Sarcoidosis in Northern Ontario hard‐rock miners: A case series

Abstract Sarcoidosis is a rare multisystem granulomatous disease traditionally considered to be of unknown etiology. The notion that sarcoidosis has no known cause is called into question with the increasing number of case reports and epidemiologic studies showing associations between occupational exposures and disease published in the past 10–20 years. Occupational exposures for which associations are strongest and most consistent are silica and other inorganic dusts, World Trade Center (WTC) dust, and metals. Occupations identified as at‐risk for sarcoidosis include construction workers; iron‐foundry and diatomaceous earth workers; WTC emergency responders; and metal workers. We report here 12 cases of sarcoidosis in a cohort of hard‐rock miners in Northern Ontario, Canada. To our knowledge sarcoidosis has not been reported previously in hard‐rock miners. The cases are all male and Caucasian, with average age 74 years. At the time of diagnosis, two were never smokers; six, former smokers; and four, current smokers. Five have extrapulmonary sarcoidosis: two cardiac and three endocrine (hypercalciuria). Using occupational histories and air sampling data from the gold, uranium, and base‐metal mines in which they worked, we examined exposure of each case to respirable crystalline silica (RCS). The annual mean RCS exposure for the 12 cases was 0.14 mg/m3 (range: 0.06–1.3 mg/m3); and the mean cumulative RCS exposure was 1.93 mg/m3 years (range: 0.64–4.03 mg/m3 years). We also considered their exposure to McIntyre Powder, an aluminum powder used for silicosis prophylaxis.


| INTRODUCTION
Sarcoidosis is a rare multisystem granulomatous disease. First described by Jonathan Hutchinson in 1877 and named "sarkoid of the skin" by Caesar Boeck in 1899 because of its resemblance to sarcoma, sarcoidosis is an immunologically mediated disorder affecting primarily the lungs and lymph nodes. [1][2][3] Other organs affected include liver, spleen, heart, eyes, and skin. The formation of noncaseating granulomas is the pathologic hallmark of the disease. 4 Major diagnostic criteria have been set forth by the American Thoracic Society. 5 These are: (1) consistent clinical presentation, (2) noncaseating granulomas in one or more tissue samples, and (3) exclusion of other diseases. For the most part sarcoidosis is a sporadic (nonfamilial) disease, occurring in families in 3.6%-9.6% of cases. 6,7 Sarcoidosis has long been considered a disease of unknown cause, that is, idiopathic. Over the past 20 years a number of case reports, epidemiologic studies of exposed workers, and scientific reviews have been published that show associations between certain workplace exposures and the development of sarcoidosis. Cases of sarcoidosis have been reported in a tunnel worker, a denim sandblaster, iron-foundry workers, and a plasterer, all exposed to silica. [8][9][10][11] In 1998 Rafnsson et al. 12 published the results of a case-control study showing increased risk of sarcoidosis in a cohort of diatomaceous earth workers in Iceland exposed to cristobalite and quartz. Increased risk for disease has been observed in construction and iron foundry workers, and in World Trade Center (WTC) emergency responders. [13][14][15][16][17] Scientific reviews of occupational exposures and sarcoidosis have been conducted by Newman and Newman, 18 and more recently by Oliver and Zarnke. 19 The strongest and most consistent associations have been observed for silica, WTC dust, and metals. [8][9][10][11][12][13][14][15][16][17][20][21][22] The purpose of this report is to describe a series of 12 cases of sarcoidosis in a group of hard-rock miners in Northern Ontario, Canada.
We believe that the occurrence of 12 cases of this rare disease in a group with occupational exposure to silica and metal dusts is consistent with previously reported associations and noteworthy. To our knowledge, this is the first such report in hard-rock miners.
There are three types of hard-rock mines in Ontario: gold, uranium and other base metal (i.e., nickel, copper, zinc). A historical perspective is helpful in assessing dust exposures incurred by hard-rock miners over In the mid-1970s personal exposures to respirable dust and respirable crystalline silica (RCS) began to be measured using portable, size-selective samplers and reported in gravimetric units of milligrams per cubic meter (mg/m 3 ). Verma et al. 23 derived conversion factors to allow for the conversion of the earlier ppcc values to mg/m 3 . It is against this backdrop that our series of sarcoidosis cases is presented.

| Study population
The sarcoidosis cases are members of a group of hard-rock miners exposed to a finely ground aluminum powder (McIntyre Powder [MP]) used by mining companies for silicosis prophylaxis during the period 1943-1979. 24,25 Gold and uranium miners were more likely to be exposed than workers in other types of mines. This practice was discontinued in 1979 after it was found to be ineffective in preventing silicosis.

| Medical and occupational history
The cohort was assembled by the recruitment of miners exposed to MP. 26 A voluntary registry of MP-exposed miners was established based on research on the use of MP in Northern Ontario mines. In 2016 intake clinics were held in two mining communities to obtain demographic information, medical and family histories, and occupational and environmental exposure histories. Participation was invited from MP registrants and members of the two mining communities.
The intake clinics were staffed by a multidisciplinary group of health professionals: experienced physicians and occupational health nurses, industrial hygienists, and ergonomists. The clinics were carried out with the cooperation and assistance of representatives of labor and Ontario-government-funded organizations and agencies.
One of these organizations, Occupational Health Clinics for Ontario Workers (OHCOW), was instrumental in providing financial and organizational support for the intake clinics and for the collection, organization, and subsequent analysis of the information collected.
Intake clinic staff administered detailed questionnaires designed to obtain health information, a chronologic lifetime work history, and job-specific exposure information. Where the miner was deceased or incapacitated due to illness, interviews were conducted with next-ofkin or the executor of the miner's estate (often the same). Mandatory training was held for interviewers.
Registration of MP-exposed miners has continued following the intake clinics and is ongoing in 2021. Telephone interviews are conducted by an experienced occupational health nurse (D. P.) and questionnaires administered. In addition, medical records and work-

| Case definition
Cases in the series are miners in the MPPD who answered "yes" to the question "Have you ever been diagnosed with sarcoidosis, sarcoid-like disease, or granuloma?" or for whom a review of their medical records indicated a diagnosis of sarcoidosis. In each case, a detailed medical record review was then carried out to determine level of certainty for the diagnosis of sarcoidosis.
"Definite" sarcoidosis was defined based on the following: a consistent clinical picture; noncaseating granulomas in at least one tissue sample; and exclusion of other causes of granulomatous disease. 3 For example, in two cases with the potential for occupational exposure to beryllium (Be), negative results of Be lymphocyte proliferation tests (LPTs) were used to exclude chronic beryllium disease.
"Probable" sarcoidosis was defined as meeting the same criteria, with one exception: Although the medical record described biopsyconfirmed sarcoidosis, there was no confirmatory histopathology report in the record. In most cases, the report was inaccessible because the biopsy was performed more than 25 years earlier. "Possible" sarcoidosis cases were those with diagnosis by a treating physician but a file that lacked sufficient confirmatory information. Cases were considered "unlikely" when alternative diagnoses had been made. Approximately 65% of the records in OMED are for respirable dust, RCS, and radon. The remainder of the records are for a wide range of other contaminants in the mining environment. The OMED database has been developed further by OHCOW to make it searchable using a number of criteria (i.e., mine, type of contaminant, type of sample, task or location, etc.). Although some sampling data are available from the mid-1950s, the majority of data are from 1970 to 1991. More than 4200 RCS measurements from gold, uranium, and nickel mines are contained in the OMED database. OMED was used as the source for our RCS exposure estimates.
Using detailed work histories and qualitative exposure information available for each miner from the intake questionnaires and confirmed by the Ontario MMF, we searched OMED by mine worked, job title and/or work tasks, and time period, and extracted RCS exposure data. A limitation of OMED is that sampling data are not available for all mines or for all periods worked by the cases. Where results for a specific mine and/or occupation or task were unavailable, overall data for the type of mine were used (e.g., all gold mines combined for the same job title or task and period). For the period 1950-1976, dust counts in ppcc were converted to mg/m 3 using the conversion factors derived by Verma et al. 23 Cumulative RCS exposures were calculated by multiplying the total number of years by the means and ranges of RCS exposure.
Latency was calculated by subtracting the year of initial RCS exposure from the year of sarcoidosis diagnosis.

| McIntyre Powder
Ontario gold and uranium miners were required to inhale MP for a prescribed time before each work shift. MP was administered at an airborne concentration of 35.6 mg/m 3 in a custom-designed airtight locker room (the mine dry) for 10 min before each shift, for an 8-h time-weighted average exposure of 0.74mg/m 3 (35.6 mg/m 3 × 10 min/480 min). 24,25 The standardization of the MP aluminum prophylaxis program makes it likely that airborne concentration of MP was fairly constant across sites.
MP was originally reported to be composed of 15% metallic aluminum and 85% aluminum oxide, but contemporary analysis of the powder has shown it to be primarily composed of aluminum hydroxide. 24

| Other contaminants
Underground miners in Ontario were exposed to other airborne contaminants such as diesel exhaust, metal dust (i.e., zinc, copper), blasting agents, oil mist, and tungsten carbide. Although OMED contains some data on these contaminants, we determined that the data are too limited for use in quantitative estimates. 23 However, these findings are noteworthy in a qualitative sense to underscore the range of exposures encountered by Ontario miners.

| RESULTS
As of May 21, 2021, a total of 506 miners were registered and interviewed. Of these, 16 miners reported a history of sarcoidosis. In one additional case, initial review of the medical records obtained as part of the registration and intake process revealed a diagnosis of sarcoidosis by treating physicians. Health and work histories were obtained from the miners themselves in all but one case. In this case, because of the miner's diagnosis of dementia, information was obtained from his daughter who held Power of Attorney. Twelve cases were categorized as definite (n = 8) or probable (n = 4) sarcoidosis.
Three were categorized as possible and 2 as unlikely. Data analysis was limited to definite or probable cases.

| Demography and clinical findings
Demographic variables and smoking history are shown in Table 1. All are White males. Average age for the group as a whole is 74 years (range: 65-88 years). Distribution by smoking status at the time of sarcoidosis diagnosis is as follows: nonsmoker 2 (16.7%), former smoker 6 (50%), and current smoker 4 (33.3%).
Clinical findings and workers' compensation status are shown in Table 2. Diagnosis of sarcoidosis was made based on mediastinal/ hilar lymph node biopsy in 11 cases and lung biopsy in 1. The diagnosis was made in the usual course of medical care and not as a result of participation in Ontario's Ministry of Labour Mining Surveillance Program, which included periodic chest X-rays, spirometry, and physical examination. In two cases, occupational history revealed the potential for Be exposure; BeLPTs were negative in both cases.
Average age at diagnosis is 48.7 years (range: 29-71) for the group as a whole. Eleven had mediastinal/hilar lymph node involvement; and five, parenchymal disease. Five (41.6%) had extrapulmonary sarcoidosis, with clinical manifestations of disease in the endocrine system (hypercalciuria) in three (25%) and the heart in two (16.7%). 28

| Case 3
This 84-year-old White male was diagnosed with sarcoidosis in 2008 at age 71. CT scan showed right middle lobe atelectasis and a masslike area of increased density in the right hilum. He was asymptomatic; PFTs showed mild obstruction with mildly impaired gas exchange. Bronchoscopy and cervical mediastinoscopy with lymph node biopsies were performed. Pathologic interpretation was "Con-    Using provincial employment records, the OCRC matched 36,821 current and former hard-rock miners with Ontario health database records covering the period between 1991 and 2018. 29 Of these, close to 14,000 were exposed to MP during the course of their employment. Our sarcoidosis cases came from this group. To our knowledge, this is the first report of sarcoidosis in hard-rock miners and the first to examine RCS exposures in detail.

| Case characteristics
The cases in our series are unusual in certain respects. These include demography, smoking status, and clinical phenotype.

| Demography
Our cases are male and White; whereas sporadic cases of sarcoidosis in the general population occur at higher rates in women and in African Americans. 6,30 Gender and race likely reflect the Northern Ontario mining population from which they came, which is almost exclusively male and largely Caucasian. 29 With regard to age at diagnosis, our cases resemble the overall population averages reported by Arkema and Cozier. 31

| Smoking status
Smoking appears to have a protective effect with regard to risk for sarcoidosis in the general population. 31,32 Most of our cases were current or former smokers at the time of diagnosis. Jonsson et al. 13 in their study of a cohort of silica-exposed Swedish construction workers observed an increase in risk among ever-smokers and no increase in risk among never-smokers. A potentially confounding factor is the selection of sarcoidosis cases from the national inpatient register, as smokers are more likely than nonsmokers to be hospitalized.

| Extrapulmonary sarcoidosis
An estimated 30%-50% of sarcoidosis cases in the general population have extrapulmonary involvement. 6 Twenty-five percent of our cases had evidence of endocrine sarcoid, compared to 10%-30% of the general population. 28 None of the NYC firefighters had abnormal calcium metabolism.

| Type of presentation
Acute presentation of sarcoidosis was observed in one of our cases.
Consistent with the more typical presentation in the context of Lofgren's syndrome (LS), symptoms resolved spontaneously within a 2-year period of time. 37 Human leukocyte antigen (HLA)-type genes have been associated with increased risk for LS. 37 A commonly held assumption is that surface mining operations have much lower RCS exposures than those in underground mining.
However, the OMED data and our findings show that surface operations such as milling or refining generate RCS concentrations that are similar to or greater than those of underground operations.
The effect of MP exposure on risk for sarcoidosis is unclear. As an aluminum powder, MP may have contributed directly to granuloma formation in the cases in our series. Peters et al. 39 conducted a mortality study of Australian gold miners exposed to MP in the 1950s and 1960s for silicosis prophylaxis. Although sarcoidosis was not examined as an outcome, no excess death from pneumoconiosis was observed.
Aluminum exposure in refinery and production workers has been associated with pulmonary fibrosis and granuloma formation. 40 The incidence of granulomatous reactions in the lungs of aluminum- Clinical work-up for sarcoidosis, including Kveim test, was negative.
Aluminum LPT using peripheral blood lymphocytes was positive.
Analytical electron microscopy of lung tissue obtained by transbronchial biopsy revealed aluminum particles within the granuloma cells. In a report of two cases of granulomatous lung disease in a battery-manufacturing worker and an aluminum-processing worker, Tomioka et al. 44 attributed the lung disease to aluminum exposure based on elemental analysis showing aluminum widely distributed in the granulomas.
We did not have the opportunity to conduct elemental analyses of granulomatous tissue in our cases. We hope to investigate the specific contribution of aluminum-containing MP in a case-control study of sarcoidosis in the population of hard-rock miners in Ontario, comparing prevalence of sarcoidosis in MP-exposed miners to prevalence in miners not exposed to MP.

| Gene-exposure interactions
Grunewald et al. 38 45,46 For example, in a case-control study of sarcoidosis in NYC firefighters exposed to WTC dust, Cleven et al. 47 found 17 allele variants of HLA and non-HLA genes in cases that were not present in WTC-exposed firefighter controls without sarcoidosis. Less attention has been paid to clinical phenotypes. Cardiac sarcoid has been associated with HLA-DQB1*0601; multiorgan involvement with non-HLA gene CCL5/RANTES,17q.12; and acute self-limiting sarcoidosis (vs. chronic sarcoidosis) with the non-HLA gene TGF-β2,1q41. 38 Gene-exposure interactive effects on such clinical manifestations have not been reported to our knowledge. Effects of such interactions on risk for disease and on clinical phenotype are hypothetical at OLIVER ET AL.
| 277 the moment and require additional research in exposed populations for further clarification and verification.

| CONCLUSIONS
Our observation of 12 sarcoidosis cases in a group of 506 Northern Ontario hard-rock miners is consistent with and provides support for the associations between occupational exposure to RCS and sarcoidosis reported in the scientific literature. Our case series is unique in its detailed examination of occupational histories specific to each case, with quantification of cumulative RCS exposure based on air sampling data from mines in which they worked. Neither our case series nor published reports demonstrate a causal relationship between RCS exposure and sarcoidosis, but both inform our assessment of the association between the two.
Questions raised by this case series are several: (1)