Inorganic Arsenic and Basal Cell Carcinoma in Areas of Hungary, Romania, and Slovakia: A Case-Control Study

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BACKGROUND: Inorganic arsenic (iAs) is a potent carcinogen, but there is a lack of information about cancer risk for concentrations < 100 [micro]g/L in drinking water.

OBJECTIVES: We aimed to quantify skin cancer relative risks in relation to iAs exposure < 100 [micro]g/L and the modifying effects of iAs metabolism.

METHODS: The Arsenic Health Risk Assessment and Molecular Epidemiology (ASHRAM) study, a case control study, was conducted in areas of Hungary, Romania, and Slovakia with reported presence of iAs in groundwater. Consecutively diagnosed cases of basal cell carcinoma (BCC) of the skin were histologically confirmed; controls were general surgery, orthopedic, and trauma patients who were frequency matched to cases by age, sex, and area of residence. Exposure indices were constructed based on information on iAs intake over the lifetime of participants. iAs metabolism status was classified based on urinary concentrations of merhylarsonic acid (MA) and dimethylarsinic acid (DMA). Associations were estimated by multivariable logistic regression.

RESULTS: A total of 529 cases with BCC and 540 controls were recruited for the study. BCC was positively associated with three indices of iAs exposure: peak daily iAs dose rate, cumulative iAs dose, and lifetime average water iAs concentration. The adjusted odds ratio per 10-[micro]g/L increase in average lifetime water iAs concentration was 1.18 (95% confidence interval: 1.08, 1.28). The estimated effect of iAs on cancer was stronger in participants with urinary markers indicating incomplete metabolism of iAs: higher percentage of MA in urine or a lower percentage of DMA.

CONCLUSION: We found a positive association between BCC and exposure to iAs through drinking water with concentrations < 100 [micro]g/L.

KEY WORDS: low-dose arsenic, metabolism, methylation, skin neoplasms, urine. Environ Health Perspect 120:721-726 (2012). http://dx.cloi.org/10.1289/e4.1103534 [Online 31 January 2012]

Inorganic arsenic (iAs) is a recognized carcinogen and toxicant [National Research Council (NRC) 2001; World Health Organization (WHO) International Programme on Chemical Safety 2001] that is commonly present in groundwater. Causal relationships between long-term elevated iAs exposure and cancer of the skin, lung, and bladder have been accepted [International Agency for Research on Cancer (IARC) 2004, 2009]. Although certain populations, such as in Bangladesh, West Bengal, Taiwan, parts of China, Argentina, and northern Chile, have been exposed to very high concentrations of iAs in drinking water (several hundred micrograms per liter) (IARC 2004), there is widespread exposure worldwide to low concentrations of iAs, in the range of 5-50 [micro]g/L in drinking water and 5-100 [micro]g/kg in food, especially cereals and vegetables (European Food Safety Authority 2009; Norton et al. 2010). The NRC risk assessment (NRC 2001) indicates a comparatively high cancer risk even at concentrations as low as 10 [micro]g/L in drinking water; however, these risk estimates, as well as current WHO, European Union, and U.S. drinking water guidelines (European Council 1998; U.S. Environmental Protection Agency 2001; WHO 2011), are based on linear extrapolation of cancer risks at low doses in studies with relatively high iAs exposure, mainly in Taiwan (Chen et al. 1985, 1992; Chiou et al. 2001; Tseng et al. 1968; Wu et al. 1989). Concerns have been raised about the validity of such extrapolation, in part because accepted modes of action, which do not include direct DNA mutations, would be expected to result in a threshold dose response (Snow et al. 2005).

The effects of elevated iAs exposure on the risk of nonmelanoma skin cancer, mainly squamous cell carcinoma and basal cell carcinoma (BCC), have been recognized in highly exposed populations for some time (Cabrera and Gomez 2003; Chen and Wang 1990; Chen et al. 1985, 2003; Guha Mazurnder et al. 1998; Guo et al. 1998; Hsueh et al. 1995; Knobeloch et al. 2006; Tsai et al. 1999; Tseng 1977; Tseng et al. 1968). However, there is little direct evidence of skin cancer risk resulting from exposure to drinking water containing < 100 [micro]g/L iAs (Baastrup et al. 2008; Karagas et al. 2001).

The Arsenic Health Risk Assessment and Molecular Epidemiology (ASHRAM) study aimed to quantify the risks of several cancer types in relation to long-term low-level iAs exposure via drinking water in Hungary, Romania, and Slovakia. The associations with BCC of the skin are presented here.

Materials and Methods

For the ASHRAM study, the study areas included districts in central Slovakia where drinking water is derived from a cracked hard rock aquifer, as well as districts in eastern Hungary and western Romania located on the Great Hungarian Plain, an alluvial basin that straddles the Hungarian Romanian border. More precisely, the study included the Hungarian counties Bacs-Kiskun, Bekes, Csongrad, and Jasz-Nagykun-Szolnok; the Romanian counties Arad and Bihar; and the Slovakian districts Nitra, Nove Zamky, and Levice within Nitra County, and Banska Bystrica, Brezno, Ziar nad Hronom, and Zarnovica within Banska Bystrica County (total population 4.5 million). Routine monitoring of sources indicated that approximately 1,100,000 individuals had used water with > 10 [micro]g iAs/L, but generally < 100 [micro]g/L, at some point during the past 30 years (Hough et al. 2010). The study was conducted with individuals who provided written informed consent and were part of the majority Caucasian population, excluding the minority Roma population. Ethical approval was obtained from the Ethical Committee of the National Health Research Council and the Regional Ethical Committee of the Szentgyorgyi Albert University of Szeged (Hungary), from local hospitals and public health departments (Romania), and from ethical committees established in hospitals and state health institutes (Slovakia) included in the study.

In the absence of population registers, we worked with public health agencies to identify incident cases of BCC [International Classification of Diseases, 10th Revision (ICD-10) code C44 (WHO 1993)] and controls diagnosed among those 30-79 years of age in the same areas. Recruitment of cases and controls was carried out over 21 months (January 2003 September 2004). Because BCC cases may be diagnosed in primary or private care, a case control study of BCC based on cases identified only at hospitals may provide an incomplete ascertainment. However, we determined that pathologists at public hospitals were responsible for histological confirmation of all BCC cases in the study areas. Therefore, identification of BCC cases entailed a system whereby each pathologist would inform the local study coordinator every time a new case of BCC was diagnosed by histology, so that the identification of BCC cases did not require cooperation by the large network of hospital-and community-based clinicians responsible for diagnosing cases.

Hospital-based case control studies have been criticized because of the potential for selection bias resulting from recruitment of controls from a population systematically different from the source population for cases. In addition, selection bias would result if recruitment of cases and controls differed by geographical area that may be associated with degree of potential iAs exposure. Therefore, to ensure equivalent geographic coverage of populations for sampling both cases and controls, we recruited controls from all 24 hospitals in the study area, including six smaller hospitals in more peripheral areas that did not have …