Berylliosis in Italy: a case of "sarcoidosis" under the threshold limit value

BACKGROUND: Berylliosis is caused by a chronic immune reaction to beryllium; in Italy the first case of beryllium exposure-related disease was described in 1935 by Fabroni-Marradi and two additional cases of beryllium disease were subsequently described by Ambrosi and co-workers in 1968. No case has since been recognized using the standardized criteria including immunological testing. OBJECTIVES: To describe a case report of clinically significant berylliosis that occurred in a man exposed to beryllium for ten years in the workplace at concentrations below the permitted threshold limit value. METHODS: The man complained of dyspnoea, dry cough, weakness and weight loss for the past year and was at first diagnosed as suffering from sarcoidosis because of increased angiotensin converting enzyme levels, alteration of hepatic and renal functional indexes, the presence of diffused reticulo-nodular lung abnormalities with high resolution computed tomography that also showed enlarged mediastinal lymph nodes, abnormal lung physiology with reduced diffusion capacity and a bronchial biopsy showing granulomatous lesions. Because of the occupational history immunological testing and high resolution HLA class II typing were performed. RESULTS: The high response to beryllium in the lymphocytes proliferation test and the HLA typing which revealed the presence of the two susceptibility markers HLA-DPGlu69 and HLA-DRPhe47 led to a diagnosis of berylliosis. CONCLUSIONS: The importance is stressed of suspecting a diagnosis of berylliosis in the proper occupational contexts and encouraging the use of immunological tests for diagnosis, and also the need for critical revision of the permitted threshold limit values.     

Mineralogy of lung tissue in dental laboratory technicians' pneumoconiosis.

This article reports on a case of pneumoconiosis in a dental laboratory technician with a history of respiratory exposure to dental materials. Special attention is paid to the mineralogical analysis of the lung biopsy. The abundance of chromium, cobalt, and silica particles suggests that the dental technician's pneumoconiosis is the result of the combined effects of hard metal dusts and silica particles generated during finishing dental frameworks. Adequate technical protection such as a local ventilation system should be considered in dental laboratories to prevent respiratory exposure of dental technicians to airborne contaminants.     

Case series: use of induced sputum in the evaluation of occupational lung diseases

The authors recently reported that analysis of induced sputum may reveal the status of hazardous dust exposure (e.g., silica, hard metals) as effectively as does bronchoalveolar lavage. In the current study, the authors describe how induced sputum can assist in the evaluation and diagnosis of suspected occupational lung diseases. The 3 patients who underwent induced sputum testing included a miner with silicosis, a dental technician with berylliosis, and a teacher who suffered from undefined interstitial fibrosis and in whom induced sputum analysis revealed the presence of a high burden of calcium sulfate and silica. The data reported indicate that induced sputum--a known safe and simple procedure--can serve as a useful tool in the evaluation of patients with suspected occupational lung diseases.     

Asbestos lung burden and asbestosis after occupational and environmental exposure in an asbestos cement manufacturing area: a necropsy study

OBJECTIVE: The largest Italian asbestos cement factory had been active in Casale Monferrato until 1986: in previous studies a substantial increase in the incidence of pleural mesothelioma was found among residents without occupational exposure to asbestos. To estimate exposure to asbestos in the population, this study evaluated the presence of histological asbestosis and the lung burden of asbestos fibres (AFs) and asbestos bodies (ABs). METHODS: The study comprises the consecutive series of necropsies performed at the Hospital of Casale Monferrato between 1985 and 1988. A sample of lung parenchima was collected and stored for 48 out of 55 necropsies. The AF concentration was measured with a TEM electron microscope with x ray mineralogical analysis. The ABs were counted and fibrosis evaluated by optical microscopy. The nearest relative of each subject was interviewed on occupational and residential history. Mineralogical and histological analyses and interviews were conducted in 1993-4. RESULTS: Statistical analyses included 41 subjects with AF, AB count, and interview. Subjects without occupational exposure who ever lived in Casale Monferrato had an average concentration of 1500 AB/g dried weight (gdw); Seven of 18 presented with asbestosis or small airway lung disease (SAL). G2 asbestosis was diagnosed in two women with no occupational asbestos exposure. One of them had been teaching at a school close to the factory for 12 years. Ten subjects had experienced occupational asbestos exposure, seven in asbestos cement production: mean concentrations were 1.032 x 10(6) AF/gdw and 96,280 AB/gdw. Eight of the 10 had asbestosis or SAL. CONCLUSION: The high concentration of ABs and the new finding of environmental asbestosis confirm that high asbestos concentration was common in the proximity of the factory. Subjects not occupationally exposed and ever living in Casale Monferrato tended to have higher AB concentration than subjects never living in the town (difference not significant). The concentrations of ABs and AFs were higher than those found in other studies on nonoccupationally exposed subjects.

 

     

Skin as a route of exposure and sensitization in chronic beryllium disease

Chronic beryllium disease is an occupational lung disease that begins as a cell-mediated immune response to beryllium. Although respiratory and engineering controls have significantly decreased occupational beryllium exposures over the last decade, the rate of beryllium sensitization has not declined. We hypothesized that skin exposure to beryllium particles would provide an alternative route for sensitization to this metal. We employed optical scanning laser confocal microscopy and size-selected fluorospheres to demonstrate that 0.5- and 1.0- micro m particles, in conjunction with motion, as at the wrist, penetrate the stratum corneum of human skin and reach the epidermis and, occasionally, the dermis. The cutaneous immune response to chemical sensitizers is initiated in the skin, matures in the local lymph node (LN), and releases hapten-specific T cells into the peripheral blood. Topical application of beryllium to C3H mice generated beryllium-specific sensitization that was documented by peripheral blood and LN beryllium lymphocyte proliferation tests (BeLPT) and by changes in LN T-cell activation markers, increased expression of CD44, and decreased CD62L. In a sensitization-challenge treatment paradigm, epicutaneous beryllium increased murine ear thickness following chemical challenge. These data are consistent with development of a hapten-specific, cell-mediated immune response following topical application of beryllium and suggest a mechanistic link between the persistent rate of beryllium worker sensitization and skin exposure to fine and ultrafine beryllium particles.     

Beryllium: An etiologic agent in the induction of lung cancer,nonneoplastic respiratory disease,and heart disease among industrially exposed workers

On the basis of the clear demonstration of the carcinogenicity of beryllium in several animal species along with the suggestion of an increased risk of lung cancer mortality in humans exposed to beryllium, an epidemiologic study of workers exposed to beryllium at one production facility was undertaken. Within the limitations imposed by the selection of data for calculation of cause-specific expected mortality (use of U.S. white male cause-specific mortality rates with linear extrapolation of 1965–1967 to 1968–1975 vs use of cause-specific mortality rates for the county in which the study facility and the majority of its workers resided), the study demonstrated a statistically significant increased risk of respiratory disease (neoplastic and nonneoplastic) and of heart disease mortality. A possible explanation other than in terms of beryllium was sought for this excessive risk of cause-specific mortality among beryllium-exposed workers. The excessive risk of lung cancer mortality could not be related to an effect of age, chance, self-selection, study group selection, exposure to other agents in the study facility, or place of residence. On the basis of the frequency of cigarette smoking among those cohort members employed in 1967–1968 and the distribution of histologic types of lung cancer among deceased cohort members, it seems unlikely that cigarette smoking per se could have accounted for the increased risk of lung cancer among beryllium-exposed workers in the study cohort. Lifetime employment histories for members of the study cohort were not available, so that definitive statements about the role of other occupational exposures cannot be made. However, information on usual occupations as indicated on death certificates suggests that it is unlikely that some undefined occupational or environmental exposure other than to beryllium could account per se for the excessive lung cancer mortality. This interpretation is further supported by the residential stability of the study cohort in a county having a lung cancer rate significantly lower than that of the entire United States. The findings of a statistically significant excess of lung cancer mortality among cohort members in general (P < 0.05) and among workers observed 25 or more years since onset of beryllium exposure in particular (P < 0.01), when taken in context with the results of earlier animal bioassay and recent epidemiologic studies, are supportive of the hypothesis that beryllium is carcinogenic to man.     

Chronic Pulmonary Berylliosis in a Female Chemist

A chronic progressive granulomatous disease of the lungs is described in a female chemist who worked for about two years with a beryllium compound in the manufacture of fluorescent lighting tubes. The level of beryllium in the laboratory atmosphere was found to be 2·7 μg. per cu.m. and in other parts of the factory up to 39·1 μg. per cu.m. were recorded. Symptoms began about two years after she left this work and she died three years later. A diagnosis of chronic pulmonary berylliosis was made, and confirmation was obtained by lung biopsy when early in the course of the disease a large cyst attached to the right middle lobe was removed by thoracotomy. Tests of lung function showed that there was a low arterial saturation at rest and a normal Pco₂ in spite of marked hyperventilation. Both elastance and resistance of the lungs were greater than normal and total work of breathing was six times the normal. Pregnancy was associated with relief of symptoms which persisted for some months after a normal birth. Death occurred about seven years after exposure to beryllium ceased. At necropsy beryllium was detected in the lungs chemically and demonstrated in histological sections by special stains. Microscopic examination of the lung showed conchoidal bodies and doubly refractile crystals and the pathogenesis of these lesions is discussed. It is suggested that there is a sensitivity reaction to beryllium, which is probably combined with protein to form an antigen, and that the breakdown of necrotic foci provokes a further reaction in the lung with the repeated appearance of fresh lesions.     

A long-term follow-up of workers exposed to beryllium

ABSTRACT The relationship of features of beryllium disease to the estimated exposure to beryllium has been investigated over a 30-year period at a factory manufacturing beryllium products. The factory opened in 1952. Of the 146 men who had worked there for more than six months up to 1963, 89% were seen at that time and were followed up in 1973. The nine who continued to work in the factory and those who were engaged subsequently were examined in 1977. On each occasion a clinical interview, occupational history, chest radiograph, and assessment of lung function were carried out. The findings of the main survey were related to the beryllium content of the dust measured by mass spectrometry for 1952-60 when over 3000 determinations were made. In no part of the plant did the estimated average daily exposure exceed 2 μg m^-3, and only 9% of individual determinations exceeded this level. Twenty determinations exceeded 25 μg m^-3. During the period under review, four men developed the clinical, radiographic, and physiological features of beryllium disease. Two men acquired abnormal chest radiographs consistent with beryllium disease but without other features, and one developed probable beryllium disease despite the diagnosis not being confirmed at necropsy. The affected men were all exposed to beryllium oxide or hydroxide but in a wide range of estimated doses. In six the changes developed after exposure had ceased; trigger factors including patch testing may have contributed to their illness. Seventeen men recalled episodes of brief exposure to high concentrations of dust, two developed pneumonitis from which they recovered completely, and one developed chronic beryllium disease after a further 23 years' exposure. In subjects without clinical or radiographic evidence of disease no convincing evidence was obtained for any association between the lung function and the estimated exposure to beryllium.     

Chest imaging and lung function impairment after long-term occupational exposure to low concentrations of chrysotile

The aim of the present study was the investigation of radiographic findings in relation to lung function after occupational exposure to permissible levels of relatively pure chrysotile (0.5-3% amphiboles). We studied 266 out of the total 317 employees who have worked in an asbestos cement factory during the period 1968-2004 with chest x-ray, high-resolution computed tomography (HRCT) and lung function tests. Sensitivity of chest x-ray was 43% compared to HRCT. Abnormal HRCT findings were found in 75 subjects (67%) and were related to age, occupational exposure duration, and spirometric data. The presence of parenchymal or visceral pleural lesions (exclusively or as the predominant abnormality) was being accompanied by lower total lung capacity and diffusion capacity. HRCT was much more sensitive than chest x-ray for occupational chrysotile exposure. Lung function impairment was related with parenchymal but not with pleural HRCT abnormalities.     

Government laboratory worker with lung cancer: comparing risks from beryllium, asbestos, and tobacco smoke

Occupational medicine physicians are frequently asked to establish cancer causation in patients with both workplace and non-workplace exposures. This is especially difficult in cases involving beryllium for which the data on human carcinogenicity are limited and controversial. In this report we present the case of a 73-year-old former technician at a government research facility who was recently diagnosed with lung cancer. The patient is a former smoker who has worked with both beryllium and asbestos. He was referred to the University of California, San Francisco, Occupational and Environmental Medicine Clinic at San Francisco General Hospital for an evaluation of whether past workplace exposures may have contributed to his current disease. The goal of this paper is to provide an example of the use of data-based risk estimates to determine causation in patients with multiple exposures. To do this, we review the current knowledge of lung cancer risks in former smokers and asbestos workers, and evaluate the controversies surrounding the epidemiologic data linking beryllium and cancer. Based on this information, we estimated that the patient's risk of lung cancer from asbestos was less than his risk from tobacco smoke, whereas his risk from beryllium was approximately equal to his risk from smoking. Based on these estimates, the patient's workplace was considered a probable contributing factor to his development of lung cancer.     

Small opacities among dental laboratory technicians in Copenhagen.

After a case of advanced pneumoconiosis occurred in a dental laboratory technician, 31 other dental technicians and 30 control subjects controlled for smoking habits, sex, and age were investigated. More technicians (55%) than controls (30%) had at least grade 1 dyspnoea (p greater than 0.05). Multiple regression analysis showed that 13 technicians who had produced dental prostheses for at least 15 years had consistently lower lung function (FVC, FEV1, FEV1/FVC, MEF50, and DCO single breath), although the differences were not statistically significant. All mean lung function values for technicians and controls were within normal limits. Increases in MEF50 after breathing 80% helium and 20% O2 failed to show small airways dysfunction among the technicians. Of the six with radiological pneumoconiosis (5 simple, 1 advanced) four had symptoms. All three biopsy specimens showed varying degrees of pulmonary fibrosis. DCO single breath was diminished in four of the six. One male dental technician had scleroderma and possibly Erasmus syndrome. Blind readings showed an increased number of suspicious chest x rays films (greater than or equal to category 0/1) among older smokers and ex-smokers (p = 0.013) regardless of occupation. Our results support other evidence that dental technicians are at risk of developing pneumoconiosis. Therefore, adequate hygienic control of dental laboratories is indicated.     

Small opacities among dental laboratory technicians in Copenhagen

After a case of advanced pneumoconiosis occurred in a dental laboratory technician, 31 other dental technicians and 30 control subjects controlled for smoking habits, sex, and age were investigated. More technicians (55%) than controls (30%) had at least grade 1 dyspnoea (p greater than 0.05). Multiple regression analysis showed that 13 technicians who had produced dental prostheses for at least 15 years had consistently lower lung function (FVC, FEV1, FEV1/FVC, MEF50, and DCO single breath), although the differences were not statistically significant. All mean lung function values for technicians and controls were within normal limits. Increases in MEF50 after breathing 80% helium and 20% O2 failed to show small airways dysfunction among the technicians. Of the six with radiological pneumoconiosis (5 simple, 1 advanced) four had symptoms. All three biopsy specimens showed varying degrees of pulmonary fibrosis. DCO single breath was diminished in four of the six. One male dental technician had scleroderma and possibly Erasmus syndrome. Blind readings showed an increased number of suspicious chest x rays films (greater than or equal to category 0/1) among older smokers and ex-smokers (p = 0.013) regardless of occupation. Our results support other evidence that dental technicians are at risk of developing pneumoconiosis. Therefore, adequate hygienic control of dental laboratories is indicated.     

Immunological aspects of exposure to emissions from burning coal of high beryllium content

An epidemiological study was conducted on groups of people exposed occupationally (45 persons) and nonoccupationally (36 persons) to the combustion products of coal containing a comparatively high concentration of beryllium. The concentration of beryllium in the working atmosphere ranged between 30 and 800 × 10^?5 mg × m^?3; in the town S, dwelling place of a nonoccupationally exposed cohort between 0.39 and 1.68 × 10^?5 mg × m^?3. A group of 100 subjects who had no occupational contact with beryllium and other industrial toxic agents, and lived outside of the polluted region served as control cohort. In all examined persons the main classes of immunoglobulins and autoantibodies (lung, heart, liver, spleen, thyroid gland, suprarenals, and native DNA) and antibodies against nuclear (ANA) and mitochondrial (AMA) antigens (obtained from the lungs of intact and of experimental berylliosis rats) were determined. In both exposed groups elevated levels of IgG and IgA and increased concentrations of autoantibodies were found in comparison with the control cohort of people. Specific AMA and ANA were also found in both the exposed groups, with higher values in women. The demonstrated immunological changes in humoral immunoreactivity might be considered as signs of beryllium exposure. In the discussion the authors emphasize the increasing importance of immunological aspects in the study of environmental pollution.     

A follow-up study of lung function among ex-asbestos workers with and without pleural plaques

BACKGROUND: Pulmonary function testing is widely accepted as an integral part of medical surveillance of occupational lung diseases. There are several cross-sectional studies evaluating lung function among asbestos-exposed workers, but only few longitudinal surveys have been performed. OBJECTIVES: To evaluate, over a mean follow-up period of 3.7 (SD 1.8) years, the loss of lung function in a group of 103 workers with previous exposure to asbestos (mainly ship building/repairing), according to the presence or absence of pleural plaques at radiological examination. METHODS: Chest radiographic examination was used to ascertain the presence/absence of pleural plaques. If chest X-ray films were positive for pleural plaques, HRCT (High Resolution Computed Tomography) was used to exclude any parenchymal disease. The assessment of lung function over time included repeated measurement of vital capacity (VC), forced expiratory volume in one second (FEV1) and total lung capacity (TLC). Smoking was assessed in terms of pack-years. A Generalized Estimating Equations (GEE) approach to repeated spirometric measurement was used to investigate the relationship between the loss of pulmonary function and (i) presence/absence of pleural plaques, (ii) smoking status, and (iii) work seniority in workplaces with exposure to asbestos. RESULTS: In the ex-asbestos workers, mean age at the first examination was 49 (SD 6) years and work seniority averaged 25 (SD 7) years; 36% were non-smokers, 27% smoked < 15 pack-years, and 37% smoked > or = 15 pack-years. Thirty-six workers showed pleural plaques at radiological examination. Overall, 236 measurements of VC and FEV1, and 234 determinations of TLC were available. Multivariate GEE approach to age- and height-adjusted spirometric data showed that pleural plaques were not associated with a significant loss of pulmonary function during the follow-up. When compared with non-smokers, heavy smokers (> or = 15 pack-years) showed on average a significant loss of VC (-5.3%, IC 95%: -9.4 - -1.2%), FEV1 (-8.4%, IC 95%: -13.2 - -3.5%), and TLC (-4.0%, IC 95%: -7.4 - -0.5%). An occupational history of previous exposure to asbestos was significantly associated with an 10-year decrease in VC (-3.1%, IC 95%: -5.9 - -0.3%) and FEV1 (-4.9%, IC 95%: -8.3 - -1.5%). CONCLUSIONS: The results of this follow-up study showed that smoking and previous asbestos exposure were associated with a mild, but statistically significant, loss of lung function. Radiological findings of pleural plaques were not related to deterioration of lung function over the follow-up period.     

铝作业工人职业性慢性肌肉骨骼损伤危险因素分析

目的 了解电解铝厂工人职业性慢性肌肉骨胳损伤（ＣＭＩ）患者病情况及其危险因素。方法 采用横断面现况调查问卷与临床检查相结合的方法对各有关危险因素进行逐一询问及ＣＭＩ诊断。结果 电解铝厂工人总体ＣＭＩ患病主继６２．５％,各车间不同工种工人ＣＭＩ串病率差异无显著意义,但均高于对照组（２８．５％）。多因素Ｌｏｇｉｓｔｉｃ回归提示,ＣＭＩ患病与性别、年龄、身高、文化程度、婚姻状况、子女数、工作紧张度、工作     

Respiratory symptoms and lung function of aluminum potroom workers

The association of occupational exposure with respiratory disease and lung function was examined in a cross-sectional study of 1805 aluminum potroom workers. Work-related asthmatic symptoms occurred in 15% of the workers with an exposure of 10 years or more and in 8% of the workers who had been employed less than five years. In a multiple logistic regression analysis an odds ratio (OR) of 3.4 [95% confidence interval (95% CI) 2.1-5.8] for work-related asthmatic symptoms was estimated for long versus short duration of employment. Airflow limitation was also significantly related to years of exposure (OR 2.6, 95% CI 1.7-3.9). Current occupational exposure and the occurrence of respiratory symptoms were not significantly associated. The results suggest that exposure to air pollutants in the primary aluminum industry may lead to the development of asthmatic symptoms, as well as to reduced respiratory function.     

Oral health screening: evaluation of implementation of a national programme

BACKGROUND: The first national French oral health screening was implemented in 1998 toward young people aged from 15 to 18 Years. These adolescents were invited every year to a free dental check up performed by their dentist. The aim of this study, carried out for self-employed persons insured by compulsory national health insurance, was to measure the rate of dental checks during years 1998-1999-2000, to estimate the oral health status, to assess the factors related to the dental care consumption in 1998, and the predictive factors for a successive dental check. METHODS: We included seventy four French counties. Every teenager born in 1983 (23.874) was invited. We collected data from both the health insurance databases and the form filled in by the consulted dental surgeons. We selected four variables: gender, residence place, social, and occupational group to study the consumption in 1998. RESULTS: In 1998, 10% (2462) of teenagers have got a dental check up (EXP1). Only 0,7% participated in the three screenings (1998-1999-2000). We noted a higher female consumption and disparities between the main categories of self-employed persons. Participation by boys was higher than girls. The lowest participation rates concerned the Ile of France area and adolescents living with single parents. In 1998 (EXP1), 57% of teenagers had at least one decayed tooth. Only 69% of them received appropriate curative dental treatments in the following six-Months period. However, among teenagers followed during the three years, higher rates of care reaching 90% were observed on the second and third EXP. CONCLUSION: This small participation rate may be related to the recent implementation of screening. It should lead to optimize screening and to associate other partners in particular the state education system. It should also be helpful in focusing the oral health prevention policy toward the population with a high risk of decay.     

Occupational lung cancer. A comparison between humans and experimental animals

Many epidemiological and experimental studies have suggested that the respiratory tract is one of the most sensitive organs to environmental carcinogens. Nevertheless there is little evidence to determine the relationship between a specific environmental carcinogen and a cell type of lung cancer, because the cell types of lung cancer and their relative frequencies are highly complex compared with those of other organs and tissues. In the present paper, occupational lung-cancer characteristics, which are the clearest in the relation between cause and effect in human lung cancers, were reviewed in comparison with the results of animal experiments concerned with occupational lung carcinogens. Through accumulation of histopathological examinations of the lung cancer cases, the following relationships between cause and cell type were conjectured: chromium and squamous cell carcinoma; asbestos and adenocarcinoma; nickel and squamous cell carcinoma; beryllium and small cell carcinoma; bis (chloromethyl) ether and small cell carcinoma; mustard gas and squamous cell or small cell carcinoma; vinyl chloride and large cell or adenocarcinoma; radionuclides and small cell carcinoma. The relation pertaining to arsenic, benzotrichloride and tar could not be conjectured because of insufficient cases and information in the histological diagnosis. On the other hand, the carcinogenicity of these substances in occupational exposure has been confirmed by animal experiments administered intratracheally or by inhalation studies under relatively higher concentration. As a result of recent refinements of inhalation study, all-day and life-span exposure to extremely low concentrations, such as microgram/m3 orders, of certain substances has been possible. The characteristics of lung tumors occurring in these animals are rather different from those of human. For example, in mouse, almost all of the malignant lung tumors developed by carcinogens are adenocarcinomas and it is rare to find the squamous cell carcinoma. Moreover, small cell carcinoma and large cell carcinoma have not known to occur in the lungs of rats and mice. Therefore, future research should focus elucidating the specific relationship between cause and cell type of human lung cancer by means of animal experiments on lung cancer that give attention to the specificities of each experimental animal and the origin of the resultant lung tumor.     

实验性铍病支气管肺泡灌洗液中细胞免疫学观察

以氧化铍气道染毒豚鼠，观察铍病豚鼠支气管肺泡灌洗液细胞成分、淋巴细胞对铍盐的增殖反应及肺泡巨噬细胞产生白细胞介素－１（ＩＬ－１）的变化。发现铍染毒早期ＢＡＬＦ中多形核粒细胞显著增加，后期则淋巴细胞增加明显。与外周血铍淋转比较，ＢＡＬＦ淋巴细胞对铍盐刺激的增殖反应更为第三。     

Sparse-data bias accompanying overly fine stratification in an analysis of beryllium exposure and lung cancer risk

PurposeBeryllium's classification as a carcinogen is based on limited human data that show inconsistent associations with lung cancer. Therefore, a thorough examination of those data is warranted. We reanalyzed data from the largest study of occupational beryllium exposure, conducted by the National Institute of Occupational Safety and Health (NIOSH).MethodsData had been analyzed using stratification and standardization. We reviewed the strata in the original analysis, and reanalyzed using fewer strata. We also fit a Poisson regression, and analyzed simulated datasets that generated lung cancer cases randomly without regard to exposure.ResultsThe strongest association reported in the NIOSH study, a standardized rate ratio for death from lung cancer of 3.68 for the highest versus lowest category of time since first employment, is affected by sparse-data bias, stemming from stratifying 545 lung cancer cases and their associated person-time into 1792 categories. For time since first employment, the measure of beryllium exposure with the strongest reported association with lung cancer, there were no strata without zeroes in at least one of the two contrasting exposure categories. Reanalysis using fewer strata or with regression models gave substantially smaller effect estimates. Simulations confirmed that the original stratified analysis was upwardly biased. Other metrics used in the NIOSH study found weaker associations and were less affected by sparse-data bias.ConclusionsThe strongest association reported in the NIOSH study seems to be biased as a result of non-overlap of data across the numerous strata. Simulation results indicate that most of the effect reported in the NIOSH paper for time since first employment is attributable to sparse-data bias.