The Pattern of Sensitization Influences Exhaled and Nasal Nitric Oxide Levels in Young Adults.

Nitric oxide (NO) from upper (nasal NO, nNO) or lower airways (fractional exhaled NO, FeNO) is considered a surrogate marker for Th2-type inflammation, which is influenced by atopy. The aim of this study was to analyze nNO and FeNO in regard to qualitative and quantitative aspects of sensitization. We evaluated 244 non-smoking young adults. All of them were first-year students recruited for a longitudinal study. An inhalation allergy screening tool was used for atopy definition (specific immunoglobulin E (sIgE) to sx1 ≥ 0.35 kU/L), and also sIgE response to three inhalant perennial allergens, house dust mite (HDM, d1), cat (e1), and dog (e5), was determined in the non-pollen season. With respect to sx1, 100 subjects could be classified as atopic. Sensitization to one, two, or three perennial allergens could be demonstrated in 46, 10, and 16 students, respectively. The subjects with positive IgE response to sx1, but not sensitized to HDM, cat, and/or dog, had FeNO levels comparable to those of non-atopic subjects (13.5 vs. 13.0 ppb, respectively; p = 0.485). These levels were significantly lower compared to atopic subjects being sensitized to any perennial allergen (19.0 ppb; p = 0.0003). After grouping the atopic subjects for perennial sensitization patterns, significantly higher FeNO could be detected in subjects with poly-sensitization (n = 26; 26.0 ppb) compared to the mono-sensitized ones (n = 46; 18.0 ppb; p = 0.023). Regarding nNO, no differences could be observed. Applying a two-way ANOVA, we could reveal a significant correlation of specific HDM-IgE CAP-class with FeNO (p < 0.0001) and nNO levels (p = 0.007). Finally, a significant relationship was found between nNO and FeNO for the whole cohort (p < 0.0001). In summary, our findings support the argument that atopy and perennial sensitization should be considered for the interpretation of NO.

Cancer mortality in cohorts of workers in the European rubber manufacturing industry first employed since 1975.

BACKGROUND: Increased cancer risk has been reported among workers in the rubber manufacturing industry employed before the 1960s. It is unclear whether risk remains increased among workers hired subsequently. The present study focused on risk of cancer mortality for rubber workers first employed since 1975 in 64 factories. PATIENTS AND METHODS: Anonymized data from cohorts of rubber workers employed for at least 1 year from Germany, Italy, Poland, Sweden, and the UK were pooled. Standardized mortality ratios (SMRs), based on country-specific death rates, were reported for bladder and lung cancer (primary outcomes of interest), for other selected cancer sites, and for cancer sites with a minimum of 10 deaths in men or women. Analyses stratified by type of industry, period, and duration of employment were carried out. RESULTS: A total of 38 457 individuals (29 768 men; 8689 women) contributed to 949 370 person-years. No increased risk of bladder cancer was observed [SMR = 0.80, 95% confidence interval (CI) 0.46; 1.38]. The risk of lung cancer death was reduced (SMR = 0.81, 95% CI 0.70; 0.94). No statistically significant increased risk was observed for any other cause of death. A reduced risk was evident for total cancer mortality (SMR = 0.81, 95% CI 0.76; 0.87). Risks were lower for workers in the tyre industry compared with workers in the general rubber goods sector. Analysis by employment duration showed a negative trend with SMRs decreasing with increasing duration of employment. In an analysis of secondary end points, when stratified by type of industry and period of first employment, excess risks of myeloma and gastric cancer were observed each due, essentially, to results from one centre. CONCLUSION: No consistent increased risk of cancer death was observed among rubber workers first employed since 1975, no overall analysis of the pooled cohort produced significantly increased risk. Continued surveillance of the present cohorts is required to confirm the absence of long-term risk.

Spirometry or Body Plethysmography for the Assessment of Bronchial Hyperresponsiveness?

Methacholine testing is one of the standard tools for the diagnosis of mild asthma, but there is little information about optimal outcome measures. In this study a total of 395 college students were tested by the ATS dosimeter protocol for methacholine testing, with minor modification. Body plethysmography and spirometry were measured after each inhalation step. The end-of-test-criteria were (i) decrease in forced expiratory volume in 1 s (FEV1) of ≥ 20 % and (ii) doubling of specific airway resistance and its increase to ≥ 2.0 kPa∙s. The results were expressed by receiver operating characteristic (ROC) plots using questionnaire answers as a reference. The areas under the ROC curves were iteratively calculated for a wide range of thresholds for both measures. We found that ROC plots showed maximal sensitivities of about 0.5-0.6 for FEV1 and about 0.7 for specific airway conductance (sGt), with similar specificities of about 0.7-0.8 taking questions with the known high specificity as references. Accordingly, larger maximal areas under the ROC curve were observed for body plethysmography, but the differences were small. A decrease in FEV1 of about 15 % and a decrease of sGt of about 60 % showed the largest areas under the ROC curves. In conclusion, body plethysmography yielded better sensitivity than spirometry, with similar specificity. However, replacing the common spirometric criterium for a positive test (20 % decrease in FEV1 from baseline) by the optimal body plethysmographic criterium would result in an increase of false positive tests from about 4 to 8 % in healthy young adults.

Biomarker research with prospective study designs for the early detection of cancer.

This article describes the principles of marker research with prospective studies along with examples for diagnostic tumor markers. A plethora of biomarkers have been claimed as useful for the early detection of cancer. However, disappointingly few biomarkers were approved for the detection of unrecognized disease, and even approved markers may lack a sound validation phase. Prospective studies aimed at the early detection of cancer are costly and long-lasting and therefore the bottleneck in marker research. They enroll a large number of clinically asymptomatic subjects and follow-up on incident cases. As invasive procedures cannot be applied to collect tissue samples from the target organ, biomarkers can only be determined in easily accessible body fluids. Marker levels increase during cancer development, with samples collected closer to the occurrence of symptoms or a clinical diagnosis being more informative than earlier samples. Only prospective designs allow the serial collection of pre-diagnostic samples. Their storage in a biobank upgrades cohort studies to serve for both, marker discovery and validation. Population-based cohort studies, which may collect a wealth of data, are commonly conducted with just one baseline investigation lacking serial samples. However, they can provide valuable information about factors that influence the marker level. Screening programs can be employed to archive serial samples but require significant efforts to collect samples and auxiliary data for marker research. Randomized controlled trials have the highest level of evidence in assessing a biomarker's benefit against usual care and present the most stringent design for the validation of promising markers as well as for the discovery of new markers. In summary, all kinds of prospective studies can benefit from a biobank as they can serve as a platform for biomarker research. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.

Evaluation of a 4-steps-1-day whole body challenge protocol for the diagnosis of occupational asthma due to diisocyanates.

Inhalative challenges are important in the diagnosis of occupational asthma due to diisocyanates. As existing protocols are time-consuming and costly, it was the aim of this study to develop a short duration whole body exposure protocol. Ninety three subjects with suspected occupational diisocyanate-induced asthma and verified current or previous occupational exposure to diisocyanates and ten control subjects without diisocyanate exposure but with bronchial hyperresponsiveness were investigated. After baseline examination on the first day, subjects underwent a standardized whole body multiple-steps-1-day challenge with exposures of up to four times 30 min to concentrations of 5, 10, 20, and 30 ppb of the dominant diisocyanate used at work on the second day. Common spirometric and body plethysmographic parameters were used as positivity criteria. Overall, 14 subjects demonstrated a positive diisocyanate challenge, 19 were considered doubtful, and 60 were negative. All controls had negative challenges. Positive reactions occurred during the challenge (n = 10) or during follow-up (n = 4). Eight subjects showed >40 % fall of FEV1. These severe reactions occurred after 5 ppb (n = 2) or 10 ppb (n = 3), while isolated late reactions after 2 h of follow-up were not observed. Multivariate analysis showed an association between a positive challenge and both the degree of previous occupational exposure and the presence of baseline bronchial hyperresponsiveness. In summary, the proposed 4-steps-1-day diisocyanate challenge protocol induced pronounced bronchial reactions in a small number of subjects. As these reactions were more likely to occur after low concentrations, it is recommended to shift the initial concentration/dose step to lower exposures.

Quantitative relationship between silica exposure and lung cancer mortality in German uranium miners, 1946-2003.

BACKGROUND: In 1996 and 2009, the International Agency for Research on Cancer classified silica as carcinogenic to humans. The exposure-response relationship between silica and lung cancer risk, however, is still debated. Data from the German uranium miner cohort study were used to further investigate this relationship. METHODS: The cohort includes 58677 workers with individual information on occupational exposure to crystalline silica in mg m(-3)-years and the potential confounders radon and arsenic based on a detailed job-exposure matrix. In the follow-up period 1946-2003, 2995 miners died from lung cancer. Internal Poisson regression with stratification by age and calendar year was used to estimate the excess relative risk (ERR) per dust-year. Several models including linear, linear quadratic and spline functions were applied. Detailed adjustment for cumulative radon and arsenic exposure was performed. RESULTS: A piecewise linear spline function with a knot at 10 mg m(-3)-years provided the best model fit. After full adjustment for radon and arsenic no increase in risk <10 mg m(-3)-years was observed. Fixing the parameter estimate of the ERR in this range at 0 provided the best model fit with an ERR of 0.061 (95% confidence interval: 0.039, 0.083) >10 mg m(-3)-years. CONCLUSION: The study confirms a positive exposure-response relationship between silica and lung cancer, particularly for high exposures.

[Bladder cancer screening with urine-based tumour markers - occupational medical experience]. / Das Screening von Harnblasenkarzinomen mittels urinbasierter Tumormarker - Erfahrungen aus der Arbeitsmedizin.

OBJECTIVE: Bladder cancer responds favourably to treatment and has a good survival rate, provided it is diagnosed at an early stage. Established methods exist for the early detection, however, their specificity and positive predictive value are not yet satisfactory. Innovative markers have been proposed, but still require validation in prospective studies. We provide a literature-based short overview on the currently available and some proposed markers for the early detection of bladder cancer and evaluate the need for validation in further studies. We further provide some first results of such a recently finished study in an occupational setting. MATERIAL AND METHODS: We conducted a prospective screening study over seven years in 1610 males with former occupational exposure to carcinogenic aromatic amines. Annual bladder cancer screening according to statutory requirements was offered. In addition to the regularly performed check for hematuria and urine cytology, the markers NMP22, UroVysion™ and survivin were performed in voided urine samples of the participants. Positive findings (not for survivin) were further followed through urethrocystoscopy. RESULTS AND CONCLUSIONS: A total of 7219 urine samples were screened. During the study period 16 incidental and 4 recurrent bladder tumours, thereof three papillomas, occurred in a total of 19 participants. 14 out of twenty tumours were marker-positive, and all but two were early stage findings. Cell-based markers (cytology, UroVysion™) und molecular markers (NMP22, survivin) were largely complementary, thus acting as a "multi-marker panel". Eight of the tumours were identified by a positive cytology. Six tumours were not detected by any of the tumour markers. The results will be further evaluated through the inclusion of confounding factors, which have so far rarely been examined in other studies. This may lead to the development of tiered diagnostic strategies with the aim to reduce the number of invasive diagnostic procedures in the future.

Performance of biomarkers SMRP, CA125, and CYFRA 21-1 as potential tumor markers for malignant mesothelioma and lung cancer in a cohort of workers formerly exposed to asbestos.

The aim of the study is to examine the cancer-predictive values of SMRP (soluble mesothelin-related peptides), CA125, and CYFRA21-1 as potential tumor markers for lung cancer and malignant mesothelioma in a cohort of workers formerly exposed to asbestos. A voluntary surveillance program has been established for German workers with former asbestos exposure. A subgroup of 626 subjects with a mean age of 63 years (range 53-70 years) at baseline was enrolled in an extended health examination program with high-resolution computer tomography (HRCT) of the chest and blood drawing between 1993 and 1997. Serum concentrations of SMRP, CA125, and CYFRA21-1 were measured in archived serum samples in 2005 and 2006. A mortality follow-up was conducted through 2007. So far, 12 cases with lung cancer and 20 cases with malignant mesothelioma have been observed in this cohort. The average time between sample collection and diagnosis was 4.7 years. Analyzed biomarkers showed low sensitivities (5-25%) and positive predictive values (4-30%) for both cancer sites. Marker combinations resulted in sensitivities between 5 and 50% and positive predictive values ranging from 3 to 14%. Even in those cases, where biomarker concentrations were available within 36 months before diagnosis, no trend for increasing biomarker levels was observed. The analyzed tumor markers were characterized by high specificities, but low sensitivities. SMRP, CA125, and CYFRA21-1 alone or in combination were less suitable to serve as predictors for the diagnosis of lung cancer or malignant mesothelioma. However, a prospective study with annual sampling might reveal a better predictive value of these markers.

The German experience 10 years after the latex allergy epidemic: need for further preventive measures in healthcare employees with latex allergy.

OBJECTIVES: Powdered latex gloves or latex gloves with high allergen content are forbidden in Germany since 1998. It was the aim of this study to test the hypothesis that nationwide preventive measures enable health care workers with latex allergy to work without health risks about 10 years afterwards. METHODS: Ninety-one health care workers who had been reported to the accident insurance between 1996 and 2004 for occupational latex allergy were examined in 2007. The survey included a questionnaire, a physical examination, spirometry, methacholine testing, skin prick testing and serum IgE measurements to latex and environmental allergens. RESULTS: Recent work-related possibly allergic symptoms were reported by 32 subjects (35%), among them 18 subjects (20%) with symptoms of the eyes, nose or airways. Current sensitization to latex was detected in 61 subjects (67%), and 60 subjects (66%) were atopic. Eleven subjects (12%) showed mild airway obstruction, and 27 subjects (30%) were considered hyperresponsive to methacholine. Whereas overall recent symptoms of the eyes, nose or airways were associated with current latex sensitization (OR 4.5; 95% CI 1.3-16.2), this was not the case for objective outcome parameters (spirometry, bronchial hyperresponsiveness). CONCLUSIONS: Although most subjects had only mild disease, ongoing work-related symptoms of the eyes, nose or airways in a substantial number of subjects with latex allergy suggest the need for further secondary preventive measures in German healthcare.

Trends in suspected and recognized occupational respiratory diseases in Germany between 1970 and 2005.

BACKGROUND: Respiratory diseases represent a major proportion of occupational diseases in many countries. Little information is available about their incidences over the past several decades. METHODS: Based on the reports of the three German federal accident insurance agencies, the numbers of suspected and recognized cases of occupational respiratory diseases between 1970 and 2005 were collected and combined. The trends in the rates per 100,000 insured workers were calculated. RESULTS: In total, a decline in occupational respiratory diseases since 1998 could be observed. This trend is mainly based on the decrease in non-malignant respiratory diseases due to silica and obstructive airway diseases. In contrast, asbestos-induced diseases showed a leveling off or an increase (mesothelioma) during the last 10years. CONCLUSIONS: Although trends in occupational disease may be influenced by several factors, the presented data indicate that prevention has been effective in reducing some ofthe most frequent occupational respiratory diseases in Germany.

Exposure to inhalable dust and its cyclohexane soluble fraction since the 1970s in the rubber manufacturing industry in the European Union.

OBJECTIVES: As exposures to airborne particulates in the European rubber industry might still be causing genotoxic risks, it is important to assess trends in levels of inhalable dust and its cyclohexane soluble fraction (CSF) between the 1970s and 2003. METHODS: 13 380 inhalable and 816 respirable dust and 5657 CSF measurements, collected within the framework of the European Union Concerted Action EXASRUB, were analysed. Hierarchical mixed effects models were applied to assess exposure trends, taking into account between-factory, between-worker/location and day-to-day variances. RESULTS: Geometric mean levels of inhalable dust and CSF exposure changed by -4% (range -5.8 to +2.9%) and -3% (range -8.6 to 0%) per year, respectively. Significant reductions in inhalable dust concentrations were found in all countries for handling of crude materials and mixing and milling (-7% to -4% per year), as well as for miscellaneous workers (-11% to -5% per year), while significant CSF exposure reductions were found in curing (-8.6% per year) and maintenance and engineering departments (-5.4% per year). CONCLUSION: These analyses suggest that on average exposure levels of inhalable dust and its CSF in the European rubber manufacturing industry have steadily declined. Most likely genotoxic risks have also lessened over time since exposure levels have decreased and the most toxic chemicals have been replaced. In addition to differences in exposure reductions and levels among various stages of the production process, large differences across countries were noted. These patterns should be taken into account in retrospective assessment of exposure for epidemiological studies assessing cancer risk in the rubber industry.

Occupational exposure to NDMA and NMor in the European rubber industry.

Many nitrosamines are suspected of being human carcinogens, with the highest concentrations in the environment being measured in the rubber industry. Time trends of personal exposure to N-nitrosodimethylamine (NDMA) and to N-nitrosomorpholine (NMor) during the past two decades in the German rubber industry were analysed and compared with cross-sectional studies in the same period in the Netherlands, Poland, the UK and Sweden. In the majority of the surveyed departments exposures reduced over time, but considerable heterogeneity was present between departments and sectors. Significant reductions were primarily found in curing and post-treating departments and ranged from -3% year(-1) to -19% year(-1). In contrast, NDMA levels increased (+13% year(-1)) in maintenance and engineering in the tyres industry. Average NDMA-levels in general rubber goods (GRG) and NMor-levels in tyre production in Germany did not decrease significantly in the past two decades, whereas NDMA-levels in tyre production (-10% year(-1)) and NMor-levels in GRG (-7% year(-1)) declined significantly after the introduction of an exposure limit for total nitrosamines in Germany in 1988. Confidence intervals of average exposures in other studied countries largely overlap trends observed in Germany. Exposure to N-nitrosamines decreased on average two-to-five fold in the German rubber industry with comparable concentration levels in other European countries. Although average levels are well below the current limits exposure has not been eliminated, and incidental high exposures do still occur.

Determinants of IV heparin treatment in patients with ischemic stroke.

Management of acute ischemic stroke with IV unfractionated heparin is subject to debate. The authors evaluated patient-related and institutional factors influencing its use in 42 hospitals. Cardioembolic stroke type, carotid stenosis, atrial fibrillation, and treatment in stroke units or intensive care units significantly increased the probability of use. However, there are large unexplained variations in IV heparin use among hospitals.

Challenges to environmental toxicology and epidemiology: where do we stand and which way do we go?

Modern toxicology investigates a wide array of both old and new health hazards. Priority setting is needed to select agents for research from the plethora of exposure circumstances. The changing societies and a growing fraction of the aged have to be taken into consideration. A precise exposure assessment is of importance for risk estimation and regulation. Toxicology contributes to the exploration of pathomechanisms to specify the exposure metrics for risk estimation. Combined effects of co-existing agents are not yet sufficiently understood. Animal experiments allow a separate administration of agents which can not be disentangled by epidemiological means, but their value is limited for low exposure levels in many of today's settings. As an experimental science, toxicology has to keep pace with the rapidly growing knowledge about the language of the genome and the changing paradigms in cancer development. During the pioneer era of assembling a working draft of the human genome, toxicogenomics has been developed. Gene and pathway complexity have to be considered when investigating gene-environment interactions. For a best conduct of studies, modern toxicology needs a close liaison with many other disciplines like epidemiology and bioinformatics.

Different methods to calculate effect estimates in cross-sectional studies. A comparison between prevalence odds ratio and prevalence ratio.

OBJECTIVES: According to results from the epidemiological literature, it can be expected that the prevalence odds ratio (POR) and the prevalence ratio (PR) differ with increasing disease prevalence. We illustrate different concepts to calculate these effect measures in cross-sectional studies and discuss their advantages and weaknesses, using actual data from the ISAAC Phase III cross-sectional survey in Münster, Germany. METHODS: We analyzed data on the association between self-reported traffic density and wheeze and asthma by means of the POR, obtained from a logistic regression, and the PR, which was estimated from a log-linear binomial model and from different variants of a Poisson regression. RESULTS: The analysis based on the less frequent disease, i.e. asthma with an overall prevalence of 7.8%, yielded similar results for all estimates. When wheezing with a prevalence of 17.5% was analyzed, the POR produced the highest estimates with the widest confidence intervals. While the point estimates were similar in the log-binomial model and Poisson regression, the latter showed wider confidence intervals. When we calculated the Poisson regression with robust variances, confidence intervals narrowed. CONCLUSIONS: Since cross-sectional studies often deal with frequent diseases, we encourage analyzing cross-sectional data based on log-linear binomial models, which is the 'natural method' for estimating prevalence ratios. If algorithms fail to converge, a useful alternative is to define appropriate starting values or, if models still do not converge, to calculate a Poisson regression with robust estimates to control for overestimation of errors in the binomial data.

[Infection surveillance in North Rhine-Westphalia--standard reports, barometer and early warning system]. / Infektionssurveillance in NRW--Standardberichte, Barometer und Frühwarnsystem.

The increasing significance of communicable diseases requires new surveillance tools. Modern electronic instruments in analysis and communication replace the former "handbased" statistics and allow the development of early warning systems. In North Rhine-Westphalia (NRW) the Institute of Public Health started an approach to develop a modular surveillance system prior to the the implementation of the new German infectious disease protection act. The first module called "Automated infectious disease notifications and information system (AIM+)" generates various standard hypertext reports which are published as "Infectious disease reports NRW" on the internet (www.loegd.nrw.de). In addition the infectious disease information is linked with a geographical information system (GIS) giving spatial and temporal patterns. The second module called "Infectious disease barometer NRW" offers a quick actual overview highlighting several selected diseases. It can be electronically sent out to any interested person. The third module "Early warning system" realizes an effective early detection system by combining six statistical procedures with a total of 11 separate methods. In case of detecting clusters and outbreaks it automatically generates warning reports to the responsible parties. All three modules together improve the epidemiological surveillance of the population in NRW, support the translation of information to prevention and control measures, and therefore strengthen epidemiological policy-making.

[Influence of institutional factors in neurological, medical and geriatric departments on length of stay in patients with stroke]. / Ausstattungsmerkmale von Krankenhäusern und ihr Einfluss auf die Liegezeit von Schlaganfallpatienten.

BACKGROUND: Length of hospital stay (LOS) is determined not only by medical procedures or complications but also by institutional factors. We examined the influence of various institutional factors in neurological, medical and geriatric departments on LOS in patients with ischemic stroke. METHODS: We used data of 12,410 patients from the Westphalian Stroke Register for the years 2000 and 2001. Forty-two centres including 24 neurological, 13 medical and five geriatric departments participated in the register. The register is based on a standardized data assessment, including patient-related sociodemographic and clinical items, diagnostic and treatment procedures, complications, and status at discharge. RESULTS: 7855 patients with ischemic stroke from 37 centres (median age: 73 years, 51 % female) were included in the analysis. In neurological departments, the LOS decreased with increasing numbers of stroke patients treated per centre and year, presence of a stroke unit or a rehabilitation unit. Conversely, the ratio beds to number of physicians was positively associated with LOS. In geriatric departments, a significant decrease in LOS with an increasing number of stroke cases and availability of a rehabilitation unit was also observed. In departments of medicine, no significant influence on LOS was found for the institutional factors analysed. CONCLUSIONS: Institutional factors have a significant influence on LOS in patients with stroke. In this analysis, the influence varied between the different medical specialties. Institutional factors gain importance in the management of stroke patients, when Diagnosis Related Groups (DRG) are introduced.

Second malignancies after ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study.

BACKGROUND: Ewing tumor treatment involves high cumulative doses of alkylating agents and topoisomerase inhibitors, drugs capable of inducing second cancers. We analyzed the second cancer risk in a large cohort of consistently treated patients. PATIENTS AND METHODS: Six hundred ninety Ewing tumor patients were treated between 1992 and 1999 with local therapy and vincristine. doxorubicin, ifosfamide and/or cyclophosphamide, and antinomycin D, with or without etoposide as a randomized question. Second cancer incidences were estimated by competing risk analyses; standardized incidence ratios (SIR) in comparison to registry data were compiled. RESULTS: After a median observation time of 56 months (32 months for survivors), 6 of 690 patients had developed second cancers: MDS/AML, two, ALL/NHL, two, squamous cell carcinoma, one, liposarcoma, one. SIR were increased 20-30 fold in comparison to the general population. The cumulative second cancer risk five years after diagnosis of the Ewing tumor was 0.0093 for the total group, zero for patients without etoposide, and 0.0118 with etoposide. Additional phase II high-dose therapy increased the risk to 0.0398 after five years. CONCLUSIONS: The second cancder risk observed was in the range to be expected in cancer survivors. High-dose therapy, and less markedly, etoposide, may contribute to the overall second cancer risk.

Exposure to nitrosamines, carbon black, asbestos, and talc and mortality from stomach, lung, and laryngeal cancer in a cohort of rubber workers.

There is sufficient evidence for an excess occurrence of stomach and lung cancer among rubber workers. However, evidence for causal associations with specific exposures is still limited. A cohort of 8,933 male German rubber workers was followed for mortality from January 1, 1981 through December 31, 1991. Work histories were reconstructed using routinely documented cost center codes. For each cost center code, calendar time-and plant-specific levels of exposure to nitrosamines, asbestos, talc (low, medium (m), and high (h)), and carbon black (two levels) were estimated by industrial hygienists. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, with the lowest exposure level used as the reference category. Exposure was lagged 10 years to account for latency. Exposure-response relations between exposure to asbestos and lung cancer mortality (RRm = 1.3, 95% CI: 0.9, 1.9; RRh = 2.0, 95% CI: 0.9, 4.1) and between exposure to dust (talc and asbestos combined) and stomach cancer mortality (RRm = 1.8, 95% CI: 0.9, 3.8; RRh = 2.7, 95% CI: 1.0, 7.1) were observed. Exposure to nitrosamines was not associated with mortality from stomach or lung cancer. These results suggest that the increased mortality from lung and stomach cancer among rubber workers is associated with exposure to asbestos and dust, respectively.