Deliverables
To supplement the data from the molecular epidemiology study on sino-nasal cancer, epidemiological case-control studies are being carried out in France, Denmark and Finland to generate overall risk estimates. The studies utilize similar study designs and exposure assessment methods, with the aim to pool the data for increased statistical power.
The in vitro studies carried out with human lung epithelial cells show that exposure to wood dust resulted in DNA strand-breaks in four out of seven wood dusts examined. DNA strand breaks occurred before the inflammation had reached its maximum, which suggests that wood dusts themselves may have genotoxic potential. The distribution of the species that caused strand breaks, and those that did not, was randomly distributed between the hardwood and softwoods. Cytokine responses were induced by all seven species. The lowest and highest responses were found among the hardwoods, and the responses of the softwoods were between the extremes found among hardwoods.
Results of the our in vitro investigations with murine macrophages demonstrate that wood dust is able to induce a heterogeneous expression of cytokines and chemokines in mouse macrophage RAW 264.7 cell line. The effects of the two studied wood dust groups, softwood and hardwoods, on the cytokine and chemokine expression of RAW 264.7 cells appeared to be at comparable levels in general. However, some differences were also detected in responses in RAW 264.7 cells. Oak dust was weaker inducer of cytokine and chemokine expression than birch dust in RAW 264.7 cells.
Our in vivo studies demonstrate that repeated exposure to wood dust can elicit lung inflammation in mice. Both oak and birch dusts are able to induce the recruitment of macrophages, lymphocytes, neutrophils, and eosinophils into the lungs of mice. Oak and birch dust exposure elicited quantitative and qualitative differences in pulmonary inflammation suggesting that different wood species may also have differences in elicitation of inflammatory responses. Of note was the finding that in mice in vivo, in the presence of all resident lung cells, repeated oak dust exposure induced stronger cytokine and chemokine expression than birch dust.
The studies with the mouse model demonstrated that repeated exposure to wood dust is able to modulate allergic asthma. In all, our results suggest that both hardwood and softwood dusts can influence the development of the inflammatory process through macrophages by modulating the expression of macrophage derived cytokines and chemokines, which are the key molecules in the regulation of leukocyte recruitment to the site of inflammation.
Respiratory symptoms, impaired lung function, and asthma have been reported in workers exposed to wood dust in a number of epidemiological studies. The underlying pathomechanisms, however, are not well understood. By the secretion of various cytokines, alveolar macrophages and type II lung epithelial cells are involved in the initiation and modulation of the inflammatory reaction in the lung.
The in vitro data from experiments carried out using primary rat alveolar macrophages and lung epithelial cells indicate that:
- Dusts from various hardwood and softwood species as well as dust from MDF are able to induce the release of proinflammatory mediators in primary alveolar macrophages by a mechanism that is, at least in part, mediated by ROS and
- The release of proinflammatory mediators from wood dust-exposed macrophages may be important in stimulating cytokine release from lung epithelial cells, thus amplifying the inflammatory response.
The role of occupational exposure to wood dust in causation of sino-nasal cancer has long been established by numerous epidemiological studies, with the highest risks, in some earlier studies extremely high ones, observed for hardrwood dusts and adenocarcinoma histology. Mechanisms by which exposure to wood dust increases the risk of sino-nasal cancer (SNC) are nevertheless largely unknown.
The present study involved a large collection of SNC tumours, to our knowledge by far the largest one studied so far (>400 cases), collected in three Eurpean countries (Denmark, Finland and France) which vary in major types of woodworking industries and principle types of wood species used.
The tumours included in the study underwent a common review of histo-pathological diagnoses carried out by a panel of pathologists.
The on-going study revealed a very high frequency of TP53 mutations (70-80 %) in sino-nasal tumours. Our preliminary data shows that mutation frequency was highest in adenocarcinoma, the cell type known to exhibit highly elevated risk ratios for occupationally hardwood dust exposure. Also, the mutation frequencies and types exhibit some variation according to country.
Additional immunohistochemistry analyses were performed. After completion of exposure assessment (occupational exposure histories and tobacco smoke exposure) will allow analysis of relationships between occupational wood dust exposure and mutations. In summary, based on our current molecular analysis, it appears apparent that mutational mechanisms are frequently involved in the process of tumourigenesis in SNC.
Epidemiological studies show that the highest risks of sino-nasal cancer in association with occupational exposure have been observed for hardrwood dusts and adenocarcinoma histology. According to previous studies, KRAS oncogene mutations have been found to occur in adenocarcinoma of the nose and paranasal sinuses. In the present investigation, the SNC tumour collection from Denmark, Finland and France was analysed for KRAS mutations.
The series of tumours under investigation (~300 tumours) included a representative collection of confirmed adenocarcinomas. However, the frequency of KRAS mutations detected in the tumours remained low. The KRAS mutation analysis is part of the overall molecular epidemiology study on SNC for which the data analysis will be performed after completion of exposure assessment for the cases. In summary, our current molecular analysis indicates, unlike earlier data, that mutations in the tumour suppressor gene p53, rather than those of the KRAS gene, are common in SNC.
The work carried out with in human bronchial epithelial cells in vitro show that exposure to wood dust (pine, birch, oak) activate ROS production and that they have an effect on both necrotic and programmed cell death (apoptosis) on human bronchial epithelial cells. These results are well in line with the data obtained from other cell types and cell lines exposed to same types of wood dusts in the WOOD-RISK Project.
The Project estimated occupational exposure to inhalable wood dust in 25 EU member states. National labour force statistics, country questionnaires (i15 member states), company surveys (Finland, France, Germany and Spain), exposure measurements (Denmark, Finland, France, Germany, the Netherlands and the United Kingdom), and expert judgments were used for preliminary estimates according to industrial class (6 wood industries, 4 other sectors) and level of exposure (5 classes). The estimates were reviewed by national experts from 15 member states. Crude estimates were produced for 10 new member states.
In 2000-2003, about 3.6 million workers (2.0% of the employed) were occupationally exposed to inhalable wood dust in EU. Construction employed 1.2 million exposed workers (33%), 700000 (20%) were exposed in furniture industry, 300000 (9%) in manufacture of builders carpentry, 200000 (5%) in sawmilling, 15,000 (4%) in forestry, and <100000 in other wood industries. The highest number of exposed workers was in Germany (700000). The highest exposure levels were in construction sector and furniture industry. About 560000 workers (16% of the exposed) may be exposed to levels exceeding 5mg/m3. Mixed exposure was very common, but reliable data on exposure to different species of wood could not be retrieved.
The basic data and final estimates of occupational exposure to inhalable wood dust by country, industry, the level of exposure and type of wood dust in 25 member states of the European Union (EU-25) have been compiled into the WOODEX database currently available on CD. The database is to be accessible over the internet as a combined WOODEX/WOODRISK database (International Information System on Occupational Exposure and Health Effects of Wood Dust) containing also relevant scientific literature data (summaries) on health effects of wood dust exposure. The WOODEX data have been distributed via the network of national contact person created during the course of the Project.
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