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Microcystins from tap water could be a risk factor for liver and colorectal cancer: A risk intensified by global change
Medical Hypotheses 72 (2009) 539–540
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Microcystins from tap water could be a risk factor for liver and colorectal cancer: A risk intensified by global change Juan Martínez Hernández a,b,*, V. López-Rodas b, E. Costas b a b
Servicio de Medicina Preventiva, Hospital Carlos III, C/Sinesio Delgado 10, 28029 Madrid, Spain Genética, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 31 October 2008 Accepted 5 November 2008
s u m m a r y An increasing number of people drink water from fresh water supply reservoirs. However, with the global change a lot of reservoirs become eutrophic, which facilitates the occurrence of toxin-producing cyanobacterial blooms. Microcystins (powerful hepatotoxic water–soluble heptapeptides) are the most important cyanobacterial toxins affecting humans. High doses of microcystins produce hepatic necrosis. Consequently, WHO Guidelines limit microcystins to 1 ppb in drinking waters. However, microcystins are present frequently in tap water at lower doses. Here, we hypothesized that chronic consume of tap water containing low doses of microcystins may be a risk factor for liver and colorectal cancer. Two kinds of evidences support this hypothesis. On one hand some epidemiological data (mainly in China). On the other hand, the molecular mechanism of microcystins toxicity (inhibition of protein phosphatases PP1 and PP2) is just like okadaic acid (a potent tumor promoter). Cancer risk from drinking water is certainly less than smoking, occupational exposures or some foods. But it is significant and with a rapid increase of toxic cyanobacterial blooms by eutrophycation, become more frequent. Ó 2009 Elsevier Ltd. All rights reserved.
Nowadays, billions of human beings drink water from fresh water supply reservoirs. Quality of this tap water varies largely dependent on characteristic of the water supply reservoirs (i.e., eutrophy level) as well as the treatments for drinkability. Although usually microbiological and chemical treatments prepare water for use, sometimes water contain traces of toxic substances, which could to increase incidence of cancer. Furthermore, cities as New York and Rome have recommended consume tap water, to reduce waste [1]. As an example, different species of cyanobacteria usually proliferating in water supply reservoirs are known to produce potent hepatotoxins. Of all toxic species of cyanobacteria, the hepatotoxin-producing Microcystis aeruginosa (Kützing) is the most important cause of toxic cyanobacterial blooms affecting humans. M. aeruginosa produce microcystins, a family of water–soluble cyclic heptapeptides, which are powerful hepatotoxic agents. High doses of microcystins produce hepatic necrosis and chronic microcystin exposure induces hepatocyte proliferation [2]. On one hand, the acute toxicity for people of the microcystin was firmly established after the incidents of Caruaru, Brazil, in which 101 patients undergoing haemodialysis suffered liver failure and 50 died while receiving inadequately treated water containing the toxin [3,4]. On
* Corresponding author. Address: Servicio de Medicina Preventiva, Hospital Carlos III, C/Sinesio Delgado 10, 28029 Madrid, Spain. Tel.: +34 914532611/+34 660632167; fax: +34 917336614. E-mail address: [email protected] (J.M. Hernández). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.11.041
the other hand, chronic microcystin exposure is considered one of the first cause of liver cancer in China together with aflatoxins and hepatitis B virus infection [5]. In fact, quality drinking water is considered a cornerstone for the prevention of liver cancer in China [6]. The International Agency for Research on Cancer (IARC) considers microcystins possibly carcinogenic to humans [7]. Microcystins are able to induce proliferation at low doses, which probably explains its carcinogenic effect for the liver [8]. Liver cancer is among the most important tumors in incidence and mortality. Globally, made happen around 607,000 deaths in 2001 (1.1% in mortality from all causes in the world) and caused the loss of more than nine million disability adjusted life years (DALYs) [9]. Special importance reaches in China, where its mortality rate was 20/100.000 in 1990. The strong known risk factors for this cancer are chronic infection by hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol abuse [10]. Aflatoxins (AF), produced by fungi (Aspergillus sp.), and the ingestion of contaminated water with MC-LR have emerged as major risk factors in developing countries [11]. The co-ingestion of microcystin-LR and AF multiply by three the risk of hepatocellular carcinoma of AF alone, in laboratory animals [12]. Another tumor strongly related to the intake of contaminated water with microcystins is colorectal cancer, which is increasing rapidly in developed countries. Colorectal cancer is associated with consumption of meat and animal fats [13,14], and with contaminated food consumption by okadaic acid [15]. However, the toxic effect of okadaic acid (a toxic polyester produced by marine dinoflagellates and concentrated by shellfish) is due to inhibition of
540
J.M. Hernández et al. / Medical Hypotheses 72 (2009) 539–540
protein phosphatases (PP1 and PP2) just the same effect that produces microcystins. In this sense, recent epidemiological studies in China showed that the consumption of water with more than 50 pg/ml microcystins multiplies by 7.9 the risk of colorectal cancer [16]. The limit in Water Drink WHO Guidelines [17] as well as in many European Union countries legislation [18] is 1 lg/l of microcystin-LR equivalent (i.e. 20-fold higher than the limit considered as positive in this study). In a developed country as Spain, the level of microcystins in drinking water it is not controlled except in cities. In addition, Spaniards consumed directly tap water much more than bottled water. Consequently, many people could be usually exposed to not known doses of microcystins, increasing health risks. Furthermore, the sporadic ingesting of water in recreational hipertrophic reservoirs could be also risk factor because the toxin intake can be much higher than the chronic ingestion from tap water. Cancer risk from drinking water is small and certainly less than smoking, occupational exposures or some foods. But it is significant and in the nowadays-global change scenario, with a rapid increase of inland water eutrophycation, blooms of toxin-producing cyanobacteria become more frequent [19,20]. A society of citizens informed, responsible for their health, should influence the administration to invest in prevention and control measures on drinking water, as one of the classic pillars of health and public welfare of citizens. References [1]. [2] Clark SP, Ryan TP, Searfoss GH, Davis MA, Hooser SB. Chronic microcystin exposure induces hepatocyte proliferation with increased expression of mitotic and cyclin-associated genes in P53-deficient mice. Toxicol Pathol 2008;36(2):190–203. Epub 2008 March 18. [3] Pouria S, de Andrade A, Barbosa J, Cavalcanti RL, Barreto VT, Ward CJ, et al. Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil. Lancet 1998;352:21–6.
[4] Jochimsen EM, Carmichael VV, An JS, Cardo DM, Cookson ST, Holmes CE, et al. Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil. N Engl J Med 1998;338:873–8. [5] Ueno Y, Nagata S, Tsutsumi T, Hasegawa A, Watanabe MF, Park HD, et al. Detection of microcystins, a blue–green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay. Carcinogenesis 1996;17(6):1317–21. [6] Lin NF, Tang J, Ismael HS. Study on environmental etiology of high incidence areas of liver cancer in China. World J Gastroenterol 2000;6(4):572–6. [7] Cogliano VJ, Baan RA, Straif K, Grosse Y, Secretan B, El Ghissassi F. Use of mechanistic data in IARC evaluations. Environ Mol Mutagen 2008;49(2):100–9. [8] Herfindal L, Selheim F. Microcystin produces disparate effects on liver cells in a dose dependent manner. Mini-Rev Med Chem 2006;6:279–85. [9] Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367(9524):1747–57. [10] Franceschi S, Montella M, Polesel J, La Vecchia C, Crispo A, Dal Maso L, et al. Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy. Cancer Epidemiol Biomarkers Prev 2006;15(4):683–9. [11] Yu SZ. J Primary prevention of hepatocellular carcinoma. Gastroenterol Hepatol 1995;10(6):674–82. [12] Liam M, Liu Y, Yu Sz, Qian GS, Wan SG, Dixon KR. Hepatitis B virus gene and cyanobaterial toxins promote aflatoxin B1-induced hepatotumorigenesis in mice. World J Gastroenterol 2006;12(19):3065–72. [13] Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323:1664–72. [14] Key TJ, Allen NE, Spencer EA, Travis RC. The effect of diet on risk of cancer. Lancet 2002;360:861–8. [15] Manerio E, Rodas VL, Costas E, Hernandez JM. Shellfish consumption: a major risk factor for colorectal cancer. Med Hypotheses 2008;70(2):409–12. [16] Zhou L, Yu H, Chen K. Relationship between microcystin in drinking water and colorectal cancer. Biomed Environ Sci 2002;15(2):166–71. [17] World Health Organization. Guidelines for drinking-water quality (electronic resource): incorporating first addendum, recommendations, 3rd ed., vol. 1. p. 407–8. [18] Real Decreto 140/2003 de 7 de febrero, por el que se establecen los criterios sanitarios de la calidad del agua de consumo humano (BOE n° 45 de 21 de febrero de 2003). [19] Woodruff DS. Declines of biomes and biotas and the future of evolution. Proc Natl Acad Sci USA 2001;98:5471–6. [20] López-Rodas V, Costas E, Bañares E, García-Villada L, Altamirano M, Rico M, et al. Analysis of poligenic traits of Microcystis aeruginosa (Cyanobacteria) strains by restricted maximum likelihood (REML) procedures: 2. Microcystin net production, photosynthesis and respiration. Phycologia 2006;45(3):243–8.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Microcystins from tap water could be a risk factor for liver and colorectal cancer: A risk intensified by global change Juan Martínez Hernández a,b,*, V. López-Rodas b, E. Costas b a b
Servicio de Medicina Preventiva, Hospital Carlos III, C/Sinesio Delgado 10, 28029 Madrid, Spain Genética, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain
a r t i c l e
i n f o
Article history: Received 31 October 2008 Accepted 5 November 2008
s u m m a r y An increasing number of people drink water from fresh water supply reservoirs. However, with the global change a lot of reservoirs become eutrophic, which facilitates the occurrence of toxin-producing cyanobacterial blooms. Microcystins (powerful hepatotoxic water–soluble heptapeptides) are the most important cyanobacterial toxins affecting humans. High doses of microcystins produce hepatic necrosis. Consequently, WHO Guidelines limit microcystins to 1 ppb in drinking waters. However, microcystins are present frequently in tap water at lower doses. Here, we hypothesized that chronic consume of tap water containing low doses of microcystins may be a risk factor for liver and colorectal cancer. Two kinds of evidences support this hypothesis. On one hand some epidemiological data (mainly in China). On the other hand, the molecular mechanism of microcystins toxicity (inhibition of protein phosphatases PP1 and PP2) is just like okadaic acid (a potent tumor promoter). Cancer risk from drinking water is certainly less than smoking, occupational exposures or some foods. But it is significant and with a rapid increase of toxic cyanobacterial blooms by eutrophycation, become more frequent. Ó 2009 Elsevier Ltd. All rights reserved.
Nowadays, billions of human beings drink water from fresh water supply reservoirs. Quality of this tap water varies largely dependent on characteristic of the water supply reservoirs (i.e., eutrophy level) as well as the treatments for drinkability. Although usually microbiological and chemical treatments prepare water for use, sometimes water contain traces of toxic substances, which could to increase incidence of cancer. Furthermore, cities as New York and Rome have recommended consume tap water, to reduce waste [1]. As an example, different species of cyanobacteria usually proliferating in water supply reservoirs are known to produce potent hepatotoxins. Of all toxic species of cyanobacteria, the hepatotoxin-producing Microcystis aeruginosa (Kützing) is the most important cause of toxic cyanobacterial blooms affecting humans. M. aeruginosa produce microcystins, a family of water–soluble cyclic heptapeptides, which are powerful hepatotoxic agents. High doses of microcystins produce hepatic necrosis and chronic microcystin exposure induces hepatocyte proliferation [2]. On one hand, the acute toxicity for people of the microcystin was firmly established after the incidents of Caruaru, Brazil, in which 101 patients undergoing haemodialysis suffered liver failure and 50 died while receiving inadequately treated water containing the toxin [3,4]. On
* Corresponding author. Address: Servicio de Medicina Preventiva, Hospital Carlos III, C/Sinesio Delgado 10, 28029 Madrid, Spain. Tel.: +34 914532611/+34 660632167; fax: +34 917336614. E-mail address: [email protected] (J.M. Hernández). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.11.041
the other hand, chronic microcystin exposure is considered one of the first cause of liver cancer in China together with aflatoxins and hepatitis B virus infection [5]. In fact, quality drinking water is considered a cornerstone for the prevention of liver cancer in China [6]. The International Agency for Research on Cancer (IARC) considers microcystins possibly carcinogenic to humans [7]. Microcystins are able to induce proliferation at low doses, which probably explains its carcinogenic effect for the liver [8]. Liver cancer is among the most important tumors in incidence and mortality. Globally, made happen around 607,000 deaths in 2001 (1.1% in mortality from all causes in the world) and caused the loss of more than nine million disability adjusted life years (DALYs) [9]. Special importance reaches in China, where its mortality rate was 20/100.000 in 1990. The strong known risk factors for this cancer are chronic infection by hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol abuse [10]. Aflatoxins (AF), produced by fungi (Aspergillus sp.), and the ingestion of contaminated water with MC-LR have emerged as major risk factors in developing countries [11]. The co-ingestion of microcystin-LR and AF multiply by three the risk of hepatocellular carcinoma of AF alone, in laboratory animals [12]. Another tumor strongly related to the intake of contaminated water with microcystins is colorectal cancer, which is increasing rapidly in developed countries. Colorectal cancer is associated with consumption of meat and animal fats [13,14], and with contaminated food consumption by okadaic acid [15]. However, the toxic effect of okadaic acid (a toxic polyester produced by marine dinoflagellates and concentrated by shellfish) is due to inhibition of
540
J.M. Hernández et al. / Medical Hypotheses 72 (2009) 539–540
protein phosphatases (PP1 and PP2) just the same effect that produces microcystins. In this sense, recent epidemiological studies in China showed that the consumption of water with more than 50 pg/ml microcystins multiplies by 7.9 the risk of colorectal cancer [16]. The limit in Water Drink WHO Guidelines [17] as well as in many European Union countries legislation [18] is 1 lg/l of microcystin-LR equivalent (i.e. 20-fold higher than the limit considered as positive in this study). In a developed country as Spain, the level of microcystins in drinking water it is not controlled except in cities. In addition, Spaniards consumed directly tap water much more than bottled water. Consequently, many people could be usually exposed to not known doses of microcystins, increasing health risks. Furthermore, the sporadic ingesting of water in recreational hipertrophic reservoirs could be also risk factor because the toxin intake can be much higher than the chronic ingestion from tap water. Cancer risk from drinking water is small and certainly less than smoking, occupational exposures or some foods. But it is significant and in the nowadays-global change scenario, with a rapid increase of inland water eutrophycation, blooms of toxin-producing cyanobacteria become more frequent [19,20]. A society of citizens informed, responsible for their health, should influence the administration to invest in prevention and control measures on drinking water, as one of the classic pillars of health and public welfare of citizens. References [1]
[4] Jochimsen EM, Carmichael VV, An JS, Cardo DM, Cookson ST, Holmes CE, et al. Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil. N Engl J Med 1998;338:873–8. [5] Ueno Y, Nagata S, Tsutsumi T, Hasegawa A, Watanabe MF, Park HD, et al. Detection of microcystins, a blue–green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay. Carcinogenesis 1996;17(6):1317–21. [6] Lin NF, Tang J, Ismael HS. Study on environmental etiology of high incidence areas of liver cancer in China. World J Gastroenterol 2000;6(4):572–6. [7] Cogliano VJ, Baan RA, Straif K, Grosse Y, Secretan B, El Ghissassi F. Use of mechanistic data in IARC evaluations. Environ Mol Mutagen 2008;49(2):100–9. [8] Herfindal L, Selheim F. Microcystin produces disparate effects on liver cells in a dose dependent manner. Mini-Rev Med Chem 2006;6:279–85. [9] Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367(9524):1747–57. [10] Franceschi S, Montella M, Polesel J, La Vecchia C, Crispo A, Dal Maso L, et al. Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy. Cancer Epidemiol Biomarkers Prev 2006;15(4):683–9. [11] Yu SZ. J Primary prevention of hepatocellular carcinoma. Gastroenterol Hepatol 1995;10(6):674–82. [12] Liam M, Liu Y, Yu Sz, Qian GS, Wan SG, Dixon KR. Hepatitis B virus gene and cyanobaterial toxins promote aflatoxin B1-induced hepatotumorigenesis in mice. World J Gastroenterol 2006;12(19):3065–72. [13] Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323:1664–72. [14] Key TJ, Allen NE, Spencer EA, Travis RC. The effect of diet on risk of cancer. Lancet 2002;360:861–8. [15] Manerio E, Rodas VL, Costas E, Hernandez JM. Shellfish consumption: a major risk factor for colorectal cancer. Med Hypotheses 2008;70(2):409–12. [16] Zhou L, Yu H, Chen K. Relationship between microcystin in drinking water and colorectal cancer. Biomed Environ Sci 2002;15(2):166–71. [17] World Health Organization. Guidelines for drinking-water quality (electronic resource): incorporating first addendum, recommendations, 3rd ed., vol. 1. p. 407–8. [18] Real Decreto 140/2003 de 7 de febrero, por el que se establecen los criterios sanitarios de la calidad del agua de consumo humano (BOE n° 45 de 21 de febrero de 2003). [19] Woodruff DS. Declines of biomes and biotas and the future of evolution. Proc Natl Acad Sci USA 2001;98:5471–6. [20] López-Rodas V, Costas E, Bañares E, García-Villada L, Altamirano M, Rico M, et al. Analysis of poligenic traits of Microcystis aeruginosa (Cyanobacteria) strains by restricted maximum likelihood (REML) procedures: 2. Microcystin net production, photosynthesis and respiration. Phycologia 2006;45(3):243–8.