A physiologically-based kinetic (PBK) model for work-related diisocyanate exposure: Relevance for the design and reporting of biomonitoring studies.

Diisocyanates are highly reactive substances and known causes of occupational asthma. Exposure occurs mainly in the occupational setting and can be assessed through biomonitoring which accounts for inhalation and dermal exposure and potential effects of protective equipment. However the interpretation of biomonitoring data can be challenging for chemicals with complex kinetic behavior and multiple exposure routes, as is the case for diisocyanates. To better understand the relation between external exposure and urinary concentrations of metabolites of diisocyanates, we developed a physiologically based kinetic (PBK) model for methylene bisphenyl isocyanate (MDI) and toluene di-isocyanate (TDI). The PBK model covers both inhalation and dermal exposure, and can be used to estimate biomarker levels after either single or chronic exposures. Key parameters such as absorption and elimination rates of diisocyanates were based on results from human controlled exposure studies. A global sensitivity analysis was performed on model predictions after assigning distributions reflecting a mixture of parameter uncertainty and population variability. Although model-based predictions of urinary concentrations of the degradation products of MDI and TDI for longer-term exposure scenarios compared relatively well to empirical results for a limited set of biomonitoring studies in the peer-reviewed literature, validation of model predictions was difficult because of the many uncertainties regarding the precise exposure scenarios that were used. Sensitivity analyses indicated that parameters with a relatively large impact on model estimates included the fraction of diisocyanates absorbed and the binding rate of diisocyanates to albumin relative to other macro molecules.We additionally investigated the effects of timing of exposure and intermittent urination, and found that both had a considerable impact on estimated urinary biomarker levels. This suggests that these factors should be taken into account when interpreting biomonitoring data and included in the standard reporting of isocyanate biomonitoring studies.

Effectiveness of pulmonary rehabilitation at high-altitude compared to sea-level in adults with severe refractory asthma.

BACKGROUND: Beneficial effects of pulmonary rehabilitation at high-altitude (HAPR) in patients with severe refractory asthma have been reported earlier, but evidence for the effectiveness is limited. AIM: To investigate the effectiveness of high-altitude pulmonary rehabilitation to comparable treatment at sea-level (LAPR) on patient outcome parameters. METHODS: Adults with severe refractory asthma living in The Netherlands were included. Treatment consisted of a 12-week personalized multidisciplinary rehabilitation program either at high-altitude (Davos Switzerland) (n = 93) or in a tertiary lung center at sea-level in The Netherlands (n = 45). At baseline, after treatment, and during 12 months follow-up asthma related quality of life (AQLQ), asthma control (ACQ), pulmonary function and OCS-dose were assessed. Patients could not be randomized resulting in different asthma populations. Groups were compared using linear regression analysis (ANCOVA) adjusted for baseline values, in addition to age, atopy, smoking history, BMI and gender. RESULTS: After treatment, and at 12 months follow-up, improved AQLQ(0.92,p < 0.001 and 0.82,p = 0.001, respectively), ACQ(-0.87,p < 0.001 and -0.69,p = 0.008, respectively) and lower maintenance OCS dose (Unadjusted linear regression analysis-5.29 mg, p = 0.003 and Crude Odds Ratio-1.67, p = 0.003, respectively) were observed in the HAPR-group compared to the LAPR group. Patients receiving HAPR also had less asthma exacerbations (≥1 exacerbation: 20% vs 60%,p < 0.001) and showed improvement in lung function (%predFEV1 3.4%,p = 0.014) compared to the LAPR group, but at 12 months no differences between groups were observed. CONCLUSION: HAPR resulted in a larger improvement in patient outcome parameters compared to LAPR, on the long run the improvement in patient reported symptoms and lower maintenance OCS-dose persists. Underlying factors that explain this observed effect need to be investigated.

Stability of individual LPS-induced ex vivo cytokine release in a whole blood assay over a five-year interval.

OBJECTIVE: In epidemiological and clinical studies, whole blood assay (WBA) has been used as a measure to characterize inter-individual differences in the cytokine response of individuals exposed to inflammatory agents, such as endotoxins. Several short-time repeatability studies have shown stable cytokine levels in individuals over periods of days, weeks or months, but little is known about the long-term stability of cytokine reactivity. METHODS: We studied cytokine response levels in LPS-stimulated whole blood in a cohort of 193 farmers and agricultural industry workers at two time points with a five-year interval. RESULTS: IL-10 and IL-1ß responses measured with a five-year time interval showed a weak positive correlation (r = 0.22 and 0.27, respectively), whereas no correlation was observed for TNFα (r = 0.06). Cytokine reactivity measured repeatedly at the same time point showed high correlations (IL-10 r = 0.80, IL-1ß r = 0.53 and TNFα r = 0.74), suggesting that the observed weak correlations over time are reflective of actual variations in cytokine reactivity over time. CONCLUSIONS: Repeatability of ex vivo cytokine reactivity showed to be differential for the measured cytokines, being more stable for IL-10 and IL-1ß than for TNFα. However, in general, repeatability of ex vivo cytokine reactivity was weak, reflecting that cytokine reactivity can mostly be explained by (short term) intra-individual (immunological) or time varying environmental factors and less by genetic or other time-invariant factors. Therefore, WBA should be regarded as a viable tool to study relationships with current health status and exposure, and only partially as a predictor for a future response.

Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis.

BACKGROUND: B-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms. METHODS: We investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts. RESULTS: Our analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection. CONCLUSIONS: This is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Cause-specific mortality of Dutch chlorophenoxy herbicide manufacturing workers.

OBJECTIVE: A retrospective cohort study was conducted in two chlorophenoxy herbicide manufacturing factories, producing mainly 2,4,5-trichlorophenoxyacetic acid (factory A) and 4-chloro-2-methylphenoxyacetic acid, 4-chloro-2-methylphenoxy propanoic acid and 2,4-dichlorophenoxyacetic acid (factory B). Previously, we have shown elevated risks for mortality and cancer mortality in this cohort. The purpose of the current, third follow-up, is to provide an updated assessment of cause-specific mortality for both factories. METHODS: The study population was defined as all persons working in one of the two factories during 1955-1985 for factory A, or during 1965-1986 for factory B. Analyses were performed using Cox proportional hazard models, using attained age as the timescale. Exposure to phenoxy herbicides and dioxins was expected to be different for factory A and factory B and the factories were therefore analysed separately. RESULTS: Previously reported increased risks for respiratory cancer, non-Hodgkin's lymphoma and ischaemic heart disease in factory A could not be confirmed in the present analysis. However, increased risks were observed for all cancers in both factory A (hazard ratio (HR) 1.31; 95% CI 0.86 to 2.01) and factory B (HR 1.54; 95% CI 1.00 to 2.37). Increased risks for urinary cancers (HR 4.2; 95% CI 0.99 to 17.89) and genital cancers (HR 2.93; 95% CI 0.61 to 14.15) were observed in factory A, consistent with earlier reported results in this population. More detailed analyses showed that this increased risk for urinary and genital cancers in exposed workers was not due to selection of healthy controls and could not be attributed to specific products or departments. CONCLUSION: The results of this study showed only slight increases in cancer mortality risk. The increased risk for urinary cancers is noteworthy, but could not be linked to a specific exposure and needs to be confirmed in similar cohorts.

Immunoglobulin G4 antibodies to rat urinary allergens, sensitization and symptomatic allergy in laboratory animal workers.

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.

Lung function decline in laboratory animal workers: the role of sensitisation and exposure.

BACKGROUND: Little is known about the relation between allergic sensitisation and subsequent long term lung function changes in working populations exposed to sensitising agents. AIMS: To investigate whether exposure and work related sensitisation to laboratory animals are associated with lung function decline. METHODS: The relation between exposure and sensitisation to laboratory animal allergens and changes in lung function was investigated in a longitudinal study (median follow up 2.0 years) among 319 laboratory animal workers. Subjects who had been working with laboratory animals for less than 4 years (n = 102) were analysed separately, since an earlier cross sectional analysis had suggested a strong healthy worker effect in more experienced workers. RESULTS: In multiple regression analyses both sensitisation and exposure appeared to contribute independently to lung function decline in subjects who had been working with laboratory animals for less than 4 years, adjusting for gender, age, smoking, and atopy. Lung function decline was most pronounced in sensitised subjects who continued to be in contact with the animals to which they were sensitised, with estimated average excess declines in FEV1, FVC, and MMEF of 83 ml/y (p < 0.05), 148 ml/y (p < 0.01), and 7 ml/s/y (p = 0.9). CONCLUSIONS: We conclude that exposure to laboratory animals is a significant risk factor for accelerated lung function decline, and that sensitised workers are especially at risk.

Low prevalence of atopy in young Danish farmers and farming students born and raised on a farm.

BACKGROUND: Recent studies have shown that in several countries atopic sensitization to common allergens (common atopy) and atopic symptoms are markedly less prevalent in children living on a farm, compared with non-farm children living in the same rural areas. Living conditions on farms may, however, vary largely between different countries. It is also not yet known whether the "protective" effect of a farm environment can also be found in adults. MATERIALS AND METHODS: Common atopy and respiratory health were assessed by skin prick tests (SPT), questionnaire and measurement of bronchial hyper-responsiveness (BHR) in the Sund Stald (SUS) study, a cohort study on respiratory health in Danish farming students and conscripts from the same rural areas as controls. Results of SPT were confirmed by IgE serology in all SPT+ subjects and a subset of SPT- subjects. Prevalences of common atopy, respiratory symptoms and bronchial hyper- responsiveness were compared for farmers and controls, and for those who had or had not lived on a farm in early childhood. RESULTS: In multiple logistic regression analyses adjusting for ever smoking and a familial history of allergy, both being a farmer (ORs 0.62-0.75) and having had a farm childhood (ORs 0.55-0.75) appeared to contribute independently to a lower risk of sensitization to common allergens as assessed by SPT and IgE serology. A farm childhood was also inversely associated with high total IgE (OR 0.68), presence of respiratory symptoms (ORs 0.69-0.79) and BHR (OR 0.61) in these analyses. Direction and strength of the association between being a farmer and respiratory symptoms or BHR varied widely (ORs 0.69-1.28). CONCLUSION: The "anti-atopy" protective effect of a farm childhood could be confirmed in Danish farming students: prevalences of positive SPT, specific and total IgE, allergic symptoms and BHR were lower in those being born or raised on a farm. Past exposure to the farm environment in early childhood may therefore also contribute to a lower risk of atopic sensitization and disease at a later age.

Effect of 3 months vitamin E supplementation on indices of the cellular and humoral immune response in elderly subjects.

It has been suggested that decreased immune responsiveness in the elderly may be counteracted by the antioxidant vitamin E. In a 3-month double-blind placebo-controlled intervention trial among elderly subjects aged 65 years and over we studied the effects of a daily dose of 100 mg dl-alpha-tocopheryl acetate on the cellular immune responsiveness (n 52) measured by the in vitro response of peripheral blood mononuclear cells (PBMC) to the mitogens concanavalin A (ConA) and phytohaemagglutinin (PHA). Also effects on the humoral immune responsiveness (n 74) were investigated by measuring immunoglobulin (Ig)G, IgG4 and IgA antibody concentrations against various common antigens. In the vitamin E group plasma alpha-tocopherol increased by 51% (P = 0.0001) during intervention whereas no significant changes were observed in the control group. Initial proliferative PBMC responses differed between the vitamin E group and the control group whereas all other baseline characteristics were comparable. No significant changes were observed in cellular immune responsiveness when adjusted for initial values in either the control group or the vitamin E group and, after the trial period, responses in the two groups were not significantly different. Similarly, in the vitamin E group no significant changes were found in levels of IgG and IgA raised against Penicillium or IgG4 raised against egg, milk, or wheat proteins. In the control group small but significant increases in IgG anti-Penicillium (P < 0.05) and decreases in IgG4 against milk proteins (P < 0.05) were observed. Thus, the results of this study performed with the relatively low dose of 100 mg dl-alpha-tocopheryl acetate do not support the claims of a beneficial effect of vitamin E intake on the overall immune responsiveness of elderly subjects.