Treating the Disease, Not the Symptom: Beyond NSAIDs.

Mitigating inflammation is clearly important in cancer prevention and control. Traditionally, pharmaceuticals have taken the lead in this problem. In an attempt to 'head them off at the pass', this Forum takes a hard look at the concept of 'better living through chemicals' and limiting proinflammatory chemicals entering the body.

Systematic review: the etiology of esophageal squamous cell carcinoma in low-income settings.

INTRODUCTION: Esophageal carcinoma causes over 380 000 deaths per year, ranking sixth worldwide in mortality amongst all malignancies. Globally, the squamous cell subtype is most common and accounts for 80% of esophageal cancers. Nonetheless, esophageal squamous cell carcinoma is much more poorly understood than esophageal adenocarcinoma, including what is driving such high prevalences, why it often presents in young patients, and shows such marked geographical delineations Areas covered: The current literature was searched for articles focusing on aetiopathogenesis of squamous cell esophageal carcinoma via a systematic review, particularly in low-resource settings. This was supplemented by papers of interest known to the authors. Expert commentary: Current putative mechanisms include polycyclic aromatic hydrocarbons, nitrosamines, acetaldehyde, cyclo-oxygenase-2 pathways, androgen and their receptor levels, as well as smoking & alcohol, micronutrient deficiencies and diet, mycotoxins, thermal damage, oral hygiene and microbiotal factors, inhaled smoke, viral infections such as HPV, and chronic irritative states. Etiology is likely multifactorial and varies geographically. Though smoking and alcohol play a predominant role in high-income settings, there is strong evidence that mycotoxins, diet and temperature effects may play an under-recognized role in low and middle-income settings.

Discontinuity in the cancer slope factor as it passes from high to low exposure levels--arsenic in the BFD-endemic area.

BACKGROUND: The ingestion of inorganic arsenic causes bladder and lung cancers demonstrably at >400-500ug/L but questionably below 100-200ug/L. Using the standard 42-village cancer mortality dataset from the Blackfoot-disease (BFD) endemic area of southwest Taiwan (Wu et al., 1989), we examined the risk from low exposures by excluding the high exposures. METHOD: Poisson regression analyses with the sequential removal of the highest exposure village have been performed using the median, mean, or maximum village well water arsenic level and demonstrated graphically. RESULTS: Risk estimates are positive when villages with exposures of 200-400ug/L are included and significantly so when villages with >400ug/L are included. Risk estimates for exposures below 100ug/L are negative but rarely significantly so. The inflection point where the slope is no longer positive occurs in the range of 100-200ug/L, depending upon whether the exposure metric used is the median, the mean or the maximum. CONCLUSION: There is a discontinuity in the cancer slope factor or risk from arsenic exposure that occurs in the range of 100-200ug/L. Above these levels, there are significantly positive risks, while below these levels there are not. The analysis reveals within this dataset an intrinsic non-linearity in the cancer risk. The literature speaks to this discontinuity, but this is the first demonstration within a single dataset that shows the discontinuity across the full exposure range and where the low-dose data are not compromised with high-dose data.

Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin.

More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk-Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk-Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive agents, such as curcumin, effective in suppressing TCC-induced cellular pre-malignancy.

Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy.

Chinese herbs nephropathy (CHN) and Balkan endemic nephropathy (BEN) are chronic tubulointerstitial renal diseases associated with urothelial carcinoma. The clinical expression and pathological lesions observed at different stages of CHN and BEN are strikingly similar. Both have been linked to exposure to aristolochic acid (AA), a powerful nephrotoxin and human carcinogen. Jelakovic et al. present molecular epidemiological evidence relating urothelial carcinoma in patients with BEN to dietary exposure to AA. It is time to abandon the terms 'CHN' and 'BEN' and introduce 'aristolochic acid nephropathy' to cover both clinical conditions.

[Results of study concerning possible influence of rocket space activities on public health].

Using special medical examination results and specified criteria of objective evaluation, the authors summarized results of studies concerning health state of population dwelling in area possibly influenced by rocket space activities factors.

Environmental exposure to emissions from petrochemical sites and lung cancer: the lower Mississippi interagency cancer study.

To investigate potential links between environmental exposure to petrochemical plant emissions and lung cancer, a population-based case-control study (LMRICS) was conducted in eleven Louisiana parishes bordering the Mississippi River. Cases and age, gender, and race-matched controls were interviewed regarding potential risk factors. Residential history was geocoded to provide indices of long-term proximity to industrial sites. Cases were more likely to have lived near a petrochemical site. Models adjusted for other risk factors, however, showed small or no association with lung cancer (odds ratio for residence within a half-mile of a site = 1.10, 95% confidence interval 0.58-2.08). While associations were strongest for exposures exceeding 15 years, none approached statistical significance and there was no clear dose-response across exposure duration, distance categories, or when sites were grouped according to carcinogenicity rating of chemical releases. Residential proximity to petrochemical plants along the lower Mississippi thus showed no significant association with lung cancer.

Expert assessment of exposure to carcinogens in Norway's offshore petroleum industry.

This study presents and evaluates an expert group's assessment of exposure to carcinogens for defined job categories in Norway's offshore petroleum industry, 1970-2005, to provide exposure information for a planned cohort study on cancer. Three university and five industry experts in occupational hygiene individually assessed the likelihood of exposure to 1836 combinations of carcinogens (n=17), job categories (n=27) and time periods (n=4). In subsequent plenary discussions, the experts agreed on exposed combinations. Agreement between the individual and the panel assessments was calculated by Cohen's kappa index. Using the panel assessment as reference, sensitivity and specificity were estimated. The eight experts assessed 63% of the 1836 combinations in plenary, resulting in 265 (14%) convened exposed combinations. Chlorinated hydrocarbons, benzene and inhalation of mineral oils had the highest number of exposed job categories (n=14, 9 and 10, respectively). The job categories classified as exposed to the highest numbers of carcinogens were the mechanics (n=10), derrick workers (n=6) and process technicians (n=5). The agreement between the experts' individual assessments and the panel assessment was kappa=0.53-0.74. The sensitivity was 0.55-0.86 and specificity 0.91-0.97. For these parameters, there were no apparent differences between the university experts and the industry experts. The resulting 265 of 1836 possible exposure combinations convened as "exposed" by expert assessment is presented in this study. The experts' individual ratings highly agreed with the succeeding panel assessment. Correlation was found between years of experience of the raters and agreement with the panel. The university experts and the industry experts' assessments had no apparent differences. Further validation of the exposure assessment is suggested, such as by new sampling data or observational studies.

[Uranium exposure and cancer risk: a review of epidemiological studies]. / Exposition à l'uranium et risque de cancer: une revue des études épidémiologiques.

OBJECTIVE: At the end of 2000, certain diseases including leukemia were reported among soldiers who participated in the Balkan and in the Gulf wars. Depleted uranium used during these conflicts was considered as a possible cause. Its radiotoxicity is close to that of natural uranium. This paper reviews the epidemiological knowledge of uranium, the means of exposure and the associated risk of cancer. METHODS: The only available epidemiological data concerns nuclear workers exposed to uranium. A review of the international literature is proposed by distinguishing between uranium miners and other workers of the nuclear industry. French studies are described in details. RESULTS: In ionizing radiation epidemiology, contamination by uranium is often cited as a risk factor, but the dose-effect relationship is rarely studied. Retrospective assessment of individual exposure is generally insufficient. Moreover, it is difficult to distinguish between uranium radiotoxicity, its chemical toxicity and the radiotoxicity of its progeny. A causal relation between lung cancer and radon exposure, a gas derived from the decay of uranium, has been demonstrated in epidemiological studies of miners. Among other nuclear workers exposed to uranium, there is a mortality deficit from all causes (healthy worker effect). No cancer site appears systematically in excess compared to the national population; very few studies describe a dose-response relationship. CONCLUSION: Only studies with a precise reconstruction of doses and sufficient numbers of workers will allow a better assessment of risks associated with uranium exposure at levels encountered in industry or during conflicts using depleted uranium weapons.

[Examination of nickel and chromium contents in selected herbs, herbal fruit teas and their infusions]. / Badanie zawartosci niklu i chromu w wybranych ziolach, herbatkach ziolowo-owocowych oraz w ich naparach.

The aim of this study was to determine the contents of nickel and chromium (the trace elements that are necessary for the human organism only in specified amounts) in selected dry herbs, herbal-fruit teas and their water extracts. This examination was expected to answer the question whether infusions or decoctions may constitute the additional source of these elements, or whether the amounts of nickel and chromium included in them may be dangerous for the human organism. The samples were dry mineralized at the temperature of 450 degrees C. Atomic absorption spectrometry (AAS) was performed using SOLAAR M5 appliance produced by a US-based Thermo Elemental company; nickel contents were determined from the organic phase, and chromium directly from the mineralisate. Nickel contents ranged on average from 0.56 microg/g to 2.68 microg/g in herbs and from 0.99 microg/g to 1.70 microg/g in herbal fruit teas. On average 40.0% to 82.5% of the amount present in dry, raw material passed into the infusions. The determined amounts of chromium ranged from 0.57 microg/g to 1.36 microg/g in herbs, and from 0.47 microg/g to 1.17 microg/g in herbal fruit teas (average values). The maximum extraction of this element into the infusion or decoction equaled 85.0%. The contents of nickel and chromium in the examined dry herb samples were comparable to results obtained by authors of the other papers. Infusions or decoctions of the examined herbs and herbal fruit teas contain the amounts of these elements that do not harm health and may constitute an additional source of nickel and chromium for the human organism.

Oxidative-stress markers in blood of lung cancer patients occupationally exposed to carcinogens.

The study covered 152 lung cancer patients and 210 controls. The results of the study indicated decreased selenium (Se) concentrations and lowered activity of erythrocyte antioxidant enzymes (glutathione peroxidase, superoxide dismutase, glutathione-S-transferase) in the blood of lung cancer patients, as well as significantly increased concentrations of vitamin E in erythrocytes and thiobarbituric acid reactive substances in the plasma of the study population. Low plasma Se concentrations (< 45.7 microg/L) enhance the estimated risk of lung cancer (odds ratio = 3.047, p < 0.001). A more precise exposure assessment is required to identify the association between lung cancer incidence and occupational exposure to carcinogens.

[Life expectancy in the Plock area caused by lymphatic and erythrocyte line leukemia]. / Deficyt zycia z powodu nowotworów zlosliwych tkanki limfatycznej i krwiotwórczej w rejonie Plocka.

Among all specific environmental pollution the chemical compounds released in the oil refine process seem to hold the biggest interest. At Medical University of Warsaw we have been studying the influence of the Plock petroleum refinery plant pollution to citizens' health status for over 30 years. The high amount of hydrocarbons--including benzene--were presented in emission. One of the study objectives was to analyze death causes in Plock and Kutno and in the Plock area--according to environmental criteria. The population of the non-petrochemic polluted city Kutno was chosen as the control group. The previous analysis in 1984-1993 showed increased lymphatic or erythrocyte line leukaemia mortality in Plock population vs Kutno population. Similar situation was observed between the area of increased environmental petrochemical pollution and non-polluted area. In this article the Potential Years of Life Lost ratio was used to estimate the life deficiency as the measure of health needs due to mentioned neoplasms. Data indicate that the health needs are bigger than the mortality analysis has shown.

Breast cancer: dietary and environmental oestrogens.

Breast cancer is among the most common of the cancers that occur in women living in western societies. It is a much-feared disease and the risks are confusing and often badly reported. Oestrogen levels are a known risk factor. But is it possible to lower the risk? And where are all the oestrogens coming from?

Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China.

Arsenic is an environmental toxicant and a human carcinogen. Epidemiology studies link human arsenic exposure to various diseases and cancers, including liver diseases and hepatocellular carcinoma. However, the molecular mechanisms for arsenic toxicity and carcinogenicity are poorly understood. To better understand these mechanisms, we used the human cancer cDNA expression array to profile aberrant gene expression in arsenic-exposed populations in Guizhou, China. The selected patients had a history of exposure to environmental arsenic for at least 6-10 years, and had arsenic-induced skin lesions and hepatomegaly. Samples were obtained by liver needle biopsy. Histology showed degenerative liver lesions, such as chronic inflammation, vacuolation, and focal necrosis. The University of North Carolina Hospitals provided normal human liver tissues from surgical resection or rejected transplants. Microarray was performed with total RNA from liver samples, and signal intensities were analyzed with AtlasImage software and normalized with 9 housekeeping genes. Means and SEM were calculated for statistical analysis. Approximately 60 genes (10%) were differentially expressed in arsenic-exposed human livers compared to controls. The differentially expressed genes included those involved in cell-cycle regulation, apoptosis, DNA damage response, and intermediate filaments. The observed gene alterations appear to be reflective of hepatic degenerative lesions seen in the arsenic-exposed patients. This array analysis revealed important patterns of aberrant gene expression occurring with arsenic exposure in human livers. Aberrant expressions of several genes were consistent with the results of array analysis of chronic arsenic-exposed mouse livers and chronic arsenic-transformed rat liver cells. Clearly, a variety of gene expression changes may play an integral role in arsenic hepatotoxicity and possibly carcinogenesis.

Using splines to analyse latency in the Colorado Plateau uranium miners cohort.

BACKGROUND: Different approaches have been proposed to investigate latency in epidemiologic studies where detailed exposure histories are available. METHODS: We demonstrate the application of a flexible, yet parsimonious, spline function model to investigate latency patterns for radon progeny exposure and lung cancer in the Colorado Plateau uranium miners cohort. The model extends a previously proposed bilinear model. RESULTS: The excess relative risk (ERR) reached a maximum of 0.6 per 100 working level months, for exposures received 14 years previously. The ERR then declined, and was estimated to approach zero for exposures received 35 years and more in the past. The point-wise 95% confidence intervals supported ERRs > 0 for the period 9-32 years before the event. The estimated latency curve was homogeneous across categories of attained age, duration of exposure, rate of exposure, and smoking. CONCLUSIONS: The proposed spline model is a flexible tool for latency analyses, and extends previously used methods.

Histopathologic findings of lung carcinoma in German uranium miners.

BACKGROUND: This study evaluates the histopathology of lung carcinoma in relation to underground radon exposure. METHODS: Two hundred forty uranium miners of the former Wismut Company in Eastern Germany with histologically or cytologically confirmed primary lung carcinoma were recruited from 3 study clinics between 1991 and 1995. Information on smoking history was obtained by personal interviews, whereas job histories were derived from original payrolls provided by the Wismut Company. Quantitative estimates of occupational radon exposure were based on a job-exposure matrix. RESULTS: Squamous cell carcinoma (SqCC) was the predominant cell type (43%), followed by adenocarcinoma (AC; 26%), small cell lung carcinoma (SCLC; 23%), and other cell types (8%). Nearly all patients were smokers. Time since first occupational exposure was 42 years on average, the mean cumulative radon exposure 506 working level months. Adenocarcinoma appeared to be more likely than both SCLC and SqCC among miners with low cumulative radiation exposure, long time since first exposure, an older age at diagnosis, and among ex- and never-smokers. In current smokers, lung carcinomas developed at a much lower level of radiation exposure than in ex- and never-smokers. The increase in the relative frequency of SCLC and SqCC at the expense of AC with increasing cumulative radiation exposure was more pronounced among ex- and never-smokers and seemed to be masked among current smokers. CONCLUSION: The authors' data suggest that all cell types were associated with radon exposure, but high radiation exposure tended to increase the proportion of SCLC and SqCC.

Chemoprevention of lung cancer.

Chemoprevention is defined as the use of specific natural or pharmacologic agents to reverse, suppress, or prevent the carcinogenic process to the development of invasive cancer. The basic idea behind lung cancer chemoprevention is the concept that diffuse injury of the respiratory epithelium results from chronic carcinogen exposure. The rationale for chemoprevention arose from epidemiologic data demonstrating the existence of dietary inhibitors of carcinogenesis, basic studies of epithelial carcinogenesis, and laboratory evidence from animal models. Many of the studies evaluating specific agents focused on vitamin A and its synthetic analogs, the retinoids. Chemoprevention trials have investigated the effect of retinoids and other agents on bronchial metaplasia and dysplasia and sputum atypia; many of these trials have reported conflicting results. Several ongoing multi-institutional trials are evaluating chemoprevention regimens for prevention of second primary aerodigestive tract cancers, the results of which are eagerly awaited. Primary prevention trials to prevent lung cancer have reported sobering results, which negate the protective effects of beta-carotene against lung cancer development and provide no justification for consuming supplemental beta-carotene for cancer chemoprevention. In the future, the use of biomolecular markers as intermediate end points in chemoprevention trials may reduce the cost and time commitment required for these trials and aid in selecting a patient population that would benefit most from chemopreventive intervention or approaches such as gene therapy.

Latency analysis in epidemiologic studies of occupational exposures: application to the Colorado Plateau uranium miners cohort.

BACKGROUND: Latency effects are an important factor in assessing the public health implications of an occupational or environmental exposure. Usually, however, latency results as described in the literature are insufficient to answer public health related questions. Alternative approaches to the analysis of latency effects are warranted. METHODS: A general statistical framework for modeling latency effects is described. We then propose bilinear and exponential decay latency models for analyzing latency effects as they have parameters that address questions of public health interest. Methods are described for fitting these models to cohort or case-control data; statistical inference is based on standard likelihood methods. APPLICATION: A latency analysis of radon exposure and lung cancer in the Colorado Plateau uranium miners cohort was performed. We first analyzed the entire cohort and found that the relative risk associated with exposure increases for about 8.5 years and thereafter decreases until it reaches background levels after about 34 years. The hypothesis that the relative risk remains at its peak level is strongly rejected (P < 0.001). Next, we investigated the variation in the latency effects over subsets of the cohort based on attained age, level and rate of exposure, and smoking. Age was the only factor for which effect modification was demonstrated (P = 0.014). We found that the decline in effect is much steeper at older ages (60+ years) than younger. CONCLUSION: The proposed methods can provide much more information about the exposure-disease latency effects than those generally used.