The Broad Scope of Health Effects From Chronic Arsenic Exposure

Update on a Worldwide Public Health Problem

Marisa F. Naujokas; Beth Anderson; Habibul Ahsan; H. Vasken Aposhian; Joseph H. Graziano; Claudia Thompson; William A. Suk


Environ Health Perspect. 2013;121(3):295-302. 

In This Article

Health Outcomes of Arsenic Exposure

Dermatological Effects

Cutaneous lesions are one of the best-known clinical manifestations of chronic arsenic exposure and can occur within months or after several years of exposure (Das and Sengupta 2008; WHO 2005). Clinical photos of different types of arsenic-associated lesions are shown in Figure 1. Melanosis (hyperpigmentation) is considered an early and more common manifestation (Figure 1A), whereas keratosis (Figure 1B) is considered a sensitive marker of more advanced stages of arsenicosis (Das and Sengupta 2008; Sengupta et al. 2008). Leucomelanosis (hypopigmentation) also occurs but less frequently than melanosis or keratosis. Arsenic-related melanosis can be diffuse or patchy, or exhibit a distinctive "rain drop" pattern, and these lesions often appear on the trunk of the body. Keratotic lesions tend to appear mainly on the palms and soles. Sudden increases in the size of keratotic lesions, or cracks or bleeding of lesions, suggest malignant transformation—often to squamous cell carcinoma (Figure 1C,D). Analyses of numerous epidemiological studies of skin lesions suggest that most persons with skin lesions had consumed water with arsenic concentrations of > 100 μg/L, although lesions have been reported at arsenic concentrations of < 50 μg/L (Argos et al. 2011; Smith and Steinmaus 2009). Nutritional, economic, and smoking status are contributing factors for susceptibility to skin lesions as are sex and age, with a greater prevalence of skin lesions in older men (Pierce et al. 2010). A recent report from the HEALS prospective study found that the risk of skin lesions did not decrease after reducing exposure for up to several years (Argos et al. 2011). Therefore, lesions can appear several years after exposure diminishes. The vast majority of exposed individuals (even with high levels of chronic exposure) will not develop skin lesions but are still at risk of arsenic-related skin and internal cancers and other noncancer diseases (Argos et al. 2010; Chen Y et al. 2011; Parvez et al. 2010).

Figure 1.

Skin manifestations of chronic arsenic exposure. (A) Hyperpigmentation (melanosis); (B) hyperkeratosis (keratosis); (C) squamous cell carcinoma in situ (Bowen's disease); (D) invasive squamous cell carcinoma; and (E) basal cell cancer.

Arsenic Exposure and Cancer

Arsenic is a known carcinogen in skin, lung, bladder, liver, and kidney, with evidence suggesting lung cancer is the most common cause of arsenic-related mortality (IARC 2012; National Toxicology Program 2011). Skin cancer has long been associated with chronic arsenic exposure (ATSDR 2007; Yu et al. 2006). Squamous cell carcinoma in situ (Bowen's disease; Figure 1C), invasive squamous cell carcinoma (Figure 1D), and basal cell carcinoma (Figure 1E) are the most common types of skin cancer associated with chronic arsenic exposure. Studies from arsenic-endemic regions of Taiwan revealed that the overall prevalence of skin cancer was 10.6 per 1,000 persons and was associated with increased arsenic drinking-water concentrations (Tseng 1977) and increased urinary concentrations of certain arsenic metabolites (Tseng 2007). In the United States, where arsenic exposure is generally lower, significantly increased risks for squamous cell and basal cell carcinomas occurred in individuals in the top 97th percentile of toenail arsenic concentrations (Karagas et al. 2001), particularly among individuals carrying susceptible genotypes for the nucleotide excision repair genes (Applebaum et al. 2007).

Chronic arsenic exposure is also associated with an increased risk of lung cancer (IARC 2012). In the Chilean cohort that was exposed to high arsenic concentrations in drinking water (> 850 μg/L) for a limited period of time (1958–1971), the peak mortality rate ratio (MRR) for lung cancer was highest at 3.61 (95% CI: 3.13, 4.16) for men in 1992–1994 (Table 4), suggesting a 34- to 36-year latency period (Marshall et al. 2007). Arsenic is carcinogenic in the lung regardless of oral or inhalation pathways of exposure, and it is well established that lung cancer is associated with exposure to > 100 μg/L arsenic in drinking water. However, it is unclear whether such an association exists for exposure to < 100 μg/L arsenic (Chen CL et al. 2010a; Heck et al. 2009; Putila and Guo 2011; Smith et al. 2009; Steinmaus et al. 2010).

Increasing evidence supports the hypothesis that arsenic exposure can increase cancer risks in other organs. Increased risk of bladder cancer is significantly associated with increasing arsenic exposure, particularly with longer exposure periods (> 40 years) and higher drinking-water concentrations (> 600 μg/L) (Chen CJ et al. 1992; Chen CL et al. 2010b; Chiou et al. 2001; Gibb et al. 2011; Marshall et al. 2007). For kidney cancer, mortality rates increased in a dose-dependent manner for drinking-water concentrations ranging from 170 to 800 μg/L in Taiwan (Chen CJ et al. 1988a); the MRRs at 800 μg/L were 196 for men and 37.0 for women. Results from other studies in Taiwan support this finding (Smith et al. 1992). More studies with larger sample sizes are warranted to evaluate associations at drinking-water concentrations of < 100 μg/L.

A causal association between arsenic exposure and liver cancer, particularly liver angiosarcoma, was suspected as early as 1957, and several studies have substantiated that suspicion (e.g., Liaw et al. 2008; Smith et al. 1992). A number of studies from the Taiwan cohort have demonstrated increases in liver cancer deaths with increasing concentrations of arsenic in drinking water. For example, a significant dose-dependent linear trend in MRRs for liver cancer was reported with increasing arsenic concentrations in drinking water ranging from 170 to 800 μg/L (Chen CJ et al. 1988a; Wu et al. 1989). Links between arsenic exposure and liver cancer have also been supported by other reports (Chen CL et al. 2010b; Chen and Ahsan 2004; Chiu et al. 2004; Liaw et al. 2008; Morales et al. 2000). Taking epidemiological, rodent, and in vitro studies together, the evidence shows that the liver is a target organ of arsenic carcinogenicity (Liu and Waalkes 2008).

Other Effects on Multiple Bodily Systems

A multitude of other health effects are linked to chronic arsenic exposure. These arsenic-associated health problems affect nearly every major organ and organ system in the body ( Table 3 ). A comprehensive review of the literature for these effects is beyond the scope of this review; therefore, this section addresses the broad range of harmful effects of arsenic in the human body and makes apparent the impact of arsenic-contaminated drinking water on public health. Taken together, the body of data drives home the critical importance of monitoring for arsenic in food sources and drinking-water sources, including private wells.

Significant neurological impairments are evident in children and adults who exhibit impaired cognitive abilities and motor functions after arsenic exposure (Chen Y et al. 2009; Dong and Su 2009; Gong et al. 2011; Hamadani et al. 2011; Parvez et al. 2011; Vahidnia et al. 2007; Wasserman et al. 2004, 2007). Cognitive impairments were observed in children at 6 and 10 years of age (Wasserman et al. 2004, 2007). One recent study reported impairments in verbal and full-scale IQ in girls but not boys (Hamadani et al. 2011). In adults, arsenic exposure in drinking water is linked to significantly lower scores on tests of cognitive ability as well as lower education levels (Gong et al. 2011). Peripheral neuropathy and painful muscle spasms are also known to occur with arsenic exposure (Sengupta et al. 2008; Vahidnia et al. 2007).

In addition to lung cancer, chronic arsenic exposure is associated with other respiratory system effects. Mortality from pulmonary tuberculosis was increased in arsenic-exposed individuals in the Chilean cohort (Smith et al. 2011). In the same cohort, increased mortality from bronchiectasis was significant for those exposed to arsenic during early life with a standardized mortality ratio (SMR) of 50.1 ( Table 4 ) (Smith et al. 2006). Reduced forced expiratory volume and forced vital capacity is associated with early-life exposure to arsenic, with a magnitude of reduction similar to smoking throughout adulthood (Dauphine et al. 2011). Other respiratory symptoms include chronic cough, blood in the sputum, and other breathing problems (Parvez et al. 2010).

The cardiovascular system is affected in several ways by arsenic (Abhyankar et al. 2012; Chen Y et al. 2009, 2011; States et al. 2009; Yuan et al. 2007). Cardiovascular effects include carotid atherosclerosis (Huang et al. 2009) and ischemic heart disease (Abhyankar et al. 2012; Chen Y et al. 2011; States et al. 2009). Furthermore, an association between hypertension and arsenic exposure is evident in some studies, and additional larger studies are needed to substantiate the link (Abhyankar et al. 2012; Abir et al. 2012).

Immune system effects of arsenic exposure are evident in several contexts. Effects include altered immune-related gene expression and cytokine production in lymphocytes (Andrew et al. 2008; Morzadec et al. 2012) and in lung (Lantz et al. 2007). Arsenic is significantly associated with increased infant morbidity from infectious diseases (Rahman et al. 2010b). Furthermore, maternal urinary arsenic during pregnancy is significantly associated with increased inflammation and reduced numbers of T cells as well as altered cytokine profiles in cord blood (Ahmed et al. 2011) and reduced thymic function in infants (Ahmed et al. 2012).

Multiple endocrine effects of arsenic exposure are suggested from studies in human and animal studies. These include affecting hormone regulation via the retinoic acid, thyroid hormone, and estrogen receptors (Barr et al. 2009; Davey et al. 2007, 2008; Ettinger et al. 2009; Smith and Steinmaus 2009; Watson and Yager 2007). Increased occurrence of diabetes is also linked to arsenic exposure, particularly at higher doses and with exposure periods of > 10 years (Chen CJ et al. 2007; Del Razo et al. 2011; Islam et al. 2012; Jovanovic et al. 2012).