Claudia Hopenhayn-Rich

Bladder cancer mortality associated with arsenic in drinking water in Argentina.

Inorganic arsenic (In-As) is known to be a human carcinogen, causing lung cancer by inhalation and skin cancer by ingestion. Ecologic studies in Taiwan have found a dose-response relation between ingestion of In-As from drinking water and bladder cancer, but questions have been raised concerning the validity and generalizability of the findings. Several areas of Argentina have had high exposures to arsenic from naturally contaminated drinking water, particularly the eastern region of the province of Córdoba. In this study, we investigated bladder cancer mortality for the years 1986–1991 in Córdobas 26 counties, using rates for all of Argentina as the standard for comparison. Bladder cancer standardized mortality ratios (SMRs) were consistently higher in counties with documented arsenic exposure. We grouped counties into low-, medium-, and high-exposure categories; the corresponding SMRs [with 95% confidence intervals (CI)] were 0.80 (95% CI = 0.66–0.96), 1.42 (95% CI = 1.14–1.74), and 2.14 (95% CI = 1.78–2.53) for men, and 1.21 (95% CI = 0.85–1.64), 1.58 (95% CI = 1.01–2.35), and 1.82 (95% CI = 1.19–2.64) for women. The clear trends found in a population with different genetic composition and a high-protein diet support the findings in Taiwan.

Arsenic in drinking water and bladder cancer.

Inorganic arsenic is a metallic element found throughout the earths crust. Human exposure to high levels of this element is primarily through inhalation of contaminated dusts in occupational settings or ingestion of drinking water contaminated with arsenic from naturally occurring sources. Despite limited findings in animal testing, there is extensive human epidemiologic evidence that inhaled arsenic causes lung cancer and ingested arsenic causes skin cancer. Based on this evidence, the International Agency for Research on Cancer has classified arsenic as an established human carcinogen (1). In addition to skin cancer, mounting evidence shows that ingested arsenic is also carcinogenic to various internal organs. Results from highly exposed populations in Taiwan and other countries have shown that ingested arsenic may cause cancer of the bladder, lung, and kidney. which are cancers that have a greater impact on mortality than skin cancer (2-8). Moreover, these results provide evidence that significant cancer risks may be associated with arsenic exposures at or below the current U.S. drinking water standard of 50 pg/l(9,10). Because millions of people throughout the world are currently drinking water contaminated with arsenic at or above this level, ingested arsenic may be causing extensive preventable cancer mortality. Research that links drinking water arsenic to internal cancers has not been without controversy (1 l) , and the use of this research to estimate cancer risks at low doses and to establish a potentially costly new arsenic drinking water standard has been hotly debated. After a brief overview of the general pharmacokinetics of arsenic, this article reviews the major epidemiologic evidence linking ingested arsenic to bladder cancer and discusses the controversy surrounding this research. Our present focus is on bladder cancer because evidence indicates that it has higher mortality ratios associated with ingested arsenic than other target organs (2,6). We then review the current controversy regarding the estimated cancer risks from ar-

Relationship of urinary arsenic to intake estimates and a biomarker of effect, bladder cell micronuclei

The purpose of this study was to investigate methods for ascertaining arsenic exposure for use in biomarker studies. Urinary arsenic concentration is considered a good measure of recent arsenic exposure and is commonly used to monitor exposure in environmental and occupational settings. However, measurements reflect exposure only in the last few days. To cover longer time periods exposure can be estimated using arsenic intake data, calculated by combining measures of environmental arsenic and inhalation/ingestion rates. We compared these different exposure assessment approaches in a population chronically exposed to arsenic in drinking water in northern Chile. The study group consisted of 232 people, some drinking water low in arsenic (15 micrograms/l) and others drinking water with high arsenic concentrations (up to 670 micrograms/l). First morning urine samples and questionnaire data, including fluid intake information, were collected from all participants. Exfoliated bladder cells were collected from male participants for the bladder cell micronuclei assay. Eight different indices of exposure were generated, six based on urinary arsenic (microgram As/l urine; microgram As/g creatinine; microgram InAs/l urine; microgram MMA/l urine; microgram DMA/l urine; microgram As/h, excreted), and two on fluid intake data (microgram As/day, ingested; microgram As/l fluid ingested-day). The relationship between the different exposure indices was explored using correlation analysis. In men, exposure indices were also related to a biomarker of effect, bladder cell micronuclei. While creatinine-adjusted urinary arsenic concentrations had the strongest correlations with the two intake estimates (r = 0.76, r = 0.81), unadjusted urinary arsenic showed the strongest relationship with bladder cell micronuclei. These data suggest that, in the case of the bladder, unadjusted urinary arsenic concentrations better reflect the effective target organ dose compared to other exposure measures for biomarker studies.

Heterogeneity of Ovarian Cancer: Relationships Among Histological Group, Stage of Disease, Tumor Markers, Patient Characteristics, and Survival

Epidemiological studies have established associations between various reproductive factors and risk of ovarian cancer; it has also been observed that some of these risk factors are only associated with specific histological subgroups. To investigate the correlation of genetic alterations with these risk factors, we examined a consecutive series of 158 ovarian cancer cases treated at the University of Kentucky (1990–96). Common molecular genetic alterations (LOH on chromosome 17, P53 alterations, K-RAS mutations), histological and clinical characteristics of the disease, demographic patient information and survival were evaluated. These latter data were from the Kentucky Cancer Registry. Univariate analysis showed higher frequencies of chromosome 17 loss and P53 mutations in tumors of advanced stage and grade, and in older and post-menopausal women. Non-mucinous tumors were more likely to be classified as late stage, high-grade cancers, and to have chromosome 17 loss and P53 mutations. Survival analysis indicated that stage was the only independent significant variable. When stage was the outcome variable in multiple logistic regression analysis, histology and chromosome 17 loss were significantly associated with poor survival. This case-case study provides evidence that ovarian cancers of mucinous and non-mucinous histology are significantly different with respect to clinical characteristics, survival and molecular alterations. It also lends support to the hypothesis that ovarian cancer is a heterogeneous disease with distinct etiological factors and clinical outcomes, which may require different approaches to treatment.

Rationale for selecting exfoliated bladder cell micronuclei as potential biomarkers for arsenic genotoxicity.

Biomarkers of effect have important potential in epidemiology, since they may enable ascertainment of exposure-effect associations in relatively inexpensive cross-sectional studies, with confirmation by short follow-up after cessation of exposure. Arsenic is known to cause human skin and lung cancer, and may also cause various internal cancers including bladder, kidney, and liver cancer. The strongest epidemiological association between arsenic ingestion and an internal cancer is that with bladder cancer. Epidemiological studies of a Taiwanese population exposed to high levels of arsenic from drinking water reported relative risks for bladder cancer well above any other known environmental carcinogen. Populations at increased risk for bladder cancer from other exposures, such as smoking and schistosomiasis infection, have elevated frequencies of micronuclei in exfoliated bladder cells. We have therefore proposed that the bladder cell micronucleus assay could be an appropriate biological marker of genotoxic effect of arsenic exposure. In this paper, we present the rationale for choosing the bladder cell micronucleus assay as a potential biomarker of effect for arsenic. We also briefly describe the studies we are conducting using this biomarker in currently exposed populations.

Reproductive and Developmental Effects Associated with Chronic Arsenic Exposure

Publisher Summary Chronic exposure to inorganic arsenic (Asi) is known to cause cancer and non-cancer health effects in humans. The evidence from animal studies clearly shows that As is teratogenic, and the findings of limited human studies suggest that Asi may be associated with several reproductive/developmental outcomes including increased rates of spontaneous abortion, low birth weight, congenital malformations, preeclampsia, and infant mortality. The city of Antofagasta, located in northern Chile, has a history of high As exposure in drinking water. Due to changes in the sources of water, there were considerably high As levels in the public drinking water supply from 1958 to 1970 (over 800 μg/L), which decreased gradually to the current concentrations close to 50 μg/L. A number of studies have reported various health effects associated with the high exposure period, including skin alterations typically linked to As exposure and increases in bladder and lung cancer. An ecologic study was conducted of infant mortality rates in Chile from 1950 to 1996, comparing Antofagasta to the low As exposure areas. Temporal and cross-regional comparisons showed a general steady decline over time in late fetal, neonatal, and post-neonatal mortality rates, for all locations, consistent with improvements in standard of living and health care. However, comparatively high rates were observed in Antofagasta for the three outcomes studied during the 12-year period of the highest As exposure, compared to Santiago and Valparaiso, two locations used as reference groups. While not definitive, these findings support a role for As in the observed increases in mortality rates.