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      Rapid Reduction in Breast Cancer Mortality With Inorganic Arsenic in Drinking Water

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          Abstract

          Background

          Arsenic trioxide is effective in treating promyelocytic leukemia, and laboratory studies demonstrate that arsenic trioxide causes apoptosis of human breast cancer cells. Region II in northern Chile experienced very high concentrations of inorganic arsenic in drinking water, especially in the main city Antofagasta from 1958 until an arsenic removal plant was installed in 1970.

          Methods

          We investigated breast cancer mortality from 1950 to 2010 among women in Region II compared to Region V, which had low arsenic water concentrations. We conducted studies on human breast cancer cell lines and compared arsenic exposure in Antofagasta with concentrations inducing apoptosis in laboratory studies.

          Findings

          Before 1958, breast cancer mortality rates were similar, but in 1958–1970 the rates in Region II were half those in Region V (rate ratio RR = 0.51, 95% CI 0.40–0.66; p < 0.0001). Women under the age of 60 experienced a 70% reduction in breast cancer mortality during 1965–1970 (RR = 0.30, 0.17–0.54; p < 0.0001). Breast cancer cell culture studies showed apoptosis at arsenic concentrations close to those estimated to have occurred in people in Region II.

          Interpretation

          We found biologically plausible major reductions in breast cancer mortality during high exposure to inorganic arsenic in drinking water which could not be attributed to bias or confounding. We recommend clinical trial assessment of inorganic arsenic in the treatment of advanced breast cancer.

          Highlights

          • •

            We report major reductions in breast cancer mortality during high exposure to inorganic arsenic in drinking water.

          • •

            Our breast cancer cell studies showed apoptosis at low concentrations of arsenic.

          • •

            We recommend clinical trial assessment of inorganic arsenic in the treatment of advanced breast cancer.

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          Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide.

          David Scheinberg, S L Soignet, S Jhanwar … (1998)
          Two reports from China have suggested that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL). We evaluated this drug in patients with APL in an attempt to elucidate its mechanism of action. Twelve patients with APL who had relapsed after extensive prior therapy were treated with arsenic trioxide at doses ranging from 0.06 to 0.2 mg per kilogram of body weight per day until visible leukemic cells were eliminated from the bone marrow. Bone marrow mononuclear cells were serially monitored by flow cytometry for immunophenotype, fluorescence in situ hybridization, reverse-transcription-polymerase-chain-reaction (RT-PCR) assay for PML-RAR-alpha fusion transcripts, and Western blot analysis for expression of the apoptosis-associated proteins caspases 1, 2, and 3. Of the 12 patients studied, 11 achieved complete remission after treatment that lasted from 12 to 39 days (range of cumulative doses, 160 to 495 mg). Adverse effects were relatively mild and included rash, lightheadedness, fatigue, and musculoskeletal pain. Cells that expressed both CD11b and CD33 (antigens characteristic of mature and immature cells, respectively), and which were found by fluorescence in situ hybridization to carry the t(15;17) translocation, increased progressively in number during treatment and persisted in the early phase of complete remission. Eight of 11 patients who initially tested positive for the PML-RAR-alpha fusion transcript by the RT-PCR assay later tested negative; 3 other patients, who persistently tested positive, relapsed early. Arsenic trioxide induced the expression of the proenzymes of caspase 2 and caspase 3 and activation of both caspase 1 and caspase 3. Low doses of arsenic trioxide can induce complete remissions in patients with APL who have relapsed. The clinical response is associated with incomplete cytodifferentiation and the induction of apoptosis with caspase activation in leukemic cells.
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            Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water.

            Darcey Smith, M Antonia Biggs, R Haque … (1998)
            Studies in Taiwan and Argentina suggest that ingestion of inorganic arsenic from drinking water results in increased risks of internal cancers, particularly bladder and lung cancer. The authors investigated cancer mortality in a population of around 400,000 people in a region of Northern Chile (Region II) exposed to high arsenic levels in drinking water in past years. Arsenic concentrations from 1950 to the present were obtained. Population-weighted average arsenic levels reached 570 microg/liter between 1955 to 1969, and decreased to less than 100 microg/liter by 1980. Standardized mortality ratios (SMRs) were calculated for the years 1989 to 1993. Increased mortality was found for bladder, lung, kidney, and skin cancer. Bladder cancer mortality was markedly elevated (men, SMR = 6.0 (95% confidence interval (CI) 4.8-7.4); women, SMR = 8.2 (95% CI 6.3-10.5)) as was lung cancer mortality (men, SMR = 3.8 (95% CI 3.5-4.1); women, SMR = 3.1 (95% CI 2.7-3.7)). Smoking survey data and mortality rates from chronic obstructive pulmonary disease provided evidence that smoking did not contribute to the increased mortality from these cancers. The findings provide additional evidence that ingestion of inorganic arsenic in drinking water is indeed a cause of bladder and lung cancer. It was estimated that arsenic might account for 7% of all deaths among those aged 30 years and over. If so, the impact of arsenic on the population mortality in Region II of Chile is greater than that reported anywhere to date from environmental exposure to a carcinogen in a major population.
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              Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water.

              Yan Yuan, Guillermo Marshall, Jane Liaw … (2007)
              Region II of Chile (the second most northerly administrative region) experienced dramatic increases in average arsenic water concentrations beginning in 1958, followed by marked declines in the 1970s when water treatment plants were installed. This history provides a unique opportunity to study time trends in the development of arsenic-related cancers, including lung and bladder cancers. We investigated lung and bladder cancer mortality from 1950 to 2000 for region II compared with region V, where drinking water was not contaminated with arsenic. Mortality data were obtained from 218,174 death certificates for the two regions for 1950-1970 and from mortality data tapes that identified 307,541 deaths in the two regions for 1971-2000. Poisson regression models were used to identify time trends in rate ratios (RRs) of mortality from lung and bladder cancers comparing region II with region V. Lung and bladder cancer mortality rate ratios for region II compared with region V started to increase about 10 years after high arsenic exposures commenced and continued to rise until peaking in 1986-1997. The peak lung cancer mortality RRs were 3.61 (95% confidence interval [CI] = 3.13 to 4.16) for men and 3.26 (95% CI = 2.50 to 4.23) for women. The peak bladder cancer RRs were 6.10 (95% CI = 3.97 to 9.39) for men and 13.8 (95% CI = 7.74 to 24.5) for women. Combined lung and bladder cancer mortality rates in region II were highest in the period 1992-1994, with mortality rates of 153 and 50 per 100,000 men and women, respectively, in region II compared with 54 and 19 per 100,000 in region V. Such large increases in total population cancer mortality rates have, to our knowledge, not been documented for any other environmental exposure. The long latency pattern is noteworthy, with mortality from lung and bladder cancers continuing to be high until the late 1990s, even though major decreases in arsenic exposure occurred more than 25 years earlier.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 13 October 2014
                Publication date Collection: November 2014
                Publication date (Electronic): 13 October 2014
                Volume: 1
                Issue: 1
                Pages: 58-63
                Affiliations
                [a ]Arsenic Research Group, School of Public Health, University of California, Berkeley, Berkeley, CA, United States
                [b ]Departamento de Estadística, Facultad de Matemáticas, Pontificia Universidad Catòlica de Chile, Santiago, Chile
                [c ]Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, United States
                [d ]Breast Cancer Oncology Program, Stanford Cancer Institute, Stanford, CA, United States
                [e ]Departamento de Salud Pública, Escuela de Medicina, Pontificia Universidad Catòlica de Chile; Advanced Center for Chronic Diseases ACCDIS, Santiago, Chile
                Author notes
                [* ]Corresponding author at: Arsenic Research Group, School of Public Health, University of California, Berkeley, 50 University Hall, MC7360, Berkeley, CA 94720-7360, United States.
                Article
                Publisher ID: S2352-3964(14)00007-3
                DOI: 10.1016/j.ebiom.2014.10.005
                PMC ID: 4286879
                PubMed ID: 25580451
                SO-VID: dd82c0e9-4bfb-49c8-bd87-fc7beaf68aa7
                Copyright © © 2014 The Authors. Published by Elsevier B.V.
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 15 September 2014
                Date revision received : 8 October 2014
                Date accepted : 9 October 2014
                Categories
                Subject: Original Article

                Keywords: arsenic,breast cancer,breast cancer cell line studies,cancer therapy,chile,drinking water,epidemiology
                Data availability:
                Keywords: arsenic, breast cancer, breast cancer cell line studies, cancer therapy, chile, drinking water, epidemiology

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