Polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes, CYP1A1 xenobiotic metabolism gene, and tobacco are associated with bladder cancer susceptibility in Tunisian population.

Other than the established environmental risk factors associated with bladder cancer (BC), little is known about the genetic variations determining the individual susceptibility of this complex disease. This study aimed to investigate the relationship of BC with environmental agents and polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes and CYP1A1, CYP2D6, NAT1, and NAT2 xenobiotic metabolism genes through a hospital-based case-control study in Tunisia. The selection of the single nucleotide polymorphisms (SNPs) (rs25487, rs 13181, rs415407, rs446421, rs1058172, rs4921880, and rs1208) was performed using the dbSNP database. DNA genotyping was determined by PCR-RFLP after DNA extraction from whole blood. The risks of BC associated with every polymorphism as well as the studied environmental factors were estimated by multivariate-adjusted logistic regression using R software. In addition, gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results showed that tobacco smoking and chewing parameters were significantly associated with BC risk. Single-gene variant analysis showed significant associations of the TT genotype of CYP1A1 and the rare GG genotype of ERCC2 with bladder cancer susceptibility (OR = 1.34, 95% CI 1.22-1.40, P < 0.0001). According to GMDR analysis, our findings indicated a significant association between BC and gene-gene interaction among the CYP1A1, ERCC3, and XRCC1. The present results suggest a potential role of XRCC1, ERCC2, ERCC3, and CYP1A1 besides tobacco intake in susceptibility to BC.

Cytotoxicity and genotoxicity effects of arsenic trioxide on SQ20B human laryngeal carcinoma cells.

This study investigates the cytotoxicity and the genotoxicity induced by arsenic trioxide As2O3in human laryngeal SQ20B carcinoma cell line. SQ20B cells were exposed to graded concentrations of arsenic trioxide (2 and 5µM) for 48h. Comet assay and γ-H2AX foci formation were used for measuring DNA damages, flow cytometry was used to identify cell cycle alterations and apoptosis, while cell morphology was visualized using transmission electron microscopy. The results show a dose-dependent induction of DNA damages and double strand breaks, alterations in cell cycle and morphologic alterations of cells. These results prove that As2O3 is highly cytotoxic and genotoxic at the micromolar range ina human laryngeal carcinoma cell line.

Gene-environment interactions between ERCC2, ERCC3, XRCC1 and cadmium exposure in nasal polyposis disease.

Gene-environment interactions have long been known to play an important role in complex disease aetiology, such as nasal polyposis (NP). The present study supports the concept that DNA repair gene polymorphisms play critical roles in modifying individual susceptibility to environmental diseases. In fact, we investigated the role of polymorphisms in DNA repair genes and cadmium as risk factors for Tunisian patients with NP. To the best of our knowledge, this is the first report on the impact of combined effects of cadmium and ERCC3 7122 A>G (rs4150407), ERCC2 Lys751Gln (rs13181) and XRCC1 Arg399Gln (rs25487) genes in the susceptibility to NP disease. Significant associations between the risk of developing NP disease and ERCC2 [odds ratio (OR) = 2.0, 95 % confidence interval (CI) = 1.1-3.7, p = 0.023] and ERCC3 (OR = 2.2, 95 % CI = 1.2-4.1, p = 0.013) genotypes polymorphisms were observed. Blood concentrations of Cd in NP patients (2.2 µg/L) were significantly higher than those of controls (0.5 µg/L). A significant interaction between ERCC3 (7122 A>G) polymorphism and blood-Cd levels (for the median of blood-Cd levels: OR = 3.8, 95 % CI = 1.3-10.8, p = 0.014 and for the 75th percentiles of blood-Cd levels: OR = 2.7, 95 % CI = 1.1-7.2, p = 0.041) was found in association with the risk of NP disease. In addition, when we stratified ERCC2, ERCC3 and XRCC1 polymorphism genotypes by the median and 75th percentiles of blood-Cd levels, we found also significant interactions between ERCC2 (Lys751Gln) and ERCC3 (7122 A>G) genotypes polymorphism and this metal in association with NP disease. However, no interaction was found between XRCC1 (Arg399Gln) polymorphism genotypes and Cd in association with NP disease.

Genotoxic effects of cadmium in human head and neck cell line SQ20B.

As cadmium may be involved in the etiology of head and neck cancers, we investigated in the present work, the cytotoxic and genotoxic effects of Cd on human larynx cells. SQ20B cells were exposed to 25 and 50 µM Cd for 48 and 72 h. Results showed a dose-dependent decrease in cell viability, especially after 48 h, associated with mitochondria alterations as showed by transmission electronic microscopy. Surprisingly, the flow cytometry shows that the cells treated with Cd have a normal proliferative cycle like the untreated cell especially in G1 or G2 phase of cell cycle. DNA damages were investigated by comet assay and immunofluorescence for gamma layer of the H2AX (g-H2AX) foci formation. Results show a strong induction of DNA double-strand breaks after Cd exposure. Overall, our results demonstrate the cytotoxicity and genotoxicity of Cd in human larynx cells and support the view that Cd could be an etiologic factor of head and neck cancers.

Association between blood arsenic levels and nasal polyposis disease risk in the Tunisian population.

Although the pathophysiology underlying nasal polyposis (NP) formation is not fully understood, systemic, local, and environmental factors appear to contribute to NP disease development. This study aimed to explore the relationship between metal blood levels and NP risk. To the best of our knowledge, the current research represents the first scientific contribution reporting levels of Cr and As in blood of NP patients. In this context, 90 NP patients and 171 controls were recruited and blood samples were analyzed to determine the concentrations of As and Cr. Metal blood levels of As in patients (2.1 µg/L) were significantly higher than those of controls (1.2 µg/L). However, no significant difference in blood Cr levels was found between cases and controls. Arsenic blood levels of cigarette smokers were significantly higher than those of non-smokers. Environmental exposure and shisha consumption presented the most significant association with NP disease (OR = 10.1 and 14.1, respectively). High levels of blood As were significantly associated with NP disease (OR = 2.1). Cr blood levels were found to be associated with the four stages of polyps in both nasal cavities. This study found a strong association between nasal polyposis disease and As blood levels. These findings merit further investigation.

Heavy metals in normal mucosa and nasal polyp tissues from Tunisian patients.

Despite growing evidence that bacteria, fungi, allergens, and superantigens play a prominent role in the pathophysiology of nasal polyps (NP), the exact cause of polyposis is still unknown. The etiology of NP is considered multifactorial. Until now, there is no information on the presence of heavy metals, such as cadmium (Cd), chromium (Cr), nickel (Ni), and arsenic (As) or of their role, in the pathogenesis of NP disease. In this study, concentrations of these four metals in tissue of NP were determined using Atomic Absorption Spectrometry. The Ni, Cr, and As levels in NP tissues were 2.1-, 3.2-, and 8.0-fold higher than those of normal mucosa (p < 0.05), respectively. A strong effect of cumulative smoking as expressed in the number of pack per year (PY), Ni, As, and Cd levels in NP tissue samples of patients ever-smokers (1-20 and >20 PY) are significantly higher than those of non-smokers (p = 0.006, 0.002, and < 0.001, respectively). The highest As concentrations among patients lived at polluted areas (1-25 and > 25 years) were observed in both nasal mucosa and NP tissues. The Ni and As in both nasal mucosa and NP tissues of patients occupationally exposed were significantly higher than non-exposed group. Cr and As levels were found to be associated with NP stage classification (p < 0.05). This is the first report to describe an association between concentrations of metals (Cr, As, and Ni) in human NP tissues and the risk of NP disease. Tissue metal levels have increased due to smoking, environmental, and occupational exposure. Therefore, heavy metal exposure may increase the risk of NP in the Tunisian population. The considerable risk in the category of highest cumulative exposure argues for an association between heavy metals exposure and nasal polyposis risk. Future investigations with larger samples should better elucidate this association.

Cadmium and nickel in blood of Tunisian population and risk of nasosinusal polyposis disease.

Nasosinusal polyposis (NSP) is a chronic inflammatory disease of the nasal mucosa. Although the pathophysiology underlying NSP formation is not fully understood, environmental factors appear to be contributed the development of this disease. A case-control study of Tunisian patients was examined to assess the levels of cadmium (Cd) and nickel (Ni) in blood and reparse the association between the exposure to these metals and the risk of nasosinusal polyposis disease. Mean blood levels of Cd in patients (2.2 ± 12.8 µg/L) were significantly higher than those of controls (0.5 ± 0.7 µg/L). Levels of blood Cd were positively correlated with tobacco smoking and chewing among controls. The Cd and Ni concentrations among control (p = 0.001) and patient (p = 0.018) tobacco consumers (smoking, chewing, and shisha) were significantly higher than those nonconsumers. Additionally, Ni blood levels of patient and control smokers were significantly higher than those of nonsmokers. Cd levels in blood samples of NSP patients occupationally exposed for more than 14 years were eight times higher than that of nonexposed. Drinking water was also found to be incriminated as exposure sources. Among risk factors, shisha consumption, environmental exposure, and occupational exposure presented the most significant association with NSP disease (odds ratio (OR) = 14.1, 10.1, and 1.7, respectively). High levels of blood Cd (OR = 3.5) were strongly associated with NSP disease (p = 0.027). Ni blood levels were shown to be associated with the four stages of polyps in both nasal cavities (right and left) (p < 0.05). This investigation suggested a potential role of toxic metals in the mechanism of NSP disease development. Exposure assessment investigations encompassing a wider population are needed.

Cytogenetic damage in the oral mucosa cells of bladder cancer patients exposed to tobacco in Southern Tunisia.

Bladder cancer was associated to exposure to several pollutants which can be absorbed, inhaled, or possibly ingested. We analyzed the frequency of micronuclei (MNC) and binucleated cells (BNC) in exfoliated cells of the oral mucosa of 24 bladder cancer (BC) patients and 48 controls residing in Southern Tunisia. An assessment was carried out on the incidence of MNC and BNC in 1,000 cells per individual. The data were analyzed with SPSS, using the chi-square and the Mann-Whitney U test, α = 0.05. The frequency of MN cells in BC cases was 2.5-fold higher, than in the control group (P < 0.001), while the difference for BNC between both groups was not significant. The smoking habits, age, and gender significantly influenced the MN but not the BNC alterations. The results of our study showed significantly increased frequencies of MN but not of BNC in exfoliated oral cells of BC patients associated with the smoking status, sex, and age. This study provides preliminary evidence that the frequency of MN in oral mucosa could be a predictive biomarker for cancers in parts of the body other than the upper aerodigestive tract, such as BC. Further scrupulous investigations are certainly warranted in order to implement this assay as a routine test in the planning and validation of cancer surveillance and prevention programs.

Inter-ethnic differences in genetic polymorphisms of xenobiotic-metabolizing enzymes (CYP1A1, CYP2D6, NAT1 and NAT2) in healthy populations: correlation with the functional in silico prediction.

Several studies have shown that many polymorphisms of the xenobiotic-metabolizing enzymes (XME) affect either enzymatic functions or are associated with various aspects of human health. Owing to the presence of these single nucleotide variants (SNVs), differences in detoxification capacity have been observed between many ethnicities. The aim of this investigation was to study the prevalence of four polymorphisms in XME among various ethnic groups. Attention was focused on polymorphisms of CYP2D6 (rs1058172, G>A, p.Arg365His), CYP1A1 (rs4646421, c.-26-728C>T), NAT1 (rs4921880, c.-85-1014T>A) and NAT2 (rs1208, A>G, p.Arg268Lys). These polymorphisms were analyzed in 261 healthy Tunisians individuals in comparison with different ethnic backgrounds from hapmap database. In addition, in silico functional prediction was also performed to determine the loss of function variants. Our results demonstrated that population's origins widely affect the genetic variability of XME enzymes and Tunisians show a characteristic pattern. In silico predictions showed a deleterious effect for p.Arg268Lys substitution on CYP2D6 function, findings confirmed its key role played in cancer susceptibility. These data show that detoxification genes structures depend on the studied population. This suggests that ethnic differences impact on disease risk or response to drugs and therefore should be taken into consideration in genetic association studies focusing on XME enzymes. Our results provide the first report on these SNV in Tunisian population and could be useful for further epidemiological investigations including targeted therapy.

Association of CYP1A1 and CYP2D6 gene polymorphisms with head and neck cancer in Tunisian patients.

The purpose of this study was to investigate the relationship between head and neck cancer (HNC) and environmental agents and polymorphisms in CYP1A1, CYP2D6, NAT1 and NAT2 metabolic enzymes genes. To the best of our knowledge, this is the first report on polymorphisms in CYP1A1 6310C>T, CYP2D6 Arg365His, NAT1 52936A>T and NAT2 Arg268Lys (NAT2*12A) genes and susceptibility to HNC in Tunisian population. We study the prevalence of these polymorphisms in 169 patients with HNC and 261 control subjects using polymerase chain reaction based methods in a Tunisian population. We detected an association between HNC and CYP1A1 6310C>T (TT) and CYP2D6 Arg365His (His/His) variant carriers (OR 1.75, P = 0.008 and OR 1.66, P = 0.016, respectively). No association was found between the polymorphisms genotypes of NAT1 52936T>A and NAT2 Arg268Lys and risk of HNC. An association between HNC and CYP1A1 (TT) genotype was found among patients with smoking (P = 0.011) and drinking habit (P = 0.009). The combinations of NAT1 (AT or AA) and NAT2 (AA) at-risk genotypes increased HNC risk (OR 4.23, P = 0.005 and OR 3.60, P = 0.048, respectively). However, the combinations of CYP1A1 (AA) and CYP2D6 (CC) genotypes decreased risk of HNC (OR 0.20; P = 0.006). Genetic polymorphisms in CYP1A1 and CYP2D6 may significantly associate with HNC in the Tunisian population. The results of this study suggest a possible gene-environment interaction for certain carcinogen metabolizing enzymes, but larger studies that fully evaluate the interaction are needed.

Biomonitoring of cadmium, chromium, nickel and arsenic in general population living near mining and active industrial areas in Southern Tunisia.

The human health impact of the historic and current mining and industrial activities in Tunisia is not known. This study assessed the exposure to metals in the population of Southern Tunisia, using biomonitoring. The aim of this pilot study was to evaluate metal exposure on 350 participants living near mining and active industrial areas in the South of Tunisia. Blood specimens were analyzed for metals (Cd, Cr, As, and Ni) by Atomic Absorption Spectrometer equipped with Zeeman background correction and AS-800 auto sampler by graphite furnace and graphite tubes with integrated L'vov platform. The sample population was classified according to different age groups, sex, smoking habit, sea food and water drinking consumption, occupational exposure, amalgam fillings and place of residence. The blood As, Cd, Cr and Ni values expressed as mean ± SD were 1.56 ± 2.49, 0.74 ± 1.15, 35.04 ± 26.02 and 30.56 ± 29.96 µg/l, respectively. Blood Cd and Ni levels in smokers were 2 and 1.2 times, respectively, higher than in non-smokers. Blood Cd levels increase significantly with age (p = 0.002). As, Cd and Ni were significantly correlated with gender and age (p < 0.05). Cd level in blood samples of subjects occupationally exposed was 1.3 times higher than that of non-exposed. Blood metals were not significantly affected by amalgam fillings, place of living and sea food and drinking water consumption. This first biomonitoring study of metal exposure in the South of Tunisia reveals a substantial exposure to several metals. The pathways of exposure and health significance of these findings need to be further investigated.

Risk of laryngeal and nasopharyngeal cancer associated with arsenic and cadmium in the Tunisian population.

Chronic exposure to heavy metals has long been recognized as being capable of increasing head and neck cancer (HNC) incidence, such as laryngeal (LC) and nasopharyngeal (NPC), among exposed human populations. The aim of the present study was to evaluate the concentrations of arsenic (As) and cadmium (Cd) in the blood of 145 patients (LC and NPC) and 351 controls in order to establish a potential relationship between these factors and the occurrence of LC and NPC. Mean blood levels of As and Cd in patients (5.67 and 3.51 µg/L, respectively) were significantly higher than those of controls (1.57 and 0.74 µg/L, respectively). The blood levels of As and Cd were mostly significantly higher than those of controls (p<0.05) after controlling the other risk factors of HNC including tobacco smoking and chewing, and alcohol drinking. Cd levels in blood increase significantly with the number of occupational exposure years for patients (p<0.05). However, seafood was not found to be contributing as an exposure source. Among these risk factors, smoking (>30 pack years) and occupational exposure (>20 years) presented the most significant association with HNC (OR=10.22 and 10.38, respectively, p<0.001). Cd level in blood sample of cases that are occupationally exposed/tobacco users (smokers and chewers) were higher than that of non-occupationally exposed/nontobacco users (p<0.001). The logistic regression model illustrated that HNC (LC+NPC) was significantly associated with blood levels of As (OR=2.41, p<0.001) and Cd (OR=4.95, p<0.001).

DNA repair gene polymorphisms and risk of head and neck cancer in the Tunisian population.

Altered activity of DNA repair enzymes may be involved in modulating cancer susceptibility and pathogenesis of head and neck cancer (HNC). We conducted a case-control study to test the association between three common single-nucleotide polymorphisms of XRCC1, ERCC2, and ERCC3 genes with HNC risk in Tunisian patients. To the best of our knowle dge, this is the first report on polymorphisms in XRCC1, ERCC2, and ERCC3 and susceptibility to HNC in our population. The genotype analyses of XRCC1 Arg399Gln, ERCC2 Lys751Gln, and ERCC3 7122 A>G polymorphisms for 169 HNC patients, and 261 controls were performed using the PCR-based restriction fragment length polymorphism. Stratification of the populations according to smoking and drinking habits and occupational exposure highlighted the importance of tobacco, alcohol, and toxic substance as three risk co-factors for the development of HNC. Our study suggests that only the XRCC1 Arg399Gln polymorphism was associated with the risk of HNC in the Tunisian population (OR = 2.04; P = 0.001). Furthermore, the risk of HNC was associated with XRCC1 Arg399Gln polymorphism stratified by occupational exposure status (OR = 2.29; P = 0.024). However, no statistically significant association was observed between the risk of developing HNC and the ERCC2 Lys751Gln and ERCC3 A>G polymorphisms. These data suggest that the XRCC1 Arg399Gln polymorphism is associated with an increased risk of developing HNC, because it correlates with occupational exposure in Tunisian population.

Polymorphisms in the human cytochrome P450 and arylamine N-acetyltransferase: susceptibility to head and neck cancers.

The occurrence of head and neck cancer (HNC) is associated with smoking and alcohol drinking. Tobacco smoking exposes smokers to a series of carcinogenic chemicals. Cytochrome P450 enzymes (CYP450s), such as CYP1A1, CYP1B1, and CYP2D6, usually metabolize carcinogens to their inactive derivatives, but they occasionally convert the chemicals to more potent carcinogens. In addition, via CYP450 (CYP2E1) oxidase, alcohol is metabolized to acetaldehyde, a highly toxic compound, which plays an important role in carcinogenesis. Furthermore, two N-acetyltransferase isozymes (NATs), NAT1 and NAT2, are polymorphic and catalyze both N-acetylation and O-acetylation of aromatic and heterocyclic amine carcinogens. Genetic polymorphisms are associated with a number of enzymes involved in the metabolism of carcinogens important in the induction of HNC. It has been suggested that such polymorphisms may be linked to cancer susceptibility. In this paper, we select four cytochrome P450 enzymes (CYP1A1, CYP1BA1, CYP2D6, and CYP2E1), and two N-acetyltransferase isozymes (NAT1 and NAT2) in order to summarize and analyze findings from the literature related to HNC risk by focusing on (i) the interaction between these genes and the environment, (ii) the impact of genetic defect on protein activity and/or expression, and (iii) the eventual involvement of race in such associations.

Cytogenetic abnormality in exfoliated cells of buccal mucosa in head and neck cancer patients in the Tunisian population: impact of different exposure sources.

Chromosome/DNA instability could be one of the primary causes of malignant cell transformation. The objective of the present study was to evaluate the spontaneous genetic damages in exfoliated cells of buccal mucosa of head and neck cancer (HNC) by counting micronucleus (MN) and binucleated (BN) cells frequencies. MN and BN frequencies were significantly increased in HNC patients compared with controls (5.53 ± 3.09/1000 cells, 5.63 ± 2.99/1000 cells versus 2.36 ± 2.11/1000 cells, 3.09 ± 1.82/1000 cells, P < 0.001). Regarding the gender and the age, the frequencies of the MN and BN were significantly higher than those of controls (P < 0.01). The evaluation of the MN and BN frequencies revealed a significant increase (P < 0.001) in the cases in relation to the control group after controlling the risk factors (tobacco smoking and chewing and occupational exposure) of HNC. Moreover, MN and BN frequencies were significantly increased in smokers and chewers compared with nonsmokers and nonchewers among patients (P < 0.05). MN frequency was significantly (P = 0.014) different between patients occupationally exposed (6.99 ± 3.40/1000 cells) and nonexposed (4.70 ± 2.48/1000 cells) among HNC group. The logistic regression model illustrated that HNC was significantly associated with frequencies of MN (OR = 8.63, P < 0.0001) and BN (OR = 5.62, P = 0.001). Our results suggest that increased chromosome/DNA instabilities may be associated with HNC.

Cadmium in blood of Tunisian men and risk of bladder cancer: interactions with arsenic exposure and smoking.

Prior investigations identified an association between low-level blood arsenic (As) and bladder cancer risk among Tunisian men but questions remain regarding confounding by cadmium (Cd), a well-established bladder carcinogen. A case-control study of Tunisian men was re-examined to assess the levels of cadmium in blood and reparse the association between the simultaneous exposure to these metals and bladder cancer risk. Levels of blood Cd were significantly twice higher among cases than in controls (P<0.05) and were positively correlated with smoking and age. Additionally, analysis of metal levels among non-smokers according to the region of residence showed very high blood Cd and As levels for the coastal regions of Sfax and central Tunisia. After controlling for potential confounders, for low blood As levels (<0.67 µg/L), the OR for blood Cd was 4.10 (95 % CI 1.64-10.81), while for higher levels (>0.67 µg/L), it was reduced to 2.10 (CI, 1.06-4.17). Adjustment for Cd exposure did not alter the risk associated to As exposure. This study is the first to report the relationship between Cd exposure and risk of bladder cancer occurrence in interaction with smoking and As exposure. Smoking is shown to be the main exposure source to Cd in the Tunisian population but also environmental pollution seems to be responsible of Cd exposure among non-smokers. Exposure assessment studies encompassing a wider population are needed.

Blood nickel and chromium levels in association with smoking and occupational exposure among head and neck cancer patients in Tunisia.

Chronic exposure to chromium (Cr) and nickel (Ni) has long been recognized as being capable to increase head and neck cancer (HNC) incidence among exposed human populations. This study represents the first biomonitoring of Cr and Ni exposure in Tunisia and focuses on a possible association with HNC risk. The aim of the present study was to evaluate the concentrations of Cr and Ni in the blood of HNC patients and controls. Metals blood levels of 169 HNC patients and 351 controls were determined using a Perkin-Elmer Analyst 800 Atomic Absorption Spectrometer. Mean blood levels of Cr and Ni in HNC cases (52.15 and 111.60 µg/L, respectively) were significantly higher than those of controls (37.04 and 30.50 µg/L, respectively). Cases' blood levels of Cr and Ni were significantly higher than those of controls after controlling for the other risk factors of HNC, including smoking, shisha consumption, occupational exposure, and nearby environment (P<0.05). Among these risk factors, smoking and occupational exposure presented the most significant association with HNC (odds ratio (OR)=6.54 and 7.66, respectively, P<0.001). Cr and Ni levels in blood sample of cases and controls that are smoker/occupationally exposed were higher than that of non-smoker/non-occupationally exposed (P<0.05). Smokers who are occupationally exposed present the most significant association with HNC (OR=25.08, P<0.0001). High levels of blood Cr (OR=2.09) and high levels of blood Ni (OR=8.87) were strongly associated with HNC after other potential confounders were controlled (P=0.004 and P<0.0001, respectively). This study suggested a potential role of Cr and Ni in the mechanism of HNC development.

Arsenic, cadmium, chromium and nickel in cancerous and healthy tissues from patients with head and neck cancer.

Chronic exposure to heavy metals has long been recognized as being capable to increase head and neck cancer incidence among exposed human populations. Head and neck cancer is a significant public health issue in Tunisia. The aim of the present study was to evaluate the concentrations of As, Cd, Cr and Ni in healthy and tumor tissues of head and neck cancer patients. Metal concentrations were determined in tumor and healthy tissues of 101 head and neck cancer patients, using Atomic Absorption Spectrometry. The As, Cd, Cr, and Ni levels in tumor tissues were 3.4, 2.5, 1.3 and 1.5 times higher than those of healthy tissues (p<0.05), respectively. Tumor tissue metal levels were higher in men than in women. As and Cd levels in tumor and healthy tissue samples of patients smokers are significantly higher than those of non-smokers (p<0.05). A strong effect of cumulative smoking as expressed in the number of pack per year, and tumor tissue Cd levels were positively associated with three groups of age (<40, 51-60 and >60 years) in both never-smokers and ever-smokers (<20 and ≥20 pack per year). Healthy tissue Cd levels were negatively associated with age in those three groups of smokers. The highest Cd and Cr concentrations among both workers and non-workers were observed in tumor tissues. The Cd and Cr in tissues of farmers, bricklayers and painters were all significantly higher among the workers as compared with the non-workers group. Tissue metal levels have increased due to smoking and occupational exposure. Heavy metal exposure via tobacco smoking and occupational exposures may increase the risk of head and neck in the Tunisian population.

Low-level arsenic exposure is associated with bladder cancer risk and cigarette smoking: a case-control study among men in Tunisia.

Although exposure to high levels of arsenic is associated with excess bladder cancer risk, lower exposures generally are not. This study represents the first biomonitoring of arsenic exposure in Tunisia and focuses on a possible association with bladder cancer risk. In this context, 124 male bladder cancer cases and 220 controls were recruited and blood samples were analyzed to determine the concentration of As. The study subjects were stratified into median groups based on concentrations of arsenic in their blood. Blood arsenic (B-As) was significantly two to threefold higher in bladder cancer cases than in controls (p<0.05). The arsenic concentrations were significantly higher among both smokers and workers in construction. However, neither drinking water nor seafood was found to be incriminated as exposure sources. The adjusted risk ratios for B-As concentration categories 0.1-0.67 and ≥ 0.67 µg/L were 0.18 (95% CI=0.014-2.95) and 2.44 (95% CI=1.11-5.35), respectively. Arsenic levels were not found to be associated with tumor grade or stage. The considerable risk in the category of highest cumulative exposure argues for an association between bladder cancer risk and low-level arsenic exposure. Future investigations with larger samples and using techniques that allow the distinction of the different arsenic species should better elucidate this association. Furthermore, the modulation of arsenic level according to the histological grade may be of potential to be used as a diagnostic marker of the disease process and its possible relationship etiologically.