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Lorenzo Tomatis and Benedetto Terracini have shared study and research experiences since 1948. This paper describes various phases of Tomatis scientific adventure leading to outstanding results (in particular as Director of the International Agency for Research on Cancer) despite the various difficulties met and the tendency to ignore scientific findings which in fact were adequate to implement preventive measures addressed to environmental carcinogenic hazards.

MATline is a tool that can be used to predict which industrial processes can be expected to involve the use of a substance that is considered carcinogenic as documented in the literature. The database includes agents carrying risk phrases R45, R49 and R40 according to the method of classification adopted by the EU and/or agents in categories 1, 2A and 2B as classified by the International Agency for Research on Cancer (IARC). Each agent is associated with a list of industrial processes coded according to the tariff headings used by the National Institute of Insurance against Occupational Injuries and Diseases (Istituto Nazionale per l'Assicurazione contro gli Infortuni sul Lavoro, INAIL). The main sources of information are the IARC Monographs and databases available through the National Library of Medicine's TOXNET portal. The matrix currently includes 600 carcinogenic agents, 23 classes of agents and some 7000 links between agents and industrial processes. MATline can be viewed on the www.dors.it website.

Radon is known to cause lung cancer in humans; however, there remain uncertainties about the effects associated with residential exposures. This case-control study of residential radon and lung cancer was conducted in five counties in New Jersey and involved 561 cases and 740 controls. A year long alpha-track detector measurement of radon was completed for approximately 93% of all residences lived in at the time of interview (a total of 2,063). While the odds ratios (ORs) for whole data were suggestive of an increased risk for exposures >75 Bq m(-3), these associations were not statistically significant. The adjusted excess OR (EOR) per 100 Bq m(-3) was -0.13 (95% CI: -0.30 to 0.44) for males, 0.29 (95% CI: -0.12 to 1.70) for females and 0.05 (95% CI: -0.14 to 0.56) for all subjects combined. An analysis of radon effects by histological type of lung cancer showed that the OR was strongest for small/oat cell carcinomas in both males and females. There was no statistical heterogeneity of radon effects by demographic factors (age at disease occurrence, education level and type of respondent). Analysis by categories of smoking status, frequency or duration did not modify the risk estimates of radon on lung cancer. The findings of this study are consistent with an earlier population-based study of radon and lung cancer among New Jersey women, and with the North American pooling of case control radon seven studies, including the previous New Jersey study. Several uncertainties regarding radon measurements and assumptions of exposure history may have resulted in underestimation of a true exposure-response relationship.

Since the issue of the first regulations concerning the remediation of contaminated sites, the Istituto Superiore di Sanità, on the basis of specific requests, has drawn up various technical opinions regarding the proposed reference values (quality standards) for soils and underground waters, to be achieved when remediating contaminated sites, for substances for which no standard limit values did not exist at that time. These reference values, widely used throughout the country and accepted and adopted as "remediation aim" values by various territorial bodies responsible for the approval and monitoring of remediation projects, have been collected in a specific reclamation oriented data bank known as the "Banca Dati Bonifiche (BDB)" (Reclamation Data Bank). The BDB contains the related standardized "rationale" for each reference value, in order to serve as a useful reference for the national bodies concerned with the remediation of contaminated sites.

This paper is dedicated to Lorenzo Tomatis, former director of the International Agency for Research on Cancer (IARC), promoter of prevention principles with a precautionary approach, supported by an important scientific foundation. He has recommended an appropriate consideration of both "false negatives" and "false positives" errors in the evaluation of epidemiological and experimental data on toxicological and carcinogenic risk. The current rules for IARC Monographs preparation include both a full transparency of the data used and of the possible conflicts of interest of the experts involved. Tomatis has also underlined that "Dismissing animal carcinogenicity findings would lead to human cases as the only means of demonstrating carcinogenicity of environmental agents. This is an unacceptable public health policy". The main role of experimental studies is presently included in both the new preamble of IARC Monographs and the method adopted for the World Health Organization Air Quality Guidelines for low-dose carcinogenic risk assessment.

This paper presents a Bayesian model that allows for the joint prediction of county-average radon levels and estimation of the associated leukaemia risk. The methods are motivated by radon data from an epidemiologic study of residential radon in Iowa that include 2726 outdoor and indoor measurements. Prediction of county-average radon is based on a geostatistical model for the radon data which assumes an underlying continuous spatial process. In the radon model, we account for uncertainties due to incomplete spatial coverage, spatial variability, characteristic differences between homes, and detector measurement error. The predicted radon averages are, in turn, included as a covariate in Poisson models for incident cases of acute lymphocytic (ALL), acute myelogenous (AML), chronic lymphocytic (CLL), and chronic myelogenous (CML) leukaemias reported to the Iowa cancer registry from 1973 to 2002. Since radon and leukaemia risk are modelled simultaneously in our approach, the resulting risk estimates accurately reflect uncertainties in the predicted radon exposure covariate. Posterior mean (95 per cent Bayesian credible interval) estimates of the relative risk associated with a 1 pCi/L increase in radon for ALL, AML, CLL, and CML are 0.91 (0.78-1.03), 1.01 (0.92-1.12), 1.06 (0.96-1.16), and 1.12 (0.98-1.27), respectively., (Copyright 2007 John Wiley & Sons, Ltd.)

We have recently proposed that lifestyle-related factors, screening and aging cannot fully account for the present overall growing incidence of cancer. In order to propose the concept that in addition to lifestyle related factors, exogenous environmental factors may play a more important role in carcinogenesis than it is expected, and may therefore account for the growing incidence of cancer, we overview herein environmental factors, rated as certainly or potentially carcinogenic by the International Agency for Research on Cancer (IARC). We thus analyze the carcinogenic effect of microorganisms (including viruses), radiations (including radioactivity, UV and pulsed electromagnetic fields) and xenochemicals. Chemicals related to environmental pollution appear to be of critical importance, since they can induce occupational cancers as well as other cancers. Of major concerns are: outdoor air pollution by carbon particles associated with polycyclic aromatic hydrocarbons; indoor air pollution by environmental tobacco smoke, formaldehyde and volatile organic compounds such as benzene and 1,3 butadiene, which may particularly affect children, and food pollution by food additives and by carcinogenic contaminants such as nitrates, pesticides, dioxins and other organochlorines. In addition, carcinogenic metals and metalloids, pharmaceutical medicines and cosmetics may be involved. Although the risk fraction attributable to environmental factors is still unknown, this long list of carcinogenic and especially mutagenic factors supports our working hypothesis according to which numerous cancers may in fact be caused by the recent modification of our environment.

Lung carcinogenesis is a complex process requiring the acquisition of genetic mutations that confer the malignant phenotype as well as epigenetic alterations that may be manipulated in the course of therapy. Inflammatory signals in the lung cancer microenvironment can promote apoptosis resistance, proliferation, invasion, metastasis, and secretion of proangiogenic and immunosuppressive factors. Here, we discuss several prototypical inflammatory mediators controlling the malignant phenotype in lung cancer. Investigation into the detailed molecular mechanisms underlying the tumor-promoting effects of inflammation in lung cancer has revealed novel potential drug targets. Cytokines, growth factors and small-molecule inflammatory mediators released in the developing tumor microenvironment pave the way for epithelial-mesenchymal transition, the shift from a polarized, epithelial phenotype to a highly motile mesenchymal phenotype that becomes dysregulated during tumor invasion. Inflammatory mediators within the tumor microenvironment are derived from neoplastic cells as well as stromal and inflammatory cells; thus, lung cancer develops in a host environment in which the deregulated inflammatory response promotes tumor progression. Inflammation-related metabolic and catabolic enzymes (prostaglandin E(2) synthase, prostaglandin I(2) synthase and 15-hydroxyprostaglandin dehydrogenase), cell-surface receptors (E-type prostaglandin receptors) and transcription factors (ZEB1, SNAIL, PPARs, STATs and NF-kappaB) are differentially expressed in lung cancer cells compared with normal lung epithelial cells and, thus, may contribute to tumor initiation and progression. These newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapy and prevention in lung cancer.

Background: Previous studies of DDT and breast cancer assessed exposure later in life when the breast may not have been vulnerable, after most DDT had been eliminated, and after DDT had been banned., Objectives: We investigated whether DDT exposure in young women during the period of peak DDT use predicts breast cancer., Methods: We conducted a prospective, nested case-control study with a median time to diagnosis of 17 years using blood samples obtained from young women during 1959-1967. Subjects were members of the Child Health and Development Studies, Oakland, California, who provided blood samples 1-3 days after giving birth (mean age, 26 years). Cases (n = 129) developed breast cancer before the age of 50 years. Controls (n = 129) were matched to cases on birth year. Serum was assayed for p,p'-DDT, the active ingredient of DDT; o,p'-DDT, a low concentration contaminant; and p,p'-DDE, the most abundant p,p'-DDT metabolite., Results: High levels of serum p,p'-DDT predicted a statistically significant 5-fold increased risk of breast cancer among women who were born after 1931. These women were under 14 years of age in 1945, when DDT came into widespread use, and mostly under 20 years as DDT use peaked. Women who were not exposed to p,p'-DDT before 14 years of age showed no association between p,p'-DDT and breast cancer (p = 0.02 for difference by age)., Conclusions: Exposure to p,p'-DDT early in life may increase breast cancer risk. Many U.S. women heavily exposed to DDT in childhood have not yet reached 50 years of age. The public health significance of DDT exposure in early life may be large.

The capital city of Prague is one of the most polluted localities of the Czech Republic. The effect of exposure to carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) adsorbed onto respirable air particles (<2.5 microm) on chromosomal aberrations was studied in a group of city policemen (street patrol, aged 34+/-8 years) working in the downtown area of Prague and spending daily >8h outdoors (N=61) in months of January and March 2004. Ambient air particles (PM10, PM2.5) and c-PAHs were monitored using Versatile Air Pollution Sampler (VAPS), and personal exposure was evaluated using personal samplers during working shift. Chromosomal aberrations were analyzed by fluorescent in situ hybridization (FISH) and conventional cytogenetic analysis. Urinary cotinine, plasma levels of vitamins A, E and C, folate, total cholesterol, HDL, LDL cholesterols and triglycerides were also analyzed as possible effect modifiers. During the sampling period the particulate air pollution monitored by VAPS was in January versus March as follows: PM10 55.6 microg/m3 versus 36.4 microg/m3, PM2.5 44.4 microg/m3 versus 24.8 microg/m3, c-PAHs 19.7 ng/m3 versus 3.6 ng/m3, and B[a]P 4.3 ng/m3 versus 0.8 ng/m3. Significant differences were observed for all FISH endpoints studied for the sampling in January and March (%AB.C.=0.27+/-0.18 versus 0.16+/-0.17, p<0.001, F(G)/100=1.32+/-1.07 versus 0.85+/-0.95, p<0.01, AB/1000 (aberrations/1000 cells)=4.27+/-3.09 versus 2.59+/-2.79, p<0.001) while conventional cytogenetic analysis did not reveal any differences in the frequency of chromosomal aberrations. Factors associated with an increased level of translocations by FISH indicated the effect of age, cholesterol, LDL-cholesterol and vitamin C. We may conclude that FISH indicates that the city policemen in Prague represent a group of increased genotoxic risk. This is the first study reporting that translocations induced by c-PAHs in peripheral lymphocytes last only several weeks.

DNA integrity was analyzed in the lymphocytes of 65 non-smoking city policemen during January and September 2004 using the comet assay combined with excision repair enzymes. Information about inhalation exposure was obtained by (1) stationary monitoring of PM2.5 and carcinogenic polycyclic aromatic hydrocarbons (cPAHs) during the sampling periods and (2) personal exposure monitoring of cPAHs 48h before blood sampling. The data were completed by a lifestyle questionnaire. Regardless of the season of the year, policemen working outdoors (exposed group) exhibited higher levels of DNA damage than those working indoors (controls). Within the exposed group, the levels of both unspecified and oxidative DNA damage detected in January significantly exceeded those found in September. The controls did not show analogous inter-seasonal variability. The winter levels of oxidative DNA damage positively correlated with exposure to cPAHs, probably reflecting increased oxidative stress as a result of high concentrations of PM2.5. In comparison with the wild type genotype, the carriers of at least one mutated allele, CYP1A1*2C (Ile/Val), MTHFR 2656 or MS 2656, and the EPHX1-medium phenotype appeared to be more susceptible specifically to the induction of oxidative DNA damage, while the p53 MspI mutation predisposed the carrier to a higher incidence of both breaks and oxidative lesions in DNA. In contrast, GSTM1-null and vitamin C tended rather to protect DNA integrity.

The use of cytogenetic assays in the surveillance of populations occupationally exposed to genotoxic carcinogens originates from the assumption that chromosomal alterations might be causally involved in early stages of carcinogenesis. Historical cohort studies have since 1990s consistently reported an association between the level of chromosomal aberrations (CA) in peripheral lymphocytes of healthy subjects and the risk of cancer. Only in few cases, have these results been transformed into a regulatory tool for improving occupational safety. The cytogenetic surveillance program adopted for more than two decades in the Republic of Croatia is one of these few examples. Croatian workers exposed to genotoxic agents were systematically screened for CA, to identify occupational settings needing a priority intervention. Significant increases of mean CA frequency were observed in groups exposed to ionizing radiation, chemical agents, and mixed exposures when compared with a group of unexposed referents. CA data on 736 men and 584 women, monitored between 1987 and 2000, have been associated with cancer incidence. Although the small size of the cohort did not allow for reaching statistical significance, the medium tertile of the CA frequency distribution was associated with a doubling of cancer incidence rate ratio (IRR=2.40; 95% CI 0.85-6.77) when compared with the lowest tertile. For chromosome-type CA, IRR was non-significantly increased for both the medium (IRR 1.53, 95% CI 0.58-3.99) and high categories (IRR 1.69; 95% CI 0.61-4.72). Recommendations for future strategies comprise the inclusion of predictive biomarkers in surveillance programs, the definition of a regulatory framework, and their possible use for the identification of individual risk profiles.

A large number of scientific studies and reviews have addressed the potential for dietary components to influence the risk of developing cancer. One topic of particular interest has been the impact of food contaminants. Two complementary programs, among others, have reviewed and synthesized information on the carcinogenic potential of food contaminants and judged the degree of evidence linking different food contaminants to the risk of cancer in humans. These programs, the International Agency for Research on Cancer's IARC Monographs on the Evaluation of Carcinogenic Risks to Humans and the US National Toxicology Program's Report of Carcinogens have reviewed hundreds of chemicals, mixtures, and natural products and then graded the cancer risk posed to humans. Contaminants with the highest level of evidence include aflatoxin, alcoholic beverages, 2,3,7,8-tetracholordibenzo-p-dioxin. Agents with a moderate level of evidence include acetaldehyde, polycyclic aromatic hydrocarbons, some nitrosamines, and yerba mate. Agents with a low level of evidence include bracken fern, fumonsin B(1), ochratoxin, and others. This review presents a summary of the evidence for the carcinogenicity of these and other agents and the ranks provided by two important assessment programs.

Every year, in Spain 18,000 new cases of lung cancer (LC) are diagnosed. Approximately, 80-90% LC in men and women are directly attributable to tobacco abuse. Cigarette smoke contains over 300 chemicals, 40 of which are known to be potent carcinogens. In the last decade, as in Spain, prevalence of smoking in women has generally increased in the European Union. LC risk can be substantially reduced after smoking cessation, yet never reaches baseline. On the other hand, environmental tobacco smoke exposure (passive smoking) in nonsmokers appears to have a significantly increased risk of LC. An updated of etiology factors of LC, risk related to duration as well as intensity of smoking, relationship between environmental tobacco smoke exposure and LC risk, genetic predisposition and a variety of occupational and environmental exposures implicated as potential risk factors for the development of LC will be reviewed here.

The current Public Health Goal (PHG) for perchloroethylene (PCE) was derived using upper-bound estimates of fractional PCE metabolism in humans. These estimates were in part obtained from a published evaluation of the uncertainty and variability in human PCE metabolism conducted using a physiologically-based pharmacokinetic (PBPK) model in a Markov chain Monte Carlo (MCMC) analysis; however, the data used in that analysis were limited to post-exposure PCE blood and exhaled air concentrations from a single study. A more recent study [Volkel, W., Friedewald, M., Lederer, E., Pahler, A., Parker, J., Dekant, W., 1998. Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid, and N-acetyl-S-(trichlorovinyl)-l-cysteine in rats and humans after inhalation. Toxicol. Appl. Pharmacol. 153(1), 20-27.] provides data on blood concentrations of PCE and its major metabolite, trichloroacetic acid (TCA), and urinary excretion of TCA following exposure of human subjects to lower concentrations of PCE (10-40ppm) than in previous studies. In the present effort, a new MCMC analysis was performed that focused on data from this study along with two others [Fernandez, J., Guberan, E., Caperos, J., 1976. Experimental human exposures to tetrachloroethylene vapor and elimination in breath after inhalation. Am. Ind. Hyg. Assoc. J. 37, 143-150; Monster, A., Boersma, G., Steenweg, H., 1979. Kinetics of tetrachloroethylene in volunteers; influence of exposure concentration and work load. Int. Arch. Occup. Environ. Health 42, 303-309.] providing data on PCE blood concentrations and urinary excretion of TCA. To provide an accurate prediction of TCA kinetics, the PBPK model used here includes a description of the metabolism of PCE to TCA in both the liver and kidney. The resulting upper 95th percentile estimates of fraction of PCE metabolized by inhalation and oral routes were 2.1 and 5.2%, respectively, compared to 58 and 79% used in the derivation of the PHG.

The paper shows an extremely greater danger of aerogenic doses of carcinogenic substances entering with smoking products than that of an aerogenic load in the industrial centers. The individual and population risks of cancer due to smoking of the Ukraine's common cigarettes and the economic damage caused by the treatment of this number of patients to the country have been calculated. For a full assessment of the carcinogenic risk of tobacco smoke, it is necessary to determine all its carcinogenic constituents, their precursors, and possible transformation groups at high temperatures.

Superficial 'nonmuscle-invasive' bladder tumors represent a heterogeneous group of cancers, which include those that are papillary in nature and limited to the mucosa (Ta), high grade, flat and confined to the epithelium (Tis) and those that invade the submucosa or lamina propria (T1). The natural history of these bladder cancers is that of disease recurrence and progression to higher grade and stage. Furthermore, recurrence and progression rates of superficial bladder cancer vary according to several tumor characteristics. The goal in the treatment of superficial bladder cancer is twofold: reducing tumor recurrence and the subsequent need for additional therapies, such as cystoscopy, transurethral resections, intravesical therapy and the morbidity associated with these treatments; and preventing tumor progression and the subsequent need for more aggressive therapy, such as radical cystectomy. The administration of intravesical chemotherapy and immunotherapy has become an important component in accomplishing these goals. This update is the first part of two articles reviewing important contemporary concepts in the etiology, classification and natural history of superficial bladder cancer, while part II of the series will review and highlight important aspects in management of superficial bladder cancer.

Although the U.S. Environmental Protection Agency has restricted the industrial use of regulated forms of asbestos in the United States since the early 1970s, environmental exposure to asbestos remains a health concern in the United States and is a significant health issue among developing countries. Exposure to asbestos is associated with chronic pulmonary diseases and cancer of the lung, pleura, and peritoneum. The mechanism of fiber carcinogenesis is far from clear and is likely to be complex, depending on fiber dimensions, surface properties, and physical durability. The induction of reactive oxygen and nitrogen species upon phagocytosis of fibers plays an important role in fiber genotoxicity. The beta igH3, a secreted protein induced by the transforming growth factor-beta and essential for cell adhesion, is downregulated in asbestos-induced tumorigenic human bronchial epithelial cells. Ectopic expression of the beta igH3 gene abrogates the tumorigenic phenotype and suggests that the gene plays a causal role in fiber carcinogenesis. A better understanding of the carcinogenic mechanism of asbestos and other mineral fibers will provide useful information on interventional and preventive measures for asbestos-mediated diseases such as human pleural and peritoneal mesotheliomas.

SV40 is a DNA tumor virus thrust upon human populations primarily as a contaminant in various vaccine preparations. Some estimates suggest that millions of people are currently infected with the virus. The virus causes primary brain tumors, bone tumors, lymphomas, and mesotheliomas when injected into some rodent models. It has also been detected in a similar spectrum of human tumors. However, epidemiological studies have failed to conclusively demonstrate a higher incidence of disease in affected populations. To date, over 60 reports from 49 different laboratories have shown SV40 sequences in tissues from human cancer patients. Six studies, however, have failed to detect evidence of virus in similar tissues. Some have suggested that SV40 may act as a cocarcinogen with asbestos to cause mesothelioma formation, or that it may be responsible for the 10-20% of mesotheliomas with no reported history of asbestos exposure. This report briefly covers the historical evidence for SV40 carcinogenesis and then covers experiments now underway to better understand the role of SV40 in human mesotheliomas.

Danger from aerogenic dose carcinogens entering the body with smoking products is shown to be essentially greater than that from aerogenic loading in industrial centers. The individual and population risks for smoking-induced cancer and the economic damage to the country, associated with the treatment of a large number of patients are given. To make a complete assessment of the carcinogenic risk of tobacco smoking, it is necessary to estimate all its carcinogenic constituents, their precursors, and possible transformation products at elevated temperatures.

Impressive progress has been made in the understanding of biological contributions to drug abuse and addiction. An area that has only recently begun to receive attention is potential ethnic and racial differences in biological systems that contribute to, or protect from, problem drug use. This article reviews recent research on drug abuse and addiction in Hispanics in which biological questions have been addressed, including work on genes, gene products (proteins), physiology and pharmacotherapy. Taken together, work to date suggests that there are both similarities and differences between Hispanics and other ethnic groups in biological factors related to drug abuse and addiction. Although the results are intriguing, relatively few studies have been done, and those that have been done have often been inconclusive due to low numbers of Hispanic subjects. Moreover, studies have often failed to recognize the complexity and heterogeneity of Hispanic populations in the United States and around the world. After reviewing the current status of the field, recommendations are given for future research in both humans and relevant animal models that will lead to a better understanding of drug abuse and addiction in Hispanics.

To expand a cohort of chemical workers in the Kanawha Valley, we conducted a study of 33,225 workers who were employed at three locations between 1940 and 1999. We observed no increase in overall cancer mortality. Higher risk estimates were observed for lymphosarcoma and reticulosarcoma among hourly employees who worked at the Institute or South Charleston locations. This finding was limited to men hired before 1960. We observed no new cases of angiosarcoma of the liver, a cause of death previously reported in association with vinyl chloride production at the South Charleston location. Specific risk factors for lymphosarcoma and reticulosarcoma have not been identified in previous targeted studies of this population and it is unlikely that additional cause-specific research will elucidate the etiology. Updates of the entire cohort will continue and can be used as a comparison population for chemical specific studies within these three plants.

Foundry workers have increased mortality and morbidity risks from numerous causes, including various cancers. A retrospective Chinese iron-steel cohort study was conducted to examine the mortality effects of exposure to foundry work. Standardized mortality ratios (SMRs) and standardized rate ratios (SRRs) were calculated to evaluate mortality risks among male workers with exposure to 15 hazardous factors, adjusting for confounders. During 14 years of follow-up, 13,363 of 121,846 male workers died. SMR analysis showed a healthy-worker effect in comparison with the general population. SRR analysis showed increased risks for all causes, all neoplasms, and others among the exposed workers compared with non-exposed blue-collar workers. Combined exposure to polycyclic aromatic hydrocarbons and two or more dusts increased the risks of lung cancer (SRR = 654; 95% CI: 113-3,780) and other malignancies. Foundry work has adverse health effects, including carcinogenic risks.

The authors evaluated support in the literature for the hypothesis that ambient air pollution causes childhood cancer. The PubMed database was searched for original articles, which were reviewed for evidence of a relation with the main types of childhood cancer, using criteria including sample size, magnitude and precision of relative risk estimates, presence of a dose-response pattern and potential for bias. The hypothesis has been studied almost entirely with respect to traffic-related air pollution. Since derivation of the hypothesis from 2 case-control studies in Denver, USA, two further case-control studies have provided new positive evidence and 4 case-control and 7 ecological studies mainly negative evidence. The 4 case-control studies providing positive evidence were relatively small and tended to have more methodological limitations than those showing no association. Publication bias is possible. The weight of the epidemiological evidence indicates no increased risk for childhood cancer associated with exposure to traffic-related residential air pollution. Nevertheless, the limited number of studies, the methodological limitations of both positive and negative studies and the absence of consistency in the results obviate a firm conclusion of no effect. In particular, nondifferential misclassification of exposure might have masked true, weak associations., (Copyright 2006 Wiley-Liss, Inc.)

Background: The highest rates of esophageal squamous cell carcinoma (ESCC) in Brazil occur in Rio Grande do Sul, the most southern state, which has incidence rates of 20.4/100,000/year for men and 6.5/100,000/year for women. Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) through tobacco smoke and other sources may increase the risk of ESCC. The aims of the current study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of southern Brazil., Methods: Two hundred healthy adults (half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite). Urine 1-OHPG concentrations were measured using immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was measured using a dipstick test. We examined factors associated with 1-OHPG concentration using Wilcoxon tests and multiple linear regression., Results: Urine 1-hydroxypyrene glucuronide (1-OHPG) was successfully measured on 199 subjects. The median (interquartile range) of urine 1-OHPG in the 199 participants was 2.09 pmol/mL (0.51, 5.84). Tobacco smoke exposure and maté drinking were statistically significantly associated with higher urine 1-OHPG concentrations in the multivariate linear regression model., Conclusion: Tobacco smoke and maté both contribute to high levels of benzo[a]pyrene exposure in the people of southern Brazil. This high PAH exposure may contribute to the high rates of ESCC observed in this population. The increased urine 1-OHPG concentrations associated with maté suggest that contaminants, not just thermal injury, may help explain the increased risk of ESCC previously reported for maté consumption.

Background: Hexavalent chromium has been extensively investigated regarding its mutagenicity and carcinogenicity; however, its mechanism for initiating and enhancing the development of lung cancer is still obscure. Biomarkers of exposure, effect or susceptibility are required for risk assessment and for epidemiologic research studies especially in occupational settings. Since the surfactant protein system (SP) is very important for normal lung function and for mediating local airway conditions and in the clearance of the upper respiratory tract from the occupational and environmental dusts, we hypothesize that SP genes may represent good candidates to study susceptibility for lung cancer., Methods: Using PCR genotyping methods with gel electrophoresis and confirmation of results with precise DNA fragment size measurement on microchip electrophoresis, we analyzed SP-B intron-4 polymorphism in 230 subjects who were classified into groups; chromate-related lung cancer, control chromate workers who had not developed lung cancer, control individuals with non chromate-related adenocarcinoma or squamous cell carcinoma of the lungs, or healthy Japanese control individuals., Results: Our results indicated that the SP-B variants (deletion/insertion) were significantly overrepresented (61.3%) in the chromate-related lung cancer group than other groups (X2 = 47.6; DF = 4, P = 0.0001). There was a significant difference between the chromate lung cancer group and both of the control groups, healthy individuals and chromate workers who did not develop lung cancer, showing odds ratios (OR) with 95% confidence intervals (CI) of 21.9 (7.3-65.7) and 19.0 (3.78-95.4), respectively. Compared with 46 non chromate-related SCC of the lung, the SP-B variants were significantly overrepresented in the chromate-related SCC (18/28; 64.3%) than the non-chromate SCC (11/46; 23.9%) of the lung samples (X(2) = 10.27, P = 0.01), OR with 95% CI is 5.73 (2.05-16.01)., Conclusion: These findings indicate a very strong association of the SP-B intron-4 variants with mechanisms that may enhance lung cancer susceptibility, especially in workers who are employed in chromate industry. Moreover, confirmation of such results may help to suggest adding the SP-B intron-4 typing to be one of the screening tests of the pre-placement medical examination to confirm that the worker has no variations of the SP-B gene before being engaged in a chromium-related industry, with the intention of providing proper medical counseling., (Copyright 2006 Wiley-Liss, Inc.)

Assessment of relative biological effectiveness (RBE) for a radiation in the cases of inhalation of radon progeny and incorporation of plutonium in lung is based on simulation of lung cancer radiation risk for alpha and external reference types of radiation. Specific radiation risk models developed on the results of direct epidemiological studies are used for simulation. These include published risk models for nuclear workers of the Mayak facilities in the former Soviet Union exposed to incorporated plutonium (Kreisheimer et al., 2003; Gilbert et al., 2004) and underground miners exposed to radon progenies (BEIR VI, 1999). Additionally, a lung cancer risk model is developed for a case of population indoor radon exposure. Lung cancer risk related to external exposure is estimated using the risk model developed for the analyses of Japanese atomic bomb survivors (Preston et al., 2003). Uncertainties of risk models parameters are considered and the uncertainties of RBE are estimated using the results of lifetime lung cancer risk simulation, which is done implementing a Monte Carlo approach. Estimated median value of RBE in case of indoor radon exposure is 1.5 with 90% range 0.4-7. In the case of the two models developed by BEIR VI for lung cancer risk due to radon exposure in underground miners, the median values of RBE are 2.1 and 4.4 with 90% ranges 0.3-17 and 0.7-45, respectively. The two different models for lung cancer risk related to plutonium exposure resulted in close estimates of RBE: median value of 12 and 13 with 90% range 4-104 and 4-136, respectively.

Indoor radon measurements were carried out in cave dwellings of the Chinese loess plateau in Gansu province, where previously the Laboratory of Industrial Hygiene (LIH), China, and the U.S. National Cancer Institute (NCI) had conducted an international collaborative epidemiological study. The LIH-NCI study showed an increased lung cancer risk due to high residential radon levels, and estimated the excess odds ratio at 100 Bq/m3 to be 0.19 (Wang et al., 2002). The present study used two types of newly developed passive monitors: One is a discriminative monitor for radon and thoron; the other is a selective monitor for thoron decay products. The arithmetic mean concentrations of indoor radon and thoron were 91 and 351 Bq/m3, respectively. As reported by our previous study in Shanxi and Shaanxi provinces (Tokonami et al., 2004), the presence of high thoron concentration was confirmed and thoron was predominant over radon in the cave dwellings. However, the mean equilibrium equivalent thoron concentration (EETC) was found to be much lower than expected when assuming the equilibrium factor of 0.1 provided by the UNSCEAR (2000) report. The effective dose by radon and thoron decay products was estimated to be 3.08 mSv/yr. It was significantly lower than the dose of 8.22 mSv/yr estimated from the measurements that did not take into consideration any discrimination between radon and thoron. Excess relative risk of lung cancer per sievert may be much higher than the risk estimated from the LIH-NCI study, considering that discriminative measurements were not used in their study.

As other epidemiological exposure variables, indoor radon levels have a right-skewed, approximately lognormal distribution. The continuous linear trend estimator is then known to be sensitive to outlying observations. We consider trend estimators based on replacing the exposure x by a transformed variable z: (1) trimmed estimators, that is, extreme values are deleted in z; (2) winsorized estimators, that is, extreme values are replaced by a lower value; (3) categorical estimators, that is, x is categorized and the continuous variable z takes on scores such as the mean or median within categories. The latter approach is often used in meta-analyses of published odds ratios. Statistically optimal categories can be defined. The corresponding scores are the expected values within the categories, based on the assumption of a lognormal distribution. In a simulation study, it turned out that procedures with different cutpoints for cases and controls, winsorized estimators, and categorical estimators based on category medians can be badly biased upward. Categorical estimators using category means are not always robust against outlying observations. However, categorical estimators employing optimal categories with expected values are nearly unbiased, even in the presence of outliers. Cutpoints should be determined according to the overall distribution of cases and controls combined. Trimmed estimators based on this distribution are unbiased, but highly variable. For right-skewed exposure variables, we therefore suggest sensitivity analyses based on the categorical estimator with optimal cutpoints and expected value scores. In the West German case-control study on indoor radon and lung cancer, these sensitivity analyses lead to increased risk estimates.

Case-control studies on lung cancer and residential radon exposure were conducted in West and East Germany. Odds ratio (OR) estimates from primary analysis are now subject to correction for measurement error in exposure. We apply the regression calibration method adopting a bivariate multiplicative error model of the classical type; that is, we investigate the impact of errors in the exposure of primary interest, radon, and of errors in the most potent confounder, smoking. The OR estimates per 100 Bq/m3 are throughout higher after correcting for errors in radon exposure (e.g., 1.02 and 1.11 for the West and the East German study, respectively, corrected for an error of size 0.4); ignoring the clear but small correlation between radon exposure and smoking of about -0.06 would lead to less conservative corrections (1.10 and 1.13 for West and East, respectively). Accounting for a realistically sized error in the smoking variable additionally increases the OR estimates slightly. Remarkable is the fact that the naive OR estimate of the West study of 0.97 exceeds unity after correcting for errors in radon exposure larger than 0.3. We conclude that correcting for errors in radon exposure has a meaningful impact on OR estimates, that the correlation between radon exposure and the smoking variable affects the correction even if the smoking variable was error-free, and that such an analysis is extremely valuable to grasp an important issue in epidemiology, that is, the dimension of residual confounding due to adjusting for an imprecisely measured smoking variable.

Radon concentration alone may not be an adequate surrogate to measure for lung cancer risk in all residential radon epidemiologic lung cancer studies. The dose delivered to the lungs per unit radon exposure can vary significantly with exposure conditions. These dose-effectiveness variations can be comparable to spatial and temporal factor variations in many situations. New technologies that use surface-deposited and implanted radon progeny activities make more accurate dose estimates available for future epidemiologic studies.

Radon is a well-established cause of lung cancer in miners. Residents of homes with high levels of radon are potentially also at risk. Although most individual studies of indoor radon have failed to demonstrate significant risks, results have generally been consistent with estimates from studies of miners. We studied 1474 incident lung cancer cases aged 40-79 yr in Connecticut, Utah, and southern Idaho. Population controls (n = 1811) were identified by random telephone screening and from lists of Medicare recipients, and were selected to be similar to cases on age, gender, and smoking 10 yr before diagnosis/interview using randomized recruitment. Complete residential histories and information on known lung cancer risk factors were obtained by in-person and telephone interviews. Radon was measured on multiple levels of past and current homes using 12-mo alpha-track etch detectors. Missing data were imputed using mean radon concentrations for informative subgroups of controls. Average radon exposures were lower than anticipated, with median values of 23 Bq/m3 in Connecticut and 45 Bq/m3 in Utah/southern Idaho. Overall, there was little association between time-weighted average radon exposures 5 to 25 yr prior to diagnosis/interview and lung cancer risk. The excess relative risk (ERR) associated with a 100-Bq/m3 increase in radon level was 0.002 (95% CI -0.21, 0.21) in the overall population, 0.134 (95% CI -0.23, 0.50) in Connecticut, and -0.112 (95% CI -0.34, 0.11) in Utah/Idaho. ERRs were higher for some subgroups less prone to misclassification, but there was no group with a statistically significant linear increase in risk. While results were consistent with the estimates from studies of miners, this study provides no evidence of an increased risk for lung cancer at the exposure levels observed.

Cohort studies have consistently shown underground miners exposed to high levels of radon to be at excess risk of lung cancer, and extrapolations based on those results indicate that residential radon may be responsible for nearly 10-15% of all lung cancer deaths per year in the United States. However, case-control studies of residential radon and lung cancer have provided ambiguous evidence of radon lung cancer risks. Regardless, alpha-particle emissions from the short-lived radioactive radon decay products can damage cellular DNA. The possibility that a demonstrated lung carcinogen may be present in large numbers of homes raises a serious public health concern. Thus, a systematic analysis of pooled data from all North American residential radon studies was undertaken to provide a more direct characterization of the public health risk posed by prolonged radon exposure. To evaluate the risk associated with prolonged residential radon exposure, a combined analysis of the primary data from seven large scale case-control studies of residential radon and lung cancer risk was conducted. The combined data set included a total of 4081 cases and 5281 controls, representing the largest aggregation of data on residential radon and lung cancer conducted to date. Residential radon concentrations were determined primarily by a-track detectors placed in the living areas of homes of the study subjects in order to obtain an integrated 1-yr average radon concentration in indoor air. Conditional likelihood regression was used to estimate the excess risk of lung cancer due to residential radon exposure, with adjustment for attained age, sex, study, smoking factors, residential mobility, and completeness of radon measurements. Although the main analyses were based on the combined data set as a whole, we also considered subsets of the data considered to have more accurate radon dosimetry. This included a subset of the data involving 3662 cases and 4966 controls with a-track radon measurements within the exposure time window (ETW) 5-30 yr prior to the index date considered previously by Krewski et al. (2005). Additional restrictions focused on subjects for which a greater proportion of the ETW was covered by measured rather than imputed radon concentrations, and on subjects who occupied at most two residences. The estimated odds ratio (OR) of lung cancer generally increased with radon concentration. The OR trend was consistent with linearity (p = .10), and the excess OR (EOR) was 0.10 per Bq/m3 with 95% confidence limits (-0.01, 0.26). For the subset of the data considered previously by Krewski et al. (2005), the EOR was 0.11 (0.00, 0.28). Further limiting subjects based on our criteria (residential stability and completeness of radon monitoring) expected to improve radon dosimetry led to increased estimates of the EOR. For example, for subjects who had resided in only one or two houses in the 5-30 ETW and who had a-track radon measurements for at least 20 yr of this 25-yr period, the EOR was 0.18 (0.02, 0.43) per 100 Bq/m3. Both estimates are compatible with the EOR of 0.12 (0.02, 0.25) per 100 Bq/m3 predicted by downward extrapolation of the miner data. Collectively, these results provide direct evidence of an association between residential radon and lung cancer risk, a finding predicted by extrapolation of results from occupational studies of radon-exposed underground miners.

Following initial in vitro and in vivo studies and important studies of uranium miners, scientists have now completed impressive case-control studies of lung cancer risk from exposure to residential radon. Researchers have pooled these studies, in which all the information from the individual studies was reanalyzed. These pooled analyzes confirm that in the context of residential exposure, radon is now an established risk factor for lung cancer. Many of the initial uncertainties have been reduced, and health risk assessors are now confident that radon may contribute to as much as 10% of the total burden of lung cancer--that is, 2% of all cancers in the population, worldwide. To reduce residential radon lung cancer risk, national authorities must have methods and tools based on solid scientific evidence and sound public health policies. To meet these needs, the World Health Organization (WHO) has initiated the WHO International Radon Project. This three year project, to be implemented during the period 2005-2008, will include (1) a worldwide database on national residential radon levels, radon action levels, regulations, research institutions, and authorities; (2) public health guidance for awareness-raising and mitigation; and (3) an estimation of the global burden of disease (GDB) associated with radon exposure.

The earliest evidence of increased lung cancer risk associated with radon came largely from studies of highly exposed underground miners. In the United States, concerns about residential exposures became prominent in the early 1980s with the identification of the Watras home, which had remarkably elevated radon concentrations. By then, the problem of indoor radon was already recognized in Europe and the first epidemiological studies on indoor radon had been reported. The concern about the risk of indoor radon motivated a series of case-control studies of residential radon and lung cancer in the United States, Canada, China, and a number of European countries. In 1999, the U.S. National Research Council Committee on the Biological Effects of Ionizing Radiation (BEIR VI) weighed the scientific evidence available at that time on this issue and concluded that residential radon was an important contributor to the lung cancer burden and that risks were appropriately estimated by a linear nonthreshold model. Since individual case-control studies have not provided consistent direct evidence of excess lung cancer risk at residential exposure levels, combined analyses of residential radon studies have been undertaken in both North America and Europe. These combined analyses, including the North American pooled analysis described in this issue, represent an important complement to the findings of the miner studies and further support the linear no-threshold model for cancer risk adopted by the BEIR VI Committee and other groups.

Lung cancer has held the distinction as the most common cancer type worldwide since 1985 (Parkin et al., 1993). Recent estimates suggest that lung cancer accounted for 1.2 million deaths worldwide in 2002, which represents 17.6% of the global cancer deaths (Parkin et al., 2005). During 2002, the highest lung cancer rates for men worldwide reportedly occurred in North America and Eastern Europe, whereas the highest rates in females occurred in North America and Northern Europe (Parkin et al., 2005). While tobacco smoking is the leading risk factor for lung cancer, because of the magnitude of lung cancer mortality, even secondary causes of lung cancer present a major public health concern (Field, 2001). Extrapolations from epidemiologic studies of radon-exposed miners project that approximately 18,600 lung cancer deaths per year (range 3000 to 41,000) in the United States alone are attributable to residential radon progeny exposure (National Research Council, 1999). Because of differences between the mines and the home environment, as well as differences (such as breathing rates) between miners and the general public, there was a need to directly evaluate effects of radon in homes. Seven major residential case-control radon studies have been conducted in North America to directly examine the association between prolonged radon progeny (radon) exposure and lung cancer. Six of the studies were performed in the United States including studies in New Jersey, Missouri (two studies), Iowa, and the combined states study (Connecticut, Utah, and southern Idaho). The seventh study was performed in Winnipeg, Manitoba, Canada. The residential case-control studies performed in the United States were previously reviewed elsewhere (Field, 2001). The goal of this review is to provide additional details regarding the methodologies and findings for the individual studies. Radon concentration units presented in this review adhere to the types (pCi/L or Bq/m3) presented in the individual studies. One picocurie per liter is equivalent to 37 Bq/m3. Because the Iowa study calculated actual measures of exposure (concentration x time), its exposures estimates are presented in the form WLM(5-19) (Field et al., 2000a). WLM(5-19) represents the working level months for exposures that occurred 5-19 yr prior to diagnosis for cases or time of interview for control. Eleven WLM(5-19) is approximately equivalent to an average residential radon exposure of 4 pCi/L for 15 yr, assuming a 70% home occupancy.

Hexavalent chromium compounds are well-documented human carcinogens. In vitro experiments show Cr (VI) induces cell death by apoptosis by activating p53 protein. The aim of this study was to evaluate Cr (VI)-induced apoptosis in a human bronchial epithelial cell line (BEAS-2B) and in a lymphoblastic leukemia cell line (MOLT-4). Cr (VI) caused a dose- and time-dependent increase in the apoptosis rate in both cell lines. Western blotting showed increased p53 protein expression in MOLT-4 cells, but not in BEAS-2B cells, after exposure to 0.5 and 3 muM hexavalent chromium for 12 hours and 4 hours, respectively. Apoptotic cell death induced by Cr (VI) was not decreased by pretreatment with caspase-3, -8, and -9 inhibitors. These preliminary results provide evidence of Cr (VI)-induced apoptosis, which deserves further investigation in occupationally exposed workers.

Worldwide, in the new millennium, standards for the protection of workers and the general population from as-bestos risks are not equally stringent in all countries. The present review analyzes some arguments which in recent years have been proposed as a rationale for the reconsideration of the scientific background of a total asbestos ban, such as that adopted in the European Union. The conclusion is that in order to ensure adequate protection, there is no alternative to a total ban. The evidence for carcinogenicity of chrysotile is as good as for the amphiboles, the carcinogenic potency of chrysotile is lower than that of the amphiboles, but risk estimates must also be based on extent of exposure (nowadays chrysotile represents 95% of asbestos used worldwide). The fact that induction of mesothelioma by asbestos results from the interaction of environmental exposure and genetic factors reflects a general phenomenon in carcinogenesis and does not warrant any re-consideration of the role of asbestos. The role of SV40 as yet is unclear: even assuming that current risk estimates are correct (which is debatable), this agent would interact with asbestos in only a faction of mesothelioma cases. The effectiveness of protocols suggested for "controlled use" has not been tested with a scientfiic approach: they seem hardly practicable, particularly in the countries which are currently the major consumers of asbestos.

Objective: To study the methylation of O-6-methylguanine-DNA methyltransferase (MGMT) and p16 gene in the sputum cells of radon-exposed population. To provide the experimental base for finding the molecular biomarker of the high risk population of the radon-induced lung cancer., Methods: 91 radon-exposed workers were divided into 4 groups, high dosage group (> 120 WLM), middle dosage group (between 60 and 120 WLM), low dosage group (between 30 and 60 WLB) and lower dosage group (between 2 and 30 WLM) according to the accumulated exposure dosage of the radon daughters. The abnormal methylation of p16 and MGMT gene in the sputum cells of the population in the four groups was detected with the methylation specific PCR (MSP)., Results: There was significantly upward trend for the p16 gene methylation rate (0.00%-20.00%), the MGMT gene methylation rate (0.00%-28.00%) and the total methylation rate (0.00%-40.00%) with the increase of the accumulated exposure dosage of the radon daughters (P < 0.01)., Conclusion: The methylation of p16 and MGMT gene is related to the accumulate exposure dosage of the radon daughters.

Study Objective: To investigate the possible relation between bladder cancer mortality among white men and women and private water use in New England, USA, where rates have been persistently raised and use of private water supplies (wells) common., Design: Ecological study relating age adjusted cancer mortality rates for white men and women during 1985-1999 and proportion of persons using private water supplies in 1970. After regressing mortality rates on population density, Pearson correlation coefficients were computed between residual rates and the proportion of the population using private water supplies, using the state economic area as the unit of calculation. Calculations were conducted within each of 10 US regions., Setting: The 504 state economic areas of the contiguous United States., Participants: Mortality analysis of 11 cancer sites, with the focus on bladder cancer., Main Results: After adjusting for the effect of population density, there was a statistically significant positive correlation between residual bladder cancer mortality rates and private water supply use among both men and women in New England (men, r = 0.42; women, r = 0.48) and New York/New Jersey (men, r = 0.49; women, r = 0.62)., Conclusions: Use of well water from private sources, or a close correlate, may be an explanatory variable for the excess bladder cancer mortality in New England. Analytical studies are underway to clarify the relation between suspected water contaminants, particularly arsenic, and raised bladder cancer rates in northern New England.

Background: In order to test some hypotheses of risk factors for oropharyngeal cancer (neoplasm of base of tongue, palate and tonsils) matched case-control study was conducted in Belgrade, Serbia and Montenegro, during the period 1998-2000., Methods: Study comprised 100 incidence cases with oropharyngeal cancer and 100 controls with some non-malignant diseases of head and neck., Results: According to multivariate analysis, ever smoking, interaction between smoking and alcohol consumption, and occupational exposure to wood dust were found to be independent risk factors for oropharyngeal cancer (odds ratio-OR=5.10 95% confidence intervals-95% CI=1.70-15.27, OR=2.61 95% CI=1.54-4.41, and OR=4.16 95% CI=1.45-11.91, respectively)., Conclusion: The results of the present study are in line with other authors' findings showing that smoking and alcohol consumption are the main risk factors for oropharyngeal cancer. The effect of occupational exposure to wood dust warrants further investigation.

Background: Multiple risk factors possibly associated with lung cancer were examined as part of a large-scale residential radon case-control study conducted in Iowa between 1994 and 1997. We were particularly interested in stratifying risk factors by smoking status. Relatively little risk factor information is available for Midwestern rural women., Methods: Four hundred thirteen female lung cancer cases and 614 controls aged 40-84, who were residents of their current home for at least 20 years, were included. Risk factors examined included cigarette smoking, passive smoking, occupation, chemical exposure, previous lung disease, family history of cancer, and urban residence. Multiple logistic regression analysis was conducted after adjusting for age, education, and cumulative radon exposure., Results: As expected, active cigarette smoking was the major risk factor for lung cancer. While cessation of smoking was significantly associated with a reduced risk for lung cancer, the risk remained significantly elevated for 25 years. Among all cases, asbestos exposure was a significant risk. Among ex-smokers, pack-year history predominated as the major risk. Among never smokers, a family history of kidney or bladder cancer were significant risk factors (OR=7.34, 95% CI=1.91-28.18; and OR=5.02, 95% CI=1.64-15.39, respectively), as was a history of previous lung disease (OR=2.28, 95% CI=1.24-4.18) and asbestos exposure. No statistically significant increase in lung cancer risk was found for occupation or urban residence., Conclusions: Smoking prevention activities are urgently needed in rural areas of the United States. Relatives of individuals with smoking-related cancers are potentially at increased risk. Genetic risk factors should be more fully investigated in never smokers.