Azienda sanitaria di Firenze. francesco.carnevale@asf.toscana.it

A thought back on the “epic of asbestos” scanning the fundamental steps, from the “discovery” of the adverse effects for the workers. A first phase, the “asbestosis one” concluded in Britain in the early thirties with the issue of a technical legislation is described. It was the first regulation shared by the Unions and the asbestos companies, some of which were or will then become leaders all over the world. The main effect of this legislation enforcement is the reduction of the exposure in some units of the asbestos textile industry; no effects were observed instead in other asbestos industrial divisions where it’s consumption for insulations and asbestos cement increased massively. The second phase lasting approximately thirty years next sees together to a formidable diffusion of all the asbestos fibres including the crocidolite ones, advertised and accepted like “indispensable” for the economical and social development, an absolute leadership of the companies in the management of health effects information for the workers and therefore also those on the pulmonary cancerogenicity. Such selfish and aggressive leadership, receives in return from government, labour and consumers organizations just inertia, impotence and incredulity. This attitude will also continue in the third phase, beginning in the early sixties of the last century. The time period will be dominated by mesothelioma with all its new and terrible meanings, the dangerousness of asbestos exposure especially to the blue one even at lower levels than those observed in the past for other pathologies and the long latency before the appearance of the effects. Discussing about asbestos substitutes was out of the agenda, indeed just in the period where the mining and the consumption of asbestos touched the highest levels. The initiatives assumed in some countries like the auto limitation of the use of crocidolite and a more rigorous reduction of the occupational exposures will only turn out useful in order to lower the risk for asbestosis and, probably, the one for pulmonary tumour. In the United States, the judicial litigation for compensation between the workers and the companies begins. The same phenomenon will characterize also in the other countries industrializes the fourth phase of the epic, until our days; it is just in these years, and especially during the eighties, that industry starts thinking about the substitution of asbestos; the lively public debate will favour initiatives oriented to obtain economic compensation for damages caused by past occupational and environmental exposures. These legal actions will carry to bankruptcy all the asbestos companies and later to the ban of asbestos. The judicial debates will also uncover “confidential” information useful to better reconstruct the epic, to formulate more dispassionate historical judgments and to allow everyone on answering to more complex questions and more important than how much generally it was previously believed; all this should happen contextualizing the ages in which the scientific acquaintances on the effects of asbestos have been published and disproving prejudgments, able to affect some conclusions of the past.

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International Environmental Research Foundation, P.O. Box 3459, Grand Central Station, New York, NY 10163-3459, USA.

This paper summarizes the weight of epidemiological evidence to evaluate the hypothesis that asbestos exposure is causally associated with increased risk of gastrointestinal (GI) cancers as suggested by Selikoff in an early study of insulation workers. This review looks at populations that develop GI cancers, namely stomach, colorectal, colon and rectal. Guidelines for assessing causality are strength of association, biological gradient and consistency of the associations. Exposure-response (E-R) was evaluated using three methods to estimate exposure. Rate Ratios (RRs) for lung cancer and percent of mesothelioma are used as surrogate measures of asbestos exposure for all the cohorts of exposed workers. Quantitative or semi-quantitative estimates of cumulative exposure to asbestos were also used to assess E-R trends and were compared to E-R trends for lung cancer and mesothelioma in individual studies. Surrogate measures are important since there are few individual studies that have assessed E-R. None of the various methods to estimate asbestos exposure yielded consistent E-R trends and the strength of the associations were consistently weak or non-existent for the four types of GI cancers. The epidemiological evidence detracts from the hypothesis that occupational asbestos exposure increases the risk of stomach, colorectal, colon, and rectal cancer. Findings are briefly summarized below.

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Division of Biostatistics, Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.

Asbestos and benzo(a)pyrene diol epoxide (BPDE) are pulmonary carcinogens with synergistic interaction in causing lung cancer. We used Affymetrix microarrays to study gene modulation in vitro using normal human bronchial epithelial cells exposed to chrysotile asbestos and/or BPDE for 4 or 24 h. Linear models were used to compare treated cells to controls at each time point to identify statistically significant up- or downregulation of genes. Profiles of genes regulated by chrysotile were dominated by cytokines, growth factors, and DNA damage. Profiles of genes with BPDE and chrysotile regulation were correlated with proliferation, DNA damage recognition and nucleotide-excision repair, cytokines, and apoptosis. Chemokines, growth-regulated oncogene-alpha (Gro-alpha, CXCL-1), and IL-8, were significantly increased, and these had previously been observed in bronchoalveolar lavage from asbestos workers or in animal models. Interestingly, the Hermansky-Pudlak gene, which is mutated in an autosomal recessive form of pulmonary fibrosis, was downregulated threefold by BPDE at 4 h. This is an interesting example of gene (Hermansky-Pudlak syndrome) and environment (BPDE) interaction. Transcription factors, including activating transcription factor 3 and Cbp/p300-interacting transactivator, were upregulated by chrysotile. Real Time PCR for IL-8, ATF-3, GADD45B, CXC Ligand 1, and CTGF compared to GAPDH validated microarray findings at 24 h. These in vitro findings in NHBE cells model environment-gene interaction for asbestos and BPDE, highlighting effects of inflammation, fibrosis, proliferation, and DNA damage recognition and repair.

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Unit of Molecular Epidemiology, National Cancer Research Institute, Genoa, Italy.

Exposure to asbestos fibers is a major risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on alpha1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes.

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Università Politecnica delle Marche, Dipartimento di Patologia Molecolare e Terapie Innovative, Clinica di Medicina del Lavoro, Tronto 10/a, 0020 Torrette, AN. m.amati@univpm.it

Improved detection methods for diagnosis of asymptomatic malignant pleural mesothelioma (MPM) are essential for an early and reliable detection and treatment of this disease. Thus, focus has been on finding tumour markers in the blood. 94 asbestos-exposed subjects, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the significance of 8-hydroxy-2′-deoxy-guanosine (80HdG) in white blood cells and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors (PDGFbeta, HGF, bFGF, VEGFbeta), and matrix proteases (MMP2, MMP9, TIMP1, TIMP2) for potential early detection of MM. The area under ROC curves (AUC) indicates that 80HdG levels can discriminate asbestos-exposed subjects from controls but not from MPM patients. Significant AUC values were found for SMRP discriminating asbestos-exposed subjects from MPM patients but not from controls. VEGFbeta can significantly differentiate asbestos-exposed subjects from control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, TIMP2. The sensitivity and specificity results of markers were calculated at defined cut-offs. The combination of 80HdG, VEGFbeta and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MPM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

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