Diet and bladder cancer: a meta-analysis of six dietary variables
Steinmaus, C, Nuņez S, Smith AH.
Am J Epidemiol, 2000 Apr 1;151(7):693-702.

In 1996, more than 300,000 new cases of bladder cancer were diagnosed worldwide. Besides tobacco smoking, occupation, and other factors, diet may play a role in causation of this illness. The performed a meta-analytical review of epidemiologic studies linking six dietary factors to bladder cancer. These factors include retinol, beta-carotene, fruits, vegetables, meat, and fat. Increased risks of bladder cancer were associated with diets low fruit intake (relative risk (RR) = 1.40, 95% confidence interval (CI): 1.08, 1.83), and slightly increased risks were associated with diets low in vegetable intake (RR = 1.16, 95% CI: 1.01, 1.34). Elevated risks were identified for diets high in fat intake (RR = 1.37, 95% CI: 1.16, 1.62) but not for diets high in meat intake (RR = 1.08, 95% CI: 0.82, 1.42). No increased risks were found for diets low in retinol (RR = 1.10, 95% CI: 0.83, 1.23) or beta- carotene (RR = 1.10, 95% CI: 0.93, 1.30) intake. These results suggest that a diet high in fruits and vegetables and low in fat intake may help prevent bladder cancer, but the individual dietary constituents that reduce the risks remain unknown.


Validation of fluorescent SSCP analysis for sensitive detection of p53 mutations
Moore LE, Godfrey T, Eng C, Smith AH, Ho R, Waldman FM.
Biotechniques, 2000 28:986-92.

We have developed a fluorescence-based single strand conformation polymorphism (SSCP) method that offers fast and sensitive screening for mutations in exons 5-8 of the human p53 gene. The method uses an ABI 377 DNA sequencer for unique color detection of each strand, plus accurate alignment of lanes for better detection of mobility shifts. To validate the method, 21 cell lines with reported mutations in p53 exons 5-8 were analyzed by SSCP using various gel conditions. The sensitivity for mutation detection was 95% for all cell lines studied, and no false positives were seen in 10 normal DNA samples for all four exons. Experiments mixing known amounts of tumor and normal DNA showed that mutations were detected even when tumor DNA was mixed with 80% normal DNA. Fluorescent SSCP analysis using the ABI sequencer is a useful tool in cancer research, where screening large numbers of samples for p53 mutations is desired.


Cancer risks from arsenic in drinking water: implications for drinking water standards
Smith AH, Biggs ML, Moore LE, Haque R, Steinmaus C, Chung J, Hernandez AL, Lopipero P.
Arsenic esposure and health effects: proceedings of the Third International Conference on Arsenic Exposure and Health Effects, July 12-15, 1998, San Diego, California. Oxford: Elsevier Science, Ltd., pp. 191-99, 1999.

The current drinking water standard for arsenic in the U.S. and much of the world is 50 ug/L. The WHO has recommended lowering permissible concentrations to 10 ug/L, and the U.S. EPA to 2 ug/L, in each case based on extrapolation of skin cancer risks from a population in Taiwan with high levels of arsenic in their drinking water. Evidence from studies in Taiwan, Argentina and Chile is presented in this paper to show that, more important than skin cancer which is usually non-fatal, ingestion of inorganic arsenic in drinking water is also a cause of several internal cancers. For lifetime consumption of inorganic arsenic in drinking water containing around 500 ug/L, it is estimated that on the order of 10% of all deaths in adults would be attributable to ingestion of arsenic, mainly as a consequence of lung and bladder cancer. This extremely high cancer mortality risk estimate is based primarily on investigations in Region II of Chile, but is also supported by studies of other exposed populations, particularly Taiwan.

Linear risk extrapolation from 500 ug/L to lifetime consumption of water with an arsenic concentration of 50 ug/L, the current drinking water standard, results in cancer mortality risk estimates reduced by a factor of ten to around 1 in 100 adult deaths being attributable to arsenic. Consideration is given to evidence for possible sub-linearity in the dose-response relationship which would make this estimate excessively high. The evidence is mixed, but neither human epidemiological studies, nor consideration of potential carcinogenic mechanisms, give assurance that the dose-response relationship would be significantly sub-linear in the dose range resulting from consumption of water between 50 and 500 ug/L arsenic in water. Even if marked sub-linearity were present, and risks at 50 ug/L were ten times lower than predicted from linear extrapolation, risk estimates would still be roughly of the order of 1 in 1000 persons dying due to arsenic in drinking water.

Since such high cancer risks are unacceptable by any yardstick, it might be thought that the drinking water standard should be drastically reduced, even to lower concentrations than the 2 ug/L suggested by the U.S. EPA However natural food sources become the predominant source of inorganic arsenic ingestion once water arsenic concentrations are reduced to about 10 ug/L and below. Because such food sources cannot be altered, the WHO recommendation of a standard of 10 ug/L seems more reasonable than 2 ug/L, even though it was not derived with food sources in mind. It is concluded that although much more research on arsenic is needed, the need for such research should not be used as an excuse to delay implementation of an inorganic arsenic drinking water standard considerably lower than the current 50 ug/L.


Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water
Smith AH, Goycolea M, Haque R, Biggs ML.
Am J Epidemiol, 1998 Apr 1;147(7):660-9.

Studies in Taiwan and Argentina suggest that ingestion of inorganic arsenic from drinking water results in increased risks of internal cancers, particularly bladder and lung cancer. The authors investigated cancer mortality in a population of around 400,000 people in a region of Northern Chile (Region II) exposed to high arsenic levels in drinking water in past years. Arsenic concentrations from 1950 to the present were obtained. Population-weighted average arsenic levels reached 570 microg/liter between 1955 to 1969, and decreased to less than 100 microg/liter by 1980. Standardized mortality ratios (SMRs) were calculated for the years 1989 to 1993. Increased mortality was found for bladder, lung, kidney, and skin cancer. Bladder cancer mortality was markedly elevated (men, SMR = 6.0 (95% confidence interval (CI) 4.8-7.4); women, SMR = 8.2 (95% CI 6.3-10.5)) as was lung cancer mortality (men, SMR = 3.8 (95% CI 3.5-4.1); women, SMR = 3.1 (95% CI 2.7-3.7)). Smoking survey data and mortality rates from chronic obstructive pulmonary disease provided evidence that smoking did not contribute to the increased mortality from these cancers. The findings provide additional evidence that ingestion of inorganic arsenic in drinking water is indeed a cause of bladder and lung cancer. It was estimated that arsenic might account for 7% of all deaths among those aged 30 years and over. If so, the impact of arsenic on the population mortality in Region II of Chile is greater than that reported anywhere to date from environmental exposure to a carcinogen in a major population.


Diesel exhaust exposure and lung cancer
Bhatia R, Lopipero P, Smith AH.
Epidemiology, 1998 Jan;9(1):84-91.

We evaluated the relation between occupational exposure to diesel exhaust and cancer of the lung in a meta-analysis of 29 published cohort and case-control studies. Twenty-one of the 23 studies meeting the inclusion criteria had observed relative risk estimates greater than one. Pooled effect measures weighted by study precision indicated an increased relative risk (RR) for lung cancer from occupational exposure to diesel exhaust [RR = 1.33; 95% confidence interval (CI) = 1.24-1.44]. Subanalysis of case-control (RR = 1.33; 95% CI = 1.18-1.51) vs cohort studies (RR = 1.33; 95% CI = 1.21-1.47) and of studies that controlled for smoking (RR = 1.35; 95% CI = 1.20-1.52) vs those that did not (RR = 1.33; 95% CI = 1.20-1.47) produced results that did not differ from those of the overall analysis. On the other hand, cohort studies using internal comparisons (RR = 1.43; 95% CI = 1.29-1.58) showed higher relative risks than those using external comparisons (RR = 1.22; 95% CI = 1.04-1.44). Heterogeneity between studies was reduced when we stratified studies by the occupational setting in which exposure occurred. A positive duration-response relation was evident in those studies that were stratified by employment duration. This meta-analysis supports a causal association between increased risks for lung cancer and exposure to diesel exhaust.



Meta-analysis and Risk Assessment
Wright C, Lopipero P, Smith AH.
Topics in Environmental Epidemiology Eds. Steenland K and Savitz DA: Oxford University Press, 1996.

Although arsenic is not discussed in this chapter, it is pertinent here because it includes issues and methods concerning the use of epidemiologic studies to estimate population risks at low levels of exposure. It was noted that apparent nonlinearity at low exposure points in studies can be fitted with statistical models that have a profound impact on risk extrapolations to lower doses. However, the empirical evidence for nonlinearity may be extremely weak, and there are often no good biological reasons for rejecting linearity. For these and other reasons, we stated that it would be preferable to use the linear relative risk model for quantitative risk assessment using epidemiologic data, unless there are good reasons to reject it (i.e. clear evidence of nonlinearity).



Decrease In Bladder Cell Micronucleus Prevalence After Intervention To Lower The Concentration Of Arsenic In Drinking Water
Moore, LE, Smith AH, Hopenhayn-Rich C, Biggs ML, Kalman DA, Smith MT.
Cancer Epidemiol Biomarkers & Prev, 1997 Dec;6(12):1051-6.

Water low in arsenic content (45 ug/L) was provided to 34 highly exposed participants in the cross-sectional study in Chile (publication 21 above). Mean urinary arsenic levels in this sub-group decreased from 742 to 225 ug/L during the intervention. Bladder cell micronucleus (MNC) prevalence decreased from 2.63/1000 to 1.79/1000 cells post-intervention (p<0.05). When the analysis was limited to individuals previously having subcytotoxic urinary arsenic levels (<700 ug/L), the change between pre- and post-intervention MNC was more pronounced: from 3.54 to 1.47/100 cells respectively (p=0.002). The primary changes occurred among smokers, suggesting that smoker's bladder cells could be more susceptible to genotoxic damage caused by arsenic. The reduction in bladder cell MNC prevalence with reduction in inorganic arsenic intake provides further evidence that arsenic is genotoxic to bladder cells.



Micronuclei In Exfoliated Bladder Cells Among Individuals Chronically Exposed To Arsenic In Drinking Water
Moore LE, Smith AH, Hopenhayn-Rich C, Biggs ML, Kalman DA, Smith MT.
Cancer Epidemiol Biom & Prev, 6: 31-6, 1997.

Using the same towns as the methylation study in Chile described in the previous publication summary, this cross-sectional study was confined to male participants in view of the extensive exfoliation of squamous cells as well as transitional bladder cells which occurs in females.

There were 70 high-exposure participants (average urinary arsenic 616 ug/L) and 55 low-exposure participants (average urinary arsenic 66 ug/L). The prevalence of micronuclei increased three-fold (95% CI 1.9-4.6) from the lowest exposure quintile (less than 53.8 ug/L arsenic in urine) to those in the second highest exposure quintile (414-729 ug/L urinary arsenic). Surprisingly, those in the highest exposure quintile (more than 729 ug/L urinary arsenic) did not have any increase in micronucleus prevalence. This finding is not fully explained, but could be due to cytostasis or cytotoxicity at these high exposure levels.

The centromeric probe classification of micronuclei suggested that chromosome breakage was the major cause of micronucleus formation. It is noteworthy that the prevalence of micronuclei in bladder cells was elevated even in the second to lowest quintile of exposure (urinary arsenic levels between 53.9 and 137.3 ug/L, prevalence ratio 2.1, 95% CI 1.4-3.4), which raises the possibility that arsenic has genotoxic effects on bladder cells at relatively low levels of exposure.


Relationship Of Urinary Arsenic To Intake Estimates And A Biomarker Of Effect, Bladder Cell Micronuclei
Biggs ML, Kalman DA, Moore LE, Hopenhayn-Rich C, Smith MT, Smith AH.
Mutat Res, 1997 Jun;386(3):185-95.

The primary purpose of this study was to investigate methods for ascertaining arsenic exposure for use in biomarker studies. The study population was the same as the population in the metabolism and bladder cell micronucleus study conducted in Chile. Exposures were assessed by an interviewer-administered questionnaire concerning volumes and sources of fluid intake. Urinary inorganic arsenic measurements including methylated species were measured in first-morning samples. Creatinine was measured to allow for adjustment for overly concentrated urine. As expected, creatinine adjusted urinary arsenic concentrations had a stronger relationship with the questionnaire-based estimates of arsenic intake than the unadjusted urinary concentrations. Interestingly, the unadjusted urinary arsenic measures had the stronger relationship with bladder cell micronucleus prevalence. This finding is plausible since the unadjusted urinary arsenic concentrations may better reflect target site dose to the bladder, which is exposed to the actual concentration of arsenic in urine.


Consideration of background exposures in the management of hazardous waste sites: a new approach to risk assessment
Smith AH, Sciortino S, Goeden H, Wright CC.
Risk Anal, 1996 Oct;16(5): 619-25.

The current approach to health risk assessment of toxic waste sites in the U.S. may lead to considerable expenditure of resources without any meaningful reduction in population exposure. Risk assessment methods used generally ignore background exposures and consider only incremental risk estimates for maximally exposed individuals. Such risk estimates do not address true public health risks to which background exposures also contribute. The purpose of this paper is to recommend a new approach to risk assessment and risk management concerning toxic waste sites. Under this new approach, which we have called public health risk assessment, chemical substances would be classified into a level of concern based on the potential health risks associated with typical national and regional background exposures. Site assessment would then be based on the level of concern for the particular pollutants involved and the potential contribution of site contaminants to typical background human exposures. While various problems can be foreseen with this approach, the key advantage is that resources would be allocated to reduce the most important sources of human exposure, and site remediation decisions could be simplified by focussing on exposure assessment rather than questionable risk extrapolations.


Chrysotile asbestos is the main cause of pleural mesothelioma
Smith AH, Wright CC.
Am J Ind Med, 1996 Sep;30(3): 252-66.

In contrast to amphibole forms of asbestos, chrysotile asbestos is often claimed to be only a minor cause of malignant pleural mesothelioma, a highly fatal cancer of the lining of the thoracic cavity. In this article we examine the evidence from animal and human studies that relates to this issue. Reported data do not support widely quoted views regarding the relative inertness of chrysotile fibers in mesothelioma causation. In fact, examination of all pertinent studies makes it clear that chrysotile asbestos is similar in potency to amphibole asbestos. Since asbestos is the major cause of mesothelioma, and chrysotile constitutes 95% of all asbestos use world wide, it can be concluded that chrysotile asbestos is the main cause of pleural mesothelioma in humans.


Use Of The Fluorescent Micronucleus Assay To Detect The Genotoxic Effects Of Radiation And Arsenic In Human Exfoliated Epithelial Cells
Moore L, Warner ML, Smith AH, Kalman D, Smith MT.
Environ and Molecular Mutagen, 1996;27(3):176-84.

A new rapid method was used, which involves fluorescent in situ hybridization (FISH) to determine the mechanism of micronucleus formation in epithelial tissues exposed to carcinogenic agents (as previously described in Titenko-Holland N, Moore LE, Smith MT. Measurement and characterization of micronuclei in exfoliated human cells by fluorescence in situ hybridization with a centromeric probe. Mutat Res 271:69-77, 1992.) The findings concerning micronuclei in exfoliated bladder cells obtained from arsenic-exposed subjects in Nevada suggested that arsenic may have both clastogenic and weak aneuploidogenic properties.


Elevated symptom prevalence associated with ventilation type in office buildings
Mendel MJ, Fisk WJ, Deddens JA, Seavey WG, Smith AH, Smith DF, Hodgson AT, Daisey JM, Goldman LR.
Epidemiology, 1996 Nov; 7:(6) 583-9.

The California Healthy Building Study was designed to assess relations between ventilation system type and office worker symptoms in a set of U.S. buildings selected without regard to worker complaints. Twelve public office buildings in northern California meeting specific eligibility criteria were studied in the summer of 1990: three naturally ventilated, three mechanically ventilated (without air conditioning), and six air-conditioned buildings. Questionnaire data were collected from 880 workers in selected spaces within the study buildings. We adjusted effect estimates for various ventilation types for personal, job, and work place factors using logistic regression, and alternatively, using a mixed effects model (SAS/GLIMMIX) to adjust for correlated responses within study spaces. Higher adjusted prevalences of most symptom outcomes were associated with both mechanical and air-conditioned ventilation, relative to natural. With a conservative adjustment for problem building status, the highest adjusted prevalence odds ratios from logistic regression models were for dry or itchy skin [mechanical: odds ratio (OR) = 6.0, 95% confidence interval (CI) = 1.6-22; air-conditioned: OR = 6.0, 95% CI = 1.7-21] and lower respiratory symptoms (mechanical: OR = 2.9, 95% CI = 0.7-11; air-conditioned: OR = 4.0, 95% CI = 1.1-15). GLIMMIX estimates were similar, with slightly wider confidence intervals. Reporting bias was small. These findings of symptom increases within mechanically ventilated and air-conditioned U.S. buildings support previous findings available only from European buildings.





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