Objective The effect marker club cell protein (CC16) is secreted by the epithelium of the small respiratory tract into its lumen and passes into the blood. Increased amounts of CC16 in serum are observed during acute epithelial lung injury due to air pollutants. CC16 in serum was determined as part of this cross-sectional study in underground potash miners on acute and chronic health effects from exposures to diesel exhaust and blasting fumes. Methods Nitrogen oxides, carbon monoxide, and diesel particulate matter were measured in 672 workers at a German potash mining site on a person-by-person basis over an early shift or midday shift, together with CC16 serum concentrations before and after the respective shift. CC16 concentrations and CC16 shift-differences were evaluated with respect to personal exposure measurements and other quantitative variables by Spearman rank correlation coefficients. CC16 shift-differences were modeled using multiple linear regression. Above-ground workers as reference group were compared to the exposed underground workers. Results Serum concentrations of CC16 were influenced by personal characteristics such as age, smoking status, and renal function. Moreover, they showed a circadian rhythm. While no statistically significant effects of work-related exposure on CC16 concentrations were seen in never smokers, such effects were evident in current smokers. Conclusion The small airways of current smokers appeared to be vulnerable to the combination of measured work-related exposures and individual exposure to smoking. Therefore, as health protection of smokers exposed to diesel exhaust and blasting fumes, smoking cessation is strongly recommended.

Background.Diesel engine exhaust (DEE) and some of the polycyclic aromatic hydrocarbons (PAH) it contains are carcinogenic to humans (for example benzo(a)pyrene) and can cause lung cancer in workers. The objective of this study was to assess exposures to DEE and its component PAH and the potential associations between these two health hazards in a salt and potash mining population.Methods.Between 2017 and 2019, 1003 underground workers (mining n = 801, maintenance n = 202) and 243 aboveground facility workers from two German mines participated. Personal exposure to DEE was assessed in air as elemental carbon for diesel particulate matter (EC-DPM), whereas exposure to PAH was assessed in pre- and postshift urine samples in terms of 1-hydroxypyrene (1-OHP). Associations between EC-DPM and 1-OHP were studied using linear regression models.Results.The highest EC-DPM exposures were measured in mining workers (median 0.06 mg/m3) followed by workers in the maintenance (0.03 mg/m3) and facility areas (<0.02 mg/m3). Exposures above the current German occupational threshold level of 0.05 mg/m3 were observed in 56%, 17%, and 5% of mining, maintenance and facility workers, respectively. 1-OHP increased statistically significantly across a work shift in underground workers but not in facility workers. Regression analyses revealed an increase of post-shift 1-OHP by almost 80% in mining and 40% in maintenance compared with facility workers. 1-OHP increased with increasing EC-DPM among underground workers. However, internal exposure of 1-OHP mainly remained at levels similar to those of the German general population in more than 90% of the urine samples.Conclusions.While exposures to DEE above the current German OEL for EC-DPM are quite common in the studied population of underground salt and potash miners (39.5% overall), urinary concentrations of 1-OHP did not reflect these findings.

OBJECTIVE:The aim of the study was to assess the effect of exposure to copper-containing dust on lung function and inflammatory endpoints among workers of a German copper plant, effects rarely studied before. METHODS:One hundred four copper-exposed smelter workers and 70 referent workers from the precious metal and lead facilities were included, with different metal exposures in both groups due to the different process materials. Body plethysmography, exhaled nitric oxide (FeNO) measurements, and blood sampling were conducted in all workers. Smoking status and the use of respiratory protective equipment were considered. In a subgroup of 40 nonsmoking volunteers (28 copper-exposed and 12 referents), sputum biomarkers were assessed. RESULTS:Median lung function values of both copper-exposed and the referent groups were within reference ranges of "healthy" individuals, and statistical differences between the groups were mostly not evident. Similarly, differences in blood and sputum biomarkers were too small to be biologically relevant. CONCLUSION:The results suggest the absence of the detectable effects of copper-containing dust exposure on lung function or chronic inflammation within the investigated cohort.

PURPOSE:Occupational exposure limits (OEL) for nitrogen oxides (NO, NO2) and diesel exhaust (EC-DPM) were reassessed by the German authorities in 2016/2017. We performed a clinical cross-sectional study among salt and potash underground workers exposed to these substances at relatively high levels to examine possible indicators of acute effects on workers' health.METHODS:We measured post- versus pre-shift differences in cardiovascular, inflammatory, immune, and respiratory effect biomarkers and assessed their associations with personal exposures measured during the same shift. We also compared post- versus pre-shift differences in biomarker levels between exposure groups defined based on work site and job type.RESULTS:None of the above-ground workers exceeded the OEL for NO2 and only 5% exceeded the OEL for EC-DPM exposure. Among underground workers, 33% of miners and 7% underground maintenance workers exceeded the OEL for NO2; the OEL for EC-DPM was exceeded by 56% of miners and 17% of maintenance workers. Some effect biomarkers (thrombocytes, neutrophils, MPO, TNF-α, IgE, FeNO) showed statistically significant differences between pre- versus post-shift measurements; however, there were no consistent associations between pre- and post-shift differences and exposure group or personal exposure measurements during the shift.CONCLUSIONS:We did not find evidence of associations between workplace exposure to NO, NO2 or EC-DPM and clinically relevant indicators of acute cardiovascular, inflammatory and immune, or respiratory effects among salt and potash underground workers in Germany.

Objective: Significantly lower permissible occupational exposure limits for copper dust are being discussed in Europe and other jurisdictions. However, little data are published on exposures in occupational settings and copper-specific effects in humans. Hence, a health surveillance study was performed among workers employed at a copper smelter between 1972 and 2018. Methods: Possible effects of long-term exposures to dust containing copper on lung function were assessed. Specifically, declines in forced expiratory volume in 1 second (FEV1) were compared between a copper-exposed and control group. Cumulative copper exposures were derived from historical airborne monitoring data. Results: FEV1 declines among exposed and control never smokers were similar to a typical age-dependent decline of 29 mL/y. Conclusion: The study findings indicate that cumulative inhalable copper dust exposure averaging 4.61 mg/m(3)-years over an exposure duration of similar to 22 years is not associated with adverse effects on lung function.

Since the iron-age and throughout the industrial age, humans have been exposed to iron oxides. Here, we review the evidence from epidemiology, toxicology, and lung bioavailability as to whether iron oxides are likely to act as human lung carcinogens. Current evidence suggests that observed lung tumors in rats result from a generic particle overload effect and local inflammation that is rat-specific under the dosing conditions of intratracheal instillation. This mode of action therefore, is not relevant to human exposure. However, there are emerging differences seen in vitro, in cell uptake and cell bioavailability between "bulk" iron oxides and nano iron oxides. Bulk particulates, as defined here, are those where greater than 70% are >100 nm in diameter. Similarly, nano iron oxides are defined in this context as particulates where the majority, usually >95% for pure engineered forms of primary particulates (not agglomerates), fall in the range 1-100 nm in diameter. From the weight of scientific evidence, bulk iron oxides are not genotoxic/mutagenic. Recent evidence for nano iron oxide is conflicting regarding genotoxic potential, albeit genotoxicity was not observed in an in vivo acute oral dose study, and nano iron oxides are considered safe and are being investigated for biomedical uses; there is no specific in vivo genotoxicity study on nano iron oxides via inhalation. Some evidence is available that suggests, hypothetically due to the larger surface area of nano iron oxide particulates, that toxicity could be exerted via the generation of reactive oxygen species (ROS) in the cell. However, the potential for ROS generation as a basis for explaining rodent tumorigenicity is only apparent if free iron from intracellular nano scale iron oxide becomes bioavailable at significant levels inside the cell. This would not be expected from bulk iron oxide particulates. Furthermore, human epidemiological evidence from a number of studies suggests that iron oxide is not a human carcinogen, and therefore, based upon the complete weight of evidence, we conclude that bulk iron oxides are not human carcinogens.

Objective: To quantify silicosis and lung cancer risks among porcelain workers occupationally exposed to respirable crystalline silica. Methods: We reread historical radiographs to identify silicosis and estimated exposure on the basis of detailed work history and about 8000 industrial hygiene measurements. Cox proportional hazards models estimated risks by cumulative and average exposure. Results: Adjusted silicosis hazards ratios were 5.3 (95% confidence interval [CI], 1.6 to 17.3); 7.3 (95% CI, 2.6 to 20.8); and 6.8 (95% CI, 3.0 to 15.3) for cumulative exposures >4 to 5; >5 to 6; and >6 mg/m3-years, and 3.3 (95% CI, 0.8 to 14.7), 13.6 (95% CI, 4.2 to 44.4) and 23.2 (95% CI, 8.2 to 65.8) for average exposures >0.1 to 0.15; >0.15 to 0.2 and >0.2 mg/m3, respectively. Exposure was not associated with any cause of death including lung cancer. Conclusions: Respirable crystalline silica exposure more than 4 mg/m3-years (cumulative) or more than 0.15 mg/m3 (average) were strongly associated with silicosis, but unrelated to lung cancer risks.

A time-dependent quantitative exposure assessment of silica exposure among nearly 18,000 German porcelain workers was conducted. Results will be used to evaluate exposure-response disease risks. Over 8000 historical industrial hygiene (IH) measurements with original sampling and analysis protocols from 1954-2006 were obtained from the German Berufs- genossenschaft der keramischen-und Glas-Industrie (BGGK) and used to construct a job exposure matrix (JEM). Early measurements from different devices were converted to modern gravimetric equivalent values. Conversion factors were derived from parallel historical measurements and new side-by-side measurements using historical and modern devices in laboratory dust tunnels and active workplace locations. Exposure values were summarized and smoothed using LOESS regression; estimates for early years were derived using backward extrapolation techniques. Employee work histories were merged with JEM values to determine cumulative crystalline silica exposures for cohort members. Average silica concentrations were derived for six primary similar exposure groups (SEGs) for 1938-2006. Over 40% of the cohort accumulated <0.5 mg; just over one-third accumulated >1 mg/m(3)-years. Nearly 5000 workers had cumulative crystalline silica estimates >1.5 mg/m(3)-years. Similar numbers of men and women fell into each cumulative exposure category, except for 1113 women and 1567 men in the highest category. Over half of those hired before 1960 accumulated >3 mg/m(3)-years crystalline silica compared with 4.9% of those hired after 1960. Among those ever working in the materials preparation area, half accumulated >3 mg/m(3)-year compared with 12% of those never working in this area. Quantitative respirable silica exposures were estimated for each member of this cohort, including employment periods for which sampling used now obsolete technologies. Although individual cumulative exposure estimates ranged from background to about 40 mg/m(3)-years, many of these estimates reflect long-term exposures near modern exposure limit values, allowing direct evaluation of lung cancer and silicosis risks near these limits without extrapolation. This quantitative exposure assessment is the largest to date in the porcelain industry.

Objectives: To evaluate mortality due to lung cancer, silicosis, renal cancer, renal disease and other causes among German porcelain production workers potentially exposed to crystalline silica. Methods: Seventeen thousand six hundred forty-four medical surveillance participants (1985–1987) were followed through 2005 for mortality. Cause-specific Standardized Mortality Ratios (SMR) and 95% confidence intervals were estimated. Results: Women (SMR = 0.85; 95% CI = 0.78 to 0.93), but not men, demonstrated a healthy worker effect. Lung and renal cancers, and renal disease (non-malignant renal disease) were not associated with employment or exposure surrogates. Mortality was increased from silicosis (SMR = 7.20; 95% CI = 2.32 to 16.8) liver (SMR = 1.99; 95% CI = 1.29 to 2.93) and pancreatic (SMR = 1.71; 95% CI = 1.18 to 2.41) cancers among men, and diabetes among women (SMR = 1.74; 95% CI = 1.07 to 2.65). A sub-cohort of Bavarian workers generated similar but generally higher SMRs. Conclusions: Silicosis mortality was increased in this, among the largest studies to date. However, associations previously observed between crystalline silica exposure and renal or lung cancers or non-malignant renal disease were not supported.

To the Editor: Michaels et al attempt to “put in accurate context” our recent paper on an epidemiological study of lung cancer mortality among a cohort of German chromate industry workers.1 We address each of the three specific points relevant to our research, as well as an overarching policy issue, raised by Michaels et al. First, Michaels et al claim that “these data were withheld from a federal rulemaking proceeding.” We conducted the original study under a contract between Applied Epidemiology, Inc. and the Industrial Health Foundation (IHF) and submitted our 139-page technical report to IHF (dated April 7, 2003) completing our contractual obligation. It is standard in the consulting industry to undertake client assignments on a confidential basis. Although the IHF study was undertaken on such a basis, we had the right to publish the results after considering (without obligation) client comments. Without any further contract with IHF, we began preparing manuscripts long before the Occupational Safety and Health Administration (OSHA) review. At the urging of the U.S. Office of Management and Budget, however, we accelerated this process so that at least the basic results from the U.S. and the German cohorts might be published and available to the OSHA process. The U.S. paper2 was accepted for publication immediately, whereas the German paper was held up in review by a different journal for many months—ironically until the end of the OSHA comment period—and rejected. We then submitted it to JOEM and, after revision (results and interpretations unchanged), it was accepted and provided to OSHA. Michaels et al's second point is that “these data were actually part of a larger study that refutes the authors' conclusion.” That the German paper was part of a larger study effort is of course correct, as described in both the U.S. and the German papers, as well as in a response to Michaels et al's earlier criticisms of the U.S. paper.3 That the results refute our conclusion that the data suggest a threshold is inaccurate and based on information taken out of context. Originally, the German cohort was part of a study that combined this group with a cohort of U.S. chromate industry workers to maximize statistical power. However, as explained in both papers and in response to Michaels et al's earlier criticisms, several substantial differences between the cohorts complicated the analyses. Specifically, differences were seen by gender (only the U.S. plants included women), age (U.S. employees were substantially younger at hire and at end of follow up), ethnicity (U.S. plants included black and Hispanic workers, German plants had nearly no minorities), smoking prevalence (U.S. plants had lower rates), and—perhaps most importantly—exposure data (U.S. plants only had air monitoring data, German plants relied mainly on urinalysis). Because of these potentially important differences by country, and the fact that 88% of the lung cancer deaths were observed among the German subcohort, colleagues attending the Epidemiology in Occupational Health Symposium held in Barcelona in 2002, where the study was publicly presented,4,5 recommended that the results be stratified by country and reported separately. This suggestion had also been made after review of the study protocol by a senior academic epidemiologist who served as an external advisor. While stratifying the results by country resulted in a U.S. report with low statistical power (fully acknowledged in the paper), it was felt that those results should be made available to the scientific community through a peer-reviewed publication. Consequently, a more straightforward statistical analysis of the German data was possible with statistical power only slightly lower than that of the combined cohorts. Because the risk for the U.S. plants was not elevated, and all U.S. deaths occurred in the lowest exposure category, the resulting lung cancer standardized mortality ratio (SMR) for the German plants increased relative to the combined cohorts. SMR analysis by level of cumulative exposure (see Table 4 in the German paper) generated similar results to the combined cohort (also reflected in two additional tables in the client report) leading to our suggestion of a threshold. We performed logistic regression analyses in the original study and, as described in our article, to investigate simultaneously the influences on the risk estimates of cumulative exposure, peak exposure, and smoking. We do not consider the results presented in Michaels et al's Table 1 to be reliable largely because of the substantial differences between the U.S. and German cohorts. Also, we note the instability of the models as reflected in the wide confidence intervals, the uncertain adequacy of the fit of the model, and the fact that the logistic regression did not take into account the time dependency of the cumulative exposure metric. The results of the logistic regression analysis for the German plants, described in our article and partially included in Michaels et al Table 2, were taken directly from Table 19 of the client report and were not, as suggested by Michaels et al, produced after the decision to report results separately by country. We have explained in both the publication and the client report that a “low” exposure category estimate was technically impossible, because there were no cases with all necessary data available in the “low” category in the German cohort. Michaels et al's third point largely reiterates (by quoting OSHA) our own words: “Demonstrating a clear (and statistically significant) threshold response in epidemiological studies is difficult especially, as in this study, the number of available cases is relatively small, and the precise estimation of small risks requires large numbers.”1 We hope, however, that by presenting such results—even if only suggestive—we will stimulate additional useful epidemiologic research and expand scientific inquiry. Finally, although offering no solution, Michaels et al do raise a legitimate regulatory/policy point: how can the regulatory community obtain all scientifically sound and relevant evidence for their deliberations? Policymakers and regulators readily rely on material published in the peer-reviewed scientific journals. It is understood—correctly or incorrectly—that the peer review process imparts some degree of consistency with current standards and therefore quality. Michaels et al previously asserted that “Parties involved in the rulemaking process should also be required to certify that they have submitted all relevant data to the public record, whether or not those data have undergone peer review.”6 They apparently include material that is not published and not subject to rigorous peer review to be among the “best available evidence” that OSHA is to use. We believe that this is not so straightforward and that fuller discussion is warranted. We are disappointed that Michaels et al have chosen to speculate about (or at least not read carefully and represent accurately) our work for IHF and the publications derived from that work (especially because we did attempt to discuss these very points directly with Michaels during several phone conversations around May 2005). Nevertheless, we are grateful to the editor of JOEM for the opportunity (not offered by the journal in which Michaels et al first published their story6) to respond and to offer a clearer perspective on our research. Thomas Birk, Dipl rer soc ENVIRON Germany GmbH Essen, Germany Kenneth A. Mundt, PhD Linda D. Dell, MS Rose S. Luippold, MS Diane J. Mundt, PhD ENVIRON International Corporation Amherst, Massachusetts Leopold Miksche, MD ENVIRON Senior Medical Advisor and Former Corporate Medical Director (retired) Bayer AG Leverkusen, Germany Wolfgang Steinmann-Steiner-Haldenstaett, MD Bayer Industry Services GmbH & Co. OHG SUA-GHS Gesundheitsschutz Uerdingen Leitung, Germany

Objectives. Of an estimated 500,000 workers in the USA potentially exposed to perchloroethylene (PCE), the largest share is employed in the dry-cleaning industry. PCE, a non-flammable solvent, has commercial applications as a chemical intermediate, metal degreaser and, since the 1950s, primary solvent in the dry-cleaning industry. The International Agency for Research on Cancer (IARC) currently finds sufficient evidence to designate PCE as carcinogenic in animals, with limited evidence in humans. With regard to occupational exposure through dry-cleaning, PCE is considered to be possibly carcinogenic to humans. This review was conducted to assess the current epidemiological literature on PCE and specific cancers. Methods. A comprehensive search was conducted to identify all available epidemiological literature pertaining to the carcinogenic effects of PCE. Forty-four papers that provided reasonable data on up to 17 cancer sites were critically reviewed in the context of the available background literature for each cancer site and were assessed on the basis of specified methodological and scientific quality criteria. Results. While all the epidemiological studies selected for review investigated similar exposure-health outcome relationships, there was a broad diversity of proxy measurements of exposure to PCE, as well as numerous specific cancer outcomes of interest. The widespread lack of valid exposure measurements or other adequate indicators of potential for exposure were consistent limitations. We found no evidence of an association between breast, prostate, skin or brain cancer and exposure to PCE. A relationship between PCE and cancer of the following sites was considered unlikely: oral cavity, liver, pancreas, cervix lung. Scientific evidence was inadequate for laryngeal, kidney, esophageal and bladder cancers. Conclusions. The current epidemiological evidence does not support a conclusion that occupational exposure to PCE is a risk factor for cancer of any specific site. Priority areas in which additional data are most needed include cancers of the esophagus and bladder.

1991 wurde in der deutschen Kautschukindustrie mit der Durchführung einer historischen Kohortenstudie über das Berufskrebsrisiko begonnen. Zielsetzungen der Studie und Aspekte des Studiendesigns wie Auswahl der Unternehmen, Definition der Kohorte, Abschätzung der beruflichen Exposition und Wahl der Vergleichspopulation werden beschrieben und diskutiert. Die Verfahren zum Aufbau der Kohorte, zur Bestimmung des Vitalstatus und gegebenenfalls der Todesursache der Kohortenmitglieder werden dargestellt. Bei annähernd 2800 Todesfällen im Beobachtungszeitraum von 1981 bis 1991 wird es möglich sein, auch für seltene Todesursachen Aussagen zur beruflichen Gefährdung zu machen.

A historical cohort study is carried out to investigate occupational hazards in the German rubber industry since 1991. We present and discuss the study objectives and study design features such as cohort definition, assessment of occupational exposure and selection of the reference population. Cohort enumeration, assessment of vital status and cause of death ascertainment are described. With approximately 2800 deaths throughout the observation period 1981 to 1991 it will be possible also to study the occupational etiology of rare diseases.

Epidemiologic studies of occupationally exposed subjects allow to detect diseases caused by the work environment and to identify hazardous exposures. They provide the basis for preventive measures and workers compensation. Occupational epidemiology traditionally emphasized the study of work related cancer. Long latency periods for the development of most cancers and limited information about the exposure history of the study subjects are problems for all study types. The specific advantages and limitations of different study designs are discussed. Research strategies in occupational epidemiology are demonstrated using as an example two studies from the American tire and rubber industry. The specific contributions of a historical cohort study and a nested case-control study, concerning the association between lymphosarcoma and exposure to solvents, are discussed. Experiences and first results from a historical cohort study in the German rubber industry are reported. Future research in occupational epidemiology should concentrate more on the study of work related morbidity such as musculoskeletal disorders, hearing loss, accidents and the influence of the work environment on the mental and physical well being. Modern research methods such as prospective cohort studies or workforce monitoring should be used more often. Prospective cohort studies provide quantitatively and qualitatively more precise information about exposures and potential confounders, e.g. cigarette smoking or alcohol consumption, than traditional study methods. The promising perspectives of biological markers warrant further research. The situation of occupational epidemiology in Germany can only be improved if all concerned parties and institutions realize the importance of occupational epidemiology. Laws concerning data confidentiality which seriously hamper epidemiologic research must be modified.

Epidemiologische Studien an beruflich exponierten Personen erlauben, arbeitsbedingte gesundheitliche Gefährdungen und Schädigungen zu erkennen. Sie bilden damit eine Grundlage für präventive Massnahmen und für Entschädigungsfragen im Krankheitsfall. Ihren traditionellen Schwerpunkt hat die betriebliche Epidemiologie in der Erforschung des Zusammenhangs von Arbeitsumwelt und Krebsgenese. Neben den jeweils spezifischen Vor- und Nachteilen der zum Einsatz kommenden Studientypen existiert das gemeinsame Problem der langen Latenzzeiten bei der Entstehung der meisten Krebsarten und historisch nur schwer erhebbarer Angaben zur Exposition. Die Vorgehensweise der betrieblichen Epidemiologie wird anhand zweier Studien in der amerikanischen Reifen- und Gummiindustrie diskutiert. Am Beispiel einer Studie über den Zusammenhang von Lösungsmittelexposition und Lymphomen werden die spezifischen Beiträge aufgezeigt, die historische Kohortenstudien und “eingebettete” Fall-Kontrollstudien für die Erforschung eines kausalen Zusammenhangs von Exposition und Erkrankung liefern können. Forschungsstrategie, Studiendesign und erste Erfahrungen bei der Umsetzung in die Forschungspraxis eines aktuellen Forschungsprojektes in der deutschen Gummiindustrie werden vorgestellt. Perspektiven der betrieblichen Epidemiologie eröffnen sich sowohl im Bereich der Forschungsschwerpunkte als auch der Forschungsmethoden. Neben der “klassischen” Krebsepidemiologie sind es beispielsweise Erkrankungen des Stütz- und Bewegungsapparates, Hörschädigungen, Unfälle und der Einfluss der Arbeitsorganisation auf Befindlichkeitsstörungen, die stärker als bisher in das Blickfeld betriebsepidemiologischer Forschung rücken müssen. Gleichzeitig ist auch der Einsatz moderner epidemiologischer Forschungsmethoden, wie z.B. von prospektiven Kohortenstudien, in einem stärkeren Masse als bisher notwendig. Prospektive Kohortenstudien haben den Vorteil, dass sie die Exposition deutlich besser quantifizieren und qualifizieren und auch mögliche Störvariablen wie Rauchen oder Alkoholkonsum besser erfassen können. Ebenfalls sollte die Diskussion über die Einsatzmöglichkeiten von biologischen Markern in epidemiologischen Studien verstärkt geführt werden. In der Bundesrepublik Deutschland lässt sich die allgemeine Situation der betrieblichen Epidemiologie nur dann verbessern, wenn sich alle beteiligten und betroffenen Gruppen und Institutionen der Notwendigkeit betriebsepidemiologischer Forschung bewusst werden und die z.T. restriktiven Datenschutzgesetze dahingehend modifiziert werden, dass sie die Forschung über arbeitsbedingte Gesundheitsgefährdungen unterstützen und nicht behindern oder gar verhindern.