Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes.

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

Serum levels of insulin-like growth factor-I, IGF-binding protein 1 and 3, and insulin and endometrial cancer risk.

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 and 3 (IGFPB-1, IGFPB-3) are expressed in normal and neoplastic endometrium. Their role and the role of insulin in the aetiology of endometrial cancer, is unclear. We performed a population-based case-control study in Sweden, including 288 endometrial cancer patients and 392 control women and analysed total serum IGF-I, IGFBP-1, IGFBP-3, insulin and BMI levels stratified by disease and hormone replacement therapy status (HRT). Non-parametric statistical tests and logistic regression analyses were performed to assess associations with endometrial cancer. There were no substantial differences between the mean serum levels of IGF-I between cases (115.5, s.d. 61.3) and controls (110.6; s.d. 50.4; Wilcoxon P=0.84), or between subgroups of women classified according to other risk factors for endometrial cancer. There were no trends of increasing risk according to quartiles of IGF-I, IGFBP-1, IGFBP-3 and insulin serum levels. There was an increasing risk of endometrial cancer according to the serum levels of IGFBP-1, which was observed only among women who had ever used HRT. Serum IGF-I, IGFBP-1, IGFBP-3 and insulin levels seem unrelated to endometrial cancer risk. Among users of HRT, increasing IGFBP-1 levels seem to increase endometrial cancer risk.

Wine and resveratrol: mechanisms of cancer prevention?

Low alcohol consumption seems to decrease total mortality and to have beneficial properties on cardiovascular disease; data for cancer are still inconclusive. There is evidence that wine consumption decreases the risk of cancer at several sites, including cancer of upper digestive tract, lung, colon, basal cell carcinoma, and non-Hodgkin lymphoma. The presence of resveratrol, a polyphenol specifically present in red wine, may contribute to these cancer preventive effects. Resveratrol in fact inhibits the metabolic activation of carcinogens, has antioxidant and anti-inflammatory properties, decreases cell proliferation and induces apoptosis. Data on the availability of resveratrol in vivo are however still lacking. Although regular consumption of one or two glasses of wine seems reasonably safe from the health point of view, a recommendation to the general population for low wine consumption is not justified.

Is COX-2 inhibition a panacea for cancer prevention?

The epidemiologic evidence and rodent studies suggest strongly that nonselective inhibitors of cyclooxygenase (COX) enzymes such as aspirin, inhibiting both COX-1 and COX-2 isoforms, reduce the incidence of and mortality from intestinal tumors. Genetically manipulated animals show that both Cox-1 and Cox-2 disruptions decrease the tumor yield, both in genetically predisposed and in carcinogen-treated mice. The mechanisms by which COX-1 and COX-2 deficiency decrease tumorigenesis are still unknown. Cox-2 overexpression increased the tumor yield in mammary glands of the multiparous, but not virginal female transgenic mice using the murine mammary tumor virus promoter. The Cox-2 protein was strongly induced during pregnancy and lactation. These data suggest that Cox-2 overexpression may be an important target for cancer chemoprevention. This finding was supported by the observed cancer-preventive effects of the COX-2-specific inhibitors in humans and in rodents. However, based on the available data, we cannot totally attribute the cancer preventive effects of nonsteroidal antiinflammatory drugs (NSAIDs) to COX-2 alone-even COX-1 may have an important role in cancer prevention as suggested by the Cox-1-deficient Min mice. It is likely that COX-1 plays a more important role in NSAID-induced toxicity in humans, such as in gastric ulcer formation-but inhibition of COX-2 may not be without toxic manifestations either, as suggested by the poor survival of the Cox-2-nulled mice. Combinations of COX-2 inhibitors with other agents that target other pathways in carcinogenesis may be a more efficacious and a less toxic strategy in cancer chemoprevention.

[Known methods can reduce tobacco dependence drastically]. / Redan kända metoder kan minska tobaksberoendet drastiskt.

Tobacco smoking is the largest preventable risk factor for morbidity and mortality in industrialized countries. WHO estimates that tobacco will become the largest single health problem by 2020, causing an estimated 8.4 million deaths annually. Tobacco has central importance in the etiology of cancers of the lung, head and neck, urinary tract, and pancreas. Reducing the number of young people who take up smoking and helping those who have started to smoke to quit the habit are the key ways of preventing these cancers. Tobacco- or nicotine-dependence is a common, chronic, relapsing medical condition. Studies of twins have implicated genetic factors in most of the differences in vulnerability to tobacco smoke and in the persistence of the smoking phenotype. The available interventions for reducing tobacco use and treatment for nicotine dependence offer public health officials and clinicians the greatest single opportunity for disease prevention. Five medications--nicotine chewing gum, nicotine patches, nicotine inhalers, nicotine nasal sprays and bupropion--and behavioural therapy appear to be both effective and safe: they double the quitting rates and are associated with a dropout rate due to adverse events of less than 5%.

Allium vegetables and organosulfur compounds: do they help prevent cancer?

Allium vegetables have been shown to have beneficial effects against several diseases, including cancer. Garlic, onions, leeks, and chives have been reported to protect against stomach and colorectal cancers, although evidence for a protective effect against cancer at other sites, including the breast, is still insufficient. The protective effect appears to be related to the presence of organosulfur compounds and mainly allyl derivatives, which inhibit carcinogenesis in the forestomach, esophagus, colon, mammary gland, and lung of experimental animals. The exact mechanisms of the cancer-preventive effects are not clear, although several hypotheses have been proposed. Organosulfur compounds modulate the activity of several metabolizing enzymes that activate (cytochrome P450s) or detoxify (glutathione S-transferases) carcinogens and inhibit the formation of DNA adducts in several target tissues. Antiproliferative activity has been described in several tumor cell lines, which is possibly mediated by induction of apoptosis and alterations of the cell cycle. Allium vegetables and organosulfur compounds are thus possible cancer-preventive agents. Clinical trials will be required to define the effective dose that has no toxicity in humans.

Breast cancer risk in male alcoholics in Sweden.

OBJECTIVE: To investigate the association between alcoholism and risk of male breast cancer. METHODS: We conducted a retrospective population-based cohort study in Sweden of men diagnosed with alcoholism between 1965 and 1995. The cohort was followed up through interlinkages with nationwide registries (the national cancer registry, immigration registry, causes of death registry, and population registry), using the national registration numbers. Standardized incidence ratios (SIRs), calculated using the Swedish national cancer incidence rate as reference, were used as estimates of relative risks. RESULTS: A total of 145,811 men were enrolled into the cohort, contributing 1,499,504 person-years of follow-up. Sixteen incident breast cancer cases were identified, and the mean age at diagnosis was 68 years. We excluded the first year of follow-up (cases and person-years) from the analysis to avoid detection bias. The overall SIR (excluding the first year of follow-up) was 1.1 (95% CI 0.6-2.0). Although based on small numbers we found no indication of a differential SIR according to duration of follow-up, age at cohort enrolment, or age at follow-up (attained age or age at cancer diagnosis). CONCLUSION: The observed associations are not compatible with an increase in breast cancer risk among male alcoholics.

Alcoholism and risk for cancer of the cervix uteri, vagina, and vulva.

We conducted a population-based cohort study to analyze the risk of developing cancers of the female genitals among 36,856 patients with a hospital discharge diagnosis of alcoholism (ICD-7: 307, 322; ICD-8: 291, 303; ICD-9: 291, 303, 305A) in Sweden between 1965 and 1995. The follow-up was done by linkages of national registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed based on nationwide specific cancer rates. The first year of follow-up was excluded from all analyses to minimize the impact of selection bias. We found that alcoholic women had excess risks for in situ cervical cancer (SIR, 1.7; 95% CI, 1.6-1.9), for invasive cervical cancer (SIR, 2.9; 95% CI, 2.4-3.5), and for cancer of the vagina (SIR, 4.6; 95% CI, 2.2-8.5) but not for cancer of the vulva (SIR, 1.0; 95% CI, 0.4-2.0). The fact that alcoholics had an excess risk also for the in situ cancer suggests that the observed excess in invasive cervical cancer may not only be attributable to less use of Pap smear screening among them. The alcoholic women may be at higher risk for the progression from human papillomavirus infection to a malignant lesion for lifestyle-related reasons (promiscuity, smoking, use of contraceptive hormones, and dietary deficiencies). We conclude that alcoholic women are at high risk for in situ and invasive cervical cancer and for cancer of the vagina.

Smoking cessation in cancer prevention.

Tobacco smoking is the largest preventable risk factor for morbidity and mortality in industrialized countries. WHO estimates that tobacco will become the largest single health problem by 2020, causing an estimated 8.4 million deaths annually. Tobacco has central importance in the etiology of cancers of the lung, head and neck, urinary tract, and pancreas. Reducing the number of young people who take up smoking and helping those who have started to smoke to quit the habit are the key ways of preventing these cancers. Tobacco- or nicotine-dependence is a common, chronic, relapsing medical condition. Studies of twins have implicated genetic factors in most of the differences in vulnerability to tobacco smoke and in the persistence of the smoking phenotype. The available interventions for reducing tobacco use and treatment for nicotine dependence offer public health officials and clinicians the greatest single opportunity for disease prevention. Five medications -- nicotine chewing gum, nicotine patches, nicotine inhalers, nicotine nasal sprays and bupropion -- and behavioural therapy appear to be both effective and safe: they double the quitting rates and are associated with a dropout rate due to adverse events of less than 5%.

Exposure to 2,4- and 2,6-toluene diisocyanate (TDI) during production of flexible foam: determination of airborne TDI and urinary 2,4- and 2,6-toluenediamine (TDA).

Occupational exposure to 2,4- and 2,6-toluene diisocyanate (2,4- and 2,6-TDI) was measured during the production of flexible foam. The usefulness of urinalysis of the TDI-derived amines, 2,4- and 2,6-toluenediamine (2,4- and 2,6-TDA), for exposure assessment was compared with air monitoring. Urine samples were collected from 17 employees at two plants. The workers' personal exposure was measured using 1-(2-methoxyphenyl)-piperazine (2MP)-impregnated glass fibre filters for sampling and high-performance liquid chromatography (HPLC) with ultraviolet (UV) and electrochemical (EC) detection for quantification. The limit of detection (LOD) of 2,4- and 2,6-TDI was 0.01 microtg ml(-1) for a 20 microl injection. The precision of sample preparation, expressed as the relative standard deviation (RSD), was 0.6% with UV detection and 0.8% with EC detection at a 2,4-TDI concentration of 0.2 microg ml(-1) (n = 6). For 2,6-TDI, the corresponding RSDs were 0.5% and 0.8%. The urinary 2,4- and 2,6-TDA metabolites were determined after acid hydrolysis as heptafluorobutyric anhydride derivatives by gas chromatography-mass spectrometry. The LOD in urine was 0.35 nmol l(-1) for 2,4-TDA and 0.04 nmol l(-1) for 2,6-TDA. The precision (RSD) of six analyses of human urine spiked to a concentration of 100 nmol l(-1) was 3.7% for 2,4-TDA and 3.6% for 2,6-TDA. There was a trend for linear correlation between urinary TDA concentration and the product of airborne TDI concentration and sampling time. Urinalysis of TDA is proposed as a practical method for assessing personal exposures in workers exposed intermittently to TDI.

Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure.

Diisocyanates are the most common low molecular weight chemicals to cause occupational asthma. However, only some 5-10% of exposed workers develop asthma, which suggests an underlying genetic susceptibility. Diisocyanates and their metabolites may be conjugated with glutathione by glutathione S-transferases (GSTs). We examined whether polymorphisms in the GSTM1, GSTM3, GSTP1 and GSTT1 genes modify allergic responses to diisocyanate exposure. The study population consisted of 182 diisocyanate exposed workers, 109 diagnosed with diisocyanate-induced asthma and 73 without asthma. Lack of the GSTM1 gene (null genotype) was associated with a 1.89-fold risk of diisocyanate-induced asthma [95% confidence interval (CI) 1.01-3.52]. Moreover, among the asthma patients, the GSTM1 null genotype was associated with lack of diisocyanate-specific immunoglobulin (Ig)E antibodies [odds ratio (OR) 0.18, 95% CI 0.05-0.61] and with late reaction in the specific bronchial provocation test (OR 2.82, 95% CI 1.15-6.88). Similarly, GSTM3 AA genotype was related to late reaction in the specific bronchial provocation test (OR 3.75, 95% CI 1.26-11.2). The GSTP1 Val/Val genotype, on the other hand, was related to high total IgE levels (OR 5.46, 95% CI 1.15-26.0). The most remarkable effect was seen for the combination of GSTM1 null and the GSTM3 AA genotype which was strongly associated with lack of diisocyanate-specific IgE antibodies (OR 0.09, 95% CI 0.01-0.73) and with late reaction in the bronchial provocation test (OR 11.0, 95% CI 2.19-55.3). The results suggest, for the first time, that the polymorphic GSTs, especially the mu class GSTs, play an important role in inception of ill effects related to occupational exposure to diisocyanates.

Occupational exposures and cancers of the endometrium and cervix uteri in Finland.

BACKGROUND: Endometrial cancer incidence rates are low in Asia and Africa and high in North America and Northern Europe. Cervical cancer is often the most common female cancer in developing countries, and infection with human papillomavirus (HPV) is its main risk factor. However, other factors, such as occupational exposures may modify the HPV-related risk. We conducted an exploratory register-linkage study in Finland to assess the role of occupational exposures on incidence rates of cancers of the endometrium and cervix uteri. METHODS: Occupational risk factors for endometrial and cervical cancers were explored in a 25-year follow-up of female workers born 1906-1945 (N = 413,877) identified through the Population Census of Finland of 1970. Job titles in census records were converted to exposures of 31 occupational agents through a job-exposure matrix. Poisson regression models estimated relative risks (RR) for each agent, standardized for birth cohort, follow-up period, and socio-economic status. For each agent, the product of level and probability of exposure was calculated and subdivided in three categories: zero, low, and medium/high. Adjustment at the job title level was done for the turnover rate (endometrial and cervical cancers), mean parity, and age at first birth (endometrial cancer). RESULTS: Endometrial cancer (2,833 cases) was associated with exposure to animal dust (RR 1.2, low level, 174 cases) and sedentary work (RR 1.3, high level, 145 cases). Cervical cancer (1,101 cases) was associated with exposure to aliphatic and alicyclic (RR 1.3, low level, 91 cases), aromatic (RR 1.2, low level, 318 cases; RR 1.4, high level, 41 cases), and chlorinated hydrocarbon solvents (RR 1.3, low level, 50 cases), silica dust (RR 1.2, low level, 251 cases), and wood dust (RR 1.2, low level, 249 cases). CONCLUSIONS: This study suggests that occupational exposures may be associated with increased risk of endometrial and cervical cancers.

Polymorphic catechol-O-methyltransferase gene and breast cancer risk.

We examined 483 Finnish breast cancer cases and 482 population controls to determine the potential effect of catechol-O-methyltransferase (COMT) genotype in individual susceptibility to breast cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for breast cancer. When studied separately by menopausal status, the COMT-L allele-containing genotypes were inversely associated with premenopausal breast cancer, especially with advanced stage of the disease (OR, 0.44; 95% CI, 0.22-0.87). Among postmenopausal women a similar decreased risk was seen for local carcinoma associated with the COMT-LL genotype (OR, 0.55; 95% CI, 0.31-0.98). The lowest breast cancer risk was seen in the postmenopausal women with the COMT-LL genotype and low body-mass index (30 months) use of estrogen (OR, 4.02; 95% CI, 1.13-14.3), or with the COMT-L allele-containing genotypes and early age (

Alcoholism and risk for endometrial cancer.

Endogenous estrogens increase the risk of endometrial cancer and are also elevated among women with high alcoholic intake. It is incompletely known, however, whether alcohol intake in general and alcohol abuse in particular increases risk for endometrial cancer. We thus analyzed prospectively the risk for endometrial cancer among 36,856 women hospitalized with alcoholism between 1965 and 1994 through linkages between several national Swedish registers. Compared with the general population, women who were alcoholics had an overall 24% lower risk of developing endometrial cancer, a finding challenging our a priori hypothesis. However, among women below the age of 50 years at follow-up, the mean age of menopause among Swedish women, the risk was 70% higher, whereas the risk among women aged 50 years or more at follow-up was 40% lower compared with the general population. Hence, the effect of alcoholism on endometrial cancer appears to be age dependent.