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Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years prior to diagnosis (range, 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma) and matched controls. Linear mixed models, and Partial Least Square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes, and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed modelIrrespective of the model, our analyses identified associations linking blood lower immune markerslevels of and BCL incidence. In particular, we identified growth factors, and within that family, fibroblast growth factor-2 (FGF-2 , p=7.2x10 -4 ), ) and transforming growth factor alpha (TGF-α , p=6.5x10 -5 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p=7.8x10 -7 ), TGF-α (p=4.08x10 -5 ), fractalkine (p=1.12x10 -3 ), monocyte chemotactic protein-3 (p=1.36x10 -4 ), macrophage inflammatory protein 1-alpha (p=4.6x10 -4 ), and vascular endothelial growth factor (p=4.23x10 -5 ). , and vascular endothelial growth factor (VEGF), to be consistently (and inversely) associated with MM incidence. Our results also provide d marginal support for already reported associations between chemokines and diffuse large B-Cell lymphoma (DLBCL) , and cytokines and chronic lymphocytic leukemia (CLL) . Case-only analyses showed that GM-CSF levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth-factors in the incidence of MM, and of chemokine and cytokine regulation in DLBCL and CLL.

Objective: The use of measurement data in occupational exposure assessment allows more quantitative analyses of possible exposure-response relations. We describe a quantitative exposure assessment approach for five lung carcinogens (i.e. asbestos, chromium-VI, nickel, polycyclic aromatic hydrocarbons (by its proxy benzo(a)pyrene (BaP)) and respirable crystalline silica). A quantitative job-exposure matrix (JEM) was developed based on statistical modeling of large quantities of personal measurements. Methods: Empirical linear models were developed using personal occupational exposure measurements (n = 102306) from Europe and Canada, as well as auxiliary information like job (industry), year of sampling, region, an a priori exposure rating of each job (none, low, and high exposed), sampling and analytical methods, and sampling duration. The model outcomes were used to create a JEM with a quantitative estimate of the level of exposure by job, year, and region. Results: Decreasing time trends were observed for all agents between the 1970s and 2009, ranging from-1.2% per year for personal BaP and nickel exposures to-10.7% for asbestos (in the time period before an asbestos ban was implemented). Regional differences in exposure concentrations (adjusted for measured jobs, years of measurement, and sampling method and duration) varied by agent, ranging from a factor 3.3 for chromium-VI up to a factor 10.5 for asbestos. Conclusion: We estimated time-, job-, and region-specific exposure levels for four (asbestos, chromium-VI, nickel, and RCS) out of five considered lung carcinogens. Through statistical modeling of large amounts of personal occupational exposure measurement data we were able to derive a quantitative JEM to be used in community-based studies.

Summary Background and objectives We have previously reported that high rat urinary allergen (RUA) exposure was not associated with increased risk of rat allergy in long-term-exposed laboratory animal (LA) workers. We aimed to assess whether strong allergen-specific IgG4 responses could explain the absence of a dose response in these subjects. We investigated whether IgG4 was associated with allergen exposure and prevalence of sensitization or respiratory symptoms to rats. The longitudinal relation between IgG4 and rat allergy was studied using data obtained during 2 years of follow-up. Methods Five hundred and twenty-nine LA workers answered a questionnaire on respiratory symptoms and occupational history and participated in skin prick testing. Blood samples were analysed for specific IgG4 and IgE to RUA. Exposure to RUA was estimated based on personal air samples. The relation between IgG4 and newly occurring sensitization or rat allergy was studied in workers who were not sensitized or did not report respiratory symptoms to rats. Results IgG4 titres were higher in atopic than in non-atopic subjects, and increased with higher allergen exposure. Titres were highest in subjects who were sensitized and reported respiratory symptoms to rats when compared with those who were not (geometric mean [geometric standard deviation]=202 [5.7] vs. 8.4 [18.3] AU). The association between IgG4 and sensitization or symptomatic rat allergy was independent of estimated allergen exposure. IgG4 was a strong predictor of newly occurring sensitization and symptomatic rat allergy during follow-up in atopic and rat-sensitized subjects. Conclusion High exposure to RUA is associated with a strong allergen-specific IgG4 antibody response. High anti-RUA IgG4 is a strong predictor of prevalent and incident sensitization and symptomatic rat allergy in atopic and rat-sensitized subjects. IgG4 can therefore not explain the absence of a dose response between allergen exposure and allergy in long-term-exposed workers. We consider anti-RUA IgG4 to be a marker that combines aspects of exposure and susceptibility.

Background We recently reported increased risks for all cancers and urinary cancers in workers exposed to chlorophenoxy herbicides using data from the Dutch herbicide cohort study. These risks could not be linked to the qualitative exposure proxies available. Here, we re-investigate exposure–response relationships using a (semi)quantitative measure of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) exposure. Methods Plasma TCDD levels of 187 workers were used to develop a predictive model for TCDD exposure. Cox proportional hazards model was used to investigate associations between time-varying TCDD exposure and cause-specific mortality. Sensitivity analyses were performed to assess the impact of key assumptions in exposure assessment. Results Predicted TCDD levels were associated with mortality from all causes (HR 1.08; 95% CI 1.03 to 1.13), ischaemic heart disease (IHD; HR 1.19; 95% CI 1.08 to 1.32) and non-Hodgkin9s lymphoma (NHL; HR 1.36; 95% CI 1.06 to 1.74). No relationships were found between TCDD exposure and mortality from all cancers, respiratory or urinary cancers, which were previously linked to qualitative proxies of TCDD exposure in this cohort. Sensitivity analyses showed that results were relatively robust to slight changes in exposure estimation. Conclusions Modelled TCDD exposure does not explain the previously reported increased risks for cancer mortality in this cohort except for a possible association with NHL. A small increase in ischaemic heart disease was observed, however we cannot exclude that this finding was due to residual confounding. Although risk estimates for some of the rarer outcomes were still rather imprecise, we do not expect more precise estimates from longer follow-up of this cohort due to the long time-span since last exposure to TCDD.

We developed quantitative estimates of historical exposures to respirable elemental carbon (REC) for an epidemiologic study of mortality, including lung cancer, among diesel-exposed miners at eight non-metal mining facilities [the Diesel Exhaust in Miners Study (DEMS)]. Because there were no historical measurements of diesel exhaust (DE), historical REC (a component of DE) levels were estimated based on REC data from monitoring surveys conducted in 1998-2001 as part of the DEMS investigation. These values were adjusted for underground workers by carbon monoxide (CO) concentration trends in the mines derived from models of historical CO (another DE component) measurements and DE determinants such as engine horsepower (HP; 1 HP = 0.746 kW) and mine ventilation. CO was chosen to estimate historical changes because it was the most frequently measured DE component in our study facilities and it was found to correlate with REC exposure. Databases were constructed by facility and year with air sampling data and with information on the total rate of airflow exhausted from the underground operations in cubic feet per minute (CFM) (1 CFM = 0.0283 m³ min⁻¹), HP of the diesel equipment in use (ADJ HP), and other possible determinants. The ADJ HP purchased after 1990 (ADJ HP₁₉₉₀(+)) was also included to account for lower emissions from newer, cleaner engines. Facility-specific CO levels, relative to those in the DEMS survey year for each year back to the start of dieselization (1947-1967 depending on facility), were predicted based on models of observed CO concentrations and log-transformed (Ln) ADJ HP/CFM and Ln(ADJ HP₁₉₉₀(+)). The resulting temporal trends in relative CO levels were then multiplied by facility/department/job-specific REC estimates derived from the DEMS surveys personal measurements to obtain historical facility/department/job/year-specific REC exposure estimates. The facility-specific temporal trends of CO levels (and thus the REC estimates) generated from these models indicated that CO concentrations had been generally greater in the past than during the 1998-2001 DEMS surveys, with the highest levels ranging from 100 to 685% greater (median: 300%). These levels generally occurred between 1970 and the early 1980s. A comparison of the CO facility-specific model predictions with CO air concentration measurements from a 1976-1977 survey external to the modeling showed that our model predictions were slightly lower than those observed (median relative difference of 29%; range across facilities: 49 to -25%). In summary, we successfully modeled past CO concentration levels using selected determinants of DE exposure to derive retrospective estimates of REC exposure. The results suggested large variations in REC exposure levels both between and within the underground operations of the facilities and over time. These REC exposure estimates were in a plausible range and were used in the investigation of exposure-response relationships in epidemiologic analyses.

BACKGROUND: Asbestos is a well-recognized cause of lung cancer, but there is considerable between-study heterogeneity in the slope of the exposure-response relationship. OBJECTIVE: We considered the role of quality of the exposure assessment to potentially explain heterogeneity in exposure-response slope estimates. DATA SOURCES: We searched PubMed MEDLINE (1950-2009) for studies with quantitative estimates of cumulative asbestos exposure and lung cancer mortality and identified 19 original epidemiological studies. One was a population-based case-control study, and the others were industry-based cohort studies. DATA EXTRACTION: Cumulative exposure categories and corresponding risks were abstracted. Exposure-response slopes [K(L) (lung cancer potency factor of asbestos)] were calculated using linear relative risk regression models. DATA SYNTHESIS: We assessed the quality of five exposure assessment aspects of each study and conducted random effects univariate and multivariate meta-regressions. Heterogeneity in exposure-response relationships was greater than expected by chance (I(2) = 64%). Stratification by exposure assessment characteristics revealed that studies with well-documented exposure assessment, larger contrast in exposure, greater coverage of the exposure history by exposure measurement data, and more complete job histories had higher meta-K(L) values than did studies without these characteristics. The latter two covariates were most strongly associated with the K(L) value. Meta-K(L) values increased when we incrementally restricted analyses to higher-quality studies. CONCLUSIONS: This meta-analysis indicates that studies with higher-quality asbestos exposure assessment yield higher meta-estimates of the lung cancer risk per unit of exposure. Potency differences for predominantly chrysotile versus amphibole asbestos-exposed cohorts become difficult to ascertain when meta-analyses are restricted to studies with fewer exposure assessment limitations.

Background: Recent studies have reported a low prevalence of atopic sensitization and respiratory allergy in children growing up on farms. Objectives: We sought to evaluate the dose-response relationship between endotoxin and atopic sensitization in adult farmers and to assess the effect on respiratory health outcomes. Methods: Data on endotoxin exposure and serum IgE levels were available for 162 pig farmers from a cross-sectional case-control study, with case selection on the basis of respiratory symptoms. Exposure to endotoxin was modeled in detail, and respiratory health effects were assessed during a medical examination. Exploratory analysis was done by using nonparametric modeling and was followed by classical parametric regression. Results: IgE to one or more common allergens was detected in sera from 28 (17%) farmers. The average (geometric mean) total serum IgE levels was 37 IU/mL (geometric SD, 4 IU/mL). A strong inverse relationship was found between endotoxin and sensitization to common allergens for exposures of 75 ng/m 3 or less, with an odds ratio of 0.03 (95% CI, 0.0-0.34) for a 2-fold increase in endotoxin. For endotoxin exposure of greater than 75 ng/m 3, the association was weak (odds ratio, 1.2 [95% CI, 0.38-3.6]). No association was found between endotoxin exposure and total serum IgE levels. Endotoxin was associated with increased airway hyperresponsiveness to histamine and lower lung function in sensitized farmers, without evidence of a nonlinear relationship. Conclusions: The prevalence of atopic sensitization in adult pig farmers is low. Endotoxin or related exposures might protect from sensitization, even in an adult working population exposed to high levels of endotoxin, but is a risk factor for increased airway hyperresponsiveness and low lung function. © 2005 American Academy of Allergy, Asthma and Immunology.

Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is highly prevalent in pork and veal production chains. In this study, we used data from a cross-sectional survey on 2151 calves from 102 veal calf farms to identify potential risk factors, with the goal of reducing MRSA prevalence by developing intervention strategies. Overall, calves from rose veal farms had a lower risk of LA-MRSA carriage than calves from white veal farms. Data were analysed separately for white and rose veal calves, because management systems of the two production chains were largely different. Group treatment with antimicrobials appeared to be a risk factor for MRSA carriage in white veal calves in univariate analyses, but was not included in the final multiple regression model that included age of the calves and rodent control. Number of start treatment days was positively associated with LA-MRSA carriage in rose veal calves, and was the only risk factor selected for the final multiple regression model for this group. Interpretation of the results from this cross-sectional study is complicated by the strong correlation between antimicrobial use, LA-MRSA carriage and age of the calves. Other age-related factors may be more influential. However, taken together these findings emphasize the need for prudent use of antimicrobials, and point to improvement of farm hygiene as a control measure.