the bottom number indicates the major category that was given secondary

consideration. For example, a radiograph that most closely resembles the category 1

standard, but in which consideration was given to category 0, would be classified 1/0: 1

being the primary profusion, and 0 the secondary profusion. Thus, the major categories

and their respective subcategories constitute a continuum of increasing concentration of

opacities.

Profusion is rated by considering profusion over all affected zones and comparing

this integrated profusion with the standard radiographs. Where there is a marked

difference in profusion between zones of three minor categories or more, the zone or

zones with the lowest profusion are ignored. The ILO scheme also recognizes the

importance of pleural changes, any pleural thickening or pleural calcification, and also

any comments made by the radiograph reader.

Silicosis is initially characterized by small rounded opacities in the middle and

upper lung zones. Normal radiographs are categorized as 0/-. Simple, or uncomplicated,

silicosis may appear as category 1, 2, or 3 on x-ray. Complicated (or conglomerate)
322

silicosis is defined by the appearance of an opacity greater than 1 cm in diameter against

a background of opacities of category 2 or 3.

Most of the studies described here defined a case of silicosis as one having a chest

radiograph classified as ILO 1/0 or greater, or 1/1 or greater. One study of Scottish coal

miners (Miller et al., 1995, 1998; Buchanan et al., 2003) assessed exposure-response

relationships for cases having a radiograph classified as 2/1 or greater (Miller et al.

(1995) also presented data for x-ray films classified 1/0 or greater). Another study

(Steenland and Brown, 1995b) used death certificates as well as radiographs to define

cases. A study of Chinese tin miners (Chen et al., 2001) used a Chinese classification

system that closely corresponded to the ILO major categories, and defined a case as a

Class I or greater degree of perfusion (i.e., about the same as ILO Major Category 1).

Table II-10 includes the ILO category used by each study to define silicosis.

Many, but not all, of the studies relied on panels of physicians known as Breaders to classify radiographs according to the ILO system. B-readers are those who

have been trained, tested, and certified by NIOSH in the classification of chest

radiographs using the ILO system. All but one study (Hnizdo and Sluis-Cremer, 1993)

used at least three readers to classify each radiograph.

Chest radiography is not the most sensitive tool used to diagnose or detect

silicosis. In 1993, Hnizdo et al. reported the results of a study that compared autopsy and

radiological findings of silicosis in a cohort of 557 white South African gold miners. The

average period from last x-ray to autopsy was 2.7 years. Silicosis was not diagnosed

radiographically for over 60 percent of the miners for whom pathological examination of

lung tissue showed slight to marked silicosis. The study used 3 readers and defined a

profusion score of 1/1 as positive for silicosis. Sensitivity values for radiography

(compared to autopsy findings) from each of the three readers were 0.393, 0.371 and

0.236, with specificity values of 0.987, 0.965 and 0.978, respectively. This indicated that

each of the three readers produced very few false positives, but a high percentage of false

negatives. In addition, the likelihood of false negatives (negative by x-ray, but silicosis is

actually present) increased with years of mining and average dust exposure of the miners.

The low sensitivity seen for radiographic evaluation suggests that risk estimates

derived from radiographic evidence likely understate the true risk of developing fibrotic

lesions as a result of exposure to crystalline silica.

II.F.2. Summary of Silicosis Morbidity Studies.

II.F.2.a. Cross-sectional studies.

In 1996, Rosenman et al. presented the findings of a cross-sectional study of 549

active production workers, 26 active salaried workers, and 497 retired workers from an

iron foundry. All workers included in the cohort had been employed at least 5 years as of

June 1991, and about half had worked for 20 years or more. Most of the cohort members

(57.7 percent) were African-American. Employment history data was obtained from

medical and personnel records, industrial hygiene files from management and the union,
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and from personal interviews. The latest available chest radiograph was obtained from

the plant or, if unavailable, an effort was made to locate one elsewhere. Radiographs

were read independently by three B-readers and a diagnosis of silicosis was made if at

least two readers classified a radiograph as 1/0 or greater.

Exposure estimates were based on industrial hygiene data including both mass

respirable quartz monitoring and particle count data from the earlier years. Particle count

measurements were converted to mass respirable silica based on information on average

quartz content of bulk samples.

Chest films were available for nearly all active workers (96.5 percent) and most of

the retirees (79.9 percent). For 120 workers, radiographs were either unavailable or

judged unreadable. The proportion of active and retired workers who returned the

questionnaire were 77 and 72 percent, respectively. Sixty workers were found to have

pneumoconiosis of which 28 had silicosis and the remainder had radiologic findings that

were more consistent with asbestos exposure. Prevalence of silicosis increased with

years worked at the foundry, as well as with cumulative silica exposure. Those with 20

to 29 years of exposure had a silicosis prevalence of 6 percent, while those with over 30

years at the foundry had a 12% prevalence. A single subject had silicosis earlier than 20

years from first exposure.

The exposure-response relationship was examined using logistic regression with

race, smoking consumption, silica exposure outside the foundry, and either exposure

concentration or cumulative exposure used in the model. Based on the relationship

between odds ratio for silicosis and cumulative exposure, Rosenman et al. (1996)

estimated the risk of radiographic opacities to be 3 percent for a 40-year exposure to 0.1

mg/m3respirable quartz. The estimated risk for exposure to 0.05 mg/m3for 40 years was

2 percent. The investigator believed it possible that exposures for the cohort were

overestimated since cumulative exposure was calculated up to the last day at work or the

time of the radiograph, whichever was earlier. Since only the latest available radiograph

was examined, it is possible that some of the cases developed the disease earlier and their

cumulative exposure to time of onset would have thus been smaller than estimated. In

addition, there was some respirator use in the plant (although sporadic) and respirator use

was not factored in to develop exposure estimates. Finkelstein (2000) also remarked that

exposure misclassification was possible since the study did not determine when silicosis

first appeared in the affected workers.

Another cross-sectional prevalence study was that of Ng and Chan (1994) who

studied 338 current and former male employees who had worked at least a year between

1967 and 1985 in two granite quarries in Hong Kong. The cohort consisted of 206 active

workers (91 percent of those eligible) and 132 former workers (representing 61 percent of

eligible survivors). Workers were interviewed and received chest x-rays. The most

recent radiograph for each worker was classified by three readers and a case was defined

as such when at least two readers classified a film as ILO 1/1 or greater for rounded or

irregular opacities. Exposure estimates were based on particle count measurements

(which were converted to mass respirable quartz) supplemented by gravimetric respirable

quartz measurements made in 1982.
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The prevalence of silicosis was significantly related to cumulative silica exposure.

For the cohort overall, the prevalence of radiological opacities indicative of silicosis was

9.2 percent for a mean cumulative exposure of 2.81 mg/m3-years, and 24.2 percent for an

exposure of 7.04 mg/m3-years. Prevalences were higher for cohort members aged 50

years or more; for average cumulative exposures of 3.1 and 7.1 mg/m3-years, silicosis

prevalences were 12.8 and 25 percent, respectively.

Exposure-response was modeled using logistic and linear models, with age and

smoking history included in the logistic model. Both provided acceptable fits and yielded

comparable risk estimates of about 6 percent for rounded opacities and 8 percent for

irregular opacities for an average 50-year old worker with a cumulative exposure of 2

mg/m3-years. Ng and Chan (1994) stated that, although their risk estimates accounted for

the prevalence of disease that developed post-employment, there was likely to be a

selection bias since only about half of eligible survivors participated in the survey. They

noted that silicosis was the underlying cause of death in 17 of the 53 workers known to

have died, and that some of the survivors who refused to participate felt that they were

not at risk of disease because of low dust exposure. For these reasons, Ng and Chan

(1994) believed that silicosis prevalence was probably underestimated in the more highly

exposed workers, and overestimated among those with low exposure.

The male population of a small Colorado mining community was invited to

participate in a cross sectional study by Kreiss and Zhen (1996). Ninety percent of the

population participated and included 100 hardrock miners over 40 years of age and 34

control subjects from the general population. Subjects were administered a standard

respiratory questionnaire and given a chest x-ray unless one was available from the

preceding 2 years. Radiographs for all but 10 subjects were read independently by three

B-readers and a case was defined as those subjects for whom at least two readers

classified the radiograph as 1/0 or greater using the 1980 ILO system. For the remaining

10 subjects, films were read by one reader who classified one film as abnormal with

small opacity profusion of 1/1.

Most (97%) miners had been first exposed more than 20 years prior to the study

and were last exposed an average of 10 years before the survey. Job-specific gravimetric

dust measurements taken from 1974 to 1982 were used to estimate silica exposure of the

subjects. Particle count data was available for earlier years but was sparse and there was

no correlation between particle counts and gravimetric measurements for 32 jobs where

both types of measurements were available. Using the gravimetric exposure data, jobspecific dust indices were developed by the mining company industrial hygienist,

ventilation engineer, and by others familiar with the history of the mine. Job-specific

dust indices were converted to silica indices based on the data describing the quartz

content of the ore. Silica exposure data were not available for 6 of the 100 miners.

The investigators used logistic regression to model silicosis risk as a function of

average or cumulative exposure, age, years of exposure, years since last exposure, packyears of smoking, and their interactions. The authors found a high prevalence rate of

silicosis (32%) among miners aged 40 years or more and who were exposed to an

average silica concentration of 0.064 mg/m3. Silicosis risk was best predicted by a model
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incorporating cumulative exposure and time since last exposure, or a model incorporating

average exposure, duration of exposure, and time since last exposure. Predicted risks

were higher using the cumulative silica exposure indices compared to the dust indices.

For a miner with 25 years of work history and exposed to an average of 0.05 mg/m3,

Kreiss and Zhen (1996) predicted silicosis risk to be 9 percent by end of employment, 36

percent after 20 years post-exposure, and 67 percent by end of life (an additional 15

years). Using the logistic regression model by Kreiss and Zhen (1996), NIOSH estimated

that the risk of silicosis for a 45-year exposure to 0.1 mg/m3or to 0.05 mg/m3to be 90

and 30 percent, respectively.

Finkelstein (2000) questioned whether there might have been a selection bias in

this study due to over-representation of men with lung disorders. That is, those without

such disorders might have been more likely to leave the town for employment elsewhere

and not be included in the study. Such a selection bias would tend to overstate risk.

However, Kreiss and Zhen (1996) argued that selection bias could also have resulted in

an underestimate of risk in that symptomatic miners might have left the region for loweraltitude areas. They reported that available information on outmigrants following closure

of the mine provided no evidence of bias in either direction since there was no observed

difference in chest complaints or spirometry results from those who remained in the area.

The authors also point out the similarity of their risk estimates with those of others who

had similar length of follow up (i.e., Hnizdo and Sluis-Cremer, 1993; Ng and Chan,

1994; Steenland and Brown, 1995b), although their estimates were somewhat higher.

Kreiss and Zhen (1996) believed that their estimates were higher in large measure

because of the availability of job-specific silica measurements for their study, as opposed

to having to rely on dust measurements and assume a constant silica content of the dust.

Use of the silica index in their exposure-response analysis resulted in almost a doubling

of the risk as compared to using the dust index alone.

The prevalence of silicosis among black South African miners was investigated

by Churchyard et al. (2004) in a cross-sectional study. A sample of 520 miners employed

at one company was recruited to participate in a medical surveillance exam, including a

chest x-ray, over a 5-month period in 2000-2001. All miners were over 37 years of age

(range 37.1-59.9) and averaged 21.8 years on the job (range 6.3-34.5). Detailed work

histories were obtained by interview with verification from company records, and x-ray

films were read by one current and another former B-reader. A finding of silicosis was

made where x-ray findings were consistent with an ILO classification of 1/1 or higher.

Data on exposures to quartz were evaluated from two sources. First, Churchyard

et al. (2004) obtained 506 personal respirable dust measurements from over 100 workers

during the period that the research was being conducted. All samples were analyzed for

quartz content by x-ray diffraction. These data covered 26 of the 85 jobs represented by

the 520 study subjects. Data for additional jobs was obtained from the mining company’s

routine dust surveillance activities in which personal respirable dust samples are obtained

semi-annually from representative workers grouped into job categories; a random sample

of dust samples from each job category were analyzed for quartz content. A total of 715

sample records were selected to represent the jobs not covered by the investigators’
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sampling efforts. Cumulative exposures of study subjects were estimated via

construction of a job exposure matrix.

Results of the research dust samples showed a high degree of concordance with

data from the company’s routine monitoring. The mean cumulative exposure to

respirable quartz for the study group overall was 8.2 mg/m3-years, with a mean intensity

of 0.053 mg/m3. The observed prevalence of silicosis (> = ILO 1/1) was 18.3 percent

from one reader and 19.9 percent from the other. Of these, nearly half were classified as

ILO category 2 or 3 level of profusion. The authors noted that the observed silicosis

prevalence was likely an under-estimate because workers with tuberculosis are required

under law to be excluded from dusty work, and would have been selected out of the

workforce over time.

Logistic regression analysis showed highly statistically significant trend between

silicosis prevalence and cumulative exposure to respirable dust, respirable quartz, average

exposure intensity of both dust and quartz, and length of service. Among the more highly

exposed subjects, who had cumulative exposures to respirable quartz in the range of 1.48

to 3.08 mg/m3-years, the prevalence of silicosis was 33 percent. The authors also pointed

out that 90 percent of the study subjects experienced mean exposures to respirable quartz

below 0.1 mg/m3, a level below the current OSHA formula PEL for general industry.

This study had the benefit of detailed occupational histories and high-quality

exposure data derived from personal dust samples representing all of the jobs worked by

the study group. There are two limitations of this study. First, there was a lack of

historical dust monitoring data that would have allowed for better characterization of

exposures over the working life of the cohort. However, the authors believed that the

available exposure data provided a reasonable estimate of past exposures, citing other

earlier studies of South African mines that reported mean dust concentrations only

slightly higher than that estimated by the authors from their data. Second, this was a

cross-sectional study of active workers only, albeit those with fairly long work tenures,

and therefore cannot be used to characterize additional silicosis risk post exposure.

Noting that Hnizdo and Sluis-Cremer (1993) (discussed below) reported finding that

most cases of silicosis in their study were detected among retired miners, Chuchyard et

al. (2004) concluded that the prevalence of silicosis found in their cohort was “certainly

an underestimate of lifetime cumulative incidence.”

Love et al. (1999) conducted a cross-sectional study to determine the quantitative

relationship between cumulative exposure to respirable crystalline silica and risk of

radiographic abnormalities and respiratory symptoms among workers in the heavy clay

industry in the United Kingdom. Eighteen facilities in England and Scotland were

chosen where industrial processes were deemed to have changed little over recent

decades. Factories produced bricks, clay pipes, and tiles, but not refractory brick.

Exposures of workers in over 300 jobs were assessed by personal sampling for respirable

dust conducted over a 5- or 10-day period at each plant. A total of 1,465 samples were

collected, of which 1,403 were analyzed for quartz by x-ray diffraction or infrared

analysis. Workers were invited to participate in a medical survey consisting of a work

history, respiratory symptom questionnaire, and chest x-ray. Medical information and x-
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ray films for 1,831 male workers were available for analysis. X-ray films were read by

three physicians experienced in classifying pneumoconiosis according to the ILO system.

Cumulative exposure indices for respirable dust and respirable quartz were estimated for

each worker based on geometric mean exposure and time spent in each job. Exposureresponse relationships were examined by multiple logistic regression.

Quartz was detected in 97 percent of the samples, and respirable quartz

concentrations ranged from 0.01 to 3.8 mg/m3, with 97 percent below 0.4 mg/m3, the

maximum allowable limit in the U.K. at the time. Of the 1,831 workers included in the

study, 1,337 (73 percent) had cumulative exposures of less than 2 mg/m3-yrs respirable

quartz, and 120 (6.6 percent) had cumulative exposures exceeding 4 mg/m3-yrs. The

observed prevalence of chest roentgenograms with small opacities was low; based on the

median readings of the three physicians, 3.7 percent of films were classified as ILO

category 0/1 or higher, and 1.4 percent as category 1/0 or higher. Only seven films were

classified as 2/1 or higher, with the highest classification being 2/3.

The prevalence of workers with films classified as 0/1 or higher increased with

age (from zero at age ≤ 24 years to 8.5 percent at age ≥ 55 years) and cumulative

exposure (from 1.0 percent among workers exposed to ≤ 0.5 mg/m3-yrs to 10 percent

among those exposed to 4 mg/m3-yrs or more). Logistic regression analysis showed that

the risk of acquiring a radiograph classified as category 0/1 or higher increased

significantly with age and cumulative exposure to respirable quartz. Risk was further

increased among current smokers but the effect was not statistically significant. Based on

the regression model, the authors estimated the odds ratio for acquiring a radiologic

abnormality (classified under ILO as ≥ 0/1) to be 4.3 for a 55-year-old man exposed to

1.0 mg/m3-yrs respirable silica; given a reported baseline odds of 0.0062 for the lowestexposed worker, this equates to a risk to age 55 of 2.6 percent. Similarly, the odds ratio

for a 55-year-old non-smoker having a cumulative exposure of 4 mg/m3-yrs was

estimated to be 8.2, which equates to a risk of 4.9 percent. The model was not used by

the authors to estimate odds of acquiring a radiographic abnormality classified as 1/0 or

higher since only 25 workers had films so classified.

The authors concluded that the prevalence of abnormal radiographs tended toward

the lower range of prevalence reported in other cross-sectional studies of brick workers.

For example, they cited studies by Sluis-Cremer (1972), who reported a 2.3-percent

prevalence of silicosis among South African brick workers; Palmer et al. (1980) who

found a 5-percent prevalence of silicosis among brick workers in North Carolina; and

Myers (1989), who reported a silicosis prevalence of 4 percent among South African

brick workers. Love et al. (1999) suggested that the presence of clay minerals on quartz

particles could have been responsible for reducing the toxicity of quartz in these plants,

and they also acknowledged that the cross-sectional nature of the study could have biased

the study towards understating the risk due to the preferential departure of workers

previously affected by dust exposure. Despite these considerations, the authors believed

that the exposure-response analysis “...suggests considerable risks of radiologic

abnormality even at concentrations of 0.1 mg/m3of quartz.”
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Most recently, an unpublished study of silicosis prevalence among American

brick workers was conducted for the Brick Industry Association (BIA) (Hessel, 2006)

and reported finding no radiologic evidence of silicosis. The study population included

974 workers from 14 U.S. structural brick manufacturing facilities (13 selected at random

from BIA member establishments and 1 that volunteered to provide medical information

and chest x-ray films). Chest roentgenograms were obtained from 701 (72 percent)

workers and medical questionnaires from 691 (71 percent) workers. X-ray films were

read by two B-readers and disagreements were resolved by a third B-reader. Chest x-rays

were taken in 2005 for all but 84 workers for whom previous films were available (dating

back to 1999). No measurements of exposure to respirable crystalline silica were

presented.

None of the x-ray films were considered consistent with silicosis. A consensus of

the readers classified three films as 1/0 or higher but none were read as showing rounded

opacities. Eight other films were classified as 1/0 or higher by only one of the primary

readers and a consensus reading could not be obtained. Furthermore, six of these eight

films were read as having only irregular opacities and the remaining two as having mixed

shapes.

Hessel (2006) concluded that the study was consistent with other reports finding

no evidence of silicosis among structural brick workers (citing Rajhans and Budlovsky,

1972; Zuskin et al., 1998; and Wiecek et al., 1983), as well as with the Love et al. (1999)

study discussed above. However, OSHA believes that the cross-sectional study design

and lack of quantitative exposure data limit the utility of this study.

II.F.2.b. Cumulative risk studies with little or no post-employment follow up.

Muir et al. (1989 a, 1989b; Verma et al., 1989) conducted a study of 2,109 active

hardrock miners from Ontario assembled in 1940 and followed to 1982; retired and

former workers were not included. Thirty-two workers were classified as having

silicosis. Investigators used particle-count exposure measurements made by konimeter

and converted them to mass respirable crystalline silica values based on data from sideby-side sampling. The study subjects had been employed for an average of 26 years and

were exposed to dust containing 6 to 8.4% silica. Of the 2,109 miners, all but 63 (3%)

were estimated to have had cumulative exposures of 2 mg/m3-years or less, and 1,313

(62%) had exposures below 0.5 mg/m3-years (Muir et al., 1989b). Chest x-ray films,

which were taken annually on the miners, were examined by five readers using the

following approach. First, four readers independently examined the two most recent

films to screen out miners whose films clearly showed an absence of any evidence of

silicosis. Based on the initial screening, the films of 650 miners were examined further

by having each of the five readers classify the films using the 1980 ILO standard

reference films; readers were provided these films in random order. If two readers

classified the same zone of the same film as 1/1 or greater, all films for that miner were

subjected to a final examination by all five readers. Films from 48 miners were selected

for final examination, of which 32 were considered by one or more readers to have

silicosis. Risk estimates were made for various cumulative exposure levels based on a

fitted Weibull model and incorporating a 5-year exposure lag.
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Muir et al. (1989b) estimated that the cumulative risk of developing silicosis as a

result of 40 years of exposure to 0.1 mg/m3 was 2.7 percent based on a positive finding

from at least one reader, or 1.2 percent based on agreement of three or more readers;

results based on findings from each of the five readers ranged from 0.5 to 2 percent. For

an exposure level of 0.05 mg/m3, they estimated the risk to be 0.9 percent based on at

least one reader and 0.4 percent based on three or more readers. The investigators

remarked that the x-ray films were of very variable quality, which was the reason for

devising their strategy for evaluating the films (Muir et al., 1989a).

In his review of available risk studies for silicosis, Finkelstein (2000) stated that

the results from this study were not sufficiently reliable for risk assessment because the

period of follow up was too short. He pointed out that the latest x-ray for nearly half of

the subjects was obtained less than 15 years from the start of exposure and that in his

earlier study of Ontario miners who started exposure in 1950 or later, less than 20% of

the silicosis cases were diagnosed earlier than 20 years from first exposure (Finkelstein,

1994). He also believed that the results understated the true risk because there was no

adjustment for time since first exposure; that is, the calculation of the risk included

miners with latencies less than 10-15 years and, consequently, who should be regarded as

not being at risk.

Hughes et al. (1998) reported the results of their retrospective cohort study of

2,342 workers employed at a diatomaceous earth mining and processing facility for at

least one year between 1942 and 1987. Exposure estimates were made from respirable

dust monitoring data and estimates of the percent crystalline silica content of the product.

Estimates of dust concentrations prior to 1948 when measurements were first made were

based on relative rankings of exposures in different jobs and documented changes in

processes and dust controls. From this assessment, average respirable silica exposures

were estimated to be 0.9 mg/m3in 1932-43 and declined to 0.4 mg/m3in 1944-1953, 0.15

mg/m3in 1954-1973, and 0.10 mg/m3in 1974-1994. An x-ray surveillance program (at

initial hire and periodically thereafter) was initiated in the 1930s; participation was not

required and only a few films were available from some of the earlier workers. In all,

films were available for 1,983 workers; however, only the films from 1,809 workers who

had films taken more than one-month post-hire were included in the exposure-response

analysis. In addition, only 82 workers participated in the surveillance program postemployment. All available films for the cohort were screened by one reader to select the

latest film for each worker having acceptable quality. These films were read

independently by three B-readers according to the 1980 ILO system; a silicosis case was

defined if at least two readers scored the film as 1/0 or greater, or if large opacities were

identified. All films for each worker identified from the latest film as having silicosis

were read by the three readers to ascertain the dates of the last negative and first positive

film. Silicosis incidence within the cohort was assessed by Poission regression, followed

by life table analysis and parametric failure-time models to evaluate the exposureresponse relationship.

Overall, opacities in films were observed in 4.5 percent of the cohort. The

relative risk of silicosis increased significantly with cumulative exposure to silica and

was best described by a log-logistic model. However, the investigators found that
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average concentration of silica, defined as the cumulative exposure divided by the

number of years worked up to the final or first positive x-ray, was also an important

determinant. This finding was based on analysis of incidence rates and relative risks after

dividing the cohort into those whose average exposure exceeded 0.5 mg/m3and those

whose average exposure was below or equal to 0.5 mg/m3. The value of 0.5 mg/m3 was

chosen based on the average exposure among 357 workers who had cumulative exposure

of 3 mg/m3-years and for whom a relatively high incidence of disease was found.

Hughes et al. (1998) estimated that the cumulative risks of opacities at a cumulative

exposure of 4.0 mg/m3-years (equal to a 40-year exposure to 0.1 mg/m3respirable

crystalline silica) were 3.3 and 12.4 percent for workers exposed below or above an

average concentration of 0.5 mg/m3, respectively. For a cumulative exposure of 2

mg/m3-years (equal to a 40-year exposure to 0.05 mg/m3), the estimated cumulative risks

were 1.1 and 3.7 percent for workers exposed below or above 0.5 mg/m3, respectively.

Hughes et al. (1998) found that subdividing the cohort based on other average exposure

values below 0.5 mg/m3did not have any meaningful effect on the relationship between

relative risk and cumulative exposure.

According to the investigators, the finding of a steeper exposure-response

relationship with cumulative exposure for the subgroup of workers exposed to an average

concentration of 0.5 mg/m3or more suggests that exposure concentration is a risk factor

for silicosis. However, they also suggested that the observed difference could reflect an

underestimation of exposure levels for early hires, who comprised the majority of

workers exposed to the higher concentrations. If that was the case, then the risk

associated with a given cumulative exposure would have been lower than observed

among workers exposed to the higher concentrations, and thus would have been closer to

the risk among workers exposed at lower concentrations but at the same cumulative

exposure.

As with the Muir et al. (1989b) study, this study of diatomaceous earth workers is

weakened by a short follow up period. There were only 394 workers (22 percent of the

cohort) for whom the latest chest radiograph was taken 20 or more years post-hire. For

the cohort overall, the latest chest film was taken an average of 11.5 years after hire, a

period too short for silicosis to have developed. Hughes et al. (1998) recognized this

limitation and acknowledged the possibility that this led to an underestimation of risk, but

they also argued that risk would have been understated only if there was a higher rate of

disease among workers who left employment (for whom chest x-ray films were not

generally available) compared to workers who continued employment. Essentially, this

would reflect a healthy worker effect.

Park et al. (2002) conducted exposure-response analyses of a previously

assembled cohort of 2,342 white male workers in a diatomaceous earth plant, all of whom

had worked for at least a year between 1942 and 1994; this analysis was described in

detail above in Section II.C with respect to their analysis of non-malignant respiratory

disease mortality. Evaluation of silicosis morbidity was based on 70 incident cases of

silicosis. Chest x-ray films dating back to the 1930s were available for the cohort,

however almost all radiography ended with employment. Silicosis cases were defined as
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radiographs classified ILO 1/0 or greater by two of three B readers. The median date of

the first positive film was used in Poisson regression and proportional hazards analysis.

The investigators observed a skewed distribution in calendar time in which 73

percent of cases occurred during the first 13 of 53 years of follow-up. They considered

this to be a reflection of increased surveillance after 1942 during which many previously

undetected cases were revealed. According to the authors, this expansion of the

surveillance program might have resulted in cases identified after 1942 that were present

earlier but not detected. The extent to which such cases were ascertained late could have

resulted in a bias toward underestimating risk.

Risks were estimated for the cohort overall and for the cohort excluding the

highest-exposed (>10 mg/m3-years) group of workers (as with the case for the mortality

analysis). With the high-exposure group excluded, the excess lifetime risk estimates of

radiographic silicosis for a 45-year exposure to 0.1 mg/m3and 0.05 mg/m3 were 14 and

7.5 percent, respectively. With the high-exposure group included, the estimated lifetime

risks for these exposure levels were 10 and 6.8 percent, respectively.

II.F.2.c. Cumulative risk studies with post-employment follow up.

Hnizdo and Sluis-Cremer (1993) described the results of a retrospective cohort

study of 2,235 white gold miners in South Africa. These workers had received annual

examinations and chest x-rays while employed; most returned for occasional

examinations after employment. Radiographs were interpreted by a single reader and a

case was defined as one classified as ILO 1/1 or greater. A total of 313 miners had

developed silicosis and had been exposed for an average of 27 years at the time of

diagnosis. Forty-three percent of the cases were diagnosed while employed and the

remaining 57 percent were diagnosed an average of 7.4 years after leaving the mines.

The average latency for the cohort was 35 years (range of 18-50 years) from start of

exposure to diagnosis.

Cumulative exposures of the miners were estimated by converting particle count

measurements made in the 1960’s to respirable dust measurements (Du Toit 1991) and

assuming a 30-percent quartz content of the dust. The average respirable dust exposure

for the cohort overall was 0.29 mg/m3(range 0.11-0.47); this corresponds to an average

respirable silica concentration of 0.09 mg/m3(range 0.033-0.14). The average

cumulative dust exposure for the overall cohort was 6.6 mg/m3-years (range 1.2-18.7), or

an average cumulative silica exposure of 1.98 mg/m3(range 0.36-5.61).

Gibbs and Du Toit (2002) argued that the exposure estimates were understated by

about a factor of two since a higher silica content should have been assumed. According

to a footnote in Table II of Hnizdo-Slius-Cremer (1993), the assumption of a 30-percent

quartz content applied to heat-treated and acid-washed dust; Gibbs and DuToit believed

after their review that this assumption was erroneous, and that a 54-percent quartz content

value should have been used to estimate the exposures of miners to respirable quartz.
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The California Environmental Protection Agency’s Office of Environmental

Health Hazard Assessment (OEHHA, 2005) examined this issue in detail by reviewing

the underlying data presented by Page-Shipp and Harris (1972) and comparing those data

to the quartz exposures calculated by Hnizdo and Slius-Cremer based on a 30 percent

quartz content and to the exposure estimates that would result from assuming a 54

percent quartz content, as asserted by Gibbs and DuToit. OEHHA (2005) found that the

use of a 30 percent quartz value yielded exposure estimates that were consistent with

those calculated originally by Page-Shipp and Harris (1972), indicating that the

assumption by Hnizdo and Slius-Cremer of a 30 percent quartz content for untreated dust

was more likely correct. (This suggests that the footnote in Table II of Hnizdo and SluisCremer is in error and the data presented are for untreated rather than acid-washed dust.)

In addition, OEHHA (2005) cite evidence that more recent investigations have found the

quartz content of respirable dust in South African gold mines is even less than 30 percent.

For example, they cite Kielblock et al. (1997), who reported that mine dust sampled

between the late 1980’s and early 1990’s contains about 15 percent crystalline silica, and

that a summary by Hnizdo of other measurements made in the 1970’s and 1980’s have

found a quartz content to be about 20 percent. Most recently, Churchyard et al. (2003,

2004, discussed above) found a median quartz content of 13.2 percent among 506

personal dust samples taken in 2000-2001, and a median of 16.1 among almost 700

measurements made by employers. These findings indicate that the quartz content of

dust collected in South African gold mines was in fact likely to be less than the 30

percent assumed by Hnizdo and Sluis-Cremer (1993). Thus, OSHA is not persuaded by

the analysis of Gibbs and Du Toit (2002) suggesting that the exposure estimates in the

Hnizdo et al. (1997) study were understated, and other data suggests that the assumed

quartz content of the dust, and hence worker exposures, might have been overstated.

However, the need to rely on particle count data that was generated over a fairly narrow

production period and the need to make assumptions about the quartz content of the dust

to which workers were exposed does add uncertainty to the exposure estimates.

Silicosis risk increased exponentially with cumulative exposure to respirable dust

and was modeled using log-logistic regression. Using the exposure-response relationship

developed by Hnizdo and Sluis-Cremer (1993), and assuming a quartz content of 30

percent in respirable dust, Rice and Stayner (1995) and NIOSH (2002) estimated the risk

of silicosis to be 70 percent and 13 percent for a 45-year exposure to 0.1 and 0.05 mg/m3

respirable crystalline silica, respectively.

According to Finkelstein (2000), this study had good statistical power because of

the relatively large number of cases identified in the cohort. In addition, this study had

good follow up of miners post-employment as evidenced by more than half the cases

being diagnosed after employment. Finkelstein (2000) also pointed to uncertainties in the

exposure estimates as well as potential uncertainty introduced by the radiographs having

been read by a single reader. However, autopsy data presented by Hnizdo and SluisCremer (1993) indicated that the classification of radiographs most likely understated the

true prevalence of silicosis in this cohort since the sensitivity of the coding relative to

autopsy findings was 0.99 (i.e., almost no false-positive readings), whereas the specificity

was only 0.39 (i.e., a high rate of false negatives).
333

Three thousand three hundred thirty South Dakota gold miners who had worked at

least a year underground between 1940 and 1965 were studied by Steenland and Brown

(1995b). Workers were followed though 1990 with 1,551 having died. X-rays taken in

cross-sectional surveys in 1960 and 1976 and death certificates were used to ascertain

cases of silicosis. One hundred twenty eight cases were found via death certificate, 29 by

x-ray, and 13 by both. Nine percent of deaths had silicosis mentioned on the death

certificate. The loss to follow up was quite low (2%). Exposure was estimated by

conversion of impinger (particle count) data and was based on measurements indicating

an average of 13% silica in the dust. Based on these data, the authors estimated the mean

exposure concentration to be 0.05 mg/m3for the overall cohort, with those hired before

1930 exposed to an average of 0.15 mg/m3. The average duration of exposure for cases

was 20 years (sd = 8.7) compared to 8.2 years (sd = 7.9) for the rest of the cohort. This

study found that cumulative exposure was the best disease predictor, followed by

duration of exposure and average exposure. Risk analysis was based on Poisson

regression to calculate silicosis rates (cases per person-year at risk) for seven cumulative

exposure categories. Lifetime risks to age 75 were calculated from these rates using

standard life table techniques. The authors estimated a risk of 47 percent associated with

45 years of exposure to 0.09 mg/m3respirable crystalline silica, which reduced to 35

percent after adjustment for age and calendar time. OSHA used the same life table

approach as described above for estimating lung cancer and NMRD mortality risks to

estimate silicosis risk based on the silicosis rates, adjusted for age and calendar time,

calculated by Steenland and Brown (1995b, Table 2). Silicosis risk was estimated

through age 85, assuming exposure from age 20 through 65, and assuming that the

silicosis rate remains constant after age 65. All-cause mortality rates to all males for

calendar year 2006 were used to account for background competing risk. From this

analysis, OSHA estimates the risk from exposure to the current general industry PEL of

0.1 mg/m3to be 43 percent; this is somewhat higher than estimated by Steenland and

Brown (1995b) because of the use by OSHA of more recent mortality data and

calculation of risk through age 85 rather than 75. For exposure to the proposed PEL of

0.05 mg/m3, OSHA estimates the lifetime risk to be 7 percent.

Inclusion of death certificate diagnoses complicates interpretation of the risk

estimate from this study since, as noted by Finkelstein (2000), it is not known how well

such diagnoses correlate with ILO radiographic interpretations; as such, the risk estimates

derived from this study may not be directly comparable to others that rely exclusively on

radiographic findings to evaluate silicosis morbidity risk.

Miller et al. (1995, 1998) and Buchanan et al. (2003) reported on a 1990/1991

follow-up study of 547 survivors of a 1,416-member cohort of Scottish coal workers from

a single mine. These men had all worked in the mine during a period between early 1971

and mid 1976, during which they had experienced “unusually high concentrations of

freshly cut quartz in mixed coalmine dust. The population’s exposures to quartz dust had

been measured in unique detail, for a substantial proportion of the men’s working lives.”

The 1,416 men had all had previous radiographs dating from before, during, or just after

this high exposure period. Of these 1,416 men, 384 were identified as having died by

1990/1991. Of the 1,032 remaining men, 156 were untraced, and, of the 876 who were

traced and replied, 711 agreed to participate in the study. Of these, the total number of
334

miners who were surveyed was 551. Four of these were omitted, two because of a lack

of chest radiograph. The 547 surviving miners (age range of 29 to 85 years, mean = 59

years) were interviewed and received their follow-up chest x-rays between November

1990 and April 1991. The interviews consisted of questions on current and past smoking

habits, and occupational history since leaving the coal mine, which closed in 1981. They

were also asked about respiratory symptoms and were given a spirometry test.

Exposure characterization was based on extensive respirable dust sampling;

samples were analyzed for quartz content by infrared spectroscopy. Between 1969 and

1977, two coal seams were mined; one of them had produced quarterly mean

concentrations of silica substantially less than 1 mg/m3(only 10 percent exceeded 0.3

mg/m3), while the other more unusual seam (mined between 1971 and 1976) lay in

sandstone strata and generated air levels of silica such that quarterly mean exposures

exceeded 1 mg/m3(10% of the quarterly measurements were over 10 mg/m3). Thus, this

cohort allowed study of the effects of both higher and lower silica concentrations, and

exposure-rate effects on the development of silicosis.

Three physicians read each chest film taken during the current survey as well as

films from the surveys conducted in 1974 and 1978. Films from the 1970 survey were

read only if none were available from the subsequent two surveys. Silicosis cases were

identified as such if the median classification of the three readers indicated an ILO (1980)

class of 1/0 or greater, plus a progression from the earlier reading. Of the 547 men, 203

(38%) showed progression of at least one ILO category from the 1970’s surveys to the

1990-91 survey; in 128 of these (24%) there was progression of two or more steps. In the

1970’s survey 504 men had normal chest x-rays; of these 120 (24%) acquired an

abnormal x-ray consistent with ILO category 1/0 or greater at the follow-up. Of the 36

men whose x-rays were consistent with ILO category 1/0 or greater in the 1970’s

surveys, 27 (75%) exhibited further progression at the 1990/1991 follow-up. Only one

subject showed a regression from any earlier reading, and that was slight, from 1/0 to 0/1.

The earlier Miller et al. (1995) report presented results for cases classified as having xray films consistent with either 1/0+ and 2/1+ degree of profusion; the Miller et al. (1998)

analysis and the Buchanan et al. (2003) reanalyses emphasize the results from cases

having x-rays classified as 2/1+.

Evaluation of exposure-response was performed by logistic regression using

cumulative exposure expressed as g/m3-hours, assuming 1,740 work hours per year.

Thus, to estimate risk for OSHA’s purposes, exposure to 0.1 mg/m3for 45 years is about

equal to 9.00 g/m3-hours (0.0001 g/m3* 45 years * 2000 hours/year). Covariates in the

regression included smoking, age, amount of coal dust, and percent of quartz in the coal

dust during various previous survey periods. Both Miller et al. (1995 and 1998) papers

present the results of numerous regression models, and they compare the results of the

partial regression coefficients using Z statistics of the coefficient divided by the standard

error. Also presented are the residual deviances of the models and the residual degrees of

freedom. In the introduction to the results section, Miller et al. (1995) stated that, “... in

none of the models fitted was there a significant effect of smoking habit (current, exsmoker, and never smoker), nor was there any evidence of any difference between
335

smoking groups in their relationship of response with age.” They therefore presented the

results of the regression analyses without terms for smoking effects.

The logistic models developed by Miller et al., (1995) included terms for

cumulative exposure and age. In their later publication, Miller et al. (1998), presented

models similar to their 1995 report, but without the age variable included. Using logistic

regression model A from Table 7 of their report, which included only an intercept (-4.32)

and the quartz cumulative exposure variable (0.416), they estimated that exposure to

crystalline silica at an average concentration of 0.10 mg/m3for 15 years (2.6 g/m3-hr

assuming 1,750 hours worked per year) would result in an increased risk of silicosis

(ILO>2/1) of 5 percent. Using these same model coefficients, OSHA estimates that

exposure to the current general industry PEL of 0.1 mg/m3for 45 years (9.0 g/m3-hours

assuming 2,000 hours worked per year) would result in an excess risk of about 0.36, or

360 workers per 1000. Exposure to the proposed PEL of 0.05 mg/m3for 45 years (4.5

g/m3-hours) results in an estimated excess risk of about 80 cases per 1,000 workers.

A later paper and reanalysis by these same authors (Buchanan et al., 2003)

provided strong evidence of an exposure-rate effect for silicosis in this cohort. To

estimate exposure-rate effects, exposure was categorized as pre- and post-1964, the latter

period being that of generally higher quartz concentrations. For the purpose of this

analysis the results were presented for the 371 men (out of the original 547) who were

between the ages of 50 and 74 at the time of the 1990/1991 follow-up, “since they had

experienced the widest range of quartz concentrations, and showed the strongest

exposure-response relations.” Thus, combined with their exposure history, which went

back to pre- 1954, many of these men had 30 to 40+ years of highly detailed occupational

exposure histories. Of these 371, there were 35 (9.4%) who had x-ray films consistent

with ILO category 2/1+ , with at least 29 of these having progressed from less severe

silicosis since the previous follow-up during the 1970’s (from Miller et al., 1998).

The Buchanan et al. (2003) reanalysis presented logistic regression models in

stages. In the first stage they compared the effect of pre- vs. post 1964 cumulative quartz

exposures on odds ratios. This yielded a statistically significant odds ratio estimate for

post-, but not pre-1964 cumulative exposures. In the second stage, including first these

post-1964 cumulative quartz exposures in the model, the authors then added total dust

levels both pre- and post-1964, age, smoking status, and number of hours worked pre1954. In this second stage, only post-1964 cumulative exposures remained statistically

significant. Finally, in their third stage of modeling, starting with only the statistically

significant post-1964 cumulative exposures, the authors separated these exposures into,

“two quartz concentration bands, defined by the cut point 2.0 mg/m3.” This yielded the

final equation:

Prob(2/1+) = 1/ (1+exp-(-4.83 + 0.443*Cum.Expos<2 + 01.323 * Cum.Exp>2)

In this model both the cumulative exposure concentration exposure variables were

“highly statistically significant in the presence of the other.” Since these variables were

in the same units, g–hr/m3, the authors noted that coefficient for exposure concentrations

>2.0 mg/m3is 3 times that for the concentrations <2.0 mg/m3, and concluded that their
336

latest analysis has shown that “the risk of silicosis over a working lifetime can rise

dramatically with exposure to such high concentrations over a timescale of merely a few

months.”

Buchanan et al. (2003) also used this model to estimate the risk of acquiring a

chest x-ray classified as ILO category 2/1+, 15 years after exposure ends, as a function of

both low (<2.0 mg/m3) and high (>2.0 mg/m3) quartz concentrations. OSHA has chosen

to use this model to estimate the risk of radiological silicosis consistent with an ILO

category 2/1+ chest x-ray for several exposure scenarios, assuming 45 years of exposure,

2000 hours/year of exposure, and no exposure above a concentration of 2.0 mg/m3.

These are presented in Table II-11. The results show that occupational exposures to the

proposed PEL of 0.05 mg/m3lead to an estimated risk of 5.5 cases per 100 workers.

Exposure at the current general industry PEL of 0.100 mg/m3increases the estimate to

30.1 cases per 100 workers. At higher exposure levels the risk estimates rise quickly to

near certainty.

Buchanan et al., (2003) provided analysis and risk estimates only for cases having

x-ray films consistent with ILO category 2/1+ extent of profusion of opacities, after

adjusting for the disproportionately severe effect of exposure to high concentrations of

silica. Estimating the risk of 1/0+ profusions from the Buchanan (2003) or the earlier

Miller et al. (1995, 1998) publications can only be roughly approximated because of the

summary information included. This is done as follows: From Miller et. al., (1998),

Table 4 presents a cross tabulation of radiograph progression, using the 12-point ILO

scale, from the last baseline exam to the 1990/1991 follow-up visit for the 547 men at the

Scottish coal mine. From this table, among workers for whom there were early x-ray

films as well as follow-up films, there were 44 men who had progressed to 2/1+ by the

last follow up, and an additional 105 who had experienced onset of silicosis (i.e., x-rays

films were classified as 1/0, 1/1, or 1/2). Thus, by the time of the follow-up, there were

3-times more miners with silicosis consistent with ILO category 1 than there were miners

with a category 2+ level of severity ((105 + 44)/44 = 3.38). This suggests that the risk

estimates derived from the Buchanan et al. (2003) model, which reflects the risk of

progressing to ILO category 2+, understates the risk of acquiring radiological silicosis by

about 3-fold in this population of workers.

OSHA has a high degree of confidence in the estimates of silicosis morbidity risk

from this Scotland coal mine study, mainly because of the highly detailed and extensive

exposure measurements, the radiographic records, and the detailed analyses of high

exposure-rate effects. However, in another paper, the authors (Soutar et al., 2004) noted

that:

If the effects of silica vary according to the conditions of exposure, these risks are

probably towards the high end of the risk spectrum, since the silica was freshly

fractured from massive sandstone, and not derived from dirt bands where the

quartz grains are aged and accompanied by clay minerals.

In contrast to the risk estimates that reflect an ILO 2/1+ degree of profusion of small

opacities, OSHA could only crudely assess the risk of less severe silicosis from the
337

Table II-11. Summary of Silicosis Morbidity Risk Estimates

Study

Predicted Risk From Exposure Over 45

Years (Cases per 100 Workers)

0.1 mg/m30.05 mg/m3

Cross-Sectional Studies

Rosenman et al., 1996 3

a

2

a

Ng and Chan, 1994 NE 6

b

Kreiss and Zhen, 1996 90 30

Churchyard et al., 2003 NE 33c

Love et al., 1999 4.9d NE

Cumulative Risk Studies, Little or No Post-Employment Follow Up

Muir et al., 1989a, 1989b;

Verma et al., 1989 2.7a,e 0.9a,e

1.2a,f 0.4a,f

Hughes et al., 1998 3.3a,g 1.1a,g

12.4a,h 3.7a,h

Park et al., 2002 14 7.5

Cumulative Risk Studies With Post-Employment Follow Up

Hnizdo and Sluis-Cremer, 1993i77 13

Steenland and Brown, 1995bi43 7

Miller et al., 1998i36 8

Buchanan et al., 2003i30 5.5

Chen et al., 2001j59 17

Chen et al., 2005k

Tin miners

Tungsten miners

Pottery workers

32

12

6

9

2

2

Footnotes for Table II-11

a Risk assuming a 40-year working life

b Risk for an average 50-year old worker exposed to 2 mg/m3

-years

c Risk of ≥0/1 x-ray to age 55 for cumulative exposure of 4 mg/m3

-years

d

Prevalence of ≥ 1/1 x-ray for cumulative exposure of 1.48 - 3.08 mg/m3-years

e Estimates based on findings from at least one reader

f Estimates based on agreement by three or more readers

g Risk for workers exposed to average concentrations <= 0.5 mg/m3

h Risk for workers exposed to average concentrations > 0.5 mg/m3

i Estimated by OSHA, see text and Table II-12

j Estimated from the Weibull model parameters reported by Chen et al., 2001

k Estimated from Figure 2B of Chen et al., 2005
338

information available. However, it is obvious from the available information that the risk

of acquiring radiological silicosis consistent with ILO category 1/0+ (i.e., the risk of

onset of disease) are significantly greater than that for progressing to more severe disease.

From the Buchanan et al. (2003) and Miller et al. (1998) studies, the risk of acquiring

silicosis would be of the same magnitude as that reported by Hnizdo and Sluis-Cremer,

(1993).

Another factor, study participant recruitment could also affect these risk

estimates. Finkelstein (2000), commenting on Miller et al. (1998), raised the issue of

whether selection bias might have affected the risk estimates, given that only about 50

percent of the cohort participated in the interview and radiological surveillance. He also

questioned whether lung clearance impairment might have been a factor during the period

of very high silica exposure experienced by these miners. OSHA acknowledges that both

these may be factors in estimating risks from this study, but concludes that, at worst,

effects would probably tend to be in opposite directions and offset each other. First, with

respect to selection bias, this is a survivor cohort studied at least 15 years after the period

of high quartz exposure. About 10 percent of the 1,416 had already died by 1990.

Considering the high silicosis incidence and the known association of silicosis with

increased risk of both lung cancer and NMRD, this survivor cohort should lead to an

underestimate of silicosis risks. Further, selection of the 50-75 age group for use in the

latest reanalysis would tend to accentuate the survivorship effect of underestimating risks.

Second, with respect to an exposure-rate effect of high silica exposure possibly due to

lung clearance impairment, OSHA agrees that these have to be taken into account with

this cohort. OSHA concludes that the results of the Buchanan et al. (2003) regression

model showing statistically significant and differential effects of exposure to both high

and low quartz concentrations during the same exposure periods, provide superior

estimates of silicosis for OSHA’s risk assessment purposes.

OSHA also acknowledges that using these logistic regression models for

projecting risk estimates with these data has limitations and uncertainties, especially

using models with only one, two or three variables. There are significant differences in

risk estimates using different models, as displayed both here and in the Miller et al. and

Buchanan et al. papers. However, use of these models with these data has shown several

significant results. First, there is the lack of significance of smoking in producing

radiographs with silicosis profusions. Second, the models show an established

cumulative quartz exposure effect for silicosis in coal miners, and independent of the

presence of coal dust. Third there is an independent high exposure-rate effect for

silicosis, which is accounted for in the risk estimates derived from the Buchanan et al.

(2003) model.

In 2001, Chen et al. reported the results of a retrospective study of a Chinese

cohort of 3,010 underground miners who had worked in tin mines at least one year

between 1960 and 1965. They were followed through 1994, by which time 2,426

(80.6%) workers had either retired or died, and only 400 (13.3%) remained employed at

the mines.
339

The mines provided occupational histories, dust measurement and medical

examination records. Exposure data consisted of high-flow, short-term gravimetric total

dust measurements made routinely since 1950; the authors used data from 1950 to

represent earlier exposures since dust control measures were not implemented until 1958.

Conversion of total dust measurements to respirable silica values was based on respirable

dust samples taken during a survey in 1988-1989; results from this survey indicated that

respirable silica measurements were 3.6 percent (sd = 2.5 percent) of total dust

measurements. Annual radiographs were taken since 1963 and all cohort members

continued to have chest x-rays taken every 2 or 3 years after leaving work. Silicosis was

diagnosed when at least 2 of 3 radiologists classified a radiograph as being a “suspected

case” or at Stage I, II, or III under the 1986 Chinese pneumoconiosis roentgen diagnostic

criteria. According to Chen et al. (2001), these four categories under the Chinese system

were found to agree closely with ILO categories 0/1, Category 1, Category 2, and

Category 3, respectively, based on studies comparing the Chinese and ILO classification

systems. Silicosis was observed in 33.7% of the group; 67.4% of the cases developed

after exposure ended.

The investigators found that a Weibull model provided the best fit to relate

cumulative silicosis risk to eight categories of cumulative total dust exposure. The risk of

silicosis was strongly related to cumulative silica exposure. The investigators predicted a

55-percent risk of silicosis associated with 45 years of exposure to 0.1 mg/m3. The paper

did not report the risk associated with a 45-year exposure to 0.05 mg/m3, but OSHA

estimates the risk to be about 17 percent (based on the parameters of the Weibull model

provided in Chen et al., 2001).

In a later study, Chen et al. (2005) investigated silicosis morbidity risks among

three cohorts to determine if the risk varied among workers exposed to silica dust having

different characteristics. The cohorts consisted of 4,547 pottery workers, 4,028 tin

miners, and 14,427 tungsten miners selected from a total of 20 workplaces. Cohort

members included all males employed after January 1, 1950 and who worked for at least

one year between 1960 and 1974. Radiological follow-up was through December 31,

1994 and x-rays were scored according to the Chinese classification system as described

previously by Chen et al. (2001) for the tin miner study. Exposure estimates of cohort

members to respirable crystalline silica were based on the same data as described by

Chen et al. (2001), i.e., short-term area samples for total dust with respirable silica dust

exposures estimated from side-by-side measurements taken in 1988-1989 of total dust

using the Chinese sampling method and respirable dust using the U.S. method. In

addition, the investigators measured the extent of surface occlusion of crystalline silica

particles by alumino-silicate from 47 dust samples taken at 13 worksites using multiplevoltage scanning electron microscopy and energy dispersive X-ray spectroscopy

(Harrison et al., 2005); this technique measures the silicon-to-aluminum ratio for both the

whole particle (using high voltage) and the particle surface (using low voltage), which

yields estimates of the percent of particle surface that is occluded.

Compared to tin and tungsten miners, pottery workers were exposed to

significantly higher mean total dust concentrations (8.2 mg/m3, compared to 3.9 mg/m3

for tin miners and 4.0 mg/m3for tungsten miners), worked more net years in dusty
340

occupations (mean of 24.9 years compared to 16.4 years for tin miners and 16.5 years for

tungsten miners), and had higher mean cumulative dust exposures (205.6 mg/m3-years

compared to 62.3 mg/m3-years for tin miners and 64.9 mg/m3-years for tungsten miners)

(Chen et al., 2005). Applying the authors’ conversion factors to estimate respirable

crystalline silica from Chinese total dust measurements, the approximate mean

cumulative exposures to respirable silica for pottery, tin, and tungsten workers are 6.4

mg/m3-years, 2.4 mg/m3-years, and 3.2 mg/m3-years, respectively. Measurement of

particle surface occlusion indicated that, on average, 45 percent of the surface area of

respirable particles collected from pottery factory samples was occluded, compared to 18

percent of the particle surface area for tin mine samples and 13 percent of particle surface

area for tungsten mines.

The relationship between respirable silica exposure and silicosis morbidity

(defined as Stage I or higher classification of chest x-ray films under the Chinese system)

was analyzed using the Weibull model (details not provided), the results of which were

provided in graphic form. Based on Figure 2B of Chen et al. (2005), OSHA estimated

the cumulative silicosis risk associated with a cumulative exposure of 4.5 mg/m3-years

respirable silica to be 6 percent for pottery workers, 12 percent for tungsten miners, and

32 percent for tin miners. For a cumulative exposure of 2.25 mg/m3-years (i.e., 45 years

of exposure to 0.05 mg/m3), cumulative silicosis morbidity risks were estimated to be 2,

2, and 9 percent for pottery, tungsten, and tin miners, respectively. When cumulative

silica exposure was adjusted to reflect exposure to surface-active quartz particles (i.e., not

occluded), the estimated cumulative risk among pottery workers more closely

approximated those of the tin and tungsten miners, suggesting to the authors that

alumino-silicate occlusion of the crystalline particles in pottery factories at least partially

explained the lower risk seen among workers, despite their having been more heavily

exposed.

II.F.3. Summary of Risk Estimates.

Table II-11 presents a summary of the risk estimates provided by the studies

reviewed in this section. It is clear from this table and it has been pointed out by others

(Chen et al., 2001; Finkelstein, 2000; NIOSH, 2002) that lack of follow up of retired

workers consistently resulted in lower risk estimates compared to studies that included

retired workers. OSHA believes that the most reliable estimates of silicosis morbidity, as

detected by chest radiographs, come from the five studies that evaluated radiographs over

time, included radiographic evaluation of workers after they left employment, and

derived cumulative or lifetime estimates of silicosis disease risk: the U.S. gold miner

cohort studied by Steenland and Brown (1995b), the Scottish coal miner cohort studied

by Miller et al. (1995, 1998) and Buchanan et al. (2003), the Chinese tin mining cohort

studied by Chen et al. (2001), the tin, tungsten, and pottery worker cohorts studies by

Chen et al. (2005), and the South African gold miner cohort studied by Hnizdo and SluisCremer (1993).

These five studies evaluated silicosis risks in seven cohorts (with the two tin

miner cohorts overlapping). The estimates derived from the U.S. gold miner cohort

(Steenland and Brown, 1995b), the Scottish coal mining cohort (Miller et al., 1998;
341

Buchanan et al., 2003), Chinese tin mining cohorts (Chen et al., 2001; Chen et al., 2005),

and South African gold miner cohorts (Hnizdo and Sluis-Cremer, 1993) are all in

reasonable agreement and range from 30 to 77 percent for a 45-year exposure to 0.1

mg/m3respirable crystalline silica. Of these studies, OSHA believes that the study of

coalworkers by Miller et al. (1995, 1998) and Buchanan et al. (2003) is of the best overall

quality, in large part due to the availability of respirable quartz measurements taken over

several years that provided the basis for estimating exposures of individual cohort

members. In contrast, the study of U.S. gold miners (Steenland and Brown, 1995b)

required estimation of mass quartz exposures from particle count data and limited sideby-side respirable dust sampling, and the studies by Chen et al. (2001) and Chen et al.

(2005) relied on short-term total dust samples, also with limited side-by-side sampling, to

estimate exposures to respirable quartz dust. However, it is important to note that risk

estimates based on the Miller et al. (1995, 1998) and Buchanan et al. (2003) studies

reflect the risk that nodular profusion will progress such that a chest x-ray would be

classified as ILO major category 2 or higher. Such estimates understate the risk of

developing lesser degrees of profusion (i.e., ILO 1/0 or 1/1).

The highest estimate comes from the Hnizdo and Sluis-Cremer (1993) study, from

which OSHA estimates silicosis risks of 77 and 13 percent for 45 years of exposure to 0.1

and 0.05 mg/m3, respectively. It has been suggested that the exposure estimates were

understated in this study by a factor of about two (Gibbs and Du Toit, 2002). As

explained in Section II.F.2.c above, OSHA is not convinced that the exposures of the

South African miners were necessarily systematically understated in this study;

nevertheless, it must be acknowledged that there is uncertainty in the exposure estimates

of the South African miner study. The low end of the range is reflected by the risk

estimates from the two cohorts studied by Chen et al. (2005), the Chinese tungsten miners

and pottery workers. For the pottery workers, it is possible that the presence of aluminosilicate surface occlusion resulted in reduced toxicity of the quartz particles; there is

substantial evidence in animals that such coatings can reduce the fibrogenic potency of

quartz (see Section I.F of the Health Effects section), and Chen et al. (2005) found that

differences in the exposure-response relationship for pottery workers compared to miners

was at least partially mitigated after adjusting cumulative silica exposure to account for

surface occlusion. The studies by Love et al. (1999) of U.K. heavy clay workers and by

Hessel (2006) of U.S. brick industry workers also suggest that silicosis risks are lower

than has been seen in other industries, despite the cross-sectional nature of these studies.

Recently, Miller and Soutar (2007) applied the model developed from the Scottish coal

worker cohort by Buchanan et al. (2003) to compare predicted and observed silicosis

cases in the cohort studied by Love et al (1999), and found that the model predicted about

4-fold more cases of silicosis (defined as ILO 2/1+ x-ray findings) than were observed

(about 31 predicted compared to 8 observed). Miller and Soutar (2007) concluded that

the predictive model was probably not relevant for the clay industry.

There is no apparent explanation for why tungsten miners appeared to have lower

silicosis risk than tin miners, although their risk per unit cumulative silica exposure was

higher than that of pottery workers. It is possible that the difference in observed

exposure-response relationships seen among tungsten and tin miners reflects exposure

misclassification due to the need to estimate full-shift exposures to respirable quartz from
342

short-term total dust samples, or that the difference is the result of unidentified

workplace-specific factors that influenced the relative toxicities of the quartz particles

found in the tungsten and tin mines.

The considerations described above make it difficult to estimate the risk of

silicosis morbidity with a high degree of precision. However, because these five studies

examined the morbidity experience of retired workers, OSHA believes that these studies

come closest to reflecting the lifetime risk of experiencing radiological opacities faced by

workers who are exposed to crystalline silica. For crystalline silica dust that is generated

using high-energy processes (i.e., freshly cut or fractured) and not occluded, silicosis

morbidity risk associated with exposure to the current PEL over 45 years is estimated to

range between 12 and 77 cases per 100 workers, based on five studies that were judged to

have sufficient follow-up of retired workers. The range in estimated risk associated with

exposure to 0.05 mg/m3is from 2 to 17 cases per 100 workers. Of these studies, OSHA

believes that the Miller et al. (1998) and Buchanan et al. (2003) studies provide the most

reliable basis for estimating silicosis morbidity risk due to the high quality of the

underlying exposure data for the cohort, and the capability of the Buchanan et al. model

to account for possible effects of exposures to very high concentrations of respirable

silica. OSHA estimated the risk from that study to be 30 cases per 100 workers for

exposure to the current general industry PEL of 0.1 mg/m3and 5.5 cases per 100 workers

for exposure to the proposed PEL of 0.05 mg/m3. However, these estimates reflect the

risk of developing more advanced stages of silicosis than do the remaining studies, and

thus underestimate the actual risk of radiological silicosis.

II.G. Issues Related to Assessing Crystalline Silica-Related Risk.

II.G.1. Choice of Cumulative Dose as the Dose Metric.

Each of the analyses presented in this section have relied on cumulative exposure

as the exposure metric used to quantify exposure-response relationships. Some studies

have also reported finding positive exposure-response relationships based on exposure

intensity rather than, or in addition to, cumulative exposure. Such findings could suggest

that the relationship between exposure to crystalline silica and lung cancer or silicosis

reflects a dose-rate effect, where for a given cumulative exposure level, exposure to

higher concentrations would have a greater health impact than exposure to lower

concentrations. Kuempel et al. (2001) argued that a dose-rate effect is biologically

plausible given that quartz is cytotoxic and may interfere directly with the lung’s

antioxidant defenses resulting in a series of events that lead to disease. Among the

studies relied on by OSHA, only the Buchanan et al. (2003) study of silicosis risks among

Scottish coal miners has adjusted the cumulative exposure metric to account for the

effects of exposures to high concentrations.

For lung cancer, a few studies have reported finding positive exposure-response

relationships with exposure metrics other than cumulative exposure. Cherry et al. (1998)

in their case-referent study of U.K. pottery workers reported that odds ratios for lung

cancer increased with increasing concentration of crystalline silica, but not with

cumulative exposure or exposure duration (after controlling for smoking and employing
343

lags of 0, 10, and 20 years). However, the prevalence of small opacities increased with

both cumulative exposure and exposure concentration. These investigators stated that the

lack of an exposure-response relationship for lung cancer and cumulative exposure arose

directly from the cases having generally shorter durations of exposure than did controls,

which were matched on date of birth and date of first exposure. Almost half (49.2

percent) of the controls were exposed for more than 15 years compared to 38.4 percent of

cases, and more than one-third of the cases (37 percent) had less than 5 years of exposure,

compared to only 27 percent of cases. This study was of a relatively small size, including

a total of 52 lung cancer cases.

Two other studies reported finding increased lung cancer risk with increasing

exposure intensity. Hughes et al. (2001) conducted a nested case-control study of 95 lung

cancer deaths in nine industrial sand plants and found significant exposure-response

trends with both cumulative exposure and average crystalline silica concentration, after

controlling for smoking. In a separate study of industrial sand workers, Steenland et al.

(2001b) found borderline significant trends with cumulative exposure and a significant

positive trend with average exposure.

In contrast to these studies, most other epidemiological studies that examined

relationships with cumulative exposure found positive associations; for example, nine of

the ten epidemiological studies included in the pooled analysis by Steenland et al.

(2001a) showed positive exposure coefficients when exposure was expressed as

cumulative exposure (the one exception being the U.S. gold mining cohort).

Similarly, with a few notable exceptions, most of the studies of silicosis mortality

and morbidity demonstrated positive exposure-response trends with cumulative exposure;

these include each of the six cohort studies used in the pooled analysis by Mannetje et al.

(2002b) and all of the silicosis morbidity studies summarized in Section II.F.2 above. In

their analysis of diatomaceous earth workers and lung disease other than cancer, Park et

al. (2002) specifically examined the fit of several models to alternative exposure metrics

and found that in only one case did a model provide an adequate fit with average

exposure intensity (log-linear model with the highest cumulative-exposure workers

included); otherwise, most models performed best with cumulative exposure as the

exposure metric.

Two studies provide some evidence for a dose-rate effect and silicosis morbidity

as evidenced by the appearance of small opacities on chest roentgenograms. The

Buchanan et al., (2003) reanalysis of the Miller et al., (1998) Scottish coal worker study

has already been discussed in several sections above; that reanalysis found an

approximately 3-fold increased silicosis risk resulting from exposure to concentrations

above 2 mg/m3vs. that associated with equivalent cumulative exposures but to

concentrations below 2 mg/m3.

Hughes et al. (1998) found that exposure concentration was an important

determinant of the risk to diatomaceous earth workers, where the relationship between

cumulative exposure and risk of silicosis was considerably steeper among workers hired

prior to 1950 and exposed to average concentrations above 0.5 mg/m3, compared to that
344

for workers hired after 1950 and exposed to lower average concentrations. However, the

authors also suggested that the observed difference could have been the result of

underestimating exposure levels of workers hired early in the observation period when

exposures were higher but less well characterized than for later years. In addition, the

results of this study are made uncertain by a lack of follow up; for the cohort overall, the

latest chest film was taken an average of 11.5 years after hire, a period too short to ensure

that all, or nearly all, cases of silicosis that will develop could be detected.

The studies by Hughes et al. (1998) and Buchanan et al. (2003) provide evidence

for a dose-rate effect for silicosis morbidity (as defined by the appearance of small

opacities) in instances where workers are exposed to crystalline silica concentrations

several-fold to orders of magnitude above the current OSHA PEL (i.e., above

approximately 0.1 mg/m3). OSHA believes that such an effect is biologically plausible

given the cytotoxic nature of crystalline silica and its ability to interfere with its clearance

by alveolar macrophages and fuel a persistent inflammatory reaction in the lung.

However, there is little evidence that such a dose-rate effect exists at concentrations in

the range of the current PEL. As summarized in the earlier parts of this section, the

majority of studies of lung cancer and silicosis morbidity and mortality have consistently

found significant positive relationships between risk and cumulative exposure. Lacking

strong evidence of an exposure-rate effect in other studies, OSHA has chosen cumulative

exposure unadjusted for any exposure-rate effect as a reasonable exposure metric on

which to base estimates of risk to workers exposed to crystalline silica in the range of the

current PEL.

II.G.2. Physical Factors That May Influence Toxicity of Crystalline Silica.

Much research has been conducted to investigate the influence of certain physical

factors on the toxicologic potency of crystalline silica; such factors include crystal

polymorphism, particle surface characteristics, the age of fractured surfaces of the crystal

particle, the presence of impurities on particle surfaces, and coating of the particle. These

factors may vary among different workplace settings suggesting that the risk to workers

exposed to a given level of respirable crystalline silica may not be equivalent in different

work environments. These findings are summarized in this section. Further details and

discussion of additional studies may be found in Section I.F. of the Health Effects

literature review.

These physical factors primarily affect the surface of silica particles. Researchers

believe that surface characteristics of respirable crystalline particles play an important

role in the mechanism by which silica causes lung damage. Thus, any factor that

influences or modifies these surface characteristics may alter the toxicity of silica by

affecting the mechanistic process. A silica particle entering the lung has reactive sites on

its surface consisting of silicon-based free radicals. When these free radicals react with

aqueous (water-based) constituents in the lung, they generate reactive oxygen species, or

ROS, that can react with and damage cellular constituents such as DNA, proteins, lipids

and carbohydrates. Silica surface contact with water also results in the formation of

surface silanol groups. It is hypothesized that cellular response, and particularly

macrophage activation and death, is mediated by strong interactions between reactive
345

sites on the particle surface and cell membrane components. These reactive species can

cause cellular injury leading to fibrosis by several proposed mechanisms, including by

direct cytotoxicity and by stimulating alveolar macrophages leading to release of

cytotoxic enzymes, ROS, inflammatory factors (which lead to recruitment of

polymorphonuclear leukocytes and cytokine release), and other factors that initiate

fibroblast production and collagen synthesis (NIOSH, 2002). In addition, generation of

ROS from silica directly or by stimulated cells may damage the lung epithelia and may

play a role in silica-induced DNA damage or cell proliferation contributing to

carcinogenesis (Fubini et al., 2004; Shi et al., 1989; Shi et al., 1998).

IARC (1997) has determined that “crystalline silica inhaled in the form of quartz

or cristobalite from occupational sources is carcinogenic to humans.” In making this

determination, the IARC Working Group noted that “carcinogenicity was not detected in

all industrial circumstances studied.” The Working Group also stated that

“carcinogenicity may be dependent on inherent characteristics of the crystalline silica or

on external factors affecting its biological activity or distribution of its polymorphs.”

Thus, while IARC has determined that cristobalite and quartz are both carcinogenic to

humans, there has been considerable discussion among researchers as to whether the

toxicological and carcinogenic potency of crystalline silica might vary depending on

crystalline structure or surface chemistry of the particles.

Very early animal studies appeared to suggest that the crystal polymorphs

cristobalite and tridymite were more toxic to the lung than quartz. King et al. (1953),

who exposed rats by single intratracheal injection to quartz, cristobalite, or tridymite,

described the action of cristobalite as “perhaps slightly faster than quartz,” and tridymite

as having a “spectacular” fibrotic effect. However, Bolsaitis and Wallace (1996)

reviewed more recent studies showing the effect of different polymorphs on hemolytic

activity and on inflammation and fibrosis in mouse lungs induced by quartz, cristobalite,

or tridymite. The results showed that hemolytic activities were within the range of

experimental error and lung fibrosis was essentially the same among the three

polymorphs.

A difference in toxicity between cristobalite and quartz has not been observed in

epidemiologic studies (exposure to tridymite has not been the subject of epidemiologic

study). In their study of diatomaceous earth workers whose predominant exposure was to

cristobalite, Rice et al. (2001) reiterated that differential polymorph toxicity has not been

confirmed by results of epidemiological studies; however, citing results from studies of

pottery workers, they also believed that there may be some evidence of increased

mortality from lung cancer in industries with high temperature processes. These authors

concluded that differences in the carcinogenic potential of various crystalline silica

polymorphs have not been established and therefore cancer risks from workplace

exposure to silica cannot yet be attributed or limited to a particular polymorph. Steenland

et al. (2001a) also addressed the debate regarding whether the risk of lung cancer might

be higher for cristobalite vs. quartz, since one of their cohorts was primarily exposed to

cristobalite (diatomaceous earth workers). It was observed that the exposure-response

trends within this cohort did not differ notably from trends in the remaining cohorts.
346

A number of investigators have addressed the relationship between the age of

fractured crystal surfaces on respirable silica particles and their toxicologic potency.

When crystalline silica is subjected to high energy forces, as occurs in work processes

such as abrasive blasting, rock drilling, tunneling, stone carving and the production of

silica flour, the silica particles are said to be “freshly fractured.” Silica that is not

fractured by the work process is said to be “aged.” A number of studies have examined

the question of whether freshly fractured silica is more toxic than aged silica. It has been

noted that acute silicosis is associated with the generation of freshly fractured silica dust

in these occupations (Castranova et al., 1996).

Early in vitro studies demonstrated that freshly fractured silica caused more

cytotoxicity in cells than did aged silica (Vallyathan et al., 1988). Freshly fractured silica

has been shown to possess an increased ability to activate respiratory bursts in alveolar

macrophages (Shi et al., 1989), and it was found to be 4.6-fold more potent than aged

particles in the release by activated alveolar macrophages of reactive oxygen species

(Vallyathan et al.,1992). Vallyathan et al. (1988) hypothesized that freshly fractured

silica is more potent due to formation of silicon-based radicals from cleavage of the

crystal surfaces, as well as from propagation of other oxygenated radicals in aqueous

environments. They suggested that the presence of these newly formed radicals along

with those generated by macrophages may overwhelm pulmonary defense mechanisms.

However, Vallyathan et al. (1988) noted that silica aged for years still retained the ability

to stimulate alveolar macrophages and cause cytotoxicity, suggesting that silicon-based

reactive oxygen species can only partly explain the biologic reactivity of silica.

The presence of moisture also appears to affect the generation of free radicals on

particle surfaces. Elias et al. (2000) found that grinding quartz in a wet atmosphere

greatly reduced its cytotoxic and transforming potency in Syrian hamster embryo cells,

compared to that of dry-ground quartz.

Several in vivo studies have also been done to compare the effects of freshly

fractured and aged silica. Representative is a study by Vallyathan et al. (1995) (also

reported in Shoemaker et al., 1995 and Castranova et al., 1996) in which they exposed

rats to freshly fractured or aged silica for 2 weeks by inhalation. Controls were exposed

only to filtered air. In exposed rats, there were changes indicative of damage at the

alveolar blood-air barrier level) and an inflammatory response. These indices were

significantly elevated in the rats exposed to aged silica as compared to controls, and

inhalation of freshly fractured silica resulted in a substantially greater pulmonary reaction

than aged silica. The authors suggested that their study results indicated that the

pulmonary reactions of rats to short duration exposure to freshly fractured silica mimic

those seen in acute silicosis in humans.

The differential potency of freshly fractured vs. aged quartz may be dose

dependent. In a recent study, Porter et al. (2002) treated rats by intratracheal instillation

with either aged or freshly fractured silica at a dose of either 5 or 20 g once a week for

12 weeks. These doses, which are lower than has been used in other animal studies, were

chosen because they approximated exposures of surface miners to silica aerosols.

Exposure to the low dose caused the same degree of inflammatory response and alveolar
347

macrophage activation for both aged and freshly fractured quartz. At the higher dose,

freshly fractured silica was significantly more potent than aged silica in stimulating the

activation of alveolar macrophages, but both caused a similar degree of pulmonary

damage. The authors believed that their results suggested that the difference in potency

between aged and freshly fractured silica occurs only after a threshold burden of silica is

reached.

In the above in vitro and in vivo studies, silica was fractured by several different

methods such as crushing or grinding in an agate mortar and pestle or generating in a air

jet mill fitted with a polyurethane liner and stainless steel jets. However, it has been

reported that the toxicity of silica can vary depending on the method of preparation. It

was found that the toxicity of quartz particles increased when the sample was ground in a

mill rather than in a press (Shi et al., 1989). It was suggested that after crushing in a

press, the particle has a smooth surface, while the milled particle has sharp edges and a

larger surface area. It is unclear what this finding means for the many different work

processes that can create freshly fractured silica.

Castranova et al. (1998) demonstrated in rats that exposure to silica by

intratracheal instillation or by inhalation results in an increase in messenger RNA for

inducible nitric oxide synthase in bronchoalveolar lavage cells, elevated nitric oxide

production by bronchoalveolar lavage cells and an increase in nitric oxide dependent

chemiluminescence from alveolar macrophages. Freshly fractured silica was a more

potent stimulant of nitric oxide-dependent chemiluminescence than aged silica. This

study also compared similar endpoints in a healthy volunteer, a silica-exposed coal miner

with a normal chest X-ray and a silica-exposed miner with an abnormal chest X-ray with

an ILO reading of 1/0. There was some messenger RNA for inducible nitric oxide

synthase in the bronchoalveolar lavage cells of the miner with the normal chest X-ray,

there was much more in the cells of the miner with the abnormal chest X-ray. There was

also more nitric oxide-dependent chemiluminescence in cells from the miner with the

abnormal chest X-ray. Both endpoints were increased above control even in the miner

with a normal chest X-ray.

The studies described above suggest generally that exposure to freshly fractured

crystalline silica may be more hazardous than exposure to aged silica particles, and that

the difference may be attributed to formation of reactive species on the surfaces of

fractured quartz particles. However, aging quartz under laboratory conditions has not

been shown to render the silica biologically inactive, and the difference in potency

between freshly fractured and aged quartz may be dose dependent. Although studies

have demonstrated that workers in jobs where they are likely to be exposed to freshly

fractured silica show similar cellular effects to those seen in experimental animals, there

are no studies that compare workers in those jobs to workers in jobs likely to have

exposure to predominately aged silica. OSHA believes that it is not possible to determine

from the available evidence at what point or under what conditions aged silica reduces in

biological activity such that lung cancer and silicosis risks would be substantially

diminished (e.g., by an order of magnitude or more).
348

Metal impurities can also modify the surface reactivity of silica (IARC, 1997).

Transition metal ions (typically iron), adsorbed at the surface, activate the production of

free radicals in aqueous suspensions. There have been a number of studies on the effect

of metal impurities on silica toxicity. For example, in a follow-up to the Vallyathan et al.

(1995) study cited above, the investigators altered the level of iron contamination of the

freshly-fractured silica (Castranova et al., 1997). Surface radicals on freshly fractured

silica are thought to generate hydroxyl radicals upon contact with water. Since iron

chelation reduces the number of hydroxyl radicals, it is thought that trace contamination

of silica with ferrous iron can enhance hydroxyl radical generation via a Fenton-like

reaction. The finding that the production of both hydroxyl radical and silica-induced

biological reaction decrease in a similar fashion with time after fracturing suggests that a

relationship exists between hydroxyl radical generation and toxicity. The investigators

hypothesized that trace contamination with iron would increase the pulmonary responses

to inhaled silica. The study found that silica with high iron contamination produced more

reactive species, significantly more damage to the alveolar air-blood barrier, more

inflammation, increased macrophage activity and a greater level of lipid peroxidation in

the lung tissues of experimental animals than did silica with low iron contamination. The

authors concluded that the results support the hypothesis that trace iron contamination

can augment the generation of oxidants by silica and enhance its inflammatory and

cytotoxic potency in the lung. They also suggested that trace contamination of silica with

iron may occur in occupational circumstances such as rock drilling and sandblasting,

leading to increased lung damage and inflammation in workers in these occupations.

Donaldson and Borm (1998) reviewed this and other studies on the effect of iron

or aluminum contamination associated with the quartz structure. They reported that, in

contrast to the findings above, other studies have shown that iron can also reduce the

toxicity of quartz. Metallic iron was found to diminish the ability of quartz to cause

inflammation in the lungs of rats following instillation. Donaldson and Borm (1998)

pointed out, however, that the state of iron may be important. Ferrous or ferric iron

contamination was involved in the Castranova et al. (1997) study above showing

increased toxicity as opposed to metallic iron. The quantity of iron may also be

important with trace amounts increasing toxicity and a large excess decreasing toxicity.

Aluminum was also shown to lower the toxicity of quartz in several studies. Cotreatment with aluminum attenuated the fibrogenic response to the inhalation of quartz in

rats and reduced inflammation in sheep lung quartz instillation and in rats. Donaldson

and Borm (1998) proposed that the biological effects of quartz (such as silicosis and

cancer) could be understood in terms of surface reactivity and noted that a range of

substances including minerals could modify the ability of quartz to generate free radicals

and cause oxidative stress. They proposed that the hazard posed by quartz is not a

constant entity, but one that may vary depending on the origin of the silica sample or its

contact with other chemicals or minerals.

One of the authors of studies reviewed by Donaldson and Borm (1998) has

recently published a further study of the state of the surface of quartz and its relationship

to biological activity in vitro and in vivo. Fubini et al. (2004) examined the surface

properties of four commercial quartz flours. Two of the samples had been shown in

previous studies to be inflammogenic in vivo and to activate macrophages in vitro. The
349

two active samples were also genotoxic in vivo. The other two samples, which were

mostly inert, contained a higher content of impurities, including aluminum, potassium,

carbon, and iron. The authors suggested that their results were consistent with a model in

which the difference in behavior of the four dusts are mainly caused by a different level

and dispersion of contaminants on the silica surface (mainly aluminum and potassium

and possibly also iron), which changed the silanol patches that correlate with cell

damage.

Another physical factor relevant to the toxicologic potency of silica is the

presence of a mineral coating, or “occlusion” of the silica surface that might affect the

biological availability of the quartz component of the dust to which workers are exposed.

This issue has been discussed by Wallace et al. (1996), who described research

suggesting that contaminants on the surface may diminish the biological availability of

toxic surface sites by gross occlusion of the silica surface, for example, by

aluminosilicate clay. However, previous research by this author demonstrated

comparable in vitro cytotoxicity for quartz and clay-occluded quartz. Thus, Wallace et

al. (1996) commented that comparisons of pathologic potential and silica exposure must

be made on the basis of worker population epidemiological data, for which surface

properties of dust exposures typically are not investigated, or on the basis of in vivo

animal model studies. An additional factor is the persistence of the contaminating

material under conditions of particle deposition and residence in the lung. Limited tests

on the durability of occluded silica particles upon a few hours incubation in surrogate

pulmonary surfactant demonstrated the existence of aluminosilicate coating on quartz

particles. Thus, in the opinion of the authors, relatively soluble clay occlusion would be

expected to persist at least until phagocytosis, but that longer-term persistence under

conditions of residence in interstitial tissue or the lymphatics was an open question. The

authors, therefore, called for additional research to detail the nature of such occluded

particle surfaces, the geological and processing factors which affect such occlusion, and

the durability of such particles in tissue. More recently, Fubini et al. (2004), have

commented that kaolin contamination, known to reduce quartz toxicity (citing the studies

of Wallace et al., 1996 discussed above), may leave aluminum ions at the abraded quartz

surface during grinding, which would inhibit the reactivity of silanols.

Although it is evident that a number of factors can act to mediate the toxicological

potency of crystalline silica, it is not clear how such considerations should be taken into

account to evaluate lung cancer and silicosis risks to exposed workers. After evaluating

many in vitro studies that had been conducted to investigate the surface characteristics of

crystalline silica particles and their influence on fibrogenic activity, NIOSH (2002)

concluded that further research is needed to associate specific surface characteristics that

can affect potency with specific occupational exposure situations and consequent health

risks to workers. According to NIOSH, such exposures may include work processes that

produce freshly fractured silica surfaces or that involve quartz contaminated with trace

elements such as iron. NIOSH called for further in vitro and in vivo studies of the

toxicity and pathogenicity of quartz compared with its polymorphs, quartz contaminated

with trace elements, and further research on the association of surface properties with

specific work practices and health effects.
350

In discussing the heterogeneity shown across the 10 studies used in the pooled

lung cancer risk analysis, Steenland et al. (2001a) pointed to hypotheses that physical

differences in silica exposure (e.g., freshness of particle cleavage) between cohorts may

be a partial explanation of observed differences in exposure-response coefficients derived

from those cohort studies. However, the authors did not have specific information on

whether or how these factors might have actually influenced the observed differences.

Similarly, in the pooled analysis and risk assessments for silicosis mortality conducted by

Mannetje et al. (2002b), differences in biological activity of different types of silica dust

could not be specifically taken into account. Mannetje et al. (2002b) determined that the

exposure-response relationship between silicosis and log-transformed cumulative

exposure to crystalline silica was comparable between studies and no significant

heterogeneity was found. The authors therefore concluded that their findings were

relevant for different circumstances of occupational exposure to crystalline silica.

Therefore, OSHA preliminarily concludes that it is not yet possible to use

available information on factors that mediate the potency of silica to refine available

quantitative estimates of the lung cancer and silicosis mortality risks, and that the

estimates from the pooled analyses are fairly representative of a wide range of

workplaces reflecting differences in silica polymorphism, surface properties, and

impurities.

II.H. Preliminary Conclusions.

Table II-12 summarizes all of OSHA’s risk estimates based on the studies

reviewed in this section and OSHA’s implementation of the various risk models.

OSHA’s preliminary conclusions are discussed below for lung cancer, silicosis mortality

(including non-malignant lung disease risks), renal disease mortality, and silicosis

morbidity.

Lung Cancer. Risk estimates were derived from the pooled risk analysis

conducted by Steenland et al. (2001a); from studies of diatomaceous earth workers (Rice

et al., 2001) and granite workers (Attfield and Costello, 2004), which were among the ten

cohorts included in the pooled analysis; and from studies of North American industrial

sand workers (Hughes et al., 2001) and British coal miners (Miller and MacCalman,

2009). Each of these studies shows a significant exposure-response relationship with

cumulative occupational exposure to silica, which strengthens the evidence for a causal

relationship between exposure to crystalline silica and lung cancer mortality.

For exposures in the range of the current general industry PEL and the proposed

PEL, estimates of lifetime lung cancer risks are reasonably consistent among the five data

sets and seven models employed. For 45 years of exposure to the current general

industry PEL of 0.100 mg/m3, OSHA estimates the risk to be between 13 and 60 deaths

per 1,000 workers; the risk is estimated to range from 6 to 26 deaths per 1,000 for 45

years of exposure to the proposed PEL of 0.05 mg/m3. Lung cancer risk is estimated to

range from 3 to 22 deaths per 1,000 at the proposed action level. In the range of the

current general industry PEL and proposed PEL, OSHA believes that the estimates from
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Table II-12. Summary of Lifetime or Cumulative Risk Estimates for Crystalline Silica

Risk Associated with 45 Years of Occupational Exposure

(per 1,000 Workers)

Health Endpoint (Source) Respirable Crystalline Silica Exposure Level (mg/m3)

0.025 0.05 0.100 0.250 0.500

Lung Cancer Mortality (Lifetime Risk)

Pooled Analysis, Toxichemica, Inc (2004)a,b

Diatomaceous Earth Worker study (Rice et al., 2001)a,c

U.S. Granite Worker study (Attfield and Costello, 2004)a,d

North American Industrial Sand Worker study (Hughes et al., 2001)a,e

British Coal Miner study (Miller and MacCalman, 2009)a,f

9-23

9

11

7

3

18-26

17

25

15

6

22-29

34

60

34

13

27-34

81

250

120

37

36-38

152

653

387

95

Silicosis and Non-Malignant Lung Disease Mortality (Lifetime Risk)

Pooled Analysis (Toxichemica, Inc., 2004) (silicosis)g

Diatomaceous Earth Worker study (Park et al., 2002) (NMRD)h

4

22

7

43

11

83

17

188

22

321

Renal Disease Mortality (Lifetime Risk)

Pooled Cohort study (Steenland et al., 2002a)i25 32 39 52 63
352

Silicosis Morbidity (Cumulative Risk)

Chest x-ray category of 2/1 or greater (Buchanan et al., 2003)j

Silicosis mortality and/or x-ray of 1/1 or greater (Steenland and Brown, 1995b)k

Chest x-ray category of 1/1 or greater (Hnizdo and Sluis-Cremer, 1993)l

Chest x-ray category of 1or greater (Chen et al., 2001)m

Chest x-ray category of 1or greater (Chen et al., 2005)n

Tin miners

Tungsten miners

Pottery workers

21

31

6

40

40

5

5

55

74

127

170

100

20

20

301

431

773

590

400

120

60

994

593

995

1,000

950

750

300

1,000

626

1,000

1,000

1,000

1,000

700

Footnotes to Table II-12

a Lifetime risks through age 85 calculated from a life table that accounts for competing causes of death (see Appendix). Background all-cause and lung cancer

mortality rates are 2006 rates for all males (National Center for Health Statistics, 2009). Background lung cancer mortality rate is based on ICD-10 categories C33-C34, malignant neoplasms of trachea, bronchus, lung. Exposure to crystalline silica is assumed to begin at age 20 through age 65.

b Range based on three models (see Table II-2).

c. Based on the linear relative risk model with exposures lagged 10 years, RR = 1 + (0.1441*E) where E is cumulative respirable crystalline silica exposure in

mg/m3-years.

d Based on the log-linear relative risk model with exposures lagged 15 years, RR = exp(0.19*E) where E is cumulative respirable crystalline silica exposure in

mg/m3-years.

e Based on the log-linear relative risk model with exposures lagged 15 years, RR = exp(0.13*E) where E is cumulative respirable crystalline silica exposure in

mg/m3-years.

f Based on the log-linear relative risk model with exposures lagged 15 years, RR = exp(0.0524*E) where E is cumulative respirable crystalline silica exposure in

mg/m3-years.

g Estimates derived from rate ratios based on the categorical model after accounting for exposure measurement uncertainty, from Table 7 of Toxichemica, Inc.

(2004). Absolute risk calculated as 1 – exp(-∑time*rate), where rate is the rate ratio for a given cumulative exposure times a base rate of 4.7E-5.

h Estimated by OSHA based on the Park et al. (2002) linear relative rate model, RR = 1 + (0.5469*E) where E is cumulative respirable crystalline silica exposure

in mg/m3-years. Lifetime risks through age 85 calculated from a life table that accounts for competing causes of death. Background all-cause and non-malignant

lung disease mortality rates are 2006 rates for all males (National Center for Health Statistics, 2009). Non-malignant lung disease mortality rates reflect those for

ICD-10 disease codes J40-J47 (chronic lower respiratory diseases) and J60-J66 (pneumoconioses and chemical effects). Exposure to crystalline silica is assumed

to begin at age 20 through age 65.

i Estimated by OSHA based on the Steenland et al. (2002a) log-linear model with log cumulative exposure, RR = exp(0.269(lnE)) where E is cumulative

respirable crystalline silica exposure in mg/m3-days. Lifetime risks through age 85 calculated from a life table that accounts for competing causes of death.

Background all-cause and end-stage renal disease (ESRD) are 1998 rates for all males (National Center for Health Statistics, 2005). Background ESRD mortality

rates reflect those for ICD-9 disease codes 580-589. Exposure to crystalline silica is assumed to begin at age 20 through age 65 with 250 days per year of

exposure.
353

j Estimated by OSHA from the equation Prob(2/1+) = 1/ (1+exp-(-4.83 + 0.443*cum. quartz<2.0 mg/m3

)), where quartz is cumulative respirable silica exposure in

ghm-1, with one year of work = 2000 hours (250 days per year x 8 hours per day). Exposure to crystalline silica is assumed to begin at age 20 through age 65.

Age of cohort at follow-up was between 50 and 74 years.

k Lifetime risks through age 85 calculated from a life table that accounts for competing causes of death (see Appendix). Background all-cause and lung cancer

mortality rates are 2006 rates for all males (National Center for Health Statistics, 2009). Silicosis rate is age- and calendar-time-adjusted, from Table 2 of

Steenland et al. (2002). Exposure to crystalline silica is assumed to begin at age 20 through age 65, with no exposure lag.

l Estimated by OSHA from the equation CR = 1 – {1/[1 + exp(2.439/.2199)*CDE1/.2199]}, CR is cumulative risk and CDE is cumulative respirable dust exposure

in mg/m3-years; assumed quartz content of respirable dust is 30 percent. Assumed 45 years of exposure. Mean age of cohort at onset was 55.9 years (range 38-

74)

m Estimated by OSHA from the equation CR = 1-exp(-0.0076*E)2.23 where E is cumulative exposure to total dust. Respirable crystalline silica reported by Chen

et al. (2001) to be 3.6 percent of total dust. Assumed 45 years of exposure. Mean age at onset was 48.3 years.

n Estimated from Figure 2B in Chen et al. (2005) showing cumulative risk vs. cumulative exposure to respirable crystalline silica. Mean age at onset was 47.9,

41.8, and 52.5 years for tin, tungsten, and pottery workers, respectively.
354

the five data sets and model approaches are in very close agreement, which adds a degree

of confidence in the risk estimates.

OSHA did not rely on the spline model originally used by Steenland et al. (2001a)

in the pooled analysis because this model was not monotonic in the exposure range of

between 0.05 and 0.25 mg/m3; from this spline model, risk estimates remain between 15

and 17 deaths per 1,000 workers in this exposure range and do not increase consistently

with increasing exposure over this range. The lack of a monotonic response from this

spline model in this region of exposure is inconsistent with the findings from the four

single-cohort studies used for quantitative assessment of lung cancer risk (Attfield, 2004;

Rice et al., 2001; Hughes et al., 2001; Miller and MacCalman, 2009), each of which

found a strong linear lung cancer response in this region of exposure. Of the two model

forms employed originally by Steenland et al. (2001a), OSHA believes that the log-linear

model based on log cumulative exposure is the more plausible because it remains

monotonic from the origin and thus reflects that risk consistently increases with

increasing exposure. Other linear models fit the pooled data set as consistently; these

were a 2-piece spline model with untransformed cumulative exposure, and a linear

relative risk model with log-transformed cumulative exposure (Steenland, personal

communication, 2010).

Estimates of risk associated with higher exposures in the range of OSHA’s current

construction PEL are more uncertain. Estimates based on the four single-cohort studies

are 37 to 250 deaths per 1,000 for exposure to 0.25 mg/m3over 45 years, and 95 to 653

deaths per 1,000 at 0.5 mg/m3. However, estimates based on the model from the pooled

analysis (which relied on a log transform of cumulative exposure) yielded lower

estimates, (27-34 deaths per 1,000 at 0.25 mg/m3and 36-38 deaths per 1,000 at 0.5

mg/m3). The use of the log-transformed exposure metric in the pooled study, which

reflects an exposure-response model that rises more quickly at low exposures and

subsequently flattens out at high exposures, was employed to reduce significant

heterogeneity between the 10 worker cohorts that was evident with a model based on

untransformed cumulative exposure. It is not known whether the heterogeneity between

these cohorts reflected real differences between the studies in the cancer responses at

high exposures, perhaps reflecting differences in the toxicity of crystalline silica in

different workplace settings, or other issues common to occupational studies that may

have differentially affected the cohorts, such as a survivor effect in some of the cohorts,

competing silica-related mortality at high exposures, or exposure misclassification.

A categorical analysis performed by Steenland and Bartell (Steenland, personal

communication, 2010) and further modeling with linear models shows that the lung

cancer risk attenuates at higher exposures (i.e., at a cumulative exposure above that

permitted by OSHA’s general industry PEL). This is in contrast to the individual cohort

studies, which, with the exception of the high-exposure group in the granite cohort

(Attfield and Costello, 2004), do not suggest an attenuation of the exposure-response

curve at higher exposures. In the granite cohort, the lung cancer mortality rate among

workers exposed to 6 mg/m3-years or more was less than either of the preceding exposure

groups; in contrast, the lung cancer mortality rate was highest among diatomaceous earth

workers exposed to about 13 mg/m3-years or more, and no decline was seen in either the
355

industrial sand or coal worker cohorts at cumulative exposures of similar magnitude. It is

not known whether the decline in cancer risk seen among highly exposed granite workers

was the result of a survivor effect, exposure misclassification, or a substantial increase in

mortality from competing causes. OSHA believes that the risk estimates based on the

Steenland et al. (2001a) pooled cohort study reflect credible central tendency estimates of

risk across a range of industrial settings, but these estimates of risk may understate the

risk at higher cumulative exposures in at least some industry sectors, based on the

analyses derived from the single cohort studies.

Steenland and Bartell (Toxichemica, Inc., 2004) conducted an analysis of the

impact on risk estimates of uncertainties in the underlying exposure estimates developed

for each of the 10 cohorts in the pooled analysis. A Monte Carlo simulation that explored

the potential effects of uncertainties in the assignment of mean job-specific exposures and

in the estimation of respirable silica mass from particle count exposure measurements

resulted in pooled exposure-response coefficients that were, on average, only slightly

smaller than that from the original analysis with essentially no increase in the variance of

the estimate. The individual exposure-response coefficients for the diatomaceous earth

and U.S. granite cohorts were also reasonably stable with respect to unbiased uncertainty

in the exposure estimates. Assuming a biased uncertainty in each of the individual

cohorts also had little effect on the pooled exposure-response coefficient. Therefore,

OSHA believes that uncertainties in the underlying exposure estimates are not likely to

substantially affect its estimates of lung cancer risk.

Silicosis Mortality. There are two published quantitative risk assessments of

silicosis mortality; an analysis by Mannetje et al. (2002b) of pooled cohort data from six

epidemiological studies (from the ten cohorts that were part of the IARC multi-centric

exposure-response study of lung cancer, discussed above), and an exposure-response

analysis of diatomaceous earth workers (Park et al., 2002). Also, an additional

uncertainty analysis was conducted on the Mannetje et al. (2002b) data by Dr. Steenland

for Toxichemica, Inc. (Toxichemica, Inc., 2004).

Mannetje et al. (2002b) found that the best fit was provided by the log of

cumulative exposure. No significant heterogeneity was found between studies. A cubic

spline model did not fit better than the linear relative risk model with the log of

cumulative exposure. Mannetje et al. estimated the lifetime risk of death from silicosis

(to age 65), assuming 45 years of exposure to 0.1 mg/m3to be 13 deaths per 1,000

workers; at an exposure of 0.05 mg/m3, the estimated lifetime risk was 6 per 1,000. The

Toxichemica, Inc. (2004) uncertainty analysis yielded modified silicosis rate ratios based

on using a case-control design rather than the original categorical analysis performed by

Mannetje et al. (2002b). The corresponding estimated risks to age 65 (as used by

Mannetje et al.) were 7 (95% CI 2-23) and 4 (95% CI 2-12) per 1,000. The confidence

intervals of the risk estimates using the log cumulative exposure model lie within those

using the categorical model. According to Toxichemica, Inc., the decrease in estimated

risk from the original Mannetje et al. results is partly due to the incorporation of

measurement error and partly due to the use of a nested case-control analysis here versus

the Poisson regression originally performed by Mannetje et al. Based on these modified

rate ratios, OSHA estimates risks to age 85 to be 11 and 7 deaths per 1,000 for exposure
356

to the current PEL of 0.10 mg/m3or the proposed PEL of 0.05 mg/m3, respectively. For

exposure at the proposed action level, OSHA estimates the silicosis mortality risk to be 4

deaths per 1,000. For exposure in the range of the current construction PEL, the range in

estimated risk is from 17 to 22 deaths per 1,000.

Park et al. (2002) analyzed the California diatomaceous earth cohort data to

quantify the relationship between exposure to cristobalite and mortality from chronic

lung disease other than cancer (LDOC); diseases in this category included

pneumoconiosis, chronic bronchitis, and emphysema. Based on its superior fit to the

cohort data, Park et al. (2002) selected the linear relative rate model with external

adjustment and use of cumulative exposure as the exposure metric as the basis for

estimating LDOC mortality risks. Based on their model, OSHA estimates the excess

lifetime risk associated with a 45-year exposure to the proposed PEL of 0.05 mg/m3

respirable crystalline silica dust to be 43 per 1,000 (95% CI 17-150) and, for exposure to

the current general industry PEL of 0.1 mg/m3, 83 per 1,000. The estimated risk at the

proposed action level is 22 deaths per 1,000. At the higher exposure levels of 0.25 and

0.50 mg/m3, OSHA estimates the risk to be 188 and 321 deaths per 1000, respectively.

These estimates are considerably higher than those calculated for the pooled analysis of

Mannetje et al. (2002b), but are based on 67 deaths from LDOC. The Mannetje et al.

analysis included only 15 deaths from this cohort where the cause of death was coded as

silicosis or other pneumoconiosis.

Based on the available risk assessments for silicosis mortality, OSHA believes

that the estimates from the pooled study represent credible central tendency estimates of

mortality risk from silicosis across a range of industrial settings, but are likely to

understate the actual risk due to silicosis being misclassified as a cause of death. OSHA

believes that the risk estimates derived from the Park et al. (2002) study reasonably

reflects the total respiratory disease mortality risk due to exposure to respirable

crystalline silica since LDOC, as defined by this study, would capture much of this

misclassification and include risks from other lung diseases (emphysema, chronic

bronchitis) that have been associated with exposure to crystalline silica.

Renal Disease Mortality. OSHA is basing its estimates of renal disease mortality

on a case-control study performed by Steenland et al. (2002a) on the combined cohorts

from a U.S. gold miner study (Steenland and Brown, 1995a), a U.S. industrial sand study

(Steenland et al., 2001b), and a Vermont granite worker study (Costello and Graham,

1998). This is a large combined cohort (13,382) where exposure and job history data

were available for about 95 percent of the study subjects. The job-exposure matrices had

been used previously in studies showing positive exposure-response trends for silicosis

mortality and morbidity, thus lending credibility to the underlying exposure assessments.

A statistically significant excess mortality from renal disease was seen in the combined

cohort, and the case-control analysis showed statistically significant exposure-response

trends for both multiple-cause mortality (with either cumulative exposure or log of

cumulative exposure) and for underlying cause mortality (with log cumulative exposure

only). Based on the log-linear model with log cumulative exposure derived from the

underlying cause analysis, OSHA estimates that exposure for 45 years to the current

general industry and construction/shipyard PELs results in an excess risk of 39 and 52-63
357

deaths per 1,000 workers, respectively. Exposure to the proposed PEL of 0.05 mg/m3

results in an excess estimated risk of 32 deaths per 1,000. At the proposed action level,

the excess risk is estimated to be 25 deaths per 1,000. Although these estimates are based

on only 50 renal disease deaths in the pooled cohort, and are therefore less robust than

risk estimates for the other health effects discussed in this assessment, OSHA believes

that the risk estimates for renal disease are credible given the large size of the pooled

cohort study and quality of underlying exposure and job history information.

Silicosis Morbidity. OSHA has reviewed the principal studies available that have

characterized the risk to exposed workers of acquiring lung fibrosis as evidenced by the

appearance of opacities on chest radiographs. Several of these studies did not include

follow up of workers who had left employment, and some were of a cross-sectional

design that cannot provide information on disease onset or permit evaluation of disease

incidence. More useful in estimating long-term risks are those retrospective cohort

studies that included a large proportion of retired workers in the cohort and that were able

to evaluate disease status over time. OSHA identified six such studies (Chen et al., 2001;

Chen et al., 2005; Hnizdo and Sluis-Cremer, 1993; Miller et al., 1998; Buchanan et al.,

2003; Steenland and Brown, 1995b), which analyzed data from six mining cohorts

exposed to freshly cut (fractured) quartz and one pottery cohort exposed to quartz

particles for which a significant fraction of the surface was occluded by alumino-silicates.

For freshly cut crystalline silica, the range of risk associated with 45 years of exposure to

the current general industry PEL of 0.1 mg/m3is estimated to be between 120 and 773

cases per 1,000. For a 45-year exposure to the proposed PEL of 0.05 mg/m3, the range in

estimated risk is from 20 to 170 cases per 1,000 workers. At exposures at the current

construction/shipyard PEL, (0.25-0.5 mg/m3) for 45 years, the risk of acquiring an

abnormal chest x-ray approaches unity.

As is the case with the lung cancer and silicosis mortality studies, one of the

principal sources of uncertainty in the silicosis morbidity studies is the estimation of

respirable silica exposures of the cohorts. Two of the studies (Hnizdo and Sluis-Cremer,

1993; Steenland and Brown, 1995b) relied on particle count data, requiring use of a

conversion factor to estimate exposures to dust mass. The Chen et al. studies (2001,

2005) were based on gravimetric total dust sampling and use of side-by-side respirable

dust sampling to estimate historical exposures to respirable crystalline silica. Only the

studies by Miller et al. (1998) and Buchanan et al. (2003) was able to rely exclusively on

respirable dust sampling and quartz analysis performed over the entire period of

significant quartz exposure; as such, OSHA believes that risk estimates derived from that

study are the least susceptible to uncertainties in the underlying exposure assessment.

From that study, OSHA estimated the risk of silicosis (defined as ILO 2/1 or greater or

the presence of large opacities) to be 301 and 55 cases per 1,000 workers exposed to 0.1

or 0.05 mg/m3, respectively.

Another source of potential uncertainty lies in the use of chest roentgenograms to

ascertain cases. OSHA believes that the uncertainty associated with the subjective

reading of chest films by trained health professionals was likely to be mitigated by each

of the studies having relied on panels of at least three readers (except for Steenland and

Brown, 1995b) and by the use of a common reference system (i.e., the ILO system) for
358

classifying x-ray findings. Although the Chen et al. studies (2001, 2005) did not use the

ILO system, they presented data indicating that their use of the Chinese classification

system was comparable to the use of the ILO. Furthermore, the work of Hnizdo et al.

(1993) shows that reading of chest films is more likely to result in missing silicosis cases

(defined by autopsy findings) than in falsely identifying cases, due to the relative

insensitivity of chest roentgenograms, indicating that risk estimates based on reading of

chest films would likely understate the true risk.

Despite these uncertainties, the risk findings from these studies appear to be

reasonably consistent. Studies that did not have significant post-employment follow-up

resulted in lower risk estimates than did the studies that included a substantial proportion

of retired workers. In fact, the population of the study reporting the highest risk estimate

(Kreiss and Zhen, 1996) consisted exclusively of workers whose last exposure occurred

10 years or more prior to the study and who were first exposed at least 20 years before

their health status was assessed. The finding that estimated risks are higher when retired

workers are included in the study cohort is consistent with what one would expect given

the chronic nature of silicosis, and provides greater credibility in the resulting risk

estimates.

OSHA believes that risk estimates based on the Miller et al. (1993) and Buchanan

et al. (2003) study are the most reliable overall because of the availability of high-quality

exposure data, post-exposure follow up, and extensive analysis. In addition, the

Buchanan et al. study accounted for the effects of exposure to very high concentrations of

respirable quartz (i.e., > 2 mg/m3). However, these may understate the risk of developing

early signs of silicosis (i.e., corresponding to ILO x-ray film classifications of 1/0 and

1/1). The study of British coal miners by Miller et al. (1998) suggests that the risk of

disease onset in this population could be three times as high as suggested by the risk

estimates derived from the Buchanan et al. (2003) study. Thus, risk estimates that reflect

onset as well as progression of disease lies in the range of risks derived from the four

studies that included as cases those workers whose chest radiographs were categorized as

consistent with ILO major category 1.

These risk estimates reflect those associated with exposure to quartz-containing

material that has been freshly cut (fractured). One study of pottery workers (Chen et al.,

2005) suggests that the presence of significant surface occlusion by alumino-silicates

may be partly responsible for the observed decrease in silicosis morbidity risk; this is

supported by animal studies that have shown reduced fibrogenic activity of clay-coated

quartz particles. Risk estimates based on the pottery cohort are 60 and 20 cases per 1,000

workers exposed for 45 years to 0.1 and 0.05 mg/m3, respectively, which is substantially

below most of the risk estimates derived from the mining studies. Other studies have also

found silicosis risks among clay workers to be lower than is often seen in other industry

settings (Love et al., 1999; Hessel, 2006; Miller and Soutar, 2007). However, OSHA

believes that additional study is needed to more fully characterize the effect of

workplace-specific factors that affect the surface properties of crystalline silica and their

effect on silicosis risks.
359

OSHA has estimated silicosis morbidity risks associated with 45 years of

exposure to the proposed action level of 0.025 mg/m3; these estimates range from 5 to 40

cases per 1,000 workers. OSHA regards these estimates as more uncertain than those

derived for the proposed and current PELs as a result of considering available evidence

concerning a threshold for lung inflammation. Kuempel et al. (2001) employed a ratbased toxicokinetic/toxicodynamic model with extrapolation to humans using a human

lung deposition/clearance model to estimate a minimum lung burden necessary to cause

the precursor events that can lead to adverse physiological effects in the lung. These

adverse physiological effects can then lead to lung fibrosis and an indirect genotoxic

cause of lung cancer. They estimated that the threshold effect level of lung burden

associated with this inflammation (Mcrit) is the equivalent of exposure to 0.036 mg/m3for

45 years; thus, exposures below this level would presumably not lead to an excess lung

cancer risk (based on an indirect genotoxic mechanism) nor to silicosis, at least in the

“average individual.“ This might suggest that exposures to a concentration of silica at the

proposed action level would not be associated with an excess silicosis, and possible

cancer, risk. However, OSHA does not believe that the analysis by Kuemple et al. is

definitive with respect to a threshold for silica-related disease. First, since the critical

quartz burden is a mean value derived from the model, the authors estimated that a 45-

year exposure to a concentration as low as 0.005 mg/m3, or 5 times below the proposed

action level, would result in a lung quartz burden that was equal to the 95-percent lower

confidence limit on Mcrit. Therefore, the existence of a threshold lung burden that is

below that resulting from exposure to the proposed action level cannot be ruled due to

statistical uncertainty in the estimate of critical lung burden. In addition, with respect to

silica-related lung cancer, if at least some of the risk is from a direct genotoxic

mechanism (see section II.F), then this threshold value is not relevant. Although OSHA

acknowledges that a threshold exposure level might lie within the range of the proposed

action level, and thus add uncertainty to the estimated risks associated with exposure to

the action level, available information cannot firmly establish a threshold exposure for

silica-related effects.
360

APPENDIX A

Life Tables Used for Assessments of Lung Cancer,

Non-Malignant Respiratory Disease, and Renal Disease

Mortality Risks
361

Appendix A-1

Health endpoint: Lung cancer mortality

Data source: Steenland et al. (2001) Pooled Cohort Analysis

Model: Log-linear relative risk

Dose metric: Log-transformed cumulative exposure, 15-yr lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of cond prob duration cum exp exposed prob of exposed

prob of surviving of lung through at end of exposed exposed all prob of surviving cond prob

interval all cause lung cancer all-cause surviving up to lung cancer cancer end of interval lung cancer cause surviving up to of lung

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-d) hazard rate hazard rate interval interval cancer

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 1 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 1 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 1 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 1 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 1 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0 0.0074 0.9926 0.9850 0.00000 0.00000 0 1 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.2 0.0072 0.9929 0.9778 0.00001 0.00001 0 1 0.0000 0.0072 0.9929 0.9778 0.0000

8 30-34 150.4 0.6 0.0075 0.9925 0.9708 0.00003 0.00003 0 1 0.0000 0.0075 0.9925 0.9708 0.0000

9 35-39 189 2 0.0095 0.9906 0.9635 0.00010 0.00010 5 126 0.0001 0.0095 0.9906 0.9635 0.0001

10 40-44 285.9 7.3 0.0143 0.9858 0.9545 0.00037 0.00035 10 251 0.0005 0.0144 0.9857 0.9544 0.0005

11 45-49 435.3 21.6 0.0218 0.9785 0.9409 0.00108 0.00101 15 376 0.0015 0.0222 0.9780 0.9407 0.0014

12 50-54 659.7 47.5 0.0330 0.9676 0.9207 0.00238 0.00215 20 501 0.0034 0.0341 0.9665 0.9201 0.0031

13 55-59 920 88.3 0.0460 0.9550 0.8908 0.00442 0.00384 25 626 0.0065 0.0481 0.9531 0.8893 0.0056

14 60-64 1373.6 167.8 0.0687 0.9336 0.8507 0.00839 0.00690 30 751 0.0125 0.0728 0.9298 0.8475 0.0102

15 65-69 2040.2 272.4 0.1020 0.9030 0.7943 0.01362 0.01028 35 876 0.0205 0.1088 0.8969 0.7880 0.0153

16 70-74 3117.5 378.8 0.1559 0.8557 0.7172 0.01894 0.01258 40 1001 0.0287 0.1656 0.8474 0.7068 0.0187

17 75-79 4944.6 486 0.2472 0.7810 0.6137 0.02430 0.01321 45 1126 0.0370 0.2600 0.7711 0.5989 0.0195

18 80-84 7942.7 544.1 0.3971 0.6722 0.4793 0.02721 0.01076 45 1126 0.0415 0.4114 0.6627 0.4618 0.0157

sum = Ro = 0.0612 sum = Rx = 0.0902

Rx - Ro 0.0290
362

Appendix A-1 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: lung and bronchus cancer (invasive) mortality rate (x 105/year) (2006 NCHS data, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: lung cancer hazard rate for interval I (h) (= lung cancer mortality rate X number of years in interval)

column I: conditional probability of dying from lung cancer in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from lung cancer, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (includes 15-year lag beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m 3) X 250 days/yr exposed X xtime)

column L: lung cancer hazard rate in exposed (hx) (= h X exp(β X ln(xdose+1))), where

[β is the regression coefficient for the pooled analysis from Steenland et al. (2001), after correcting the

original data set (β = 0.06, se = 0.015 from Table 1 of Toxichemica, 2004)

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx 1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from lung cancer in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from lung cancer for exposed workers, = sum of conditional probabilities

across all intervals
363

Appendix A-2

Health endpoint: Lung cancer mortality

Data source: Steenland et al. (2001) Pooled Cohort Analysis

Model: Linear relative risk

Dose metric: Log-transformed cumulative exposure, 15-yr lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of cond prob duration cum exp exposed prob of exposed

prob of surviving of lung through at end of exposed exposed all prob of surviving cond prob

interval all cause lung cancer all-cause surviving up to lung cancer cancer end of interval lung cancer cause surviving up to of lung

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-d) hazard rate hazard rate interval interval cancer

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 1 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 1 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 1 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 1 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 1 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0 0.0074 0.9926 0.9850 0.00000 0.00000 0 1 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.2 0.0072 0.9929 0.9778 0.00001 0.00001 0 1 0.0000 0.0072 0.9929 0.9778 0.0000

8 30-34 150.4 0.6 0.0075 0.9925 0.9708 0.00003 0.00003 0 1 0.0000 0.0075 0.9925 0.9708 0.0000

9 35-39 189 2 0.0095 0.9906 0.9635 0.00010 0.00010 5 126 0.0001 0.0095 0.9906 0.9635 0.0001

10 40-44 285.9 7.3 0.0143 0.9858 0.9545 0.00037 0.00035 10 251 0.0005 0.0144 0.9857 0.9544 0.0005

11 45-49 435.3 21.6 0.0218 0.9785 0.9409 0.00108 0.00101 15 376 0.0016 0.0222 0.9780 0.9407 0.0015

12 50-54 659.7 47.5 0.0330 0.9676 0.9207 0.00238 0.00215 20 501 0.0035 0.0341 0.9665 0.9200 0.0031

13 55-59 920 88.3 0.0460 0.9550 0.8908 0.00442 0.00384 25 626 0.0065 0.0481 0.9530 0.8892 0.0057

14 60-64 1373.6 167.8 0.0687 0.9336 0.8507 0.00839 0.00690 30 751 0.0126 0.0728 0.9297 0.8474 0.0103

15 65-69 2040.2 272.4 0.1020 0.9030 0.7943 0.01362 0.01028 35 876 0.0205 0.1089 0.8968 0.7879 0.0153

16 70-74 3117.5 378.8 0.1559 0.8557 0.7172 0.01894 0.01258 40 1001 0.0287 0.1657 0.8473 0.7066 0.0187

17 75-79 4944.6 486 0.2472 0.7810 0.6137 0.02430 0.01321 45 1126 0.0371 0.2600 0.7710 0.5987 0.0196

18 80-84 7942.7 544.1 0.3971 0.6722 0.4793 0.02721 0.01076 45 1126 0.0415 0.4115 0.6627 0.4616 0.0157

sum = Ro = 0.0612 sum = Rx = 0.0905

Rx - Ro 0.0293
364

Appendix A-2 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: lung and bronchus cancer (invasive) mortality rate (x 105/year) (2006 NCHS data, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: lung cancer hazard rate for interval I (h) (= lung cancer mortality rate X number of years in interval)

column I: conditional probability of dying from lung cancer in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from lung cancer, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (includes 15-year lag beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m3) X 250 days/yr exposed X xtime)

column L: lung cancer hazard rate in exposed (hx) (= h X (1+(β X ln(xdose+1))), where

[β is the regression coefficient for the pooled analysis from Steenland (personal communication, 2010)

(β = 0.07495, se = 0.02412)

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from lung cancer in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from lung cancer for exposed workers, = sum of conditional probabilities

across all intervals
365

Appendix A-3

Health endpoint: Lung cancer mortality

Data source: Steenland et al. (2001) Pooled Cohort Analysis

Model: 2-piece linear spline

Dose metric: Cumulative exposure, 15-yr lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of cond prob duration cum exp exposed prob of exposed

prob of surviving of lung through at end of exposed exposed all prob of surviving cond prob

interval all cause lung cancer all-cause surviving up to lung cancer cancer end of interval lung cancer cause surviving up to of lung

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-yr) hazard rate hazard rate interval interval cancer

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 0 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 0 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 0 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 0 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 0 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0 0.0074 0.9926 0.9850 0.00000 0.00000 0 0 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.2 0.0072 0.9929 0.9778 0.00001 0.00001 0 0 0.0000 0.0072 0.9929 0.9778 0.0000

8 30-34 150.4 0.6 0.0075 0.9925 0.9708 0.00003 0.00003 0 0 0.0000 0.0075 0.9925 0.9708 0.0000

9 35-39 189 2 0.0095 0.9906 0.9635 0.00010 0.00010 5 0.5 0.0001 0.0095 0.9906 0.9635 0.0001

10 40-44 285.9 7.3 0.0143 0.9858 0.9545 0.00037 0.00035 10 1 0.0004 0.0144 0.9857 0.9545 0.0004

11 45-49 435.3 21.6 0.0218 0.9785 0.9409 0.00108 0.00101 15 1.5 0.0013 0.0220 0.9782 0.9409 0.0013

12 50-54 659.7 47.5 0.0330 0.9676 0.9207 0.00238 0.00215 20 2 0.0032 0.0338 0.9668 0.9203 0.0029

13 55-59 920 88.3 0.0460 0.9550 0.8908 0.00442 0.00384 25 2.5 0.0060 0.0476 0.9535 0.8898 0.0052

14 60-64 1373.6 167.8 0.0687 0.9336 0.8507 0.00839 0.00690 30 3 0.0115 0.0718 0.9307 0.8484 0.0094

15 65-69 2040.2 272.4 0.1020 0.9030 0.7943 0.01362 0.01028 35 3.5 0.0188 0.1072 0.8983 0.7896 0.0141

16 70-74 3117.5 378.8 0.1559 0.8557 0.7172 0.01894 0.01258 40 4 0.0263 0.1633 0.8494 0.7093 0.0172

17 75-79 4944.6 486 0.2472 0.7810 0.6137 0.02430 0.01321 45 4.5 0.0340 0.2569 0.7735 0.6025 0.0180

18 80-84 7942.7 544.1 0.3971 0.6722 0.4793 0.02721 0.01076 45 4.5 0.0380 0.4080 0.6650 0.4660 0.0145

sum = Ro = 0.0612 sum = Rx = 0.0832

Rx - Ro 0.0220
366

Appendix A-3 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: lung and bronchus cancer (invasive) mortality rate (x 10 5/year) (2006 NCHS data, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: lung cancer hazard rate for interval I (h) (= lung cancer mortality rate X number of years in interval)

column I: conditional probability of dying from lung cancer in interval I (= (h/h*) X S( i) X (1-q(i))

[Ro, the background lifetime probability of dying from lung cancer, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (includes 15-year lag beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m 3) X xtime)

column L: lung cancer hazard rate in exposed (hx) (= h X (1+(β1 X xdose)), for xdose < 2.19 mg/m3-yrs) or

(= h X [1+(β1 X 2.19) + ((β1 + β2)*(xdose - 2.19))] for xdose >= 2.19)

β1 = .13498, se = .065335

β2 = -0.149285, se = .0657

from Steenland, personal communication, March 17, 2010

column M: all-cause hazard rate in exposed workers for interval i (h*x i) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (q x) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx 1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from lung cancer in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from lung cancer for exposed workers, = sum of conditional probabilities

across all intervals
367

Appendix A-4

Health endpoint: Lung cancer mortality

Data source: Rice et al. (2001)

Model: Linear relative risk

Dose metric: Cumulative exposure, 10-yr lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of cond prob duration cum exp exposed prob of exposed

prob of surviving of lung through at end of exposed exposed all prob of surviving cond prob

interval all cause lung cancer all-cause surviving up to lung cancer cancer end of interval lung cancer cause surviving up to of lung

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-yr) hazard rate hazard rate interval interval cancer

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 0 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 0 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 0 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 0 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 0 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0 0.0074 0.9926 0.9850 0.00000 0.00000 0 0 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.2 0.0072 0.9929 0.9778 0.00001 0.00001 0 0 0.0000 0.0072 0.9929 0.9778 0.0000

8 30-34 150.4 0.6 0.0075 0.9925 0.9708 0.00003 0.00003 5 0.5 0.0000 0.0075 0.9925 0.9708 0.0000

9 35-39 189 2 0.0095 0.9906 0.9635 0.00010 0.00010 10 1 0.0001 0.0095 0.9906 0.9635 0.0001

10 40-44 285.9 7.3 0.0143 0.9858 0.9545 0.00037 0.00035 15 1.5 0.0004 0.0144 0.9857 0.9544 0.0004

11 45-49 435.3 21.6 0.0218 0.9785 0.9409 0.00108 0.00101 20 2 0.0014 0.0221 0.9782 0.9408 0.0013

12 50-54 659.7 47.5 0.0330 0.9676 0.9207 0.00238 0.00215 25 2.5 0.0032 0.0338 0.9667 0.9203 0.0029

13 55-59 920 88.3 0.0460 0.9550 0.8908 0.00442 0.00384 30 3 0.0063 0.0479 0.9532 0.8897 0.0055

14 60-64 1373.6 167.8 0.0687 0.9336 0.8507 0.00839 0.00690 35 3.5 0.0126 0.0729 0.9297 0.8480 0.0103

15 65-69 2040.2 272.4 0.1020 0.9030 0.7943 0.01362 0.01028 40 4 0.0215 0.1099 0.8960 0.7884 0.0160

16 70-74 3117.5 378.8 0.1559 0.8557 0.7172 0.01894 0.01258 45 4.5 0.0312 0.1682 0.8452 0.7064 0.0203

17 75-79 4944.6 486 0.2472 0.7810 0.6137 0.02430 0.01321 45 4.5 0.0401 0.2630 0.7688 0.5971 0.0210

18 80-84 7942.7 544.1 0.3971 0.6722 0.4793 0.02721 0.01076 45 4.5 0.0448 0.4148 0.6605 0.4590 0.0168

sum = Ro = 0.0612 sum = Rx = 0.0948

Rx - Ro 0.0336
368

Appendix A-4 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: lung and bronchus cancer (invasive) mortality rate (x 105/year) (2006 NCHS data, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: lung cancer hazard rate for interval I (h) (= lung cancer mortality rate X number of years in interval)

column I: conditional probability of dying from lung cancer in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from lung cancer, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (includes 10-year lag beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m3) X xtime)

column L: lung cancer hazard rate in exposed (hx) (= h X (1+(β X xdose)), β = .1441

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from lung cancer in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from lung cancer for exposed workers, = sum of conditional probabilities

across all intervals
369

Appendix A-5

Health endpoint: Lung cancer mortality

Data source: Attfield and Costello (2004)

Model: Log-linear relative risk

Dose metric: Cumulative exposure, 15-yr lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of cond prob duration cum exp exposed prob of exposed

prob of surviving of lung through at end of exposed exposed all prob of surviving cond prob

interval all cause lung cancer all-cause surviving up to lung cancer cancer end of interval lung cancer cause surviving up to of lung

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-yr) hazard rate hazard rate interval interval cancer

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 0 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 0 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 0 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 0 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 0 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0 0.0074 0.9926 0.9850 0.00000 0.00000 0 0 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.2 0.0072 0.9929 0.9778 0.00001 0.00001 0 0 0.0000 0.0072 0.9929 0.9778 0.0000

8 30-34 150.4 0.6 0.0075 0.9925 0.9708 0.00003 0.00003 0 0 0.0000 0.0075 0.9925 0.9708 0.0000

9 35-39 189 2 0.0095 0.9906 0.9635 0.00010 0.00010 5 0.5 0.0001 0.0095 0.9906 0.9635 0.0001

10 40-44 285.9 7.3 0.0143 0.9858 0.9545 0.00037 0.00035 10 1 0.0004 0.0144 0.9857 0.9545 0.0004

11 45-49 435.3 21.6 0.0218 0.9785 0.9409 0.00108 0.00101 15 1.5 0.0014 0.0221 0.9781 0.9408 0.0013

12 50-54 659.7 47.5 0.0330 0.9676 0.9207 0.00238 0.00215 20 2 0.0035 0.0341 0.9665 0.9202 0.0031

13 55-59 920 88.3 0.0460 0.9550 0.8908 0.00442 0.00384 25 2.5 0.0071 0.0487 0.9525 0.8894 0.0062

14 60-64 1373.6 167.8 0.0687 0.9336 0.8507 0.00839 0.00690 30 3 0.0148 0.0751 0.9276 0.8471 0.0121

15 65-69 2040.2 272.4 0.1020 0.9030 0.7943 0.01362 0.01028 35 3.5 0.0265 0.1149 0.8915 0.7858 0.0197

16 70-74 3117.5 378.8 0.1559 0.8557 0.7172 0.01894 0.01258 40 4 0.0405 0.1774 0.8374 0.7006 0.0260

17 75-79 4944.6 486 0.2472 0.7810 0.6137 0.02430 0.01321 45 4.5 0.0571 0.2801 0.7557 0.5867 0.0292

18 80-84 7942.7 544.1 0.3971 0.6722 0.4793 0.02721 0.01076 45 4.5 0.0640 0.4339 0.6480 0.4434 0.0230

sum = Ro = 0.0612 sum = Rx = 0.1212

Rx - Ro 0.0600
370

Appendix A-5 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: lung and bronchus cancer (invasive) mortality rate (x 105/year) (2006 NCHS data, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: lung cancer hazard rate for interval I (h) (= lung cancer mortality rate X number of years in interval)

column I: conditional probability of dying from lung cancer in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from lung cancer, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (includes 15-year lag beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m3) X xtime)

column L: lung cancer hazard rate in exposed (hx) (= h X exp(β X xdose)), β = .19

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from lung cancer in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from lung cancer for exposed workers, = sum of conditional probabilities

across all intervals
371

Appendix A-6

Health endpoint: Lung cancer mortality

Data source: Hughes et al. (2001)

Model: Log-linear relative risk

Dose metric: Cumulative exposure, 15-yr lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of cond prob duration cum exp exposed prob of exposed

prob of surviving of lung through at end of exposed exposed all prob of surviving cond prob

interval all cause lung cancer all-cause surviving up to lung cancer cancer end of interval lung cancer cause surviving up to of lung

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-yr) hazard rate hazard rate interval interval cancer

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 0 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 0 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 0 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 0 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 0 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0 0.0074 0.9926 0.9850 0.00000 0.00000 0 0 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.2 0.0072 0.9929 0.9778 0.00001 0.00001 0 0 0.0000 0.0072 0.9929 0.9778 0.0000

8 30-34 150.4 0.6 0.0075 0.9925 0.9708 0.00003 0.00003 0 0 0.0000 0.0075 0.9925 0.9708 0.0000

9 35-39 189 2 0.0095 0.9906 0.9635 0.00010 0.00010 5 0.5 0.0001 0.0095 0.9906 0.9635 0.0001

10 40-44 285.9 7.3 0.0143 0.9858 0.9545 0.00037 0.00035 10 1 0.0004 0.0143 0.9858 0.9545 0.0004

11 45-49 435.3 21.6 0.0218 0.9785 0.9409 0.00108 0.00101 15 1.5 0.0013 0.0220 0.9782 0.9409 0.0012

12 50-54 659.7 47.5 0.0330 0.9676 0.9207 0.00238 0.00215 20 2 0.0031 0.0337 0.9669 0.9204 0.0028

13 55-59 920 88.3 0.0460 0.9550 0.8908 0.00442 0.00384 25 2.5 0.0061 0.0477 0.9534 0.8899 0.0053

14 60-64 1373.6 167.8 0.0687 0.9336 0.8507 0.00839 0.00690 30 3 0.0124 0.0727 0.9299 0.8485 0.0101

15 65-69 2040.2 272.4 0.1020 0.9030 0.7943 0.01362 0.01028 35 3.5 0.0215 0.1099 0.8960 0.7890 0.0160

16 70-74 3117.5 378.8 0.1559 0.8557 0.7172 0.01894 0.01258 40 4 0.0319 0.1688 0.8447 0.7069 0.0207

17 75-79 4944.6 486 0.2472 0.7810 0.6137 0.02430 0.01321 40 4 0.0409 0.2638 0.7681 0.5971 0.0215

18 80-84 7942.7 544.1 0.3971 0.6722 0.4793 0.02721 0.01076 40 4 0.0458 0.4157 0.6599 0.4586 0.0172

sum = Ro = 0.0612 sum = Rx = 0.0954

Rx - Ro 0.0342
372

Appendix A-6 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: lung and bronchus cancer (invasive) mortality rate (x 105/year) (2006 NCHS data, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: lung cancer hazard rate for interval I (h) (= lung cancer mortality rate X number of years in interval)

column I: conditional probability of dying from lung cancer in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from lung cancer, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (includes 15-year lag beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m 3) X xtime)

column L: lung cancer hazard rate in exposed (hx) (= h X exp(β X xdose))

β = .13, se = 0.074

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx 1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from lung cancer in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from lung cancer for exposed workers, = sum of conditional probabilities

across all intervals
373

Appendix A-7

Health endpoint: Lung cancer mortality

Data source: Miller and MacCalman (2009)

Model: Log-linear relative risk

Dose metric: Cumulative exposure, 15-yr lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of cond prob duration cum exp exposed prob of exposed

prob of surviving of lung through at end of exposed exposed all prob of surviving cond prob

interval all cause lung cancer all-cause surviving up to lung cancer cancer end of interval lung cancer cause surviving up to of lung

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-yr) hazard rate hazard rate interval interval cancer

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 0 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 0 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 0 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 0 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 0 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0 0.0074 0.9926 0.9850 0.00000 0.00000 0 0 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.2 0.0072 0.9929 0.9778 0.00001 0.00001 0 0 0.0000 0.0072 0.9929 0.9778 0.0000

8 30-34 150.4 0.6 0.0075 0.9925 0.9708 0.00003 0.00003 0 0 0.0000 0.0075 0.9925 0.9708 0.0000

9 35-39 189 2 0.0095 0.9906 0.9635 0.00010 0.00010 5 0.5 0.0001 0.0095 0.9906 0.9635 0.0001

10 40-44 285.9 7.3 0.0143 0.9858 0.9545 0.00037 0.00035 10 1 0.0004 0.0143 0.9858 0.9545 0.0004

11 45-49 435.3 21.6 0.0218 0.9785 0.9409 0.00108 0.00101 15 1.5 0.0012 0.0219 0.9784 0.9409 0.0011

12 50-54 659.7 47.5 0.0330 0.9676 0.9207 0.00238 0.00215 20 2 0.0026 0.0332 0.9673 0.9206 0.0024

13 55-59 920 88.3 0.0460 0.9550 0.8908 0.00442 0.00384 25 2.5 0.0050 0.0466 0.9545 0.8905 0.0044

14 60-64 1373.6 167.8 0.0687 0.9336 0.8507 0.00839 0.00690 30 3 0.0098 0.0701 0.9323 0.8499 0.0081

15 65-69 2040.2 272.4 0.1020 0.9030 0.7943 0.01362 0.01028 35 3.5 0.0164 0.1048 0.9005 0.7923 0.0123

16 70-74 3117.5 378.8 0.1559 0.8557 0.7172 0.01894 0.01258 40 4 0.0234 0.1603 0.8519 0.7135 0.0154

17 75-79 4944.6 486 0.2472 0.7810 0.6137 0.02430 0.01321 45 4.5 0.0308 0.2537 0.7759 0.6079 0.0165

18 80-84 7942.7 544.1 0.3971 0.6722 0.4793 0.02721 0.01076 45 4.5 0.0344 0.4044 0.6674 0.4717 0.0134

sum = Ro = 0.0612 sum = Rx = 0.0740

Rx - Ro 0.0128
374

Appendix A-7 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: lung and bronchus cancer (invasive) mortality rate (x 105/year) (2006 NCHS data, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: lung cancer hazard rate for interval I (h) (= lung cancer mortality rate X number of years in interval)

column I: conditional probability of dying from lung cancer in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from lung cancer, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (includes 15-year lag beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m 3) X xtime)

column L: lung cancer hazard rate in exposed (hx) (= h X exp(β X xdose))

β = .0524, se = 0.0188

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx 1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from lung cancer in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from lung cancer for exposed workers, = sum of conditional probabilities

across all intervals
375

Appendix A-8

Health endpoint: Non-malignant respiratory disease (NMRD) mortality

Data source: Park et al. (2002)

Model: Linear relative risk

Dose metric: Cumulative exposure, no lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of duration cum exp exposed prob of

prob of surviving cond prob through at end of exposed exposed all prob of surviving exposed

interval all cause NMRD all-cause surviving up to NMRD of NMRD end of interval NMRD cause surviving up to cond prob

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-yr) hazard rate hazard rate interval interval of NMRD

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0.9 0.0076 0.9925 1.0000 0.00001 0.00001 0 0 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0.3 0.0012 0.9988 0.9925 0.00001 0.00001 0 0 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0.3 0.0008 0.9992 0.9913 0.00002 0.00001 0 0 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0.4 0.0010 0.9990 0.9905 0.00002 0.00002 0 0 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0.4 0.0045 0.9955 0.9895 0.00002 0.00002 0 0 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 148 0.5 0.0074 0.9926 0.9850 0.00003 0.00002 5 0.5 0.0000 0.0074 0.9926 0.9850 0.0000

7 25-29 143.4 0.6 0.0072 0.9929 0.9778 0.00003 0.00003 10 1 0.0000 0.0072 0.9928 0.9778 0.0000

8 30-34 150.4 0.7 0.0075 0.9925 0.9708 0.00004 0.00003 15 1.5 0.0001 0.0075 0.9925 0.9708 0.0001

9 35-39 189 1 0.0095 0.9906 0.9635 0.00005 0.00005 20 2 0.0001 0.0095 0.9905 0.9635 0.0001

10 40-44 285.9 2.6 0.0143 0.9858 0.9545 0.00013 0.00012 25 2.5 0.0003 0.0145 0.9856 0.9544 0.0003

11 45-49 435.3 5.5 0.0218 0.9785 0.9409 0.00028 0.00026 30 3 0.0007 0.0222 0.9780 0.9406 0.0007

12 50-54 659.7 13.4 0.0330 0.9676 0.9207 0.00067 0.00061 35 3.5 0.0020 0.0343 0.9663 0.9200 0.0018

13 55-59 920 27.6 0.0460 0.9550 0.8908 0.00138 0.00120 40 4 0.0044 0.0490 0.9522 0.8890 0.0038

14 60-64 1373.6 62.4 0.0687 0.9336 0.8507 0.00312 0.00257 45 4.5 0.0108 0.0764 0.9265 0.8465 0.0088

15 65-69 2040.2 121 0.1020 0.9030 0.7943 0.00605 0.00457 45 4.5 0.0209 0.1169 0.8897 0.7842 0.0155

16 70-74 3117.5 221.1 0.1559 0.8557 0.7172 0.01106 0.00734 45 4.5 0.0383 0.1831 0.8327 0.6977 0.0244

17 75-79 4944.6 369.8 0.2472 0.7810 0.6137 0.01849 0.01005 45 4.5 0.0640 0.2927 0.7462 0.5810 0.0322

18 80-84 7942.7 551.5 0.3971 0.6722 0.4793 0.02758 0.01091 45 4.5 0.0954 0.4650 0.6281 0.4335 0.0331

sum = Ro = 0.0378 sum = Rx = 0.1209

Rx - Ro 0.0830
376

Appendix A-8 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (2006 data from NCHS, total males)

column D: NMRD mortality rate (x 105/year) (2006 NCHS data for ICD J40-J47 (chronic lower respiratory disease) and J60-J66 (pneumoconioses), total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: NMRD hazard rate for interval I (h) (= NMRD mortality rate X number of years in interval)

column I: conditional probability of dying from NMRD in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from NMRD, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m3) X xtime)

column L: NMRD hazard rate in exposed (hx) (= h X (1+(β X xdose)), β = .5469)

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from NMRD in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from NMRD for exposed workers, = sum of conditional probabilities

across all intervals
377

Appendix A-9

Health endpoint: End-stage renal disease (ESRD) mortality

Data source: Steenland et al. (2002)

Model: Log-linear relative risk

Dose metric: Log cumulative exposure, no lag

Exposure level: 0.1 mg/m3

A B C D E F G H I J K L M N O P

exposure exposed

prob of duration cum exp exposed prob of

prob of surviving cond prob through at end of exposed exposed all prob of surviving exposed

interval all cause ESRD all-cause surviving up to ESRD of ESRD end of interval ESRD cause surviving up to cond prob

number age mortality mortality hazard interval i interval i hazard rate mortality in interval (mg/m3

-d) hazard rate hazard rate interval interval of ESRD

(i) interval (x 105

/year) (x 105/year) rate (h*) (qi

) (Si) (h) interval (xtime) (xdose) (hx) (h*x) (qx) (Sx) in interval

1 <1 756.3 0 0.0076 0.9925 1.0000 0.00000 0.00000 0 1 0.0000 0.0076 0.9925 1.0000 0.0000

2 1-4 30.5 0 0.0012 0.9988 0.9925 0.00000 0.00000 0 1 0.0000 0.0012 0.9988 0.9925 0.0000

3 5-9 15.4 0 0.0008 0.9992 0.9913 0.00000 0.00000 0 1 0.0000 0.0008 0.9992 0.9913 0.0000

4 10-14 19.6 0 0.0010 0.9990 0.9905 0.00000 0.00000 0 1 0.0000 0.0010 0.9990 0.9905 0.0000

5 15-19 90.7 0 0.0045 0.9955 0.9895 0.00000 0.00000 0 1 0.0000 0.0045 0.9955 0.9895 0.0000

6 20-24 142.3 0 0.0071 0.9929 0.9850 0.00000 0.00000 5 126 0.0000 0.0071 0.9929 0.9850 0.0000

7 25-29 139.4 0.3 0.0070 0.9931 0.9781 0.00002 0.00001 10 251 0.0001 0.0070 0.9930 0.9781 0.0001

8 30-34 163.1 0.5 0.0082 0.9919 0.9713 0.00003 0.00002 15 376 0.0001 0.0083 0.9918 0.9712 0.0001

9 35-39 213.5 0.9 0.0107 0.9894 0.9634 0.00005 0.00004 20 501 0.0002 0.0109 0.9892 0.9632 0.0002

10 40-44 305.3 1.6 0.0153 0.9849 0.9531 0.00008 0.00008 25 626 0.0005 0.0156 0.9845 0.9528 0.0004

11 45-49 450.8 3 0.0225 0.9777 0.9387 0.00015 0.00014 30 751 0.0009 0.0233 0.9770 0.9380 0.0008

12 50-54 654.1 3.9 0.0327 0.9678 0.9178 0.00020 0.00018 35 876 0.0012 0.0337 0.9668 0.9165 0.0011

13 55-59 1022.4 6.9 0.0511 0.9502 0.8883 0.00035 0.00030 40 1001 0.0022 0.0530 0.9484 0.8861 0.0019

14 60-64 1634 11.8 0.0817 0.9215 0.8440 0.00059 0.00048 45 1126 0.0039 0.0850 0.9185 0.8403 0.0031

15 65-69 2508.6 21 0.1254 0.8821 0.7778 0.00105 0.00077 45 1126 0.0070 0.1313 0.8769 0.7718 0.0050

16 70-74 3867 41 0.1934 0.8242 0.6861 0.00205 0.00128 45 1126 0.0136 0.2049 0.8148 0.6769 0.0083

17 75-79 5719.7 70 0.2860 0.7513 0.5655 0.00350 0.00172 45 1126 0.0232 0.3057 0.7366 0.5515 0.0110

18 80-84 9226.6 137.3 0.4613 0.6304 0.4248 0.00687 0.00234 45 1126 0.0454 0.4999 0.6066 0.4062 0.0145

sum = Ro = 0.0074 sum = Rx = 0.0467

Rx - Ro 0.0393
378

Appendix A-9 (Continued)

column A: interval index number (i)

column B: 5-year age intervals up to age 85

column C: all-cause mortality rate (x 105/year) (1998 data from NCHS, total males)

column D: ESRD mortality rate (x 105/year) (1998 NCHS data for ICD 580-589, total males)

column E: all-cause hazard rate (h*) (= all-cause mortality rate X number of years in age interval)

column F: probability of surviving interval (q) (= exp(-h*))

column G: probability of surviving up to interval (Si) (S(1)=1; S(i)=S(i-1) X q(i-1))

column H: ESRD hazard rate for interval I (h) (= ESRD mortality rate X number of years in interval)

column I: conditional probability of dying from ESRD in interval I (= (h/h*) X S(i) X (1-q(i))

[Ro, the background lifetime probability of dying from ESRD, = sum of conditional probabilities across all intervals]

column J: exposure duration at end of interval (beginning at age 20 thru age 65) (xtime)

column K: cumulative exposure (xdose) at end of interval (= exposure level (mg/m 3) X 250 d/yr exposed X xtime)

column L: ESRD hazard rate in exposed (hx) (= h X exp(β X ln(xdose+1)))

β = 0.269, se = 0.120 (Steenland, personal communication, 2010)

column M: all-cause hazard rate in exposed workers for interval i (h*xi) (= h*i + (hxi- hi))

column N: probability of surviving interval I for exposed workers (qx) (= exp(-h*xi))

column O: probability of surviving up to interval for exposed (Sx) (Sx 1=1; Sxi=Sxi-1 X qxi-1)

column P: conditional probability of dying from ESRD in interval I for exposed workers

(= (hxi/h*xi) X Sxi X (1-qxi))

[Rx, the lifetime probability of dying from ESRD for exposed workers, = sum of conditional probabilities

across all intervals
379

III. Response to Peer Review Comments.

In 2009, Eastern Research Group, Inc. (ERG), under contract to the Occupational Safety

and Health Administration (OSHA)3, conducted an independent, scientific peer review of two

draft documents prepared by OSHA; these were a draft Health Effects Literature Review for

Crystalline Silica, and a Preliminary Quantitative Risk Assessment for Crystalline Silica. This

section of the background document describes the review process and summarizes peer

reviewers’ comments and OSHA’s responses.

Based on input from OSHA regarding the areas of expertise required for the review, ERG

conducted a search for nationally recognized experts in occupational epidemiology, biostatistics

and risk assessment, animal and cellular toxicology, and occupational medicine who had no

conflict of interest (COI) or apparent bias in performing the review. Interested candidates

submitted evidence of their qualifications and responded to detailed COI questions. ERG also

searched the Internet to determine whether qualified candidates had made public statements or

declared a particular bias regarding silica regulation.

From the pool of qualified candidates, ERG selected seven to conduct the review, based

on:

 Their qualifications, including their degrees, years of relevant experience, number of

related peer-reviewed publications, experience serving as a peer reviewer for OSHA or

other government organizations, and committee and association memberships related to

the review topic;

 Lack of bias and lack of any actual, potential, or perceived conflict of interest; and

 The need to ensure that the panel collectively was sufficiently broad and diverse to fairly

represent the relevant scientific and technical perspectives and fields of knowledge

appropriate to the review.

OSHA reviewed the qualifications of the candidates proposed by ERG to verify that they

met the technical selection criteria. Upon receiving OSHA confirmation of the selected

reviewers, ERG contracted with the following reviewers to perform the review. Six experts

reviewed both documents; Dr. Crump reviewed only the quantitative risk assessment:

3 Task Order No. 059622303/099P28863, Contract No. GS10F0125P, with a period of performance from May 22,

2009 to May 22, 2010.
380

Reviewers were provided with the charge, review documents, and access to relevant references

and given six weeks to conduct the review.

Early in the review schedule, ERG organized and facilitated a briefing call to ensure that

reviewers understood the peer review process. OSHA representatives were available on the call

to respond to technical questions of clarification. Reviewers were invited to submit any

subsequent questions of clarification to ERG via email.

ERG checked reviewers’ written comments to ensure that each reviewer had clearly

responded to all charge questions and then submitted the individual reviewer comments,

unedited, to OSHA. ERG also organized the comments by charge questions for both documents

and submitted this version to OSHA and the reviewers in preparation for a follow-up conference

call.

The conference call, organized and facilitated by ERG, provided an opportunity for

OSHA to clarify individual reviewer’s comments. After the call, ERG directed reviewers to

revise their written comments to include the clarifications or additional information provided on

the call. ERG submitted the revised comments to OSHA, organized by charge question, and

prepared a final peer review report that is available in Docket OSHA-2010-0034. In Section

Reviewer Affiliation

Reviewed

Health

Effects

Section

Reviewed

Quantitative

Risk

Assessment

Bruce Allen Bruce Allen Consulting  

Kenneth Crump Louisiana Tech University

Foundation



Murray Finkelstein McMaster University,

Ontario

 

Gary Ginsberg Connecticut Department of

Public Health

 

Brian Miller IOM Consulting Ltd.,

Scotland

 

Andrew Salmon Private Consultant  

Noah Seixas University of Washington,

Seattle

 
381

III.A, OSHA summarizes the comments received on the draft health effects literature review and

the Agency’s responses to those comments. Section III.B presents comments received on the

draft Preliminary Quantitative Risk Assessment.

III.A. Peer Review of the Health Effects Literature Review.

In general, OSHA asked the peer reviewers to consider the strengths, weaknesses,

interpretations, and inclusion of studies the Agency used to support OSHA’s preliminary

findings. Overall, the reviewers expressed that OSHA had been very thorough in the Agency’s

review of the literature and appropriately addressed all known health endpoints. The reviewers

also agreed that OSHA was reasonable in its interpretation of the studies with regards to the

various endpoints examined, and that its conclusions were generally well founded. A number of

reviewers suggested improvements to facilitate use of the document, and OSHA revised the

document as appropriate, in particular, adding a table in the lung cancer section to summarize

information from the epidemiological studies that were reviewed and revising subheadings to

better delineate sections of the document and make it easier to find summary conclusions.

Some reviewers also found that the draft lacked sufficient explanation of how OSHA

selected studies for the literature review, or why OSHA selected certain studies but not others for

inclusion in the quantitative risk assessment. OSHA agrees with these comments that its

selection criteria for the literature review and risk assessment were not always clear and has

revised the document throughout to better reflect the Agency’s critical evaluation of the

literature. In particular, the section on lung cancer (Section I.C.1) describes OSHA’s approach

for identifying studies and evaluating their quality, and a description of the overall approach is

included in Section V of the preamble to the proposed rule (Summary of the Health Effects).

Several reviewers indicated the need for a more developed introduction to the draft that

addressed clear definitions, concepts and terminology used throughout the health effects section.

OSHA agreed with these recommendations and expanded the Introduction in Section I.A that

explains terminology related to crystalline silica, the measurement of dust exposures, and

OSHA’s current and proposed exposure limits for respirable crystalline silica. The revised

section also introduces concepts concerning characterization of long-term exposure (e.g., use of

cumulative exposure measures). OSHA also included in the introduction a more extensive

review of the analytical techniques used over the years to evaluate silica exposure. Dr. Seixas,

Dr. Miller and Dr. Salmon thought that a more thorough description of current and past

methodologies employed to measure worker exposures to dust and to crystalline silica was

necessary since this understanding is critical to properly evaluate epidemiological studies that

have relied on exposure data obtained from the use of different sampling and analytical methods

over time. The significance of early efforts to characterize worker exposures to dust on our

understanding of chronic respiratory disease was underscored by Dr. Salmon:

It is not that the gravimetric measure [of dust exposure] is intrinsically technically

superior, but rather that the availability of particle counts and size- or surface-area measurements

as well as gravimetric analysis made an important contribution to the eventual conclusion that 1)
382

long-term cumulative exposure was the chief determinant of chronic silicosis and 2) the

gravimetric measure is the appropriate dose metric related to health effects.

OSHA agreed with these comments and included a more detailed description of the

various methodologies employed in these studies and those currently in use.

Dr. Seixas commented that OSHA should explain the choice of a proposed exposure limit

based on measurement of respirable crystalline silica in air rather than the formula-based limit

currently enforced. OSHA has not included this discussion in its health effects review, but does

explain the reasons for its choice of a proposed PEL in the preamble to the proposed rule

(Section X., Summary and Explanation for paragraph (c)).

In Section B of the draft document, OSHA presented a discussion of silicosis that focused

on summarizing available data from disease surveillance programs and addressed certain issues

that are of particular interest to the Agency; these issues included the reliability and sensitivity of

chest radiographs for diagnosing silicosis, the relationship between radiological changes

indicative of silicosis and pulmonary function, and factors that influence progression of the

disease. Dr. Salmon commented that the overall perspective of the section would be improved if

it included a description of the key studies used in the risk assessment for evaluating quantitative

relationships between exposure to respirable crystalline silica and silicosis (these studies were

instead described in detail in the draft quantitative risk assessment). OSHA has retained the

detailed description of these studies in the risk assessment discussion, but OSHA agrees that the

silicosis discussion would benefit from a demonstration that an exposure-response relationship

exists for silicosis and added a summary of the findings from the key studies in Section I.B.

Dr. Salmon also commented that OSHA’s exclusive use in the draft of U.S. silicosis

mortality and morbidity statistics supported “an assumption of a relationship between silicosis

and exposure to silica”, but nevertheless provided a “limited perspective” due to their “individual

and clinical, rather than statistical” nature and because such data reflect “substantial underreporting” of disease. He went on to comment that:

For a start, [the draft discussion]...is largely confined to United States data which

itself ignores the international dimension of the problem, and may produce other

weaknesses resulting from the peculiarities of the United States health care

system. In general, apart from special projects following pre-defined cohorts,

United States data are significantly lacking compared to other countries

(especially Scandinavia and the [European Union]...where population-wide

health care systems exist.

OSHA agrees that the lack of a national disease surveillance system and resulting underreporting of silicosis deaths and cases in the U.S. limits the utility of the data for exploring

further relationships between exposure and disease. However, OSHA’s intent on presenting this

information was to characterize the extent of the problem in the U.S., recognizing that the

prevalence of silicosis mortality and morbidity is under-reported. Silicosis is unusual in that it is

one of only a handful of occupational diseases for which there are any surveillance data outside
383

of the Bureau of Labor Statistics injury and illness reporting system. Despite this underreporting, OSHA believes that the available statistics indicate that silicosis is still a significant

occupational health problem in this country.

Dr. Salmon also suggested that OSHA include a recently published article describing

pneumoconiosis among Californian agricultural workers exposed to crystalline silica-containing

dusts (Schenker et al., 2009). This study reported finding histological evidence of mixed-dust

pneumoconiosis among deceased agricultural workers. OSHA is also aware of a recent article

(Swanepoel et al., 2010) that reported finding exposures to respirable crystalline silica exceeding

0.1 mg/m3among South African farmworkers. This survey and other literature describing

exposures to respirable quartz dust among farmworkers, Swanepoel et al. (2010) concluded that

there is convincing evidence of a respirable quartz risk to workers on sandy farms; however, they

also reported that there was “scant evidence” of associated disease in the literature, possibly due

to a healthy worker effect, underreporting of disease, low cumulative exposures of farmworkers,

or that the potency of silica particles in farm soil may be low. OSHA further discusses the issue

of silica exposure in the agricultural industry in the preamble to the proposed rule dealing with

scope issues (Section X, Summary and Explanation).

In reviewing the available surveillance data on silicosis mortality, Dr. Seixas commented

on the implications of the significant decline in mortality seen since the late 1960’s:

Lessons learned from these data systems, along with their limitations, were well

discussed. However, one comes away with an important question. Given the

rapid and consistent reduction in mortality, and the continuing exposure levels

over the current PEL, one must ask if the remaining disease observed is not

completely due to illegal (i.e., > PEL) exposures, rather than the inadequacy of

the current standard. I think some discussion of this, in particular the limitations

in assessing non-silicosis outcomes (e.g., COPD and [lung cancer]...) in relation

to silica exposures, is warranted....Given the limitations of the various

surveillance data sources (both exposure and outcomes), it should be pointed out

that the best information about the disease comes from well constructed

epidemiological studies where the cohort can be adequately defined, exposure can

be sufficiently quantified, and outcomes can be thoroughly ascertained.

OSHA believes that Dr. Seixas makes a strong point with respect to making inferences

from surveillance data, and OSHA has echoed this in its discussion. NIOSH (CDC, 2005) cited

two main reasons for the observed decline: (1) many of the early deaths were likely the result of

high exposures experienced before national standards were established in 1971, and (2) declining

employment in heavy industries where silica exposures were prevalent would be reflected in

declining numbers and rates of silica-related mortality. It is not possible from the available data

to attribute the remaining risk solely to non-compliance with current exposure limits, nor to draw

any conclusions about the adequacy of current exposure limits. As Dr. Seixas indicates, such

evaluations are best made from well-conducted epidemiological investigations and analyses of

exposure-response relationships as part of a formal risk assessment.
384

Dr. Salmon and Dr. Seixas believed the discussion on radiographic tools (x-rays,

computerized tomography (CT) and high-resolution CT (HRCT) (Section 1.B.1.b) was

appropriate, particularly for pointing out the relative insensitivity of radiography in detecting

silicosis. Other reviewers suggested various changes be made in the discussion, including

updating the literature on the efficacy of CT and HRCT. OSHA amended this section as

appropriate and added more recent studies by Sun et al. (2008), Lopes et al. (2008), and Blum et

al. (2008) on the use of HRCT for detecting early silicosis. Dr. Seixas pointed out that the

discussion contained no conclusions that could be used for recommending silicosis screening or

surveillance systems. OSHA has included such a discussion in the preamble to the proposed rule

to support its proposed medical surveillance requirements (Section XVI, Summary and

Explanation for paragraph (h)).

Reviewers generally thought OSHA’s discussion of pulmonary function as it relates to

radiological signs of silicosis (Section I.B.3) was reasonable and defensible. Dr. Miller

suggested that OSHA emphasize how inter-individual variability in lung function measurements

can complicate interpretation of cross-sectional studies and OSHA has added language to that

effect.

Dr. Ginsberg commented that the discussions in the draft on the insensitivity of radiology

to detect early silicosis and on the relationships between radiographic findings and pulmonary

function declines were reasonable, but that OSHA failed to provide any perspective on how these

findings influenced the Agency in the interpretation of epidemiological studies or quantitative

assessment of health risks. He stated that:

Does this [information] affect OSHA’s case definition of silicosis (e.g., only if

there is associated functional decline)? Does it affect the way OSHA interprets

the epidemiology? Does OSHA have a degree of silicosis it is trying to

prevent....The decision affects how the epidemiology is interpreted and risk

assessment conducted. For example, if the dose-response is from a study whose

sensitivity was for mild to moderate silicosis, OSHA may not want to weigh that

study as heavily as one with a more sensitive case definition.

OSHA believes that Dr. Ginsberg raises issues that the Agency typically addresses as part

of its analysis of the significance of risk, a discussion of which is presented in section VII of the

preamble to the proposed rule. To promulgate standards dealing with hazardous substances such

as crystalline silica, OSHA must make findings that workers are exposed to a significant risk of

material impairment of health or loss of functional capacity. OSHA’s goal in the health effects

analysis and quantitative risk assessment is to provide the information necessary for OSHA to

then evaluate at what point a demonstrated health effect or endpoint constitutes material

impairment of health, for example, whether an x-ray described as ILO category 1/0 constitutes

material impairment in the affected worker. OSHA’s approach in its health effects review and

risk assessment was to develop the information and analysis necessary to then permit the Agency

to combine the scientific findings with the legal and policy considerations that must be dealt with

in order to make its material impairment and significant risk findings, which ultimately justify

the regulatory decisions made. In the case of silicosis, OSHA’s purpose was to characterize the
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morbidity risk to the extent that the available information permitted, and to review information

that would best inform the Agency on the issues of material impairment, in particular of the

health implications of radiographic findings of silicosis.

In the review of lung cancer studies, OSHA concluded in the draft that studies of cohorts

in four industry sectors (diatomaceous earth, U.S. granite, North American industrial sand, and

British pottery workers) among the more than 20 such cohorts examined provided the strongest

evidence for a causal relationship between exposure to respirable crystalline silica and lung

cancer mortality. These studies were selected primarily on the strength and quality of underlying

exposure data available for these studies, and because investigators adequately adjusted for or

otherwise addressed the influence of smoking and co-exposure to potential confounders.

Reviewers generally agreed with OSHA’s conclusion, but made several remarks. Mr. Allen

questioned why OSHA excluded two studies where exposures were low; these were the U.K.

industrial sand study by Brown and Rushton (2005a, 2005b) and the Ulm et al. (1999) study of

German stone, quarry, and ceramic workers. Mr. Allen commented that “...inclusion of studies

with low exposures as part of a dose-response analysis is very useful precisely because such

studies help constrain and define the low-dose...shapes that can be considered consistent with

the data....” OSHA agrees that such studies can be particularly useful. However, neither of

these studies demonstrated an exposure-related effect with respect to lung cancer mortality, and

OSHA believed that the lack of an observed effect was largely due to the low exposures

experienced by the cohorts and lack of power that these studies had to detect risks associated

with these low exposures. The Brown and Rushton study (2005a, 2005b) was of 2,703 industrial

sand workers exposed to a geometric mean of 0.09 mg/m3respirable quartz. However,

cumulative exposures of the cohort were very low. Over half of the 764 cohort deaths had less

than 10 years of service and the mean cumulative exposure of the cohort was 0.31 mg/m3-years,

less than one-tenth that permitted by the current OSHA quartz PEL for a 45-year working life.

Other reasons were provided by OSHA in the draft, and OSHA also cited remarks by Steenland

(2005a) who also noted an unusual distribution of lung cancer deaths among relatively shortterm workers as being a reason to discount the study. With respect to the Ulm et al. (1999) casecontrol study, cases and controls with silicosis were eliminated from the study (thus eliminating

higher-exposed workers) and controls had known exposure to silica, which would further reduce

the power of the study. OSHA noted that the authors themselves acknowledged that the low

exposures may have reduced the power of the study to detect small risks. In addition, OSHA

cited possible misclassification of exposure as another reason for discounting the study. OSHA

believes that its reasons for discounting these two studies are clear, but agrees with Mr. Allen

that it might not have been clear how these reasons related to the selection criteria laid out in the

draft. OSHA believes that inclusion of the summary table in Section I.C and its description of

how it evaluated the lung cancer studies clarifies the basis upon which OSHA determined which

studies provide the strongest evidence for evaluating the carcinogenicity of crystalline silica.

Dr. Finkelstein agreed with OSHA that it is appropriate to weight most highly those

studies with the least confounding, but that there was little mention made of exposure

misclassification as a cause for heterogeneity (i.e., conflicting observations among studies with

respect to finding exposure-related effects or differences in observed exposure-response

relationships). In particular, he described the exposure data underlying the studies of Vermont
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granite sheds as being “sparse and [requiring] much interpolation of uncertain data.” Despite the

uncertainties that result from using such studies in risk assessment, he commented that:

Nevertheless, I believe that it is important to make the best use of whatever data

are available. I thus support pooling of data from individual studies [such as was

done in the 10-cohort pooled study by Steenland et al. (2001a)]. I recognize that

the pooling of poor quality data will tend to obscure any relations between

exposure and response. Should an exposure-response relationship emerge from

these analyses, despite the weaknesses, then I believe that this supports the

existence of a real association between exposure and disease.

Quality of underlying exposure estimates used in the epidemiological studies reviewed by

OSHA was a factor in selecting what the Agency believes to be the most reliable studies on

which to base its preliminary conclusions, and OSHA has clarified this in Section I.C.

Dr. Miller also agreed that OSHA properly identified the strongest studies available at the

time of the review, but identified a recent lung cancer study of British coal miners, which found

an increase in lung cancer mortality related to exposure to respirable quartz dust (Miller et al.,

2007; Miller and MacCalman, 2009). OSHA has included a review of these studies in the health

effects document (Section I.C.2.k) and in the preliminary quantitative risk assessment (Section

II).

Dr. Salmon also agreed that the studies identified by OSHA as being of the best quality

reflected studies having adequate power and reasonable exposure and health outcome

determinations. However, he believed that omission of the South African gold mining studies

was a “mistake” despite OSHA’s draft containing favorable comments on the later studies of

Hnizdo and Sluis-Cremer (1991) and Hnizdo et al. (1997). He further stated that

While there are some questions about the exposure measurements used and

possible confounding by radon exposure it appear[s] that most of these have been

addressed by related studies. This group of miners has been an important source

of data on silica effects over the years and historically these studies have

contributed greatly to the worldwide concern about, and understanding of, silica

exposures and health effects. The fact that a modern epidemiological study finds

a positive association with lung cancer in this group is an important and

persuasive part of the whole jigsaw puzzle. In the last analysis, however, the

most persuasive part of the argument is not any of one of the single study reports,

but the meta-analysis by Steenland et al. (2001a).

OSHA believes that its health effects literature review places appropriate emphasis on the

importance of the South African gold mining studies, and agrees that the findings by Hnizdo and

Sluis-Cremer (1991) and Hnizdo et al. (1997) add significantly to the body of evidence that

crystalline silica is a human carcinogen. OSHA also believes that the organization of its draft

summary discussion of the lung cancer evidence may have suggested that OSHA’s preliminary

finding of a causal relationship was based solely on the group of studies identified as those with
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the least potential for confounding. This was not OSHA’s intent and the present discussion (and

the Summary of Health Effects in Section V of the preamble) has been reorganized to make

clearer that OSHA is relying on the entire body of evidence, including that from the South

African mining studies, in making its preliminary conclusions.

Reviewers generally agreed with OSHA’s preliminary conclusions that evidence for a

relationship between exposure to respirable crystalline silica and cancers at sites other than the

lung is too limited and contradictory to address further in the risk assessment.

Section D of the review presented a discussion of studies that have investigated the risk

of chronic obstructive pulmonary disease (COPD) as it relates to crystalline silica exposure.

Reviewers thought that OSHA should define the relevant health endpoints up front, and the

revised document includes definitions for COPD, chronic bronchitis, and emphysema.

Dr. Ginsberg believed that the section made several important points with respect to

crystalline silica increasing the risk of COPD independent of silicosis, but thought that the

information presented was not sufficiently tied to the risk assessment. In particular, although the

health effects review provides evidence that there is an exposure-response relationship for

COPD, there was no analysis describing how COPD may add to silicosis risk or “...how this

additional respiratory disease burden could be included in a quantitative risk assessment.” Dr.

Ginsberg pointed to the study by Park et al. (2002) of diatomaceous earth workers as showing an

exposure-related response for fatal lung diseases other than cancer (LDOC) (i.e., silicosis plus

COPD) roughly 10 times more potent than for silicosis mortality, and commented that this study

“represents a reasonable estimate of silica-induced total respiratory mortality” and might more

appropriately reflect the totality of silica-induced respiratory mortality.

OSHA agrees with Dr. Ginsberg that the Park et al. (2002) study provides a reasonable

basis for evaluating non-malignant respiratory disease risk, which includes both silicosis and

COPD-related mortality, and thus would better reflect the total respiratory mortality burden

associated with exposure to respirable crystalline silica. OSHA did include the Park et al. study

in its draft risk assessment, but erroneously characterized it as an “upper bound” estimate of

silicosis-related mortality, where it is more precisely characterized as an estimate of nonmalignant respiratory mortality. OSHA has made the appropriate changes to the draft health

effects review and risk assessment to more clearly indicate why OSHA believes the Park et al.

study is included in the risk assessment and to clearly interpret the meaning of the resulting risk

estimates.

Dr. Ginsberg thought it useful that the risk assessment reported the risk estimates derived

from the study, but that “it was unclear how much weight will be given to this potency value.”

On this same point, Dr. Salmon stated that:

It is important to emphasize that these different pulmonary disease

manifestations...are all reflections of an underlying disease process related to

silica exposure....It is therefore important to look at all these disease entities in

assessing the overall disease burden from exposure to silica dust.
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OSHA believes that the revised document clarifies these points as well. In addition,

OSHA’s discussion Section VII of the preamble to the proposed rule presents the Agency’s

evaluation of the significance of the health risks, which explains how the health effects

information and risk estimates are viewed in light of the scientific and legal findings necessary to

support the proposed rule.

In Section E of the draft, OSHA presented its analysis of literature describing the risk of

renal and autoimmune disease and their relationships to crystalline silica exposure. Although

reviewers agreed with OSHA’s overall analysis supporting such relationships, opinions differed

with respect to OSHA’s preliminary determination that data were insufficient to support a

quantitative assessment of renal and autoimmune effects. Three reviewers (Drs. Finkelstein,

Ginsberg, and Miller) agreed with the view expressed in the draft. Dr. Seixas also agreed that

data were insufficient to support quantitative assessment of risks, but that “...if one were

required, it would be feasible, given the available studies.” Two reviewers (Mr. Allen and Dr.

Salmon) held opposite opinions, that the available data were sufficient and would support a

quantitative assessment. Mr. Allen pointed out that OSHA’s draft stated that some exposureresponse studies were “credible”, and that:

...it is not appropriate to base a determination...on a comparison to what is

known about silicosis or lung cancer. Certainly, other compounds have been

subjects of quantitative risk assessments with much less data than what is

available for silicosis and lung cancer, and they have been considered adequate

for some level of quantitative evaluation. One might ask oneself if, in the absence

of the silicosis or lung cancer data, one would use the renal and/or autoimmune

data for silica as a basis of a quantitative risk assessment and determination of

regulatory levels. I suspect that one would.

Dr. Salmon commented that “OSHA’s reluctance to consider a quantitative analysis of

renal disease and mortality...seems unjustified”, and endorsed use of the Steenland et al. (2002a)

pooled cohort analysis. Dr. Salmon also stated that, despite the data for autoimmune effects

being “less convincing and comprehensive, due in part to the complexity and variability of this

type of disease”, it is particularly important “to pursue an appropriate quantitative analysis where

possible.”

OSHA believes that Mr. Allen is correct that OSHA’s initial conclusion reflected a

viewpoint that data for renal effects were less robust than were available data on silicosis and

non-malignant respiratory disease, and lung cancer. In light of his and other reviewers’

comments, OSHA has re-evaluated the available information, particularly the Steenland et al.

(2002a) pooled cohort study and underlying analyses, and believes that it is appropriate to

include an analysis of renal mortality in the preliminary quantitative risk assessment. The

present health effects review and risk assessment documents accordingly reflect this change.

OSHA continues to believe that available data on autoimmune diseases is insufficient for the

purpose of quantitatively assessing risks.
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Section F of the draft health effects review evaluated toxicological and mode-of-action

information to explore issues regarding the role of pulmonary inflammation and silicosis in

promoting lung cancer, the physical factors that can affect the toxicity of crystalline silica

particles, and whether cristobalite exhibits a different toxicological potency from quartz.

Reviewers generally believed that the discussion accurately reflected scientific opinion on these

issues and raised some specific points. Dr. Ginsberg stated that “...while there is substantial

evidence that silicosis is not required for oncogenic potential”, the extent to which silicosis could

enhance the DNA damaging effects of silica, and consequently affect the dose-response for lung

cancer, is unclear. Dr. Miller remarked that “[w]hether any excess silica-related lung cancer risk

operates through fibrosis or other aspects of the silicotic response is a difficult question, and the

text [of the draft] reflects this.” Dr. Salmon pointed out that the diagnostic indicators of silicosis

(i.e., radiography and post-mortem histology) are “late” indicators of disease and cannot identify

initial stages that may or may not be important in development of lung cancer.

In the draft discussion of physical factors affecting the potency of crystalline silica,

OSHA had preliminarily concluded that there is good evidence that several factors influence the

ability of quartz particles to interact with cells and cause lung damage; such factors include the

age of fractured particles and the presence of minerals on particle surfaces. Although such

factors may explain differences observed in exposure-response relationships derived from

various studies of cohorts in different occupational settings, OSHA’s draft analysis stated that the

level of understanding was as yet insufficient to determine how such factors are likely affect

disease risk in any given workplace setting. Reviewers agreed with this assessment. For

example, Mr. Allen commented that “the manner in which [these factors]...act...does not appear

to be well understood...and certainly does not appear to be quantifiable.” He concluded that

basing decisions on a range of risk estimates that reflect some of the variation attributable to

physical modifiers of quartz toxicity was a satisfactory approach. Two reviewers (Dr. Miller and

Dr. Ginsberg) addressed the regulatory implications of evidence that quartz exhibits varying

potency in different industrial settings. Dr. Ginsberg believed that the discussion in the draft

raised “an uncertainty that is not really dealt with”, and both suggested regulatory approaches

that appear to place some emphasis on the higher potency factors seen among the various studies.

OSHA agrees that the health effects and risk assessment drafts were probably not clear with

respect to how OSHA interprets the risk information in light of the evidence on physical

modifiers of quartz toxicity, although the draft did indicate that such factors were at least a

partial explanation for the observed heterogeneity seen in exposure-response relationships for

lung cancer and silicosis morbidity. OSHA’s assessment, and in particular its evaluation of the

significance of risk (Section VII of this preamble), make clear that OSHA is relying on a range

of risk estimates that probably reflects at least some of the differences in toxic potency attributed

to modifying factors.

OSHA’s draft analysis preliminarily determined that current evidence did not support that

cristobalite was more toxic than quartz, as was historically beleived. Dr. Seixas, the only

reviewer to comment on this aspect of the analysis, agreed that current evidence indicates the

polymorphs to be of comparable toxicity.

III.B. Peer Review of the Preliminary Quantitative Risk Assessment.
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In general, the reviewers agreed that the strengths and weaknesses of the selected studies

are adequately discussed. Some reviewers suggested that other studies could be used for

quantitative risk assessment and should be included. For example, Dr. Ginsberg commented that

the draft was lacking in critical appraisal of studies and that OSHA’s selection of four studies for

the draft risk assessment, which was largely based on the investigators having developed

quantitative exposure-response models, might have introduced a selection bias. For example, Dr.

Ginsberg pointed to OSHA’s discussion of the study of Danish stone workers by Guénel et al.

(1989) and the Cassidy et al. (2007) multi-center case-control study, which he believed did not

sufficiently explain why these studies were not considered for quantitative risk assessment.

As explained above in OSHA’s responses to comments on the draft health effects

analysis, OSHA agrees that the draft did not include sufficient information describing the basis

for OSHA’s selection of studies for the risk assessment, and has made appropriate clarifying

changes throughout both documents. With respect to the studies mentioned by Dr. Ginsberg, the

Cassidy et al. study found highly significant trends in odds ratios between several indices of

silica exposure and lung cancer cases, adjusted for smoking and other occupational lung

carcinogens. OSHA has preliminarily concluded that the results of this study are “particularly

compelling” in demonstrating a relationship between exposure to crystalline silica and lung

cancer. However, the silica exposure measures were only semi-quantitative and categorized as

“low”, “medium”, and “high”, with ranges of exposure levels assigned to each category in order

to obtain “standardization in the application of the intensity index”, and data were not available

on the actual exposures experienced by most of the the study participants. For this reason,

OSHA preferred to rely on studies where exposure data were available from the actual work

environments and operations from which study cohorts were drawn. The Danish stone worker

study also found increased lung cancer risk associated with silica exposure, but there was not

enough exposure information presented to permit quantitative risk estimation.

Mr. Allen commented that OSHA’s discussion of exposure reconstruction in the studies

might not have sufficiently conveyed limitations of the approaches used by investigators. In

particular, he referred to OSHA’s discussion of the exposure assessment that was used in the

Steenland et al. (2001a) pooled cohort study, in which odds ratios for silicosis mortality were

reported by exposure quintile to show that serious exposure misclassification was unlikely to

have occurred. Mr. Allen believed that the results presented were not convincing, and

questioned whether OSHA was relying on the best evidence. The analysis discussed by OSHA

was a preliminary analysis reported by Mannetje et al. (2002a), who also published a more

rigorous evaluation of the exposure-response for silicosis mortality (Mannetje et al., 2002b). The

latter analysis was presented in OSHA’s risk assessment and shows a clear and consistent

positive response with increasing decile of cumulative exposure, although there is an anomaly in

the 9th decile. Overall, these data support a monotonic exposure-response for silicosis. Given

that silicosis is known to be strongly related to cumulative exposure, this finding suggests that

exposure has been fairly well measured by Mannetje et al (2002a) and, by extension, in

Steenland et al. (2001a), which uses the same exposure estimation. OSHA believes that this

provides stronger evidence that supports the underlying exposure assessment and has revised the

risk assessment document accordingly.
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Dr. Salmon commented that, although OSHA’s draft adequately evaluated most of the

studies included in the risk assessment, the discussion of silicosis morbidity was less convincing

in that it omitted certain studies that he believed were particularly useful for evaluating risks at

low exposure. In particular, he identified the cross-sectional study by Churchyard et al. (2004)

on black South African miners, and an analysis by California OEHHA (2005), which assessed

silicosis risks at low exposures based on many studies that were included in OSHA’s analysis.

In addition, he believed that the risk assessment overall placed undue focus on extreme endpoints

such as silicosis mortality and morbidity defined by ILO 2/1+ x-ray changes, thus lessening the

sensitivity of the assessment for low-dose extrapolation.

With respect to the Churchyard et al. (2004) study, OSHA has reviewed this study and

agrees with Dr. Salmon that it shows a significant prevalence (almost 20%) of silicosis among

older in-service black mineworkers. Unlike other studies described in the risk assessment (e.g.,

Miller et al., 1998; Hnizdo and Sluis-Cremer, 1993), the Churchyard study included prevalence

among only active workers and did not include retirees. OSHA included a discussion of the

Churchyard et al. study in the revised risk assessment, but continues to believe that the best

estimates of silicosis morbidity risk comes from studies that included both current workers and

retirees since the resulting estimates will more closely approximate the risk that accumulates

over a lifetime.

OSHA is also aware that, in identifying the Mannetje et al. (2002b) analysis of silicosis

mortality and the Miller et al. (1998) analysis of morbidity, the draft might have suggested that

OSHA would be relying most heavily on fairly insensitive indicators of silicosis in making

regulatory decisions. OSHA’s interpretation of the significance of the risk findings and how

these findings provide the basis for regulation is presented in the preamble to the proposed rule

(i.e., section VII, Significance of Risk and section X., Summary and Explanation of the

Standard). OSHA has revised potions of the preliminary risk assessment to clarify that OSHA’s

estimates of the range of silicosis risk at the current and proposed PEL include more sensitive

endpoints, in particular x-ray changes consistent with ILO 1/0+ and 1/1+.

Dr. Miller identified a recent lung cancer study on British coal miners (Miller et al., 2007;

Miller and MacCalman, 2009) that he believed should be considered for the assessment. OSHA

has reviewed these studies and found that this coalminer study had specific strengths in three

areas: the detailed time-exposure measurements of both quartz and total mine dust, detailed

individual work histories, and individual smoking histories. In addition, the study conduct and

the statistical analyses presented in the publications were well done. The results provide risk

estimates that are somewhat on the lower side of the range of lung cancer risk estimates derived

from other studies, possibly because of the individual adjustments for smoking and coal dust, or

the type of silica exposure in the mines.

As a result of further review, OSHA also added quantitative lung cancer risk estimates

based on the North American industrial sand worker study presented by Hughes et al. (2001),

and McDonald et al. (2001, 2005). OSHA believes that because of the availability of highquality exposure and work history data for these studies, as well as individual smoking data that

allowed for adjustment in the risk model, OSHA based estimates on the Hughes et al. nested
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case-control study, which provided sufficient information in the report to reasonably reproduce

the model.

For silicosis morbidity estimates, OSHA has added the analysis of Buchanan et al. (2003)

to its revised risk assessment. This study is a reanalysis of the coalminer study by Miller et al.

(1998), which was discussed in the draft risk assessment and is a follow-up study that could

account for incidence, not just prevalence, of silicosis and included both current workers and

retirees. The Buchanan et al. reanalysis was designed to account for high exposure rates, and

was reviewed in the draft to evaluate evidence for dose-rate effects for silicosis morbidity.

Reviewers had suggested that, given the Buchanan et al. model adjusts for potential dose-rate

effects, it may serve as a better model than the original study relied on by OSHA, the Miller et al.

(1998) study. OSHA agrees and the revised draft presents risk estimates derived from the

Buchanan et al study.

Reviewers believed that the uncertainty analysis conducted by Steenland and Bartow

(Toxichemica, 2004) was well designed and convincing in showing that potential biases in

exposure estimation are not likely to have a large effect on risk estimates derived from the

Steenland et al. (2001a) pooled cohort lung cancer study. Several specific comments and

suggestions were made. Mr. Allen remarked that Monte Carlo approaches typically require more

than the 50 iterations that were used in the uncertainty analysis. In addition, he suggested that it

might be informative to increase the amount of error above what was assumed in the analysis to

determine how much error in the exposure estimates might have been required to effect a

substantial change in the risk estimates, and whether it was plausible for the exposure estimates

to reflect that much error.

Clearly, more than 50 iterations could have been performed. However, the intersimulation variance of exposure-response coefficients did not appear to change much with an

increased number of iterations. For the analysis of random measurement error, the intersimulation standard error (.004) was only one-third of the average of the standard error (.014)

that resulted from incorporating random error in the model across the 50 iterations. Thus, OSHA

believes that the simulation would not have benefited substantially by running more simulations.

On Mr. Allen’s suggestion for additional analysis, OSHA agrees that it would be informative to

increase the assumed amount of error to determine at what point risk estimates are significantly

influenced. Steenland and Bartow (Toxichemica, Inc., 2004) assumed a level of uncertainty for

two types of random error based on actual data describing variation around estimates of mean

exposure level and mean percent silica content of dusts, and believes that this approach is

sufficient for the purpose of OSHA’s preliminary risk assessment.

Dr. Crump commented that the analysis could have assumed that silica concentrations

differed randomly by work area rather than by job since random sampling of jobs in the same

work area might tend to “average out variations by work area and underestimate uncertainty.” In

their analysis, Steenland and Bartow (Toxichemica, Inc., 2004) constructed job-exposure

matrices that were combinations of tasks and work areas where there was sufficient detail in the

original data for each study. OSHA has revised the text in the risk assessment to clarify this

point. Dr. Crump also suggested that assuming that the average measure of exposure assigned to
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a job is the true average could be a major source of error that is unaccounted for. Sources of

such error include the possibility that measurements were taken at times when it was believed

that a particular problem was causing higher exposures, or because historical (and presumably

higher and more influential) exposures were not always measured but projected based on

historical knowledge of operations or estimated from data obtained from different measurement

methods (i.e., particle count data). The Toxichemica, Inc. analysis assumed that the average

measurements for a given job were a fair reflection of the true average exposures of workers in

that job, on the whole. While it is possible that some measurements were systematically biased

above or below the true average for a job, there is no “gold standard” measurement available to

determine this. The Toxichemica, Inc. analysis did include consideration of some of the kinds of

error mentioned by Dr. Crump, in particular errors in the estimate of silica content of dust and

systematic bias in exposure measurements.

Dr. Seixas commented that the simulation performed for the uncertainty analysis

reflected modeling for classical, rather than Berkson, error:

The typical Monte Carlo simulation, which is what appears to have been done,

would introduce classical error. I don’t think the report should repeatedly state

that the simulation produces coefficients “adjusted for Berkson error” as I don’t

believe this is Berkson, nor that the simulation actually adjusts for it....In fact, the

results [i.e., the resulting exposure-response coefficients after

simulation]...almost all went down (toward the null), which is what is generally

expected by adding random (classical) error into the exposure variable....There is

no mention of measurement error generally reducing the effect of exposure

response relationships, and that this principle indicates that the estimated risks are

most likely to be underestimates....This is an important aspect of measurement

error with significant implications for risk assessment and should not be

overlooked.

The Toxichemica, Inc. report discusses the limitation of the simulation approach in more

detail. For example, one limitation is that the simulation did not account for correlations

between simulated Berkson errors and the disease outcomes that are implied by the specific

model. The reviewer may be correct that, without proper accounting of such limitations the

Toxichemica analysis can be viewed as an exercise in simulating the effect of additional classical

error. OSHA notes that the adjusted exposure-response coefficients are not necessarily better

estimates (which might have been implied by terming them “adjusted coefficients”), but they are

informative regarding the potential effects of measurement error on the observed dose-response

coefficients. OSHA also agrees with Dr. Seixas that classical measurement error structures

typically do bias exposure-response coefficients towards the null; however, it has also been

demonstrated that Berkson error can cause bias in either direction (Steenland and Deddens,

2000).

In the draft risk assessment document, OSHA presented lung cancer risk estimates based

on a lung dosimetry model for crystalline silica developed by Kuempel et al. (2001). This

modeling approach is a rat-based toxicokinetic/toxicodynamic modeling effort to predict human
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lung cancer risk based on lung burden concentrations necessary to cause the precursor events that

can lead to adverse physiological effects in the lung. The resulting relationship between

cumulative exposure and human lung burden were used to estimate lung cancer risks as a

function of lung burden from the diatomaceous earth and Vermont granite cohort studies.

Reviewers’ responses to the discussion were mixed, although most thought that OSHA had not

explained the Kuempel et al. model in sufficient detail. Two reviewers (Drs. Finkelstein and

Miller) thought that models such as the rat-based model would be useful in instances only when

there are no or inadequate epidemiology data. For example, Dr. Miller suggested that lung

burden ...may be the correct target organ dose metric, but epidemiological data on it is very

sparse; hence the normal focus on exposure experienced as a surrogate for dose. The

extrapolation involved requires many more assumptions than assessing risk from

epidemiological studies, and it may not be prudent to place the same degree of reliance on the

model-based estimates as on those from epidemiological observation.

In contrast, Dr. Crump thought that lung burden metrics:

...can provide a reasonable alternative to the more empirical metrics emphasized

in the papers reviewed by OSHA....Without estimating risk using the metrics

based on lung burden, the effect of these metrics upon the estimated risk will not

be known. If workers in the epidemiological studies predominately were exposed

for only a short time (e.g., a few months), different exposure metrics could predict

significantly different risks from 45 years of exposure even if they provided

equivalent fits to the epidemiological data.

OSHA has added new language to clarify the discussion of the Keumpel et al. (2001)

analysis. After considering the comments of the expert reviewers, OSHA has chosen to not rely

on the rat-based model, but instead to rely on the lung cancer risk estimates of the epidemiology

studies themselves and the exposure metrics used in those studies. OSHA notes that the

conversion by Kuempel et al. of the two epidemiology studies’ metrics of cumulative exposure

to equivalent lung burdens after the epidemiology exposure-response analysis had already been

based on cumulative exposure adds little new information. Although a risk assessment based on

silica lung burden data in humans whose mortality experience was evaluated would provide

additional useful information on exposure-response relationships, the Kuempel et al. (2001)

analysis does not provide that kind of information. OSHA believes that the available

epidemiological data provide a strong basis for estimating lung cancer risks from cumulative

exposure metrics.

The draft risk assessment summarized several published risk assessments that used a

variety of exposure-response models and statistical methodologies to evaluate them. In general,

reviewers believed the studies were adequately described but that the presentation would be

improved by greater use of summary tables to facilitate comparing modeling approaches across

studies. OSHA has expanded or added summary tables as appropriate.

Dr. Ginsberg thought the rationale for estimating risks at exposure levels above OSHA’s

current standard (of approximately 0.1 mg/m3) was unclear, and both Dr. Ginsberg and Dr.
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Salmon suggested that OSHA make an effort to estimate risks at lower exposures that were

evaluated in the draft (i.e., below 0.05 mg/m3). OSHA’s risk assessment provided risk estimates

for exposure to 0.25 and 0.5 mg/m3respirable crystalline silica over a working life to represent

the range of risks to which workers are exposed under the current PEL for construction and

maritime, which is a particle count formula rather than the gravimetric PEL that applies in

general industry. OSHA has revised the draft to emphasize this point throughout. With respect

to estimating risks at lower exposure levels, the revised draft provides risk estimates associated

with exposure to the proposed action level of 0.025 mg/m3. Given the Agency’s preliminary

findings with respect to technological feasibility of alternative PELs, OSHA believes that an

effort to estimate risk at levels below the proposed action level would have little or no impact on

the Agency’s regulatory action, and has therefore chosen not to do so.

Dr. Ginsberg also questioned whether OSHA was giving proper weight to the South

African miner study (Hnizdo et al., 1997), which, in the Steenland et al. (2001a) pooled cohort

study, showed an approximate 10-fold higher potency for lung cancer than did the other nine

cohorts included. He stated that:

In toxicology and risk assessment, one should consider whether the most sensitive

study and endpoint is of high enough quality to be the source of risk

calculations[,]...whether the entire risk range should be presented...or whether

some central tendency potency estimate should be used. It may be that the South

African gold miner study is more potent for a good reason...and should be given

serious consideration as a stand alone data point for potency estimation and risk

calculations. Or perhaps that study is no better or even inferior or less relevant

than the others.

OSHA believes that the excess lung cancer risk associated with exposure to crystalline

silica is best characterized as a range of risks across the various industries studied rather than on

a single study that reflects the highest potency, and that the estimates derived from the Steenland

et al. (2001a) pooled cohort study (and updated analyses presented in the present assessment)

reflect a reasonable approach to deriving a central tendency estimate. OSHA’s choices on how

to best characterize lung cancer risks reflects what the Agency believes is good evidence that

crystalline silica exhibits varying toxic potency in different workplace settings, as explained in

section I.F of the health effects review, and the revised risk assessment makes OSHA’s position

clear.

Dr. Ginsberg also commented that more attention could be devoted to the issue of a

threshold, particularly where addressed by the individual studies examined. OSHA addresses

this issue further in its revised assessment. Dr. Ginsberg also believed that OSHA did not

adequately address potential confounding by smoking; he explained that

[OSHA]...assumes that the only issue with smoking as an uncontrolled variable is

the potential for smoking rate to correlate with silica exposure in such a manner to

bias the disease risk high. The text goes on to assert that this is unlikely from the

available evidence and study design. However, this rationale excludes the
396

possibility that when smoking is an uncontrolled variable it will lead to elevate

cancer risk in both the reference and silica-exposed population leading to a high

and variable baseline [risk] that will tend to bias the results towards the null

hypothesis and weaken associations between silica and lung cancer.

OSHA agrees that this is an important consideration and has revised the draft

accordingly. Furthermore, OSHA has included risk analyses based on two studies that had

individual worker data on smoking and adjusted for smoking in the risk model; these are the

Hughes et al. (2001) study of North American industrial sand workers and a recent study of

British coal miners (Miller et al., 2007; Miller and MacCalman, 2009).

Dr. Crump raised a number of points concerning the use of log-transformed exposure

metrics and non-linear exposure-response models. He believed the reasons for using logtransformed cumulative exposure in the pooled cohort analysis are “faulty” given that (1) the

model based on untransformed exposure and a 15-year lag gave a better fit than that using logtransformed cumulative exposure, and (2) that the lack of any improvement in fit of the model

based on log-transformed cumulative exposure did not show improvement when interaction

terms were added, which he viewed as a disadvantage. OSHA notes that the model using

untransformed exposure, while providing a better fit nevertheless did not fit significantly better

than the model based on log-transformed exposure (log-likelihood of 21.4 vs. 18.8). Although

employing models that reduce heterogeneity in pooled cohort studies such as this is desirable,

OSHA agrees that lack of heterogeneity is not an absolute requirement for accepting a single

(“average”) coefficient from across studies in a risk assessment, and notes that random effects

models in meta-analysis routinely use such summary risk measures across heterogeneous studies.

OSHA has explored this issue further in the preliminary risk assessment using linear relative risk

models as suggested by Dr. Crump (see below) with the result that log transformation of

cumulative exposure results in approximately the same fit to the data as linear models using

untransformed exposure. However, the linear models based on use of log-transformed exposure

better captures the initially steeper slope of the exposure-response curve that is evident from the

pooled data set based on a categorical analysis, whereas the model with untransformed exposure

fails to do so. In exploring this issue, OSHA also relied on a 2-piece linear spline model, which

outperforms linear models based on either untransformed or log-transformed cumulative

exposure.

Dr. Crump also addressed the issue of model selection, in particular the choice of loglinear (i.e., log relative risk) models vs. linear relative risk models, both of which were employed

by various authors of the studies relied upon by OSHA. He stated that, “although log-linear

models are relied upon extensively, such models are generally selected for convenience...rather

than for biological plausibility.” As Dr. Crump pointed out in his comments, use of log-relativerisk models result in a supralinear exposure-response curve and, when combined with use of logtransformed exposure (as was done in the pooled cohort study), results in a sublinear exposureresponse.

In response to these comments, OSHA asked Drs. Steenland and Bartell to explore use of

linear models with the pooled data set (Steenland, personal communication, 2010), with the
397

result that the revised assessment now presents results from analyses using linear relative risk

models, with and without log-transformation of cumulative exposure. From this analysis, OSHA

preliminarily concludes that a linear model with log-transformation of exposure and a linear 2-

piece spline model with untransformed exposure provide reasonable fits to the pooled data set,

and the revised analysis presents risk estimates based on use of these models.

OSHA’s draft risk assessment was based on exposure-response models that used

cumulative exposure to respirable crystalline silica. The draft did include a discussion of the

possible dose-rate effects where, at high silica concentrations, a few studies (Hughes et al., 1998;

Buchanan et al., 2003) found that risk increases at a rate greater than would be predicted from

cumulative exposure alone (i.e., the rate of accumulation of dose influences risk). In general, the

reviewers agreed that cumulative exposure was the proper metric for estimating silica-related

health risks, and that the draft provided a good discussion of dose-rate effect. Reviewers also

agreed that available data were not sufficiently robust to adequately characterize how the rate of

exposure accumulation affects risk. However, Dr. Crump suggested that a dose-rate effect can

be present in addition to a cumulative dose effect, and that OSHA should consider using

available studies that attempted to account for a dose-rate effect. Accordingly, the revised

assessment presents estimates of silicosis morbidity risks based on the Buchanan et al. (2003)

study, which uses model parameters to account for possible dose-rate effects.

The draft risk assessment characterized excess lung cancer risks as a range of estimates

represented on the low end by the estimate derived from the Steenland et al. (2001a) pooled

cohort analysis, and by the upper end represented by estimates derived from the individual

studies on diatomaceous earth (Rice et al., 2001) and Vermont granite (Attfield and Costello,

2004) workers. Overall, the reviewers stated that the pooled IARC analysis of 10 lung cancer

mortality studies should be the basis of OSHA's "best" estimates of lung cancer risk. For

example, Dr. Salmon stated that:

The IARC multi-center study probably represents a reliable median estimate, but

by its nature is likely to underestimate the upper bound on risk in a situation

where individual cohorts show real variation in risks due to differences in the

nature and intensity of the exposure and the effectiveness in determining health

endpoints.

Dr. Crump, as described above, further argued that a linear risk model should be

employed for the pooled cohort analysis rather than a log-linear model using log-transformed

exposure metrics. Dr. Seixas questioned whether the U.S. diatomaceous earth and U.S. granite

worker studies be considered plausible upper bounds, since risk estimates derived from these

studies were based on maximum likelihood estimates (MLE) rather than on upper confidence

interval estimates.

OSHA continues to believe that lung cancer risk estimates are best represented as range,

with the estimates derived from the Steenland et al. (2001a) pooled cohort analysis providing a

reasonable median estimate of risk across the cohorts included. In the revised risk assessment,

the range of plausible lung cancer risk estimates are now derived from analysis of the Hughes et
398

al. (2001) industrial sand study and the Miller and MacCalman (2009) coal miner study, in

addition to the diatomaceous earth and U.S. granite studies included before. The revised

assessment also reports the range of lung cancer risk estimates that are derived from the linear

relative risk model coefficients for each of the individual cohorts used in the IARC multi-center

study.

One reviewer, Dr. Miller, questioned OSHA’s assumption of length of lifetime in the

analyses of both mortality and morbidity. In the draft assessment, OSHA analyzed mortality

risks based on a life table method that summed age-specific risks to age 85. However, many of

the underlying studies used age 75 to represent a lifetime, and OSHA’s assessment of silicosis

morbidity risks did not use a life table approach, but rather reflected the risk that accumulated up

to the last follow up of each cohort (which included retirees). OSHA has made appropriate

clarifications of assumptions regarding length of lifetime in its risk calculations and has included

an appendix that describes the life table calculations used.

Most reviewers commented positively on OSHA's use of cohort studies that included

retirees as the appropriate studies for OSHA's assessment of silicosis morbidity risk. Several

pointed to the overall consistency in the estimates among the various studies used; however,

some reviewers suggested that OSHA was not clear on precisely which studies were being

ultimately relied upon. Other reviewers had some specific suggestions. Dr. Crump suggested

that OSHA look for a dose-rate effect for silicosis morbidity. Dr. Salmon suggested that OSHA

review its reasoning underlying its concerns with exposure measures used in the Hnizdo and

Sluis-Cremer (1993) study of silicosis. He pointed out that the report by Churchyard et al (2004)

would provide a useful comparison with earlier South African mining studies since exposure was

measured using gravimetric methods in occupational situations similar to those from which

particle count data were obtained. In response, OSHA has clarified its discussion of the results

of the silicosis morbidity analysis, included the Buchanan et al. (2003) study of British coal

miners to better address dose-rate effect for silicosis, and revised its discussion of the exposure

data underlying the Hnizdo and Sluis-Cremer (1993) study.
399

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Supplemental Literature Review of Epidemiological Studies on

Lung Cancer Associated with Exposure to Respirable

Crystalline Silica

Occupational Safety and Health Administration

Docket OSHA-2010-0034
ii

Table of Contents

Vacek et al., 2011 – Mortality in Vermont Granite Workers and its Association with

Silica Exposure ................................................................................................................... 2

Analysis of Mundt, et al (2011) German Porcelain Workers Cohort ................................. 6

Comparison of Gamble and OSHA Reviews of Association between Respirable

Crystalline Silica and Lung Cancer .................................................................................. 13

Review of Cox (2011): An Exposure-Response Threshold for Lung Diseases and Lung

Cancer Caused by Crystalline Silica................................................................................. 37

References......................................................................................................................... 40
1

This document reviews four papers on the risk of lung disease associated with

exposure to respirable crystalline silica that have been published subsequent to

completion of the comprehensive literature review included in the OSHA background

document on Health Effects (OSHA, 2013). These papers were reviewed by the OSHA

Directorate of Standards and Guidance to ensure that OSHA has evaluated the most

current literature and to determine whether the information in these papers is consistent

with or could potentially alter the analysis presented in OSHA’s Preliminary Risk

Assessment. The papers reviewed in this document include:

1) Vacek PM, Verma DK, Graham WG, Callas PW, and Gibbs GW. (2011). Mortality in

Vermont granite workers and its association with silica exposure. Occup Environ Med.

68(5):312-8. Epub 2010 Sep 19.

2) Mundt KA, Birk T, Parsons W, Borsch-Galetke E, Siegmund K, Heavner K, and

Guldner K. (2011). Respirable crystalline silica exposure-response evaluation of silicosis

morbidity and lung cancer mortality in the German porcelain industry cohort. J

Occup Environ Med. 53(3):282-9. [Including information from Birk et al., 2009; Birk et

al., 2010, and Mundt et al., 2012 (erratum)].

3) Gamble JF. (2011). Crystalline silica and lung cancer: a critical review of the

occupational epidemiology literature of exposure-response studies testing this hypothesis.

Crit Rev Toxicol. 41(5):404-65.

4) Cox LA Jr. (2011) An exposure-response threshold for lung diseases and lung cancer

caused by crystalline silica. Risk Anal.31(10):1543-60. Epub 2011 Apr 7.
2

Vacek et al., 2011 – Mortality in Vermont Granite Workers and its Association with

Silica Exposure

Vacek et al. examined a group of 7,052 men who had worked in the Vermont

granite industry at any time between January 1, 1947 and December 31, 1998 (total of

269,253 person-years of follow-up for calculation of Standardized Mortality Ratios

(SMRs)). Cumulative silica exposures were estimated using a job exposure matrix

created from measurements taken in the Vermont granite industry between 1924 and

2004, and worker mortality was ascertained by searching the National Death Index,

Social Security Administration vital status records, Vermont State Records, commercially

available data, and death records from Quebec in cases where a worker was known to

have died in Canada. The study also relied on information from previous studies, pension

records, and state surveillance data to characterize exposure/work histories. Health

outcomes including overall mortality, silicosis mortality, and mortality from other

respiratory diseases (diseases other than silicosis, influenza, pneumonia, bronchitis,

emphysema, and asthma) were all explored by the study.

The authors found that overall mortality, including mortality from unknown

causes, was significantly increased compared to the comparison group of all U.S. white

males (SMR 1.08, 95% confidence interval (CI) 1.05 to 1.12); this was mostly due to

increased mortality from tuberculosis, malignant neoplasms, and non-malignant

respiratory diseases. The study found that most deaths from tuberculosis and silicosis

occurred in men who started working prior to 1940—the point at which dust controls

were implemented in the granite industry. Only six of the 55 men who died of silicosis

began work after 1940. Three of those started work after 1949 and worked less than 10

years in the industry (although one had 40 years of experience as a stone cutter in

Canada). All of the 55 deaths from silicosis occurred in workers born before 1925.

The study used a nested case-control analysis to explore the exposure-response

relationships between silica exposure and silicosis, other non-malignant respiratory

disease, lung cancer, and various non-malignant and malignant renal diseases. The study

did not show significant association between lung cancer risk and exposure measured in
3

several ways as continuous variables. However, silica exposure was significantly related

to both silicosis and other non-malignant respiratory disease: for each 1 mg/m3-year

increase in cumulative exposure, the risk of silicosis mortality increased by 13% (OR

1.13, 95% CI 1.05 to 1.21); the risk of mortality from other non-malignant respiratory

disease increased by 10% (OR 1.10, 95% CI 1.03 to 1.16). The study divided silica

exposure into quintiles for silicosis, other non-malignant respiratory diseases, lung

cancer, renal cancer, and non-malignant renal disease; and only showed a significant

dose-response relationship between silica exposure and the silicosis outcome. Of note,

the quintiles used in the Vacek et al. analysis were higher than typical values of

cumulative exposure to silica used in many studies upon which OSHA based its risk

assessment. In the ten studies explored by Steenland et al. (2001) and Mannetje et al.

(2002a,b), for example, median cumulative exposures ranged from 0.13 to 11.37 mg/m3-

years, with some studies exploring silica exposures spanning only the lower end of the

spectrum (e.g., Hnizdo and Sluis-Cremer, 1991; Hughes et al., 2001; and Steenland and

Brown, 1995a,b). Attfield and Costello (2004), whose exposure groups are compared to

Vacek’s in Table 1, specifically found a positive exposure-response relationship among

granite workers at the lower end of the exposure spectrum using a model that omitted the

highest exposure group in their study, reflecting the authors’ position that underlying

exposure data for the high-exposure group was weaker than for the other groups and that

competing causes of death or misdiagnoses of death may have clouded the exposureresponse relationship at higher exposure levels. The regression models used in the Vacek

study also exhibited signs of uncontrolled confounding. For instance, for every outcome

(except silicosis), workers in the second lowest exposure stratum in the models exhibited

a lower risk than those in the lowest stratum of cumulative silica exposure. In the highest

exposure (fifth) stratum , all outcomes except non-malignant respiratory disease showed a

decline in the likelihood of the outcome (calculated as odds ratio) compared to the next

lower stratum. These two problems at the high and low ends of the quintile divisions

would be more than sufficient to suppress a linear trend from being observed. Thus,

OSHA believes the use by Vacek et al. of high cumulative exposures to define exposure

groups fails to adequately explore the dose-effect relationship between silicosis and

silica, especially at the low-dose cumulative exposures typically found in modern
4

operations where silica exposure is possible. OSHA believes the study offers insufficient

evidence against lowering silica exposure limits.

Table 1. Exposure groups for Vacek et al. (2011) and Attfield & Costello (2004)

Vacek et al. Attfield & Costello

Cumulative

exposure groups*

(mg-my/m3)

Number of workers

(cases + controls)

Cumulative

exposure groups*

(mg-my/m3)

Number of workers

<1.04

1.05 - 3.64

3.65 - 6.71

6.72 – 10.21

>10.21

44

43

43

44

43

0 - <.25

.25 - <0.5

0.5 - <1.0

1.0 - <1.5

1.5 - <2.0

2.0 - <3.0

3.0 - <5.0

≥5.0

1,748

556

760

509

375

428

374

658

*Quintiles as used in Vacek’s analysis of silicosis SMR. Attfield & Costello evaluated

SMR respiratory tuberculosis, diseases of the respiratory system, pneumoconiosis,

malignancy of the kidneys, and all causes using the same exposure groups for each

outcome.

Vacek et al. also asserted that the cohort data used in their analysis, which

extended follow-up by four years compared to Attfield and Costello (2004), provided no

evidence of a relationship between lung cancer mortality and silica exposure. However,

Attfield and Costello (2004) demonstrated that excluding the highest exposure group in

the cohort from their Poisson regression model for exposure-response analysis revealed a

stronger relationship between silica exposure and lung cancer mortality compared to what

was observed when the highest exposure group was included. The Vacek et al. study’s

quintiles for lung cancer mortality analysis included 51 deaths in subjects whose

cumulative respirable free silica exposure exceeded 4.10 mg-yr/m3. Attfield and

Costello’s analysis, in contrast, excluded 30 deaths of subjects whose cumulative

exposure levels were at or above 6.0 mg-yr/m3, capping the seventh exposure group at 29

deaths among subjects whose cumulative exposure levels ranged from 3.0 to <6.0 mgyr/m3

. Additionally, Vacek found a large excess of lung cancer (almost 100 excess lung

cancer deaths, according to Table 3 of the study) that is understated by considering only a

SMR and failing to account for the healthy worker effect (HWE). The HWE is the

phenomenon that results in lower observations of morbidity and mortality among worker
5

populations compared to the general population because individuals with illnesses and

disabilities or who are otherwise less robust are either excluded from employment or selfselect out of higher-risk jobs. HWE is routinely and inappropriately ignored for cancer

outcomes (Park et al., 1991). The actual excess could correspond to a SMR at least 0.10

higher than what Vacek et al. reported.

Several other key aspects of the Vacek et al. study also limit its utility in OSHA’s

risk analysis. The authors were unable to obtain information on smoking for a number of

the workers in their cohort due to what were cited as “data confidentiality protections”;

however they nonetheless suggest that the elevated SMR for lung cancer is due, at least in

part, to differences between the smoking habits of the cohort and reference populations

(Vacek et al., 2011). Examination of Vacek et al.’s reported SMRs for causes of death

through 2004 among U.S. white males does not necessarily support this claim, however.

Although the SMR for other non-malignant lung diseases, which is often associated with

smoking, was elevated, there was no significant SMR elevation observed among deaths

caused by other smoking-associated diseases (e.g., cancers of the digestive organs,

larynx, or bladder; bronchitis, emphysema, and asthma). Elevated SMRs would be

expected if there was a significant difference in smoking between the study and reference

populations. In addition, lower mortality than expected was observed for bronchitis, heart

disease, and leukemia. Further, the population smoking estimate (37%) could be

confounded by social class (i.e., persons with higher socio-economic status tend to smoke

less); and the granite worker smoking estimate (50%) may be overestimated since the

source was a sample selected for a pulmonary function study. The comparison of the two

groups—the aging granite cohort versus the general population—also was not adjusted

for age.
6

Analysis of Mundt, et al (2011) German Porcelain Workers Cohort

The risks of silicosis morbidity and lung cancer mortality associated with

exposure to silica were examined in a cohort of German porcelain manufacturing workers

(Mundt et al., 2011). This cohort was the subject of two previous studies authored by

Birk et al.: Birk et al. (2009) and Birk et al. (2010). The first study used SMRs without

quantitative exposure estimates (Birk et al., 2009). The analysis presented in Mundt et al.

(2011) uses the quantitative exposure estimates from the second study, Birk et al. (2010).

This series of study methods was described as unique because it used data obtained from

an industry-wide medical surveillance program, including radiographs; quantitative

exposure data for creation of a job exposure matrix; and data that included female

porcelain workers, who comprised approximately half of the cohort.

The original cohort described in Birk et al. (2009) and Birk et al. (2010) included

17,644 (8,288 male and 9,356 female) German porcelain workers who had participated in

medical surveillance programs for silicosis between 1985 and 1987, had paper records of

medical surveillance, and were employed in the industry for at least 6 months. Even

though Mundt et al.’s (2011) methods reference the same 17,644 participants, Mundt

describes results for 8,291 males and 9,322 females, which resulted in more males and

less females, with 31 fewer participants than originally reported. Birk et al. (2009) and

Mundt et al. (2011) determined vital status from health insurance and pension records and

community and central population registries, for 94% of the cohort. Causes of death,

including lung cancer, were determined from death certificates, which were available for

93% of the cohort.

To assess silicosis morbidity in Mundt et al. (2011), two radiologists separately

reread and classified all radiographs according to International Labour Organization

(ILO) methods. Radiographs that scored 1/1 or greater were considered positive evidence

of silicosis, which is consistent with ASTM standard practice (ASTM, 2009). If the

findings disagreed, the two readers discussed the films to obtain a consensus reading; a

third reader was requested to resolve any remaining differences. During the first sampling

phase of rereadings, considerably fewer films were classified as positive, and rereadings
7

produced a very low false negative rate compared to original readings. Therefore, during

the second phase of rereadings, the authors decided not to read original films classified as

0/0 or 0/1 and ultimately reread 3.13% (n=552) of original participants’ (n=17,644) films.

In total, 40 cases of silicosis were observed.

Mundt et al. (2011)’s cohort was followed through the end of 2005, with an

average of 19 years of follow-up per subject. From Table 1 in Birk et al. (2009), the mean

employment duration for men was 22.5 years (range = 0.5–57.6 years) and mean age at

start of follow-up was 35.2 years (range = 15.3–63.7 years). For women, mean

employment duration was 20.6 years (range = 0.5–49.9 years) and mean age at start of

follow-up was 34 years (range = 14.6–61.7 years). Median year of hire was 1975 (range

= 1938–1991) for men and 1976 (range 1943–1996) for women. Follow-up ended at age

75 because records were not available for many cohort members older than 75 years; this

excluded 22 male and 6 female deaths from the cohort. Nine percent (n = 1610) of cohort

members had died by the end of the follow-up period, including 94 lung cancer deaths.

In contrast to the previous analysis of this cohort by Birk et al. (2009), which used

SMRs as a metric, the potential relationships between silica exposure and silicosis

morbidity or lung cancer mortality were assessed by Mundt et al. (2011) through internal

comparisons and the use of hazard ratios, based on both average and cumulative

exposure. A hazard ratio (HR) is a valid estimate of an incidence rate ratio that is

calculated from Cox proportional hazard models and accounts for person-time, rather

than only the odds or risk of an event occurring. This metric reflects the analysis of time

survived to an event and assumes the hazard pertinent to the event (e.g., death) in one

group is proportionate to the same hazard in another group, depending on the underlying

risk factors. Since hazard ratios depend on the length of follow-up, caution should be

taken when interpreting a single, average HR because this single estimate may ignore the

distribution of events during follow-up (Hernán, 2010).

Lung cancer mortality and silicosis morbidity HRs were adjusted for smoking and

employment duration, although smoking status was unknown for approximately 31% of
8

the cohort. Results were stratified by gender in the cancer mortality analysis, but adjusted

for gender in the silicosis morbidity analysis. Separate person-time estimates were used

for lung cancer mortality and silicosis morbidity. While men represented 47% of the

cohort population, 79% of lung cancer deaths and 85% of silicosis cases were observed in

men. No lung cancer deaths were observed among silicotics, so that a difference in lung

cancer incidence between silicotics and non-silicotics could not be analyzed.

Quantitative exposure estimates were developed using the job exposure matrix

(JEM) created for this study by Birk et al. (2010). The JEM was based on over 8,000

combined static (stationary area) and personal total dust, respirable dust, and respirable

crystalline silica dust industrial hygiene measurements for approximately 100 production

areas/job task code combinations during 1954 through the end of 2005. Average silica

concentrations were derived for six primary similar exposure groups between 1938 and

the end of 2005, using a historical estimation approach for the early years. Significant

reductions in average annual exposure were seen over time, with an average annual

exposure of 0.11 mg/m3for workers hired prior to 1960 compared with an average of

0.03 mg/m3for workers hired after 1960. The greatest average annual exposures were

seen among workers in the materials preparation area (0.17 mg/m3). Greater than 40% of

the cohort accumulated less than 0.5 mg/m3-years and nearly 70% of the cohort had

average annual exposures less than 0.05 mg/m3; these cutoff points determined the

respective reference groups for cumulative exposure and average annual exposure (Birk

et al., 2010; Mundt et al., 2011). Thus, the risks for average annual exposures below 0.05

mg/m3 were not evaluated for either silicosis or lung cancer in Mundt et al. (2011). The

silica exposure levels among porcelain workers in this study are lower than have been

reported in other industry studies. For example, the median of the average annual

exposure in a study of North American industrial sand workers was 0.15 mg/m3(Hughes

et al, 2001) and among U.S. granite workers it was 0.05 mg/m3(Costello and Graham,

1988).

For average annual exposure, cut points were established at ≤ 0.05 (reference), >

0.05–0.1, > 0.1–0.15, > 0.15–0.2, and > 0.2 mg/m3. Cut points used for categorizing
9

cumulative silica exposure were first set at ≤ 0.5 (reference), > 0.5–1.0, >1.0–1.5, and >

1.5–3.0 mg/m3-years; however, because the authors observed no evidence of increased

lung cancer mortality or silicosis morbidity risk in these categories, they then redefined

the reference group as ≤ 3.0 mg/m3-years and established exposure cut points at >3–4,

>4–5, >5–6, and > 6 mg/m3-years. Re-grouping the reference group and re-stratifying the

exposure categories in this manner created a baseline with a greater exposure level,

lessening the gap between reference and effect levels, and therefore diminishing effects

that could have otherwise been elucidated if the reference group remained at ≤ 0.5.

Mundt et al. (2011) reported an exposure-response trend with radiographic

silicosis hazard ratios of 5.3, 7.3, and 6.8 for cumulative exposures >4 to 5, >5 to 6, and

>6 mg/m3-year, respectively, adjusted for age, gender, and smoking. Silicosis hazard

ratios were 1.1, 3.3, 13.6, and 23.2 for average annual exposures >0.05-0.1, >0.1-0.15,

>0.15-0.2, and >0.2 mg/m3, respectively; the hazard ratios increased with increased

average annual exposure, adjusted for duration of employment.

After controlling for age and smoking, the HRs for lung cancer mortality

associated with cumulative exposure were not statistically elevated for males or females.

However, there was a fairly consistent trend of increasing risk among males, with likely

attenuation above 6.0 mg/m3-years. The female HR estimates are uninformative since

four exposure strata, including the reference level, contained only one case. The relative

HRs raise questions about individual smoking status, which was unknown for 31% of the

population; smoking status was unknown for 11 of the 20 female cases. Observing lung

cancer among non-smokers is unusual in most occupational cohorts, and it’s unknown

whether other exposures – such as glaze pigments or furnace emissions – could have

influenced the study. Short-term employees are of particular concern because they may

have been heavier smokers than long-term employees, or they may have been subjects of

exposure misclassification (i.e., left employment because of high exposure conditions

that were not accurately captured in this retrospective exposure assessment).
10

The lung cancer mortality HRs associated with average annual exposure were

statistically significant in two of the four average annual exposure groups: 2.1 (95% CI

1.1-4.0) for average annual exposure group >0.05-0.1 mg/m3and 2.4 (95% CI 1.1-5.2)

for average annual exposure group >0.15-0.2 mg/m3, controlling for age, smoking, and

duration of employment. The authors reported more than 99% statistical power to detect a

relative risk for lung cancer of 1.5 at α = 0.05. However, it was unclear whether enough

workers were exposed above 3.0 mg/m3-years to detect a trend when using exposure to <

3 mg/m3-years as the reference group (Table 2 of Mundt et al.).

Mundt et al. (2011) notes that the validity of the exposure assessment was

evidenced by the “strong and statistically significant association seen between respirable

crystalline silica exposure and silicosis,” but the study does not support exclusion of lung

cancer mortality risk based on the exposure assessment alone. Silicosis morbidity could

be a more sensitive endpoint than lung cancer mortality: Unlike lung cancer, silicosis is

well-known as a signature disease – an outcome only associated with silica exposure and

not in the general population – allowing for more definitive attribution of silicosis cases

to crystalline silica exposure. Therefore, OSHA noted several limitations that might

preclude the conclusion that there was no association between silica exposure and lung

cancer.

The mean age of the cohort at the start of follow-up was 35 years (Birk et al.,

2009); thus, this was a relatively young cohort in which to observe lung cancer, which

typically has a long latency period. Birk et al. (2009) also acknowledged that workers

who were 75 years of age or older were excluded from the analysis because records were

missing for many of those workers. The authors claimed this would not have affected the

results because there were very few person-years in this age group. However, OSHA

noted that the absence of findings of an increased risk of lung cancer mortality might

have been influenced by the relatively young age of this cohort and the short follow up

period. The reported median age at silicosis determination was only 56 years old and only

9.2% of the cohort was deceased by the end of the follow up period. Mundt et al. (2011)

acknowledges this limitation and the value of extended follow up, stating that the lack of
11

increased risk of lung cancer was a preliminary finding and that consistent associations

could not be made. There was also a very strong healthy worker effect observed for lung

cancer in this population (SMR = 0.71, 95% CI = 0.56-0.89 for men; SMR = 0.72, 95%

CI = 0.44-1.12 for women) (Birk et al., 2009).

For the lung cancer analysis, the authors did not consider lagged exposures. The

method of using the lagged exposure increased the exposure-response for silicosis, but

it’s unclear why the authors did not consider lagged exposure for cancer. Even though

silicotics in other studies were reported to have subsequently died of lung cancer (even in

studies that did not link silicosis with lung cancer), Mundt et al. (2011) did not observe

any silicotics who developed lung cancer. The fact that 75% of cohort members with

silicosis were still alive at the end of the follow-up period suggests that a longer followup period may have been a more adequate way to detect lung cancer among this

population.

A separate analysis performed for silicosis (Table 3 in Mundt et al., 2011; erratum

Table 3 in Mundt et al., 2012) determined HRs for only those workers who were hired

since 1960, apparently when there was greater certainty about exposure estimates. This

increased the HR for silicosis in the >4-5 mg/m3-years and >6 mg/m3-years group, but

there were no silicosis cases in the >5-6 mg/m3-years group. The study authors do

acknowledge some possible exposure misclassification in the lower exposure groups

because some silicosis cases were detected in those groups.

The authors suggest the possibility of a threshold for lung cancer mortality;

however, no formal threshold analysis was conducted in this study. Elevated hazard ratios

were observed among the lower exposure groups, a statistically significant finding, with

no apparent trend associated with increasing exposure.

The inclusion of female workers in this study may have depressed the effects

noticed in previous studies on male workers. Risks of silicosis were lower among

females, possibly because they did not have job assignments with exposures as high as
12

males. The number of cancer cases in females appeared to be too small (i.e., n=20) to

make conclusions; nonetheless, the authors conducted a separate analysis of lung cancer

among women, and found no pattern in the HRs by exposure group. There is no

explanation given why men and women were combined for the analysis of silicosis risk,

but not combined for the analysis of lung cancer risk.
13

Comparison of Gamble and OSHA Reviews of Association between Respirable

Crystalline Silica and Lung Cancer

In March of 2009, 27 scientists from eight countries participated in an

International Agency for Research on Cancer (IARC) review to reassess carcinogenicity

of silica, other dusts, fibers, metals, and arsenic, which were previously classified as

Group 1 carcinogens (carcinogenic to humans) (IARC, 2009). The Working Group noted

the increased risk of lung cancer observed in various silica studies and reaffirmed that

crystalline silica dust is a Group 1 carcinogen (IARC, 2012).

Gamble (2011) reviewed the studies that IARC considered in reaching its

conclusion that there is a causal link between crystalline silica and lung cancer as well as

additional studies that were published after the IARC review. Gamble’s overall

conclusions were based on 19 exposure-response trends from 18 cohorts, and he

determined whether there was evidence of causality and exposure-response relationships

between respirable crystalline silica and lung cancer in each cohort. OSHA evaluated

most of the studies that Gamble reviewed, and Table 2, organized into the cohorts

identified by Gamble, compares Gamble’s conclusions with OSHA conclusions reported

in the OSHA background document for respirable crystalline silica (OSHA, 2013). The

table also notes where OSHA and Gamble’s conclusions were based on different studies

of the same cohort.

Gamble concluded that the weight of the evidence from occupational

epidemiology studies does not support a causal association between lung cancer and

crystalline silica exposure. In contrast OSHA preliminarily concluded that the human

studies the Agency reviewed provided ample evidence that exposure to respirable

crystalline silica increased the risk of lung cancer among exposed workers.
14

Table 2. Comparison of Gamble and OSHA Interpretations for Respirable Crystalline Silica Studies

Cohort and Referencea Evidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

U.S. Gold Mining

Steenland and Brown

(1995a)

Steenland and Brown

(1995b)

No No No No

Vermont Granite

Attfield and Costello

(2004)

Graham et al. (2004)

Gamble: Vacek et al.

(2009; 2011 [2010

Epub])

No, based

on Vacek

et al. (2009

and 2011)

Yes, based

on Attfield

and Costello

No, based

on Vacek et

al. (2009

and 2011)

Yes, based

on Attfield

and

Costello.

The Graham et al. study and an apparently

unpublished study by Vacek et al. (2009) found

no difference in mortality rate between workers

hired before and after dust controls were

implemented, suggesting no association between

silica exposure and lung cancer. However, OSHA

believed that results of the Attfield and Costello

(2004) study, based on a quantitative exposure

assessment for each cohort member, provided

evidence of a causal relationship. The background

document offered possible explanations for the

reduced standardized rate ratio (SRR) in the

highest exposure group in the Attfield and

Costello study (e.g., exposure misclassification,

survivor effect). OSHA used the Attfield and

Costello study in its risk assessment. Gamble

placed greater importance than OSHA on the
15

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

“intervention design” studies by Graham et al.

and Vacek et al. (2009), noting that the

intervention study design is the most powerful

design. Gamble described an intervention design

study as comparing mortality before and after

installation of dust controls (i.e., in pre- versus

post-1940 hires). Gamble disputed the

explanations for why excluding the high exposure

group in the Attfield and Costello study was

appropriate, and stated that the findings from the

Vacek et al. (2011) exposure-response studies

supported the findings of the intervention studies.

Gamble concluded that the more recent studies by

Vacek et al. should supersede the Attfield and

Costello and the Graham et al. studies, apparently

because the Vacek et al. studies had increased

numbers of cohort members, improved exposure

estimates, and an extended follow-up period. As

explained in more detail above, OSHA noted the

following limitations in the Vacek et al. (2011)

study: the exposure-response analysis included

workers from the highest exposure groups which

were the most uncertain and disproportionally

affected the exposure-response trend, therefore

failing to explore exposure-response relationships

at lower exposures found in modern operations;

author’s conclusions that increased lung cancer is

related to smoking is not supported by findings
16

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

for other smoking-related diseases; evidence of

confounding in regression models; failure to

account for healthy worker effect; likely

overestimate of smokers; and lack of age

adjustment for granite cohort versus general

population.

Diatomaceous Earth

Checkoway et al.

(1997)

Rice et al. (2001)

No Yes No Yes OSHA noted that the authors found a positive but

not monotonic dose-response trend and the

increased risk ratio was statistically significant in

the highest exposure group. The Rice analysis

was used in OSHA’s risk assessment.

Gamble concluded that the studies were

unreliable because of bias, confounding and

exposure misclassification in pre 1930 hires, who

may have been exposed to asbestos and to lower

levels of silica than estimated. After conducting

his own analysis to reduce exposure

misclassification and confounding by eliminating

pre 1930 hires and adjusting for smoking, Gamble

found no significant associations. OSHA

discussed analyses conducted to determine

possible confounding by asbestos exposure or

smoking and those analyses demonstrated that the

Checkoway et al. findings were not likely

confounded by either smoking or asbestos. In

addition, in their analyses, Checkoway included

only workers whose exposure to silica and

asbestos could be quantified.
17

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

UK Pottery

Cherry et al. (1998)

No Yes No Yes OSHA noted that mean exposure was related to

cancer, and silica exposures were higher in cases

than controls.

Gamble noted numerous limitations including

lack of effect with cumulative exposure,

questionable adjustment for confounding,

possible contribution of polycyclic aromatic

hydrocarbons, and possible bias because of

destroyed records for many cases.

Chinese Pottery

Gamble: Chen et al.

(2007)

OSHA: McLaughlin

et al. (1992)

No,

based on

Chen et al.

Yes (weak),

based on

McLaughlin

et al.

No, based

on Chen et

al.

Yes (weak),

based on

McLaughlin

et al.

The McLaughlin et al. study provided some

evidence of an association between silica and

lung cancer but the dose-response relationship did

not show a strong trend.

Gamble noted that the updated study by Chen et

al. did not show a causal relationship between

silica and lung cancer. However, IARC (2012)

noted the high correlation between silica and

polycyclic aromatic hydrocarbon (PAH)

exposures in this cohort and that adjustments for

PAHs by McLaughlin et al. increased relative

risks. Gamble stated that the Chen et al. (2007)

study was an improvement over the original study

because it better separated out confounding

effects. The OSHA review of the Chen et al.

(2007) paper is discussed below. OSHA

concluded that because of the high correlation

between silica and PAHs, the lack of effect on

lung cancer after adjustment for PAHs simply
18

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

means that the effects of the two compounds

cannot be separated.

Sardinia, Silicotic

Miners

Carta et al. (2001)

No No No No

South African Gold

Mining

Hnizdo et al. (1997)

Yes Yes Yes Yes OSHA concluded that of the South African

mining studies, this study used the most detailed

exposure estimates, thus reducing the possibility

of exposure misclassification. Although not

conclusive in isolation, OSHA believed the body

of evidence from the South African studies is

suggestive of an exposure-related association with

lung cancer.

Although Gamble’s conclusions about this study

were consistent with OSHA’s, he concluded that

the body of evidence from mining studies did not

support an association between lung cancer and

silica exposure. He also noted the authors'

observation that results of this study are

inconsistent from other mining studies and

discussed possible confounding by radon.

South African Gold

Mining

Reid and Sluis-Cremer

Equivocal Yes

(Apparent

causality if

the database

Equivocal Nonapplicable

(N/A)

Although study authors attributed increased lung

cancer mortality to lifestyle choices, OSHA noted

associations with other health endpoints related to

silica, such as renal failure and chronic
19

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

(1996) as a whole

is

considered.)

obstructive pulmonary disease. In addition, the

elevated odds ratio (OR) was nearly statistically

significant. Therefore, OSHA did not consider

this study to be inconsistent with Hnizdo et al.

(1997).

South African Gold

Miningb

Hessel et al. (1986)

Hessel et al. (1990)

No Unreliable No Unreliable Hnizdo et al. (1991, 1997) have suggested that

these studies might have been biased towards the

null by overmatching for exposure and including

smoking as a matching criterion (Hessel et al.,

1986), or by not matching on date of birth (Hessel

et al., 1990). Gamble also expressed bias from

overmatching as a possible limitation.

Australia Gold Mining

de Klerk and Musk

(1998)

No No in nonsilicotics

Yes, in

silicotics

No N/A Regarding the observation that lung cancer was

increased in silicotics, Gamble stated “This

suggests that silicosis is an intermediary, and

therefore the usual statistical methods of adjusting

for confounders do not provide interpretable

results.”

Chinese Tungsten

Gamble: Chen et al.

(2007)

OSHA: McLaughlin

et al. (1992)

No,

based on

Chen et al.

No,

based on

McLaughlin

et al.

No,

based on

Chen et al.

No,

based on

McLaughlin

et al.

Chinese Tin-Limu Equivocal Unreliable Equivocal Unreliable OSHA concluded that because silica and arsenic

were highly correlated, quantifying the effect of
20

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

Chen and Chen

(2002)

silica was not possible.

Gamble noted the small number of cases at Limu

but noted that results did not support an exposure

response relationship. Despite the non-monotonic

exposure-response trend and instability, Gamble

classified the results as equivocal because of the

high OR in the high exposure category.

Chinese Fe/Cu Mining

Gamble: Chen et al.

(2007)

OSHA: McLaughlin

et al. (1992)

No,

based on

Chen et al.

No, based

on

McLaughlin

et al.

No,

based on

Chen et al.

No,

based on

McLaughlin

et al.

Finnish Granite

Koskela et al. (1994)

No No No No

German Stone/Pottery

Ulm et al. (1999)

No Unreliable No Unreliable OSHA discounted this study because of low

exposures, limited cohort size, and imprecise

methods of exposure classification. Exclusion of

silicotics would have tended to over select

workers with lowest exposures, and exposures

were likely below the current silica PEL. Both

OSHA and IARC (2012) noted low power of the

study. Gamble presented the following arguments

against low power of the study: (1) Loss in power

by excluding silicotics is not known; (2) the
21

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

number of cases (114) is similar to the Chinese

pottery study (n=120) and higher than the UK

pottery study (n=52); (3) cumulative exposures

seem to be comparable to the UK pottery study.

U.S. Industrial Sand

Steenland and

Sanderson (2001)

Yes Yes Yes Yes

U.S. Industrial Sand

McDonald et al.

(2001)

Hughes et al. (2001)

McDonald et al.

(2005)

Yes Yes Yes Yes OSHA believed the studies of this cohort were

the most thorough and complete of the industrial

sand studies because of exposure data for

individual cohort members based on modern

methods of collection, availability of smoking

histories, long-term work experience, and use of a

nested case-control design. Data from the Hughes

et al. (2001) study were used in the OSHA risk

assessment.

UK Industrial Sand

Brown and Rushton

(2005a)

Brown and Rushton

(2005b)

No Unreliable No Unreliable OSHA believed that these findings should be

discounted due to low cumulative exposures,

unusual distribution of lung cancer deaths among

short-tenured workers, the young cohort with

inadequate accumulation of exposure years,

possible confounding or misclassification, and

lack of nested case-control study design. IARC

(2012) also noted limitations such as low silica

exposures, unusual lung cancer distribution, and

low power.
22

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

Gamble concluded this was clearly a negative

study and refuted many criticisms of the study

(i.e., exposures were also low in the U.S. studies;

and average follow-up time of 28 years was

adequate).

OSHA did verify in the background document

that exposures were lower in the Brown and

Rushton cohort than in the ten cohorts examined

in the pooled analysis by Steenland et al. (2001).

The background document also noted that for the

Brown and Rushton cohort, over one-half of the

deaths and almost three-fourths of the lung cancer

mortalities had less than 10 years of service.

German Porcelain

Mundt et al. (2011)

No Preliminary

results,

inconclusive

No Preliminary

results,

inconclusive

As described in more detail in the review of this

study above, OSHA noted these limitations:

findings are preliminary due to deaths in only

9.2% of the cohort; the cohort was young (mean

age 35) and workers 75 years or older were

excluded; regrouping of the reference group into a

cumulative exposure category of < 3.0 mg/m3-

year and restratification of exposure categories

resulted in a baseline with greater exposures and

therefore diminished ability to see effects; it was

unclear if enough workers were exposed to levels

above 3.0 mg/m3-year to detect a trend; results

were uninformative for women due to the low

number of cases among women; the cancer

analysis was not lagged; and there was evidence
23

Cohort and ReferenceaEvidence of Causality? Evidence of Exposure

Response?

Comments

Gamble OSHA Gamble OSHA

of exposure misclassification.

a

The cohorts listed in this table were those identified by Gamble in Table 1 of his review. Most of the studies referenced in this table

were part of a series of studies of the same cohort. For simplicity, only the most recent or key studies referenced by Gamble or OSHA

are included.

b

These South African gold mining studies were not identified as a cohort by Gamble, possibly because they overlapped with the other

South African gold mining studies listed in the table. However, this study is listed in the Table on page 460 of the Gamble review, and

was listed consistently in this table here. It appears to be the basis of Gamble’s statements about his review of 19 exposure-response

analyses from 18 cohorts.
24

In addition to the studies discussed by Gamble and summarized in Table 2, above, the

OSHA background document discussed a study of British Coal miners by Miller and

MacCalman (2009). Gamble did not discuss the Miller and MacCalman study. OSHA found it to

be a credible study that provided convincing evidence of the carcinogenicity of respirable

crystalline silica, and the study was used in OSHA’s risk assessment. That study further adds to

the weight of evidence that respirable silica exposure is associated with lung cancer.

For cohorts addressed in Table 2, the section below presents Gamble’s major points as

well as the basis for the differing findings by Gamble and OSHA, where relevant.

1. Gamble noted that studies reported discordant findings and the majority showed no

association between crystalline silica and lung cancer.

For the studies of cohorts summarized in Table 2, Gamble indicated that five (two of

which he classified as equivocal) provided evidence of a causal relationship, while 14 provided

no evidence of a causal association between respirable crystalline silica exposure and lung

cancer. In contrast, OSHA preliminarily concluded that nine of the studies in Table 2 provided

evidence of an association, five did not provide evidence of an association, and five of the

studies should be discounted because of limitations.

In contrast to Gamble, OSHA interpreted the majority of reliable studies (i.e., studies that

it did not discount because of study design limitations) in Table 2 as showing evidence of an

association between respirable silica exposure and lung cancer. Apparent reasons for the

differing conclusions of Gamble and OSHA were:

 The conclusion was based on different studies of the same cohort because OSHA and

Gamble had differing opinions on which study was most appropriate (e.g., Attfield and

Costello, 2004 versus Graham et al., 2004 and Vacek et al., 2009, 2011 for the Vermont
25

granite worker cohort). Interpretation of the Vermont granite studies is discussed in

greater detail below.

 Gamble’s decision was influenced by studies that OSHA had not reviewed in the

background document (e.g., Vacek et al., 2011 study for Vermont Granite workers; Chen

et al., 2007 study for Chinese pottery workers). (Subsequent reviews of these studies did

not change OSHA’s conclusions.)

 Studies considered to be reliable by OSHA were found to be limited by Gamble (e.g.,

Checkoway et al., 1997 study for diatomaceous earth workers; Cherry et al., 1998 study

for UK pottery workers). In his reanalysis of the Checkoway et al. (1997) study, Gamble

found no association between respirable crystalline silica exposure and lung cancer.

Gamble’s reanalysis is discussed in greater detail below.

 Studies that Gamble based his conclusion on were found to be unreliable by OSHA

because of limitations (e.g., Chen and Chen, 2002 study of Chinese Tin-Limu workers;

Ulm et al., 1999 study of German stone/pottery workers; Brown and Rushton, 2005a,b

study of UK Industrial sand workers).

 When Gamble found studies to be limited, he apparently interpreted them as showing no

evidence of an association (e.g., Cherry et al., 1998; Hessel et al., 1986, 1990), whereas

the most appropriate conclusion would likely be that the study is inconclusive or

unreliable.

Differences between Gamble’s and OSHA’s conclusions about the Vermont granite and

diatomaceous earth cohorts warrant further discussion.

Vermont Granite Studies

In interpreting the Vermont Granite studies, OSHA placed greater weight on quantitative

exposure studies, such as the study by Attfield and Costello (2004), than on non-quantitative

studies. Both OSHA and IARC considered the lack of quantitative exposure information in the

Graham et al. (2004) study to be a limitation. As noted in the OSHA background document, dust
26

levels decreased gradually from the time controls were introduced in 1940 through the time they

were fully implemented in 1955. Although most workers were likely exposed to lower levels of

dust as controls were being implemented, the levels were likely higher compared to levels after

controls were fully implemented.

However, Gamble stated that “intervention design” studies, such as those by Graham et

al. (2004) and apparently an unpublished study by Vacek et al. (2009) are the most powerful for

assessing causal associations or dust control effectiveness. Gamble described an intervention

study as comparing mortality in workers hired before and after installation of dust controls (i.e.,

in pre- and post-1940 hires). Gamble stated that the intervention studies have comparable weight

to the exposure-response analyses and stated that findings from the Vacek et al. (2011)

quantitative exposure response study supported the findings from the intervention design studies.

Gamble concluded that the most recent studies by Vacek et al (2009, 2011), which had the

largest cohort numbers, improved exposure estimates, and longest follow-up period, should

supersede the earlier studies by Attfield and Costello (2004) and Graham et al. (2004). However,

OSHA found numerous limitations for the Vacek et al. (2011) study, as described in the detailed

summary above and in Table 2, and did not consider it to be the key study for the Vermont

granite cohort.

One notable, possible limitation of the Vacek et al. (2011) study is that the exposure

estimates they used (from Verma et al., 2011) may not actually be an improvement over those

used by Attfield and Costello (2004). A major difference between the two exposure estimates is

that exposures for channel bar operators were estimated to be much lower by Verma et al. than

by Attfield and Costello. Verma et al. state that their estimates for channel bar operators were

much lower because those workers were doing wet drilling, while Attfield and Costello’s

estimates are based on dry drilling. However, such an assumption about wet drilling would fail to

account for dust generated from other activities conducted in the same area or that water may

not have always been used during channel bar drilling. Actual conditions in Vermont quarries in

the 1940s can be viewed at http://quarriesandbeyond.org/.
27

The differences between the Verma et al. (2011) and Attfield and Costello (2004)

estimates for wet channel operators could result in those workers being assigned from a higher to

a lower or reference group category. If the channel bar operators were incorrectly placed in the

reference group, the exposure-response relationship would be attenuated.

Diatomaceous Earth Studies

OSHA found the Checkoway et al. (1997) study of diatomaceous earth workers to be one

of the key studies for assessing associations between respirable crystalline silica and lung cancer.

However, Gamble concluded that the study was unreliable because of bias, confounding, and

exposure misclassification before 1930, resulting from uncertain exposure estimates and possible

co-exposure to asbestos. Gamble also claimed that, before 1930, uncalcined products, consisting

mainly of amorphous silica and less than 5% quartz, were the primary products at the plant and

therefore silica exposures may have been overestimated in the pre-1930 hires. However,

Checkoway et al. (1998) stated that their exposure estimates were based on company records

reporting crystalline silica concentrations in different products and annual production of natural,

calcined, or flux-calcined diatomaceous earth.

Gamble conducted his own analysis to reduce exposure misclassification and address

confounders by eliminating pre-1930 hires and adjusting for smoking; Gamble’s reanalysis

found no significant associations between lung cancer and silica exposure. However, OSHA

previously examined possible confounding by asbestos and smoking in the Checkoway et al.

(1997) study and continues to maintain that confounding likely did not influence the outcomes of

the study (OSHA, 2013).

Checkoway et al. (1996) was able to quantitatively characterize asbestos exposures in

workers hired after 1930 and determined that asbestos did not likely confound the association

between silica exposure and lung cancer. The Checkoway et al. (1997) study, which included pre
28

1930 hires, updated the cohort from the Checkoway et al. (1993) study by excluding 317 workers

whose exposures could not be adequately quantified and including 89 previously excluded

workers whose asbestos exposures could be quantified. No confounding by asbestos was

observed in this study which included only workers with the best exposure estimates.

Gamble demonstrated that adjustment for smoking resulted in reduced relative risks for

the Checkoway et al. (1997) study. Checkoway et al. (1997) also demonstrated a decrease in

relative risk from 2.15 to 1.67 in the highest exposure category by applying a worst case estimate

of 20 times greater lung cancer risk in smokers compared to nonsmokers. Rice et al. (2001) noted

that although the two highest exposure groups had comparable smoking prevalence, they had

substantially different rate ratios (1.26 versus 2.15). They also noted that smoking prevalence

was not related to cumulative crystalline silica exposure. Therefore, the evidence suggested that

smoking did not likely confound the result in the Checkoway et al. (1997) study.

Weight of Evidence Approaches

In general, OSHA and Gamble had fundamentally different approaches for weighing the

evidence. OSHA emphasized that the findings of the best designed studies are more important

than the total numbers of studies showing or not showing associations between respirable

crystalline silica exposure and lung cancer. While Gamble tended to add up the total of positive

and negative studies, OSHA placed the greatest weight on the best designed studies. An example

of the different approaches for weighing the evidence was demonstrated by the evaluation of the

Hessel et al. (1986, 1990) studies on South African gold miners. While both OSHA and Gamble

noted bias from overmatching, OSHA considered the Hessel et al. studies to be unreliable;

Gamble, however, counted the studies as showing no association between silica and lung cancer

and included them as part of the weight of the evidence. Another example was the Cherry et al.

(1998) on British pottery workers. Although the study showed that lung cancer was related to

average silica exposure and was considered to be a key study by OSHA, Gamble felt the study

was limited by confounding and bias. Instead of labeling it as unreliable or inconclusive, though,
29

Gamble weighed it as showing no evidence of an association. As noted above, OSHA did not

consider studies it judged to be unreliable in assessing the weight of evidence for carcinogenic

potential of silica.

OSHA gave studies greater weight and consideration if they (1) included a robust number

of workers; (2) had adequate length of follow-up; (3) had sufficient power to detect modest

increases in lung cancer incidence and mortality; (4) used quantitative exposure data of sufficient

quality to avoid exposure misclassification; (5) evaluated exposure-response relationships

between exposure to silica and lung cancer; and (6) considered confounding factors including

smoking and exposure to other carcinogens.

OSHA noted that the following studies from five industry sectors met the Agency’s criteria

for the best designed studies:

 Diatomaceous earth (Checkoway et al., 1997)

 British pottery (Cherry et al., 1998)

 Vermont granite (Attfield and Costello, 2004)

 North American industrial sand (Hughes et al., 2001; McDonald et al., 2001, 2005;

Steenland and Sanderson, 2001)

 British coal mining (Miller and MacCalman, 2009)

Collectively the studies of the cohorts listed above, in addition to the pooled analysis

(Steenland et al., 2001), provided evidence of an association between exposure to respirable

crystalline silica and lung cancer.

Studies Not Included in the Background Document (OSHA 2013)

Since the background document was written, two new studies examining possible

associations between exposure to respirable crystalline silica and lung cancer were published,
30

one examining the Vermont granite cohort (Vacek et al., 2011) and one of German porcelain

workers (Mundt et al., 2011). Both of these studies are reviewed above, and OSHA did not

consider either of them to be key studies.

In addition, a study by Chen et al. (2007), examining the same cohorts of Chinese

pottery workers, iron/copper miners, and tungsten miners that were examined by McLaughlin et

al. (1992), was discussed by Gamble but was not reviewed in the OSHA background document.

Therefore we review the study at this time. Our review of the Chen et al. (2007) study is limited

to the Chinese pottery workers cohort because that was the only result that differed from that

reported by McLaughlin et al. (1992). Whereas McLaughlin et al. (1992) reported a weak

association between exposure to respirable crystalline silica and lung cancer, Chen et al. (2007)

reported no association for pottery workers.

The nested case-control study of Chinese pottery workers by Chen et al. (2007) included

120 cases and 459 controls, a greater number than the 62 cases and 238 controls in the

McLaughlin et al. (1992) study. Whereas McLaughlin et al. (1992) reported estimated

percentages of respirable dust and silica content of total dust only for facilities, Chen et al.

(2007) estimated average values for each facility, job title, and calendar year. Chen et al. (2007)

also estimated cumulative exposures by using a conversion factor for total dust and respirable

silica. They estimated exposure to polycyclic aromatic hydrocarbons (PAHs) based on

monitoring conducted between 1987 and 1988. Possible association between respirable silica

exposure and lung cancer mortality was determined by conditional logistic regression analysis, a

matched-regression method. Chen et al. (2007) reported that the method allowed for control of

residual confounding by smoking and occupational confounders such as PAH.

Chen et al. (2007) stratified cumulative respirable crystalline silica exposure into the

following quintiles: 0.1–1.1, 1.1–2.6, 2.6–5.4, 5.4–10.1, and 10.1–72.4 mg/m3-year. Exposure to

PAHs and respirable crystalline silica were highly correlated (Pearson’s correlation coefficient =

0.57–0.80). In pottery workers, odds ratios (95% CI) for lung cancer mortality, lagged for 15
31

years and adjusted for smoking, in each respective silica exposure category were 0.8 (0.29, 2.19),

1.3 (0.63, 2.64), 1.7 (0.82, 3.58), 1.5 (0.71, 3.21), and 3.5 (1.45, 8.66). When the values were

adjusted for both smoking and PAH exposure, respective odds ratios (95% CI) were 0.7 (0.25,

1.98), 0.7 (0.29, 1.81), 0.7 (0.25, 2.19), 0.5 (0.15, 1.84), and 0.9 (0.19-4.32). Therefore, Chen et

al. concluded that risk of lung cancer in Chinese pottery workers was related to PAH exposure

and not to respirable crystalline silica exposure.

However, as was noted above, exposures to respirable silica and PAHs were highly

correlated in Chinese miners and pottery workers (r = 0.057–0.80). OSHA notes that if respirable

crystalline silica and PAHs exposures are correlated, the fact that the association between

respirable crystalline silica and lung cancer becomes nonsignificant after adjustment for PAHs

does not mean that respirable crystalline silica is not a risk factor. It means that the effects of the

two exposures cannot be separated and that PAHs are adjusting out the real effect of respirable

crystalline silica. A pooled analysis of the mining and pottery cohorts also showed no association

between respirable crystalline silica exposure and lung cancer.

McLaughlin et al. (1992) did adjust for PAH exposure in their analysis, but Gamble

(2011) claimed that the Chen et al. (2007) study better separated out confounders. The IARC

working group noted the high correlation (r = 0.56) between silica and PAH exposure in this

cohort and that the original adjustment for PAHs in the analysis by McLaughlin et al. raised

rather than lowered relative risks (IARC, 2012). The 2012 monograph from the IARC working

group does not express preference for either the McLaughlin et al. or Chen et al. study Section

2.3 “Synthesis” of the IARC (2012) monograph states “in another (Chinese pottery workers),

adjustment for PAHs removed a significant crystalline silica exposure effect. . .” That statement

from the IARC working group implies that confounding could not be resolved in the cohort of

Chinese pottery workers.

Regardless, the Chinese pottery cohort was not one of the key ones that influenced

OSHA’s decision. The Chinese pottery cohort, represented by hundreds of workers, was much
32

smaller than the Vermont granite, U.S. industrial sand, UK pottery, diatomaceous earth, and UK

coal mining cohorts, which were comprised of thousands of workers. Although the Chinese

pottery cohort was included in the IARC pooled analysis, removal of the Chinese study from the

pooled analysis did not appreciably change the exposure coefficient (Steenland et al., 2001).

Therefore, the findings from the Chen et al. (2007) pottery workers cohort are unlikely to affect

the weight of evidence for determining an association between respirable crystalline silica

exposure and lung cancer.

2. Gamble noted a tendency for studies with higher cumulative exposures to have weak or

non-existent associations.

As indicated above, OSHA found that studies in diatomaceous earth workers, British

pottery workers, Vermont granite workers, North American sand workers, and British coal

mining workers were well designed and provided evidence of an association between respirable

crystalline silica exposure and lung cancer. Studies in those cohorts demonstrated exposureresponse relationships between exposure to respirable crystalline silica and lung cancer

mortality. With the exception of the British pottery worker study that demonstrated exposureresponse relationships only with average exposures (Cherry et al., 1998), the studies reported

associations with cumulative exposures (Checkoway et al., 1997; Attfield and Costello, 2004;

Graham et al., 2004; Hughes et al., 2001; McDonald et al., 2001, 2005; Steenland and

Sanderson, 2001; Miller and MacCalman, 2009). Table 3 summarizes unit risks per exposure

category of cumulative exposure for the key studies that provided that information.

As noted in Table 3, most studies demonstrated positive exposure-response trends,

especially at higher exposures. An exception was the study by Attfield and Costello (2004) that

demonstrated a negative exposure-response trend at the highest exposure category. As noted in

the OSHA background document, Attfield and Costello (2004) stated that underlying exposure

data for the highest exposure group was more likely to include unreliable exposure estimates

because 83 percent of the workers in that group had 20 or more years of exposure before the
33

introduction of controls, when exposure measurements were most uncertain. They also noted

possibilities of “a highly selected healthy worker” effect and that lung cancer may have been

obscured by competing high rates of silicosis and tuberculosis deaths. The “highly selected

healthy worker effect” describes a situation where short term workers might leave the workplace

because of disease, resulting in lower cumulative exposures or depletion of susceptible workers

(Stayner et al., 2003). Medical surveillance leading to removal of affected workers from the

exposure can also complicate exposure estimates (Park and Chen, 2012). Therefore, even given

the negative exposure-response trend in Attfield and Costello’s highest exposure category, the

key studies overall support an exposure-related trend.
34

Table 3. Unit Risks for Categories of Exposure in Key Respirable Crystalline Silica Studies

Cohort and Reference Unit Risk for Increasing Categories of

Exposure

Diatomaceous Earth

(Checkoway et al., 1997)

SRR (95% CI) for lung cancer for

cumulative exposure lagged 15 years:

1.00, 0.96 (0.47–1.98), 0.77 (0.35–1.72),

1.26 (0.62–2.57) and 2.15 (1.08–4.28);

trend slope (adjusted) = 1.05 (95% CI 0.99-

1.11)

Vermont Granite

(Attfield and Costello, 2004)

SMRs for lung cancer mortality, for

untransformed cumulative exposure lagged

15 years: 77, 98, 126, 125, 133, 147, 170,

and 116 (trend not significant with high

exposure group; p<0.005 without high

exposure group)

U.S. Industrial Sand

(McDonald et al., 2005)

For cumulative exposure lagged 15 years,

lung cancer odds ratios were: 1.00, 0.94,

2.24, and 2.66 (p for trend = 0.006).

U.S. Industrial Sand

(Hughes et al,. 2001)

Lung cancer mortality odds ratios lagged

15 years for cumulative exposures: 1.00,

0.84, 2.02 and 2.07 (p for trend = 0.04).

U.S. Industrial Sand

(Steenland and Sanderson, 2001)

Lung cancer mortality odds ratio lagged 15

years for cumulative exposure: 1.0, 1.35,

1.63 , 2.00 (p for trend = 0.08)

Consistent with Gamble, OSHA acknowledged that the associations between exposure to

respirable crystalline silica and lung cancer are not strong. OSHA further noted that the weak
35

effect makes it more difficult to detect association because errors in exposure estimates or

outcomes tend to bias results toward the null. Because it is more difficult to detect an increased

cancer risk for low-potency carcinogens, inconsistent findings are expected and do not preclude

concluding that a compound is carcinogenic. Furthermore, a study that does not show a

statistically significant increase in carcinogenicity may not necessarily be inconsistent with a

study that does show a statistically significant increase. A closer examination of the study with

the nonsignificant findings may reveal trends that are consistent with the study showing a

significant association. An example is the Hnizdo et al. (1997) and Reid and Sluis-Cremer (1996)

studies in miners.

To address the inconsistent study results, OSHA considered pooled exposure-response

analyses looking at larger numbers of subjects. IARC sponsored a pooled exposure-response and

risk assessment for lung cancer in 10 cohorts of silica-exposed workers, with 65,980 workers and

1,072 lung cancer deaths (Steenland et al., 2001). Steenland et al. (2001) found a monotonic

increase in lung cancer odds ratios with quintiles of cumulative exposure, cumulative exposure

lagged 15 years, and average respirable silica concentration. For the pooled categorical analysis

with cumulative exposure lagged 15 years, the odds ratios (95% CI) for ascending quintiles of

exposure were 1.0 (0.83-1.3), 1.3 (1.0-1.6), 1.5 (1.2-1.8), and 1.5 (1.2-1.9).

OSHA had Steenland and Bartell conduct a quantitative uncertainty analysis

(Toxichemica, 2004). The analysis resulted in a mean pooled exposure coefficient, which was

only slightly lower than the coefficient originally reported by Steenland et al. (2001), with a

variance around the estimate of the mean comparable to the level of statistical uncertainty

associated with the use of the log-linear model in the original analysis. This suggested that

uncertainties in exposure estimates were not likely so great that the finding from the original

pooled analysis should be questioned.

Gamble (2011) criticized the pooled analysis by Steenland et al. (2001) because: (1) it

included the tin miner cohort which he felt should have been excluded because of confounding

from arsenic; (2) only four of nine cohorts had statistically significant exposure-response trends;
36

and (3) five studies were excluded from the analysis. OSHA disagrees with Gamble’s criticism

because the purpose of the pooled analysis was to see if there was an overall relationship across

all studies conducted up to that time for which quantitative exposure data were available . The

OSHA background document noted that (1) analysis performed with and without the three

Chinese studies, which were possibly confounded, did not result in an appreciable change in the

pooled exposure coefficient; (2) the purpose of the pooled analysis was to address inconsistency

in study findings and would therefore include studies with no statistically significant findings;

and (3) three cohorts that had adequate quantitative exposure data were excluded from the pooled

analysis because data were unavailable or because data were incompatible with a case-control

study design. In closing, the pooled analysis conducted with large numbers of cases provided

additional evidence of an association between exposure to respirable crystalline silica and lung

cancer.

Conclusion

The main reason for the discordant conclusion regarding associations between crystalline

silica exposure and lung cancer reached by OSHA and Gamble were (1) different opinions

regarding the reliability and usefulness of individual studies in the data set and (2) different

methods for assessing weight of evidence. In the background document on respirable crystalline

silica, OSHA thoroughly evaluated the strengths and limitations of each study; the Agency

stands by its interpretations of study reliability. In weighing the evidence, OSHA considered

only the best designed studies, and believes that approach is more appropriate than simply

summing up the number of positive and negative studies. Based on substantial evidence of an

effect in the best designed studies, OSHA maintains that the weight of the evidence supports an

association between exposure to respirable crystalline silica and lung cancer.
37

Review of Cox (2011): An Exposure-Response Threshold for Lung Diseases and Lung

Cancer Caused by Crystalline Silica.

An exposure-response threshold for lung diseases in humans caused by exposure to

respirable crystalline silica has been theorized, but not conclusively demonstrated. The

extrapolation of risk observed in humans exposed to much lower levels remains problematic,

including the use of exposure-response models to extrapolate risks observed at higher exposure

levels to estimate risks at the lower end of the exposure-response curve. The paper by Cox

reviews the evidence for a quantifiable exposure-response threshold in animals based primarily

on a biological mode of action through which the inhalation of silica particles induces changes in

the lung that lead to the development of lung disease only when a critical lung burden, or

threshold, is exceeded. A mode of action is described through which exposure to poorly soluble

particles in general, and crystalline silica in particular, can lead to a variety of lung diseases,

including silicosis, chronic inflammation, fibrosis, lung cancer, and chronic obstructive

pulmonary disease. The paper reviews evidence from animal studies that suggest a threshold

exists for a lung burden that triggers inflammation that could lead to a variety of diseases,

including both silicosis and lung cancer. However, the conclusion stated in the article that the

current PEL for crystalline silica is “probably” below a threshold for lung disease in humans,

including cancer, is not supported by the evidence presented.

The paper also asserts that exposure misclassification in human epidemiological studies

leads to underestimation of exposure-response thresholds. A mathematical simulation is

presented to demonstrate the theoretical effect of exposure measurement error on the ability of an

epidemiological study to observe a hypothetical exposure-response threshold. In the simulation,

the “true” response threshold is assumed to be 15 mg/m3-years, such that the risk of disease

below the threshold is 0, and the risk above the threshold is 1. A hypothetical population of

10,000 workers is assumed to be uniformly exposed to between 0 and 20 mg/m3, so that any

employee exposed above the threshold of 15 mg/m3 would be a “case”, and employees below the

threshold remain disease free. Simulated exposure measurement error is introduced by

multiplying the assigned exposure by a random value, k, that is uniformly distributed between 0
38

and 2, with a mean of 1 (i.e. no error). The randomization results in some individuals who were

assigned exposures above the threshold (risk=1) to below the threshold (risk=0), and conversely

moves other subjects from below the threshold to above the threshold. The introduction of

random measurement error changes the slope of the hypothetical exposure response curve from a

step function to a smooth curve, with an “observed” threshold now lower than the assumed value

of 15 mg/m3-years. However, the simulation is based entirely on the unrealistic assumption that a

distinct threshold exists below which risk is zero and above which the risk is one, and therefore,

provides no empirical evidence of systematic bias in the determination of an actual exposureresponse threshold in epidemiologic studies. The author then cites a study that observed

diminished lung function at estimated exposures to respirable silica dust in excess of 0.1-0.2

mg/m3for 30 to 40 years (Rushton, 2007), and asserts that based on the simulation model, the

“true” threshold is likely to be as high as 0.4 mg/m3, but acknowledges that this estimate is based

on unproved assumptions.

OSHA believes that Kuempel et al. (2001) developed a more credible estimate of an

exposure threshold for excess risk of lung cancer in humans from exposure to respirable

crystalline silica based on biological mechanisms and statistical models. (Kuempel et al., 2001).

In this analysis, an evaluation of both linear and nonlinear (threshold) models determined that the

average minimum critical quartz lung burden (Mcrit) in rats associated with reduced pulmonary

clearance and increased neutrophil inflammation was 0.39 mg quartz/g lung tissue. Mcrit is

based on the lowest observed adverse effect level in a study in rats (Porter et al., 2002). A human

lung dosimetry model, developed from respirable coal mine dust and quartz exposure and lung

burden data in UK coal miners (Tran and Buchanan, 2000), was then used to estimate the

human-equivalent working lifetime exposure concentrations associated with lung doses such as

Mcrit. An 8-hour time-weighted average (TWA) concentration of 0.036 mg/m3over a 45-year

working lifetime was estimated to result in a human-equivalent lung burden to the average Mcrit

in rats. The human lung burdens associated with working lifetime exposure concentrations (8-

hour TWA) of 0.05 and 0.1 mg/m3– the current NIOSH REL and OSHA PEL, respectively –

were estimated to be 0.54 and 1.08 mg quartz / g lung, respectively. In addition, the 45-year
39

working lifetime 8-hour TWA concentration associated with the 95% lower confidence limit of

Mcrit in the rat was estimated to be 0.005 mg/m3. This value is consistent with the no observed

adverse effect levels for silicosis estimated in human studies (Rice and Stayner, 1995). Kuempel,

et al.’s estimates of excess lung cancer risk in humans exposed to crystalline silica, which was

based on lung burdens in rats, are similar to those based on the human occupational

epidemiology studies. It also suggests that workers exposed for a full working lifetime at current

exposure limits have an excess risk of developing lung cancer, whether these risk estimates are

derived using models that assume a biological mechanism of direct genotoxicity (low-dose

linear) or indirect genotoxicity (non-linear) acting through chronic pulmonary inflammation.

A review of epidemiologic studies has also attempted to answer the question of whether

silicosis is a necessary precursor to lung cancer in silica-exposed individuals. Checkoway and

Franzblau (2000) reviewed 17 studies of lung cancer mortality among silicotics. They concluded

that the question of whether silicosis is required for elevated lung cancer risk in silica-exposed

individuals cannot be answered from currently available epidemiologic literature, and that risk

assessments should consider silicosis and lung cancer in silica-exposed individuals as separate

entities whose cause/effect relations are not necessarily linked.
40

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