Allan H. Smith

Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and in early childhood.

Arsenic in drinking water is an established cause of lung cancer, and preliminary evidence suggests that ingested arsenic may also cause nonmalignant lung disease. Antofagasta is the second largest city in Chile and had a distinct period of very high arsenic exposure that began in 1958 and lasted until 1971, when an arsenic removal plant was installed. This unique exposure scenario provides a rare opportunity to investigate the long-term mortality impact of early-life arsenic exposure. In this study, we compared mortality rates in Antofagasta in the period 1989–2000 with those of the rest of Chile, focusing on subjects who were born during or just before the peak exposure period and who were 30–49 years of age at the time of death. For the birth cohort born just before the high-exposure period (1950–1957) and exposed in early childhood, the standardized mortality ratio (SMR) for lung cancer was 7.0 [95% confidence interval (CI), 5.4–8.9; p < 0.001] and the SMR for bronchiectasis was 12.4 (95% CI, 3.3–31.7; p < 0.001). For those born during the high-exposure period (1958–1970) with probable exposure in utero and early childhood, the corresponding SMRs were 6.1 (95% CI, 3.5–9.9; p < 0.001) for lung cancer and 46.2 (95% CI, 21.1–87.7; p < 0.001) for bronchiectasis. These findings suggest that exposure to arsenic in drinking water during early childhood or in utero has pronounced pulmonary effects, greatly increasing subsequent mortality in young adults from both malignant and nonmalignant lung disease.

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.

Lung cancer and arsenic concentrations in drinking water in Chile

Cities in northern Chile had arsenic concentrations of 860 &mgr;g/liter in drinking water in the period 1958–1970. Concentrations have since been reduced to 40 &mgr;g/liter. We investigated the relation between lung cancer and arsenic in drinking water in northern Chile in a case-control study involving patients diagnosed with lung cancer between 1994 and 1996 and frequency-matched hospital controls. The study identified 152 lung cancer cases and 419 controls. Participants were interviewed regarding drinking water sources, cigarette smoking, and other variables. Logistic regression analysis revealed a clear trend in lung cancer odds ratios and 95% confidence intervals (CIs) with increasing concentration of arsenic in drinking water, as follows: 1, 1.6 (95% CI = 0.5–5.3), 3.9 (95% CI = 1.2–12.3), 5.2 (95% CI = 2.3–11.7), and 8.9 (95% CI = 4.0–19.6), for arsenic concentrations ranging from less than 10 &mgr;g/liter to a 65-year average concentration of 200–400 &mgr;g/liter. There was evidence of synergy between cigarette smoking and ingestion of arsenic in drinking water; the odds ratio for lung cancer was 32.0 (95% CI = 7.2–198.0) among smokers exposed to more than 200 &mgr;g/liter of arsenic in drinking water (lifetime average) compared with nonsmokers exposed to less than 50 &mgr;g/liter. This study provides strong evidence that ingestion of inorganic arsenic is associated with human lung cancer.

An Emerging Role for Epigenetic Dysregulation in Arsenic Toxicity and Carcinogenesis

Background Exposure to arsenic, an established human carcinogen, through consumption of highly contaminated drinking water is a worldwide public health concern. Several mechanisms by which arsenical compounds induce tumorigenesis have been proposed, including oxidative stress, genotoxic damage, and chromosomal abnormalities. Recent studies have suggested that epigenetic mechanisms may also mediate toxicity and carcinogenicity resulting from arsenic exposure. Objective We examined the evidence supporting the roles of the three major epigenetic mechanisms—DNA methylation, histone modification, and microRNA (miRNA) expression—in arsenic toxicity and, in particular, carcinogenicity. We also investigated future research directions necessary to clarify epigenetic and other mechanisms in humans. Data sources and synthesis We conducted a PubMed search of arsenic exposure and epigenetic modification through April 2010 and summarized the in vitro and in vivo research findings, from both our group and others, on arsenic-associated epigenetic alteration and its potential role in toxicity and carcinogenicity. Conclusions Arsenic exposure has been shown to alter methylation levels of both global DNA and gene promoters; histone acetylation, methylation, and phosphorylation; and miRNA expression, in studies analyzing mainly a limited number of epigenetic end points. Systematic epigenomic studies in human populations exposed to arsenic or in patients with arsenic-associated cancer have not yet been performed. Such studies would help to elucidate the relationship between arsenic exposure, epigenetic dysregulation, and carcinogenesis and are becoming feasible because of recent technological advancements.

Health Effects of Arsenic and Chromium in Drinking Water: Recent Human Findings

Even at high concentrations, arsenic-contaminated water is translucent, tasteless, and odorless. Yet almost every day, studies report a continually increasing plethora of toxic effects that have manifested in exposed populations throughout the world. In this article we focus on recent findings, in particular those associated with major contributions since 2006. Early life exposure, both in utero and in childhood, has been receiving increased attention, and remarkable increases in consequent mortality in young adults have been reported. New studies address the dose-response relationship between drinking-water arsenic concentrations and skin lesions, and new findings have emerged concerning arsenic and cardiovascular disease. We also review the increasing epidemiological evidence that the first step of methylation of inorganic arsenic to monomethylated arsenic (MMA) is actually an activation step rather than the first step in detoxification, as once thought. Hexavalent chromium differs from arsenic in that it discolors water, turning the water yellow at high concentrations. A controversial issue is whether chromium causes cancer when ingested. A recent publication supports the original findings in China of increased cancer mortality in a population where well water turned yellow with chromium.

Arsenic Exposure During Pregnancy and Size at Birth: A Prospective Cohort Study in Bangladesh

The authors evaluated the association of prenatal arsenic exposure with size at birth (birth weight, birth length, head and chest circumferences). This prospective cohort study, based on 1,578 mother-infant pairs, was conducted in Matlab, Bangladesh, in 2002-2003. Arsenic exposure was assessed by analysis of arsenic in urine collected at around gestational weeks 8 and 30. The association of arsenic exposure with size at birth was assessed by linear regression analyses. In analysis over the full range of exposure (6-978 microg/L), no dose-effect association was found with birth size. However, significant negative dose effects were found with birth weight and head and chest circumferences at a low level of arsenic exposure (<100 microg/L in urine). In this range of exposure, birth weight decreased by 1.68 (standard error (SE), 0.62) g for each 1-microg/L increase of arsenic in urine. For head and chest circumferences, the corresponding reductions were 0.05 (SE, 0.03) mm and 0.14 (SE, 0.03) mm per 1 microg/L, respectively. No further negative effects were shown at higher levels of arsenic exposure. The indicated negative effect on birth size at a low level of arsenic exposure warrants further investigation.

Diesel exhaust exposure and lung cancer

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.

Arsenic in drinking water and mortality from vascular disease: an ecologic analysis in 30 counties in the United States.

Chronic arsenic consumption can cause vascular diseases. Adverse vascular effects of arsenic in drinking water in the United States have not been studied. This study investigated the ecological relationship between the population-weighted mean arsenic concentration in public drinking water supplies and mortality from circulatory diseases in 30 U.S. counties from 1968 to 1984. Mean arsenic levels ranged from 5.4 to 91.5 micrograms/l. Standardized mortality ratios (SMRs) for diseases of arteries, arterioles, and capillaries (DAAC) (ICD 8th/9th revision, 440-448) for counties exceeding 20 micrograms/l were 1.9 (90% confidence interval [CI] = 1.7-2.1) for females and 1.6 (90% CI = 1.5-1.8) for males. The SMRs for the three subgroups of DAAC--arteriosclerosis, aortic aneurysm, and all other DAAC--tended to be elevated. With respect to the same arsenic group, the SMRs for congenital anomalies of the heart (ICD-8/9, 746/745-746) and circulatory system (ICD-8/9, 747) also tended to be elevated. Two competing interpretations emerge as possibilities: either there are spurious associations resulting from invalid outcome data or causal associations.

Nutritional Factors and Susceptibility to Arsenic-Caused Skin Lesions in West Bengal, India

There has been widespread speculation about whether nutritional deficiencies increase the susceptibility to arsenic health effects. This is the first study to investigate whether dietary micronutrient and macronutrient intake modulates the well-established human risk of arsenic-induced skin lesions, including alterations in skin pigmentation and keratoses. The study was conducted in West Bengal, India, which along with Bangladesh constitutes the largest population in the world exposed to arsenic from drinking water. In this case–control study design, cases were patients with arsenic-induced skin lesions and had < 500 μg/L arsenic in their drinking water. For each case, an age- and sex-matched control was selected from participants of a 1995–1996 cross-sectional survey, whose drinking water at that time also contained < 500 μg/L arsenic. Nutritional assessment was based on a 24-hr recall for major dietary constituents and a 1-week recall for less common constituents. Modest increases in risk were related to being in the lowest quintiles of intake of animal protein [odds ratio (OR) = 1.94; 95% confidence interval (CI), 1.05–3.59], calcium (OR = 1.89; 95% CI, 1.04–3.43), fiber (OR = 2.20; 95% CI, 1.15–4.21), and folate (OR = 1.67; 95% CI, 0.87–3.2). Conditional logistic regression suggested that the strongest associations were with low calcium, low animal protein, low folate, and low fiber intake. Nutrient intake was not related to arsenic exposure. We conclude that low intake of calcium, animal protein, folate, and fiber may increase susceptibility to arsenic-caused skin lesions. However, in light of the small magnitude of increased risks related to these dietary deficiencies, prevention should focus on reducing exposure to arsenic.

Arsenic in Drinking Water and Skin Lesions: Dose-Response Data from West Bengal, India

Background. Over 6 million people live in areas of West Bengal, India, where groundwater sources are contaminated with naturally occurring arsenic. The key objective of this nested case-control study was to characterize the dose-response relation between low arsenic concentrations in drinking water and arsenic-induced skin keratoses and hyperpigmentation. Methods. We selected cases (persons with arsenic-induced skin lesions) and age- and sex-matched controls from participants in a 1995–1996 cross-sectional survey in West Bengal. We used a detailed assessment of arsenic exposure that covered at least 20 years. Participants were reexamined between 1998 and 2000. Consensus agreement by four physicians reviewing the skin lesion photographs confirmed the diagnosis in 87% of cases clinically diagnosed in the field. Results. The average peak arsenic concentration in drinking water was 325 &mgr;g/liter for cases and 180 &mgr;g/liter for controls. The average latency for skin lesions was 23 years from first exposure. We found strong dose-response gradients with both peak and average arsenic water concentrations. Conclusions. The lowest peak arsenic ingested by a confirmed case was 115 &mgr;g/liter. Confirmation of case diagnosis and intensive longitudinal exposure assessment provide the basis for a detailed dose-response evaluation of arsenic-caused skin lesions.