CASE-CONTROL STUDY OF LUNG CANCER RISK FROM RESIDENTIAL RADON EXPOSURE IN WORCESTER COUNTY, MASSACHUSETTS.

Paper Health Physics. The Radiation Safety Journal. 94(3):228-241, March 2008.Thompson, Richard E. *; Nelson, Donald F. +; Popkin, Joel H. ++; Popkin, Zenaida ++
Abstract: mdash;: A study of lung cancer risk from residential radon exposure and its radioactive progeny was performed with 200 cases (58% male, 42% female) and 397 controls matched on age and sex, all from the same health maintenance organization. Emphasis was placed on accurate and extensive year-long dosimetry with etch-track detectors in conjunction with careful questioning about historic patterns of in-home mobility. Conditional logistic regression was used to model the outcome of cancer on radon exposure, while controlling for years of residency, smoking, education, income, and years of job exposure to known or potential carcinogens. Smoking was accounted for by nine categories: never smokers, four categories of current smokers, and four categories of former smokers. Radon exposure was divided into six categories (model 1) with break points at 25, 50, 75, 150, and 250 Bq m-3, the lowest being the reference. Surprisingly, the adjusted odds ratios (AORs) were, in order, 1.00, 0.53, 0.31, 0.47, 0.22, and 2.50 with the third category significantly below 1.0 (p < aor =" 0.30" p =" 0.005">

Long-Term Use of Supplemental Multivitamins, Vitamin C, Vitamin E, and Folate Does Not Reduce the Risk of Lung Cancer

Division of Pulmonary and Critical Care Medicine, and 2 Department of Epidemiology, University of Washington, Seattle, Washington; 3 Epidemiologic Research and Information Center, and 4 Health Services Research and Development, VA Puget Sound Health Care System, Seattle, Washington; 5 Departments of Epidemiology and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and 6 Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington
Correspondence and requests for reprints should be addressed to Christopher Slatore, M.D., University of Washington, Division of Pulmonary and Critical Care Medicine, 1959 NE Pacific Street, Box 356522, Seattle, WA 98195-6522. E-mail: cslatore@u.washington.edu
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Rationale: Lung cancer is the leading cause of cancer-related mortality in the United States. Although supplements are used by half the population, limited information is available about their specific effect on lung cancer risk.
Objectives: To explore the association of supplemental multivitamins, vitamin C, vitamin E, and folate with incident lung cancer.
Methods: Prospective cohort of 77,721 men and women aged 50–76 years from Washington State in the VITAL (VITamins And Lifestyle) study. Cases were identified through the Seattle–Puget Sound SEER (Surveillance, Epidemiology, and End Results) cancer registry.
Measurements and Main Results: Hazard ratios (HRs) for incident lung cancer according to 10-year average daily use of supplemental multivitamins, vitamin C, vitamin E, and folate. A total of 521 cases of lung cancer were identified. Adjusting for smoking, age, and sex, there was no inverse association with any supplement. Supplemental vitamin E was associated with a small increased risk of lung cancer (HR, 1.05 for every 100-mg/d increase in dose; 95% confidence interval [CI], 1.00–1.09; P = 0.033). This risk of supplemental vitamin E was largely confined to current smokers (HR, 1.11 for every 100-mg/d increase; 95% CI, 1.03–1.19; P < 0.01) and was greatest for non–small cell lung cancer (HR, 1.07 for every 100-mg/d increase; 95% CI, 1.02–1.12; P = 0.004).
Conclusions: Supplemental multivitamins, vitamin C, vitamin E, and folate were not associated with a decreased risk of lung cancer. Supplemental vitamin E was associated with a small increased risk. Patients should be counseled against using these supplements to prevent lung cancer.

Cigarette Smoking and Risk of Fatal Breast Cancer

From the Department of Epidemiology and Statistics, American Cancer Society Atlanta, GA
Reprint requests to Dr. Eugenia E. Calle, American Cancer Society, 1599 Clifton Road, NE, Atlanta, GA 30329
The authors examined the association of fatal breast cancer and cigarette smoking in a large, prospective mortality study of US adults. After 6 years of follow-up, 880 cases of fatal breast cancer were observed in a cohort of 604,412 women who were cancer-free at interview in 1982. Cox proportional hazards modeling, adjusted for other risk factors, found that current smoking was significantly related to fatal breast cancer risk (adjusted rate ratio (RR) = 1.26, 95% confidence interval (Cl) 1.05–1.50). A negative association was observed for former smokers, but this was not statistically significant (RR = 0.85, 95% Cl 0.70–1.03). The association of current smoking with fatal breast cancer risk increased with increasing numbers of cigarettes per day and with total number of years smoked. For smokers of 40 or more cigarettes per day, the rate ratio was 1.74 (95% Cl 1.15–2.62). The authors hypothesize that these results may be due to either a poorer prognosis among breast cancer cases who smoke or a delayed diagnosis among current smokers who do not receive mammograms as often as never or former smokers. Women who smoke should be targeted for breast cancer screening services.
breast neoplasms; cohort studies; risk; smoking; women
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Enviromental Tobacco Smoke and Lung Cancer Risk in Nonsmoking Women

Heather G. Stockwell*, Allan L. Goldman, Gary H. Lyman, Charles I. Noss, Adam W. Armstrong, Patricia A. Pinkham, Elizabeth C. Candelora, Marcia R. Brusa
Department of Epideminology and Biostatistics, University of South Florida Tampa, FlaDepartment of Internal Medcine, University of South Florida Tampa, FlaDepartment of Environmental and Occupational Health, College of Public Health University of South Florida Tampa, Fla
*Correspondence to: Heather G. Stockwell, Sc.D., Department of Epidemiolgy and Biostatistics, College of Public Health Unversity of south Florida, Tampa, FL 33612–3805.
Background: Exposure to envionmental tobacco smoke (passive smoking )has been suggested to be a cause of lung cancer, although early epidemiologic studies have produced in-consistent result. Purpose: We conducted an epidemilogic case-control study to assess the relation-ship between exposure to envirmental tobacco smoke and lungcancer risk among women who have never smoked (i.e., having smoked for a total of <6 n ="210)" n =" 301)" or =" 2.4;" ci =" 1.1–5.4).">

Skin Cancer in a Subtropical Australian Population: Incidence and Lack of Association with Occupation

Queensiand Institute of Medical Research Queensiand, Australia2Sunshine Coast sQueensiand, Australia3Sullivan and Nicolaldes Gold Coast, Queensiand, Australia
Reprint requests to Dr. Adele Green, Epidemiology Unit, Queensiand Institute of Medical Research, P.O. Royal Brisbane Hospital, Queensland 4029, Australia.
Because it is not possible to monitor skin cancer accurately using routine methods, special surveys have been undertaken in Nambour, a typical subtropical community in Queensland, Australia. Estimates of incidence reported here are based on skin cancers medically treated between 1985 and 1992 and new cases diagnosed by dermatologists in two examination clinics in 1986 and 1992. Among men and women aged 18–69 years in 1986, age-adjusted incidence rates of basal cell carcinoma were 2,074 and 1,579 per 100,000 per year, respectively—the highest incidence rates of a specific cancer ever reported. Squamous cell carcinoma occurred at half the rate of basal cell carcinoma among men and at about one third the rate among women. Although as expected, fair skin, a history of repeated sunburns, and nonmalignant solar skin damage diagnosed by dermatologists were strongly associated with both types of skin cancer, outdoor occupation was not. Significant self-selection was observed among outdoor workers, whereby people with fair or medium complexions and a tendency to sunburn were systematically underrepresented among those in long-term outdoor occupations although they accounted for more than 80 percent of the community study sample. The mitigating effect of this selection bias may partly explain the paradox of the lack of quantitative evidence of a causal link between sun exposure and skin cancer in humans. Am J Epidemiol 199

cause of cancer

Alcohol Consumption and All-Cause and Cancer Mortality among Middle-aged Japanese Men: Seven-year Follow-up of the JPHC Study Cohort I.
Original Contributions American Journal of Epidemiology. 150(11):1201-1207, December 1, 1999.Tsugane, Shoichiro 1; Fahey, Michael T. 1; Sasaki, Satoshi 1; Baba, Shunroku 2; for the JPHC Study Group *
Abstract: To examine the association between alcohol consumption and mortality in Japan, where mortality and lifestyle differ substantially from Western countries, a population-based prospective study was conducted in four public health center areas as part of the Japan Public Health Center-based prospective study on cancer and cardiovascular disease (JPHC). After excluding subjects with self-reported serious diseases at baseline, 19,231 men aged 40-59 years who reported their alcohol intake were followed from 1990 through 1996, and 548 deaths were documented. The association between all-cause mortality and alcohol consumption was J-shaped. The lowest risk was observed for men who consumed 1-149 g/week (relative risk (RR) = 0.64, 95% confidence interval (CI) 0.46, 0.88), while the highest risk was seen for men who consumed >=450 g/week (RR = 1.32, 95% CI 1.00, 1.74), after adjustment for possible confounders. The association did not change after excluding deaths that occurred in the first 2 years of follow-up. However, the association was modified by smoking, and beneficial effects of moderate drinking were largely limited to nonsmokers. The risk of cancer death showed a similar trend, but increased more in heavy drinkers. The background characteristics of moderate drinkers were healthier than either nondrinkers or heavy drinkers. The authors conclude that moderate alcohol consumption was associated with the lowest risks of all-cause and cancer mortality, especially among nonsmokers.
Copyright 1999 by The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland, USA. All rights reserved.

ABSTRACT

Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States in 2008. Notable trends in cancer incidence and mortality include stabilization of incidence rates for all cancer sites combined in men from 1995 through 2004 and in women from 1999 through 2004 and a continued decrease in the cancer death rate since 1990 in men and since 1991 in women. Overall cancer death rates in 2004 compared with 1990 in men and 1991 in women decreased by 18.4% and 10.5%, respectively, resulting in the avoidance of over a half million deaths from cancer during this time interval. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. Although much progress has been made in reducing mortality rates, stabilizing incidence rates, and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.

Cancer Statistics, 2008

Ahmedin Jemal, DVM, PhD, Rebecca Siegel, MPH, Elizabeth Ward, PhD, Yongping Hao, PhD, Jiaquan Xu, MD*, Taylor Murray and Michael J. Thun, MD, MS
Dr. Jemal is Strategic Director, Cancer Surveillance, Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.Ms. Siegel is Manager, Surveillance Information Services, Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.Dr. Ward is Managing Director, Surveillance Research, Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.Dr. Hao is Senior Epidemiologist, Surveillance Research, Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.Dr. Xu is Epidemiologist, Mortality Statistics Branch, Division of Vital Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD.Mr. Murray is Manager, Surveillance Data Systems, Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.Dr. Thun is Vice President, Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA.

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Conclusion

We found no statistical significant association between arsenic concentrations in Danish drinking-water and the risk for cancers of the lung, bladder, kidney, liver, prostate, or colorectum. The results indicated inverse associations between arsenic concentrations in Danish drinking-water and risk for skin cancers, suggesting that arsenic might have a protective effect at low concentrations. The results also indicated that arsenic in drinking-water might increase the risk for breast cancer. The findings should be interpreted with caution, and more studies are needed to confirm the results.

Discussion

We found no increased risk for cancers of the lung, bladder, kidney, liver, prostate, and colorectum, and for melanoma and non-melanoma skin cancers in association with low levels of exposure to arsenic through drinking-water. The risk for skin cancers decreased with increasing exposure. Results adjusted for enrollment area showed no significant risk associations except for with breast cancer, when the time-weighted average arsenic exposure was used and for melanoma skin cancer in the quartile-based analyses.
The median and mean arsenic exposure at enrollment were 0.7 and 1.2 μg/L, respectively, which are comparable to the concentrations found in Finland (median = 0.14 μg/L) (Kurttio et al. 1999), and the United States (mean = 2 μg/L) (Agency for Toxic Substances and Disease Registry 2005) but much lower than those found in some areas of Asia and Latin America.
Although previous studies provide evidence for an etiologic relationship between arsenic in drinking-water and cancer, they do not predict the cancer risk of low doses (Karagas et al. 2001). The arsenic levels in the Danish drinking-water are 100–1,000 times lower than those reported in studies from Asia and Latin America. It is possible that arsenic concentrations in the Danish drinking-water are below a low effect level; however, the results of the present study cannot rule out a weak adverse effect that is impossible to detect with the method used and the study size.
Conflicting results have been obtained in studies of arsenic and cancer conducted in areas of low arsenic concentrations in drinking-water. A Finnish case–cohort study reported increased risk for bladder cancer in association with exposure to arsenic (Kurttio et al. 1999) based on 61 cases and significant only for exposure 2–9 years before diagnosis for one of the three exposure measures used (Kurttio et al. 1999). Interpretation of the finding is therefore not straightforward. In contrast, our study, based on 214 cases, showed no increased bladder cancer risk. In line with the results of our study, the Finnish study did not find an association with kidney cancer (Kurttio et al. 1999). Studies carried out in the United States found no increased risk for bladder cancer with increasing arsenic exposure (Bates et al. 1995; Lamm et al. 2004; Steinmaus et al. 2003) in areas with arsenic concentrations in drinking-water of 0.5–160 μg/L. In one of these studies an insignificant tendency toward decreasing bladder cancer risk was seen with increasing exposure to arsenic ranging from 3 to 60 μg/L (Lamm et al. 2004). Another study in the United States showed an increased risk for prostate cancer in association with arsenic exposure (Lewis et al. 1999). We did not find such an association.
In the present study, higher exposure to arsenic was significantly associated with a lower risk for non-melanoma skin cancer in the overall analyses. Similar risk estimates were seen for melanoma skin cancer, although the results were not significant, possibly because of the small number of cases. These findings conflict with the results of some previous studies. In Taiwan, Wu et al. (1989) found a significant dose–response relation for non-melanoma skin cancer in association with exposure to arsenic, and a study in the United States showed a 1.9 times higher risk for skin cancer (type not specified) among persons exposed to drinking-water containing > 10 μg/L arsenic than those exposed to <>Knobeloch et al. 2006). Another study of exposure to low levels of arsenic showed no association with non-melanoma skin cancer (Karagas et al. 2001). In a study of non-melanoma skin cancers in which arsenic in toenail tissue was used as bio-marker of exposure, a nonlinear dose–response relation was seen with low exposures, with an inverse association at low levels and an increasing risk with concentrations > 0.09–0.11 μg/g toenail, corresponding to 1–2 μg/L in drinking-water (Karagas et al. 2002). This result is consistent with our findings, as only a small proportion of the cohort members were exposed to drinking-water containing arsenic at > 2 μg/L.
In an experiment in cells in vitro a low dose of arsenic had a protective effect against oxidative stress and DNA damage, supporting the hypothesis that low doses of arsenic could protect against cancer. In this study, the point, at which the protective effect was out weighted by the toxic effect was 1 μmol/L corresponding to 50–60 μg/L (Snow et al. 2005). The findings of inverse risk associations for skin cancer in the present study further support the hypothesis that low doses of arsenic might be inversely associated with risk for skin cancer.
Nevertheless, the negative association between arsenic and non-melanoma skin cancer virtually disappeared when adjusted for enrollment area and when separate risk estimates were made for the two enrollment areas. This might be interpreted as confounding by some regional factor for which we did not adjust. For example, exposure to the sun is a risk factor for both melanoma and non-melanoma skin cancer (Scotto et al. 1996), and this might have confounded the results of the overall analysis if such exposure was more pronounced in the Copenhagen area, as the arsenic concentrations in drinking-water were generally higher in the Aarhus area. This interpretation is, however, contradicted by the fact that the inverse risk association for melanoma skin cancer persisted when risk estimates were calculated separately for the two enrollment areas. Further, the lower risk for confounding obtained by adjustment for enrollment area might be counterbalanced because this adjustment would make it more difficult to detect any effect of arsenic exposure, as part of the variation in exposure relates to differences between the two enrollment areas. Altogether, our finding of negative associations between arsenic and non-melanoma and melanoma skin cancers should be interpreted with caution.
To our knowledge, no epidemiologic study of an association between arsenic and cancer has included breast cancer. The borderline significance of the finding of an increased risk for breast cancer in association with arsenic exposure among cohort members enrolled in the Aarhus area should therefore be interpreted with caution, and more studies are needed to determine if arsenic in drinking-water is a risk factor for breast cancer.
Cases were identified in the virtually complete, reliable nationwide Danish Cancer Registry (Storm et al. 1997), and the Danish Population Registry provided complete follow-up of the cohort members. Although the exposure of the cohort members was assessed independently of who developed cancer, some degree of nondifferential misclassification of arsenic exposure inevitably occurred. This would in most cases be expected to bias risk estimates toward the neutral value (Rothman 2002), and it may therefore have contributed to the null results of the present study. Factors contributing to such exposure misclassification include the following: a) Recent arsenic measurement were assumed to represent historical exposure, in line with the approach of other studies (Bates et al. 2004; Kurttio et al. 1999). b) For 14% of the addresses, we assumed that the nearest water utility provided drinking-water to the address. However, exclusion of persons, who had lived at one of these addresses changed the risk estimates only marginally. c) Some water utilities might have closed during the study period, and supply structures might have changed. It is likely though that drinking-water from past and present water utilities that are spatially close would have similar arsenic concentrations, as the geologic composition of aquifers is fairly homogeneous over small geographic areas. d) There is a lack of information about exposure to arsenic through foodstuffs; however, arsenic in food occurs mainly in the less harmful organic form, and the typical Danish diet does not include arsenic-rich foods such as seaweed, skate, or stingray (Mohri et al. 1990). e) There is uncertainty in the reported intake of tap water. However, the results for time-weighted average arsenic exposure would not be affected by such misclassification, and the results for these two exposure measures gave similar results. f) Use of domestic water supply as a predictor for source of drinking-water implies some uncertainty (Jones et al. 2006). Because most of the water supply areas in the study covered large areas, such misclassification would apply mainly to persons, who traveled far between home and work.
Lack of information on residential histories before 1970 could also have led to misclassification of the exposure. Different migration patterns for cases and noncases before 1970 would imply differential misclassification, but we consider this unlikely because of the long time span between the period of unknown migrations (before 1970) and time of diagnosis for the cancer cases (after inclusion between 1994 and 1997). The strengths of our study include the large study population, the reliable population-based Danish registers, and adjustment for many potential confounding factors. Also, the precise link between place of residence and water supply and the measurements of arsenic concentrations in the drinking-water that was piped to the consumers adds strength to the study.
The limitations of the study include the overall low arsenic concentration in Danish drinking-water and lack of information on other sources of arsenic. Further, the exposure of cohort members before 1970 could not be estimated, as the residential histories before that date were unknown. Therefore we were not able to assess early-life arsenic exposure, which is an important limitation of this study because early environmental exposures might be most significant for cancer risk. Finally, measurement of arsenic in nails or urine would provide more precise estimates of the personal exposure and should be included in future studies whenever possible.

Results

Demographic, dietary, occupational, and other characteristics of the cohort members are presented in Table 1.

Table 1
Demographic, lifestyle, and dietary characteristics of the cohort.
The time-weighted arsenic exposure of the cohort members calculated from 41 years of age up to date of enrollment varied between 0.05 and 25.3 μg/L, with a median concentration of 0.7 μg/L and a mean concentration of 1.2 μg/L. The exposure was generally higher among those enrolled in Aarhus than those enrolled in the Copenhagen area. Aarhus: mean = 2.3 μg/L, median = 2.1 μg/L; Copenhagen: mean = 0.7 μg/L, median = 0.6 μg/L (Table 2).


Table 2
Time-weighted average arsenic exposure from 41 years of age to date of enrollment.
Figure 3.
illustrates a weak tendency towards increasing drilling depth over the last 18 years. Drilling depth explained 4% of the variation in arsenic concentration (R2 = 0.04; n = 3,396).
Figure 3
Groundwater drilling depths as a function of time, based on 3,396 measurements from drillings used for drinking-water.
The results without adjustment for enrollment area (Table 3)
showed no significant association between exposure to arsenic and risk for any type of cancer, except for non-melanoma skin cancer, for which higher arsenic exposure was associated with lower risk. The IRR for non-melanoma skin cancer was 0.88 [95% confidence interval (CI), 0.84–0.94] per micrograms per liter increase in time-weighted average exposure. A similar pattern was seen for cumulated arsenic exposure, with an IRR of 0.95 (95% CI, 0.92–0.97) for a 5-mg increase in exposure. The risk estimates for kidney cancer and melanoma were correspondingly low for both exposure measures but insignificant. Results adjusted for enrollment area (Table 3)
showed virtually no effect for non-melanoma skin cancer, a stronger but still insignificant inverse risk association for melanoma skin cancer, and a significantly increased risk for breast cancer in association with time-weighted average exposure to arsenic (IRR = 1.05; 95% CI, 1.01–1.10).
Table 3
Incidence rate ratios for cancer in association with arsenic exposure.
Quartile-based analyses showed an IRR of 0.73 (95% CI, 0.59–0.91) for non-melanoma skin cancer for the upper quartile compared with the lower quartile of cumulated exposure from 41 years of age to date of diagnosis, but no decrease in risk was seen after adjustment for enrollment area (IRR = 1.14). The similar IRRs for melanoma skin cancer were 0.52 (95% CI, 0.28–0.98; p = 0.04) and 0.53 (95% CI, 0.32–0.88; p = 0.01) with and without adjustment for enrollment area respectively. The risk did not differ significantly between upper and lower quartile for any of the other cancers regardless of adjustment for enrollment area or not (all p > 0.12) (results not shown).
Spline and quadratic tests showed deviation from a linear dose–response relation for cancers of the breast, lung, prostate, and liver, and for melanoma and non-melanoma skin cancers. When evaluated graphically, the dose–response relation for non-melanoma skin cancer showed a systematic nonlinear pattern, with a decreasing trend that leveled off with increasing exposure (Figure 4).
The departure from linearity appeared to be random and nonbiological for the other cancers (results not shown).
Figure 4
Dose–response curve for non-melanoma skin cancer. Reference, IRR = 1 at average time-weighted arsenic exposure of 0.05 μg/L.
In the overall analyses (Table 3,
no adjustment for area), the risk estimates were affected to only a small extent by calculating time-weighted average exposure to arsenic from 1970 for all cohort members regardless of age, by introduction of a 5-year latency or by exclusion of individuals for whom the closest water utility was used as the expected source of drinking-water at the residence (results not shown). Furthermore, these results showed no significant interaction between arsenic and smoking, as the IRR estimates for never, former, and current smokers were not significantly different for cancers of the lung or bladder or non-melanoma skin cancer (all p > 0.12) (results not shown).
Table 4
shows inconsistent directions of the risk association in the two enrollment areas for non-melanoma skin cancer and a consistent direction of the risk association (inverse) for melanoma skin cancer, which was insignificant for both enrollment areas. Further, a consistent direction of the risk association for breast cancer (higher exposure was associated with higher risk) was observed, which was statistically significant in Aarhus when the time-weighted average exposure measure was applied (IRR = 1.06; 95% CI, 1.0–1.11; p = 0.02). None of the risk estimates differed significantly between the two areas (all p > 0.15).
Table 4
Incidence rate ratios for cancer in association with arsenic exposure in the two enrollment areas.

Potential confounding factors

Potential confounding factors.
We used data on smoking, alcohol consumption, education, body mass index, daily intake of fruit/vegetables, red meat, fat and dietary fibers, skin reaction to sun, hormone replacement therapy use, reproduction, and occupation collected at enrollment into the cohort to adjust for potential confounding factors for each type of cancer. Further, data was analyzed both with and without adjustment for enrollment area.
Statistical analyses.
Statistical analyses were carried out with the PHREG procedure of SAS 8.2 software (SAS Institute Inc., Cary, NC, USA). Cox proportional hazards models were used to estimate incidence rate ratios (IRRs) for cancer associated with the time-weighted average and cumulative arsenic exposure. Age was used as the time axis to ensure that the estimates were based on comparisons of individuals of the same age. The analyses were corrected for delayed entry, so that individuals were considered at risk only from the age at entry into the cohort. All analyses were stratified by sex. The age of 41 years was chosen as the starting point for calculating exposure because the oldest person in the cohort was 41 in 1970 when the residential histories began. This ensured that the exposure assessment started at the same age for all individuals. Both exposure measures—time-weighted average exposure per micrograms per liter since age 41 and total cumulated exposure per 5 mg since age 41—were included in the model as time-dependent variables.
Cohort members were censored at age of death, emigration, cancer diagnosis or if they had moved to an address with unknown arsenic concentration.
The associations between arsenic exposure measures and cancer risk were modeled as straight lines, and the analyses were adjusted for known risk factors to control for potential confounding. The linear assumption was evaluated with a linear spline (Greenland 1995), with three boundaries placed at the quartiles of the time-weighted average exposure at the time of enrollment into the cohort. These were included as covariates in the Cox model, and linearity was assessed graphically and by a numerical test. To evaluate linearity, we also tested if an additional quadratic term improved the model fit. Further, we analyzed risk in association with quartiles of cumulated exposure at the time of diagnosis for cancer cases to investigate if the risk was higher or lower in association with the highest exposures.
Analyses were repeated using time-weighted average exposure to arsenic on the basis of addresses occupied from 1970 for all cohort members regardless of age. An additional analysis included a 5-year lag between exposure and cancer diagnosis, that is, excluding the 5 years before the cancer diagnosis in the exposure assessment of cases and a similar period for the non-cancer cohort members. We also repeated analyses after exclusion of individuals who had lived at an address for which the closest water utility was used as the expected source of drinking-water.
Arsenic concentrations were generally higher for persons enrolled in the Aarhus area than those in the Copenhagen area. This might imply confounding from risk factors that were not accounted for that differed between the Aarhus and the Copenhagen areas. Therefore, we repeated analyses with adjustment for enrollment area, knowing that such adjustment limited the exposure contrasts evaluated in the analyses.
For initial analyses (without adjustment for area) providing p-values ≤ 0.2, separate estimates of the association with arsenic exposure were calculated for the Aarhus and Copenhagen enrollment areas by including an interaction term in the model. This was to test the consistency of the results. A persistent association in both areas would strengthen the confidence in the result. We tested the null hypothesis that the effect of arsenic exposure was the same in the two areas (test for interaction).
On the basis of the results of previous studies, the associations between exposure to arsenic and cancers of the lung and bladder and non-melanoma skin cancer were estimated for never, former, and current smokers separately, and we tested for different effects of arsenic between the three smoking status categories.

Arsenic exposure

We calculated two exposures for each cohort member. The first was a time-weighted average exposure, calculated as the arsenic concentration in drinking-water multiplied by the time lived at each address, summed for all residential addresses during the study period and divided by the total observation time, with the unit micrograms per liter (Equation 1).

Second, we calculated the cumulated arsenic exposure by cumulating the products of “arsenic level × time” for each address occupied during the total observation period and multiplied by the total daily intake of tap water, with the unit milligram (Equation 2). The total daily intake of tap water was calculated as the sum of intake of tap water, coffee, tea, and fruit syrup diluted with tap water, which was reported at enrollment into the cohort.

Water supply and arsenic measurements

Arsenic concentrations in Danish drinking-water were obtained from a database managed by the Geological Survey of Denmark and Greenland (Thomsen et al. 2004), which contains the results of chemical tests in water utilities in Denmark. Since 2001, it has been compulsory for water utilities to measure arsenic in the drinking-water and to report the results to the database. The spatial locations of the water utilities were determined by their geographic coordinates, which were also registered in the database. We calculated the average arsenic concentration for each water utility on the basis of 4,954 measurements in 2,487 water utilities reported between 1987 and 2004, with most measurements dating from 2002–2004. The average at each water utility was assumed to represent arsenic concentrations throughout the study period 1970–2003. As drilling depth might affect arsenic concentrations and might have changed over time, we collected data on the drilling depth and analyzed the correlation with the arsenic concentration in drinking-water using Spearman’s correlation coefficient.
To assess the effect of arsenic in drinking-water on the risk for cancer among cohort members, it was essential to link the arsenic concentrations at the water utilities to each address of the cohort members. Therefore, information on the size and spatial location of 94 water supply areas was collected from local authorities and water utilities in 24 municipalities, covering the vast majority of the geocoded cohort addresses. Seventy-one of the collected water supply areas were supplied by only one water utility, whereas the water in 23 areas came from more than one utility. Therefore, we also collected details of the volume of water distributed from water utilities to these 23 areas to calculate water volume-weighted average arsenic concentrations. If, for example, an area received 40% of its water from one utility and 60% from another, the arsenic concentration in the area would be calculated as 0.4 × concentration at utility1 + 0.6 × concentration at utility2. The 94 water supply areas were mapped in ArcGIS 9.1 (Figure 2) and covered 84% of the cohort addresses.

Figure 2
Ninety-four water supply areas classified according to estimated average arsenic concentration (μg/L). These areas cover 84% of the 198,758 geocoded cohort addresses.
The geocoded cohort addresses, water utilities, and water supply areas with their arsenic concentrations were mapped in ArcGIS 9.1, and arsenic concentrations were assigned to the cohort members’ addresses, with the spatial join functionality. First, the 170,403 (84%) of the cohort addresses located within one of the mapped water supply areas were assigned an estimated arsenic concentration, by the “point-in-polygon” procedure. This procedure allocates the attributes of the polygon to all points within it. Second, 28,355 (14%) of the addresses were assigned the arsenic concentrations of the nearest water utility, by application of the “point-to-point”-spatial join. By this procedure all points in one data set will be given the attributes of the points in another data set based on shortest distance. The last 3,581 (2%) of the cohort addresses had no geographic reference and were allocated a “missing value” as arsenic concentration.
Arsenic exposure.
We calculated two exposures for each cohort member. The first was a time-weighted average exposure, calculated as the arsenic concentration in drinking-water multiplied by the time lived at each address, summed for all residential addresses during the study period and divided by the total observation time, with the unit micrograms per liter (Equation 1).

Materials and Methods

Study population.
The study was based on the prospective Danish cohort Diet, Cancer and Health, which has been described in detail elsewhere (Tjønneland et al. 2007). In brief, 160,725 persons 50–64 years of age and living in one of 23 municipalities in the Copenhagen or Aarhus area were invited to participate. Of these, 57,053 persons (27,178 men and 29,875 women) accepted the invitation and were enrolled between 1993 and 1997. At enrollment, information was collected including on diet, beverages, smoking, education, medical conditions, occupations, reproductive factors, body mass index, and skin reaction to sun. The study “Diet Cancer and Health” has been approved by the relevant Scientific Committees and the Danish Data Protection Agency. Informed consent was obtained from all participants to search information from medical registers including the Danish Cancer Registry.
Since establishment of the Danish Central Population Registry in 1968, all citizens of Denmark have been given a unique personal identification number, which allows accurate linkage among Danish registers. The cohort members were followed up for cancer incidence in the population-based Danish Cancer Registry (Storm et al. 1997) from the time of enrollment until the date of first cancer diagnosis, emigration, death, or 1 August 2003, whichever came first. We included cancers of the lung, bladder, liver, kidney, prostate, female breast, and colorectum, and non-melanoma and melanoma skin cancers. Only first cancers were included, although a case of cancer was included even if it had been preceded by a non-melanoma skin cancer.
Of the 57,053 cohort members, we included 56,378 persons, who filled in the lifestyle questionnaire, reported daily intake of tap water, and had not had a cancer diagnosis before the enrollment.
Residential histories.
Using the personal identification numbers of the cohort members, we traced residential histories between 1970 and 2003 by record linkage to the Central Population Registry. With this method, we identified 202,339 unique addresses, each with a unique identification code composed of a municipality code, a road code, and a house number. The date the person had moved to and from the address was noted. The addresses were then linked to a database of all official addresses in Denmark, resulting in geographic coordinates for 198,758 (98%) of the cohort addresses. Subsequently, the addresses were mapped with the ArcGIS 9.1 geographic information system software (Environmental Systems Research Institute, Inc., Redlands, California, USA), and the proportion of addresses in each of the 271 Danish municipalities was calculated in relation to the total number of geocoded cohort addresses (Figure 1).
Figure 1
Distribution of geocoded cohort addresses (n = 198,758) in 271 Danish municipalities. The proportions are calculated as number of geocoded cohort addresses in each municipality divided by the total number of geocoded cohort addresses

Risk for Cancer in Denmark

Arsenic is a ubiquitous element in the environment, where it occurs in both organic and inorganic forms; it can be found in food, water, soil, and airborne particles, and humans are widely exposed through these sources (Tchounwou et al. 2004). Arsenic can cause fatal acute poisoning, and long-term exposure has been associated with various cancers, diabetes, skin disease, chronic cough, and toxic effects in the liver, kidney, cardiovascular system, and the peripheral and central nervous systems (Vahter et al. 2006). Organic arsenic, which is less harmful than the inorganic forms, is most abundant in food, whereas inorganic arsenic compounds are found mainly in aquifers (Abernathy et al. 2003), where they accumulate by natural processes such as weathering, erosion, and biological activity, or eventually from anthropogenic contamination (Smedley and Kinniburgh 2005). Consequently, most health-related problems associated with arsenic are derived from groundwater used for drinking (Farago et al. 1997; Smedley and Kinniburgh 2005).
Epidemiologic studies in Asia (Chen et al. 1986, 1988; Tsuda et al. 1995; Wu et al. 1989) and Latin America (Ferreccio et al. 2000; Hopenhayn-Rich et al. 1996, 1998; Marshall et al. 2007) have shown that high arsenic concentrations (up to several hundred micrograms per liter) in drinking-water are associated with various internal cancers and with cancer of the skin. Some of these studies also provide evidence of a dose–response relation (Chen et al. 1986, 1988; Wu et al. 1989). However, few studies, most of which were conducted in the United States, have addressed the adverse effects of exposure to low doses of arsenic, and their results are inconsistent. Some showed a positive association between relatively low doses of arsenic and cancers of the skin, prostate, and bladder (Knobeloch et al. 2006; Kurttio et al. 1999; Lewis et al. 1999), whereas others showed no such effects (Bates et al. 1995; Karagas et al. 2001; Steinmaus et al. 2003). One study showed a nonsignificant decreasing risk for bladder cancer with increasing exposure to arsenic in the range of 3–60 μg/L (Lamm et al. 2004), and Karagas et al. (2002) found a U-shaped dose–response relation between exposure to arsenic and non-melanoma skin cancer, with a decreased risk at low levels and increased risk at higher levels. The existence of a threshold for the carcinogenic effect of arsenic has been debated, especially in the United States (Abernathy et al. 1996; Schoen et al. 2004), and some studies have suggested an interaction between exposure to arsenic and smoking in the causation of cancers of the lung, bladder and skin (Bates et al. 1995; Ferreccio et al. 2000; Knobeloch et al. 2006; Steinmaus et al. 2003; Tsuda et al. 1995).
Recent animal models for inorganic arsenic carcinogenesis suggest that the carcinogenicity of arsenic involves several mechanisms and co-exposure to other carcinogens (Burns et al. 2004; Cohen et al. 2007; Rossman et al. 2004; Waalkes et al. 2007; Wanibuchi et al. 2004). In vitro low concentrations of arsenic protected against oxidative stress and DNA damage (Snow et al. 2005), in accordance with the results of some of the epidemiologic studies (Karagas et al. 2002; Lamm et al. 2004). More studies are needed, however, to evaluate the possible carcinogenic effect of exposure to low concentrations of arsenic. The aim of this large, population-based cohort study was to determine if individual exposure to low levels of arsenic in drinking-water in Denmark is associated with a risk for cancer.

Abstract

Background.
Arsenic is a well-known carcinogen, which is often found in drinking-water. Epidemiologic studies have shown increased cancer risks among individuals exposed to high concentrations of arsenic in drinking-water, whereas studies of the carcinogenic effect of low doses have had inconsistent results.
Objective.
Our aim was to determine if exposure to low levels of arsenic in drinking-water in Denmark is associated with an increased risk for cancer.
Methods.
The study was based on a prospective Danish cohort of 57,053 persons in the Copenhagen and Aarhus areas. Cancer cases were identified in the Danish Cancer Registry, and the Danish civil registration system was used to trace and geocode residential addresses of the cohort members. We used a geographic information system to link addresses with water supply areas, then estimated individual exposure to arsenic using residential addresses back to 1970. Average exposure for the cohort ranged between 0.05 and 25.3 μg/L (mean = 1.2 μg/L). Cox’s regression models were used to analyze possible relationships between arsenic and cancer.
Results.
We found no significant association between exposure to arsenic and risk for cancers of the lung, bladder, liver, kidney, prostate, or colorectum, or melanoma skin cancer; however, the risk for non-melanoma skin cancer decreased with increasing exposure (incidence rate ratio = 0.88/μg/L average exposure; 95% confidence interval, 0.84–0.94). Results adjusted for enrollment area showed no association with non-melanoma skin cancer.
Conclusions.
The results indicate that exposure to low doses of arsenic might be associated with a reduced risk for skin cancer.
Keywords: arsenic, cancer, cohort study, drinking-water, geographic information system

Arsenic in Drinking-Water and Risk for Cancer in Denmark

Rikke Baastrup,1 Mette Sørensen,1 Thomas Balstrøm,2 Kirsten Frederiksen,1 Carsten Langtofte Larsen,3 Anne Tjønneland,1 Kim Overvad,4 and Ole Raaschou-Nielsen1
1 Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark
2 Department of Geography and Geology, University of Copenhagen, Copenhagen, Denmark
3 Geological Survey of Denmark and Greenland, Copenhagen, Denmark
4 Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
Address correspondence to R. Baastrup, Danish Cancer Society, Institute of Cancer Epidemiology, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Telephone: 45 35 25 76 86 . Fax: 45 35 25 77 31. E-mail: baastrup@cancer.dk

The authors declare they have no competing financial interests.
Received July 2, 2007; Accepted November 23, 2007.

Abstract

Pearl is generally assigned to a date of composition in the 1380s; this study argues that the poem engages in debates on legal and political theory consonant with a date in the late 1380s, and that the standpoint taken would have been congenial to a noble, but probably not royal, audience, one bilingual in French as well as English. The poet engages with political and theological arguments persistently couched in legal terms: there may have been a general cultural trend among vernacular writers, orthodox as well as radical, to pursue such discussion within a legal context. Legal language and theology cannot be kept apart. Much of the vocabulary is susceptible of legal senses and nuances, even while it relates to everyday legal transactions, and does not require extended technical knowledge of the law. His evident fondness for exploiting the rich inheritance of theocratic symbolism establishes the strangeness of the Lamb's court, while not necessarily endorsing Richard II's tendencies towards absolute rule. The poet's concern with lawful possession affirms that, though an absolute ruler, God is no ‘tyrant’. The principles of equity and the rigour of the law are wholly consonant in his realm. Ulpian's famous dictum of Roman law, that ‘What pleases the prince has the force of law’, to which the poet alludes, could, in an English context, be reconciled with a more ‘constitutional’ model in which what pleased the king was Law, authorized by his magnates, and not just his personal will. It is argued that the synthesis of legal ideas in the poem makes Pearl a very ‘English’ poem, in which God's monarchy is described in terms deriving from Roman law, as found in Giles of Rome or John of Salisbury, but also in terms derived from the law of the land. Although it is possible to read the poem as a veiled criticism of Richard II's actions from around 1388 onwards, this is to diminish the poem and compromise its ‘plot’: the transfiguration of the pearl-maiden. But it is intimately grounded in fourteenth-century developments in doctrine, expressed in contemporary legal and political terms.

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Tell the truth on Lozada,’ Puno pleads with religious

By Thea AlbertoINQUIRER.netFirst Posted 15:39:00 02/07/2008
MANILA, Philippines -- Interior Secretary Ronaldo Puno pleaded with religious who helped Rodolfo Noel Lozada Jr. to tell the truth about what happened the night the key witness in the Senate probe of the national broadband network (NBN) deal went missing after returning to the country.
"I don't understand why all of these things are being said now…I'm really disappointed with how people dealt with us," Puno told a press conference Thursday.
Lozada had been whisked away by unidentified men immediately after arriving at the Ninoy Aquino International Airport Tuesday evening, with his family claiming he had been abducted by government agents.
However, Razon claimed Lozada had sought protection and had been fetched at the airport by police. This has been denied by Lozada, who surfaced at the La Salle Greenhills school in Mandaluyong City.
Razon said the La Salle brothers and the nuns who accompanied Lozada when he surfaced early Thursday morning "knew the truth" that the witness was "free to move around" while he was in their care at the La Salle Greenhills dormitory.
"Dela Salle brothers have pity on us…tell the public the truth that…Lozada was peacefully asleep while the police who were guarding him were attacked by mosquitoes," said Puno.
Puno maintained Lozada was not abducted, as his family charge.
"If there's anybody who was hiding Lozada, that certainly was not us," he added.
Puno said the Senate must also call the religious to its probe to shed light.
"Tawagin din nila [ang] La Salle brothers na tahimik ngayon, na hindi sinasabi sa inyo [Let them call the La Salle brothers who are silent now, who are not telling] what happened," said Puno.

AMRSP Statement of Jun Lozada

Association of Major Religious Superiors of the Philippines (AMRSP) Statement on the Jun Lozada Case
“…and the Truth shall set you free!”
We thank God for having been given the rare privilege of taking an active part in the triumph of truth over lies in a culture of fear and moral bankruptcy. We believe Jun Lozada is only an example of what is happening in our government institutions.We humbly recognize that God, in His mysterious ways had made us His instrument in enabling Jun Lozada to come out with his historic revelation to the Press and to the Senate: we consider him a modern David confronting a Goliath.Being with him these past days is a genuine spiritual experience – getting to know a man who embodies what is best in the Filipino. We saw his courage unfolding before our eyes as he tried to overcome his fears and apprehensions leading to his testimony before the Senate in unparalleled authenticity, courage, honesty, humility and unfailing courtesy.As he spoke we began to realize with growing horror and increasing indignation the extent of corruption that is systemic in our government bureaucracy and its toll on our suffering people who could actually live in well-being if the resources of this country were truly used for their good.We recognize the important role of the media people in this critical moment of our country. We commend them for the support they have given to Jun Lozada and for their unrelenting pursuance of the truth.It is unthinkable for us to imagine that this basic heroic act, that is putting Jun and his family not only in danger but in a state of dislocation that sees no immediate end, would be in vain. We cannot go back to “business as usual.” We commit ourselves to pursue a crusade for TRUTH. We call on all sectors of society especially the Church to join us in this commitment.Let us heed the call of the CBCP for communal action”“Truth hurts. Truth reveals. But the truth must be served. The truth will set our country free. Only the truth - not lies and deceit will set us free. This truth challenges us now to communal action.”

LOZADA IS AFRAID OF THE SENATE

MANILA, FEBRUARY 13, 2008 (STAR) COMMONSENSE By Marichu A. Villanueva - The Senate’s inquiry into the alleged multi-million dollar kickbacks in the $329-million national broadband network (NBN) that went into the contract with the ZTE Corp. of China took up at length last Monday the purported “kidnapping” of their latest witness Rodolfo Noel Lozada Jr. This peripheral issue in the NBN-ZTE scandal has provided the latest drama into this whole mess, complete with tears and fears displayed in public by Lozada during that Senate hearing.
The cast of characters in this Senate hearing were personalities in and out of the government whose names were among those mentioned by Lozada on his allegedly being “kidnapped” last week upon his arrival at the Ninoy Aquino International Airport (NAIA). They were: Department of Environment and Natural Resources Secretary Lito Atienza; deputy executive secretary Manny Gaite; Manila International Airport Authority (MIAA) general manager Alfonso Cusi; Philippine National Police (PNP) director-general Avelino “Sonny” Razon; NAIA assistant general manager for security Gen. Angel Atutubo; private counsel Atty. Antonio Bautista, Senior Superintendent Pol Mascariñas; and former presidential chief of staff Michael Defensor.
Despite breaking down in tears at one point of the Senate hearing, Lozada gallantly faced the eight resource persons from the government side who each refuted and clarified their supposed roles in his being “kidnapped”. In many instances, the televised Senate hearing caught Lozada’s facial reactions that indicated his disagreement to the testimonies of these people while they each passionately controverted his claims of his being “kidnapped” or held against his will.
Gen. Razon who is known for his even temper, at one point, had to raise his voice a few decibels higher as he tried to disprove allegations against him and his men who provided the security for Lozada but who were now accused as “kidnappers”. The PNP chief, seated beside the latest witness on the NBN-ZTE scandal during the Senate hearing, even gestured to Lozada’s being present there unharmed before the Senators as best evidence that the PNP succeeded in its assigned mission to protect him.
While Lozada was “vague” about what he was afraid of, Gen. Razon noted during the entire testimony at the Senate hearing that the witness was consistent, though, on three counts. One, Lozada “feared” for his life. Second, he was “afraid of being arrested by the Senate.” And third, he does not want to appear at the Senate because he is afraid to testify on what he knows about the alleged “overpricing” and kickbacks that went into the government-approved NBN-ZTE deal.
I asked yesterday the PNP chief what Lozada was telling him in whisper when the two of them were photographed at the Senate hearing. “Hirap na hirap na raw siya. Ayaw n’ya talagang humarap sa Senate investigation,” Razon quoted Lozada telling him even in whispers. It was very clear what Lozada was afraid of.
Raising a similar “snatching” incident of a Senate witness, Udong Mahusay was dug up during the hearing against Defensor. However, it backfired because it gave the opportunity to the former Arroyo Cabinet official to finally put on Senate record in proper perspective what really happened in that particular case. This was in reference to Defensor’s previous involvement in “snatching” a Senate witness, Mahusay, raised by Opposition Senator Chiz Escudero. Mahusay was the witness of Senator Panfilo “Ping” Lacson when the Opposition leader exposed the alleged “Jose Pidal” bank account of First Gentleman Jose Miguel Arroyo.
As in the case of Lozada, Defensor testified that Mahusay feared for his life when he called him up and sought out his assistance because he used to work for him and his family. Defensor recalled how he went all the way to Tagaytay to fetch Mahusay and took him to the PNP camp in Silang, Cavite. Defensor recalled how fearful he was that they might be followed by the armed men who took him to the safehouse provided by Lacson.
Like Udong Mahusay, Lacson told his Senate colleagues Lozada was also his witness in the ZTE scandal whom he first met on Dec. 3. In his own testimony of his alleged “kidnapping”, Lozada struck a sour note for Lacson when he mentioned his fears that he might end up being killed or salvaged by unidentified police security escorts when they reached Dasmariñas, Cavite. “Baka, ma-Dacer ako!” Lozada told the Senators. Of course, Lozada referred to the late public relations man, Salvador “Bubby” Dacer who, along with his driver, were kidnapped and killed in that place. The principal suspects in this twin murder case were officers of Lacson when he was the PNP chief during the term of former President Joseph Estrada. The case remains among the unsolved crimes in our country. The mastermind and perpetrators of the Dacer-Corbito twin murder case remain free.
But like trick of the hat, Lozada’s testimony at the Senate on his alleged “kidnapping” and implicating the First Gentleman into the NBN-ZTE scandal became the Opposition’s fodder to renew their call for the resignation of President Arroyo and Vice President Noli de Castro. No wonder, the planned Opposition-led protest rallies starting this Friday in Makati City are being primed in time when our country marks the anniversary of the February 1986 EDSA People Power Revolution.
It is very clear that people from both the administration and Opposition were desperate to get Lozada. Thus, the ZTE witness did not know where, or who, to turn to. He ended up, though, in the protective care of the De La Salle brothers and nuns whose previous resignation calls against the President were public knowledge. Although he kept saying he does not want to identify himself with any political persuasion on his crusade to help put an end to corruption in government, the poor guy lost on his way to redeem what was left in his soul. And that’s because some people in Church have dipped their fingers again into politics.