Epidemiological association between chlorinated water and overall risk of cancer: A systematic review.

Review objective The review objective is to synthesise the best available evidence on exposure to chlorinated water and risk of cancer. Risks associated with colorectal or bladder cancers have already been established and therefore will not be considered in this systematic review. Background Public large scale use of chlorine-disinfected water began in the early years of the 20th century and resulted in dramatic reductions in observed rates of dysentery causing diseases, particularly cholera and typhoid infections1. Today in the USA 98% of water treatment plants use chlorine-based disinfectants to treat water2 and similar chlorine disinfection use patterns of water treatment occur around the world where developed systems of potable water exist. The clear reduction in dysentery causing diseases derived from chlorine disinfection of water supplies offset complaints about chlorination adversely influencing the taste of water, environmental impacts and concerns regarding potential adverse health effects1,3-8. Race in 1918 was the first to suggest that chlorine disinfection by-products could be the basis for these complaints1. The science of chlorine disinfection by-products was in its infancy at this time, as was the chlorine disinfection process. It was not until Rook in 19749 identified trihalomethanes as the potential carcinogenic agents in potable waters sourced from the Mississippi River in Louisiana (New Orleans) that chlorine disinfection by-products came under scrutiny as an important public health risk4,10-12. The potential public health risks of large scale chlorination treatment of water supplies was first eluded to by Race in 19181 but was poorly understood due to the limited knowledge base of the time. Although the knowledge base has grown, many questions remain unresolved regarding the toxicity, carcinogenicity and incidence of cancer associated with exposure to trihalomethanes and other chlorine disinfection by-products. As a result they remain an important public health issue to this day1,3,4,6-8,10,13. Water is fundamental to life, the extensive use of chlorine disinfection practices globally results in widespread exposure to chlorine treated water and therefore chlorine generated disinfection by-products. Early studies focused on ingestion as the exposure route however, dermal (showering, bathing, dishwashing and swimming) and inhalation (vaporized aerosols as created in showering, dishwashing, indoor swimming pools, spas and saunas) are now also regarded as important exposure routes13-17. As a result, early trial reports and study designs may have underestimated exposure to chlorine by-products and the impact these may have on cancer incidence and mortality. Indeed, inhalation exposure at swimming pools has been linked to a threefold increase of cancer risk (all cancers) above the USA EPA negligible risk level18. Villanueva's research on trihalomethanes, highlighted that dermal exposure was associated with a 2x increased risk for bladder cancer in men who showered or bathed with chlorinated water whether or not they drank chlorinated or bottled water13,16-18. The route of exposure also influences blood concentration and target tissue levels of chlorine disinfection by products14. The knowledge base continues to expand as these exposure routes are given more consideration in study design. Irrespective of exposure route, the evidence for an association between chlorine by-products and bowel/bladder cancers is increasing13,19,20. It is estimated one in three cancers globally are skin cancers21 the leading cause of cancer in Australia and the world. Skin cancers have been excluded from the following cancer statistics because of the generally accepted view that skin cancers are associated with depleting ozone layers and exposure to ionising radiation21. However, the association to dermal and inhalation exposure to chlorination disinfection by-products as a possible cause of skin cancer has not been previously considered as a risk factor since these routes of exposure have only recently been identified21. In Australia bowel cancer is the most common cancer after skin cancer affecting approximately 13,000 men and women each year22. According to the International Agency for Research on Cancer's Globocan 2008 project, colorectal cancer is the third most common cancer in men and second most common in women worldwide23. Almost 60% of cases occur in developed regions, the highest rates being estimated in Australia / New Zealand and Western Europe23. Stomach cancer ranks as the fourth most common diagnosed worldwide and second for cause of death worldwide23. In 2008, the most common cancers (excluding skin cancers) in descending order were lung, breast, colorectal and stomach. Oesophageal cancer ranked eighth for diagnosed and sixth for cause of death worldwide23. Chlorine disinfection by-products are also being investigated for possible association with other cancers including bladder, kidney, liver, pancreatic, leukemia, breast, gastrointestinal and lymphoma6,19,24-45. The fact that dermal and inhalation routes of exposure can have significant influence on cancer risk and have only recently begun to be considered raises the question of the role chlorine disinfection by-products has as a risk factor if any in the development of skin cancer? Chlorine disinfection by-products result from chemical reaction of chlorine with various constituents of water including naturally occurring organic matter, bromine, iodine and anthropogenic compounds13. Eleven disinfection by-products are currently regulated in the USA based on the potential association with adverse health outcomes. These include the trihalomethanes, the most common chlorine disinfection by-products formed and several haloacetic acids13,46. Two of the trihalomethanes, bromodichloromethane and chloroform, have been classed as 2B carcinogens (possibly carcinogenic to humans) by the International Agency for Research on Cancer (World Health Organisation)6 whereas the US Environmental Protection Agency has designated bromodichloromethane and bromoform as B2 carcinogens (probably carcinogenic to humans as evaluated using the U.S. EPA's 1986 Guidelines for Carcinogen Risk Assessment)18. The haloacetic acids, dichloroacetic acid and bromate have been graded by both agencies as 2B (possibly carcinogenic to humans) and B2 (probably carcinogenic to humans as evaluated using the U.S. EPA's 1986 Guidelines for Carcinogen Risk Assessment) respectively6,18. The International Agency for Research on Cancer has graded two trihalomethanes, bromoform and chlorodibromomethane as 3 (not classifiable as to its carcinogenicity in humans)6. In addition, over 600 disinfection by-products have been identified and it is estimated that many more than this exist and remain to be identified13. The toxicological data therefore is incomplete. The knowledge base for the USA regulated disinfection by-products is also inadequate, for example; Bromoacetic acid has never been tested for carcinogenicity and the remaining regulated disinfection by-products have not been graded either by the International Agency for Research on Cancer or the US Environmental Protection Agency6,13,18,46. Seventy-four disinfection by-products are defined as “emerging” by Richardson due to their moderate occurrence levels and/or toxicological properties13. One of the most toxic chlorine disinfection by-products identified to date are the halofuranones and analogues, known as MX and BMX series13,47 as assessed in animal studies designed to monitor formation of a variety of cancers and in vitro cell assays13. Of those disinfection by-products that have been identified, concentrations range from sub micro grams per litre to low to mid micrograms per litre13. Current knowledge of the carcinogenicity, genetoxicity and mutagenicity of chlorine disinfection by-products is a result of studies13 with standardised microbial and mammalian cell lines and cytology tests. As such, the mode of action of these compounds within the body therefore is poorly understood. The potency of individual or mixtures of disinfection by products, how these damage DNA and consequently interfere with cellular function leading either to carcinogenesis, mutagenesis or genetoxicity in a range of sites remains the subject of study. Gender, age, dose and duration of exposure appear to have the most influence based on current knowledge as to what potential negative health outcome is likely to be experienced. There is very little research on how complex mixtures of disinfection by-products interact and potentially compound their toxicity. This is now recognised as an area requiring further research since it is a realistic reflection of what occurs in practice13. The US EPA and other groups have applied risk assessment models to disinfection by products and potential adverse health outcomes18. In general the following four steps of analysis have been applied, hazard identification, dose response assessment, exposure assessment and risk characterization13. In the USA results from risk assessment models have been used to make changes to the regulated disinfection by-products in drinking water out of concerns for cancer and reproductive and developmental risks associated with exposure8,13,15,48,49. The US Environmental Protection Agency introduced these revisions to the national primary drinking water regulations in 20068,46. In Australia there is no mandatory regulation of drinking water standards. The Australian Drinking Water Guidelines 20113 was recently updated to include more information on potential toxic chemicals in tap water; The guide has been designed as the authoritative reference for good practice and management of drinking water supplies in this country3. Consumers today are better informed and have increasing awareness of the potential contribution disinfection by products and other contaminants (including new and emerging contaminants such as endocrine disruptors, pharmaceutical and personal care products, mixtures of organic chemicals, perfluorinated chemicals and nanoparticles) may play in adverse health outcomes including carcinogenesis and reproductive complications3,4,8,13,43,49. The current version of the Australian Drinking Water Guidelines 2011 devote 750 pages (of 1244 pages) to discussing potential toxic chemicals in tap water including disinfection by products3. Evidence of consumer knowledge exists by the common use of water filters at home and office and the extensive use of bottled waters all of which either remove chlorine and other contaminants or do not contain chlorine. The point of use treatment of water or use of alternatives like bottled water is a global phenomenon in developed nations. Today there is evidence implicating chlorine disinfection by-products in a range of adverse health outcomes including many cancers, genetoxicity and abnormalities associated with pregnancy including birth defects15,49. Asthma, eye, skin and mucus membrane irritations, allergic reactions, endocrine effects, infections and respiratory complications have also been implicated50-52. However, the magnitude of these effects is not clear and there are many gaps in the knowledge base requiring more research13. The strongest associations with cancer to date have been made with colorectal and bladder cancers16,19,20 and appears to be related to dose and length of exposure based on relative risk6. Routes of exposure, especially dermal and inhalation are now considered by some as potentially of more consequence than that of ingestion13-17. The possibility that skin cancer is related to exposure does not seem to have been considered to date since most early studies focused on ingestion only as route of exposure. Only recently have studies begun to look at new and emerging chlorine disinfection by products and although these may occur in much smaller concentrations than the trihalomethanes and other more common disinfection by-products they can be as much as 6000 times more toxic as is the case with the halofuranone MX when compared with chloroform according to the cancer potency index developed by the state of California13,47. It is the intent of this review to systematically assess the current knowledge base for research that has addressed the relationship between chlorine disinfection by-products exposure and possible association with cancers, other than colorectal and bladder, and determine the strength of evidence for an association. Inclusion criteria Types of participants This review will consider studies that include males and females of all ages. Types of intervention(s)/phenomena of interest This review will consider studies that evaluate exposure to chlorine disinfection by-products by drinking (ingesting), bathing, showering, swimming, cooking, cleaning and dishwashing (dermal and inhalation) and identify incidence and mortality outcomes of cancer (excluding colorectal and bladder) compared with exposure without chemical disinfection (chlorine) or alternative disinfection processes. Types of outcomes This review will consider studies that include the following outcome measures. Incidence, mortality and specifically measures of risk between exposure and outcome of cancers with the exception of bowel and bladder. For example the following cancers have been associated with chlorine disinfection by products, kidney/adrenal, liver, thyroid, pituitary, lymphoma and leukaemia, pancreatic, gastrointestinal (other than colorectal), testicular, breast and lung cancer. These and any other cancers identified as relevant eg. skin cancers will be included. Types of studies This review will consider epidemiological prospective and retrospective cohort studies and case control studies for inclusion. Search strategy The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilised in this review. An initial limited search of PubMed will be undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe articles. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English will be considered for inclusion in this review. Studies published since trihalomethanes were first identified as drinking water disinfection by-products in 1974 will be considered for inclusion in this review. Any other studies found and considered relevant will also be included. The databases to be searched include but are not limited to: SCOPUS Cochrane Library Web of Science Embase PubMed GOVERNMENT DATA BASES USEPA Office of Ground Water and Drinking Water (water.epa.gov/drink/index.htm) US Department of Health and Human Services US Department of Agriculture (USDA) Rural Development Utilities Programs, Water and Environmental Programs (www.usda.gov/rus/water) Health Canada; www.hc-sc.gc.ca/ewh-semt/water-eau/drink-potab/index-eng.php European Union; http://ec.europa.eu/environment/water/-drink/index_en.html Australia; www.nhmrc.gov.au/publications/synopses/eh19syn.html WATER INDUSTRY American Water Works Association (AWWA); www.awwa.org Association of State Drinking Water Administrators (ASDWA); www.asdwa.org Association of Metropolitan Water Agencies (AWMA); www.amwa.net National rural Water Association (NRWA); www.nrwa.org National Association of Water Companies (NAWC); www.nawc.com Water Research Foundation; www.waterresearchfoundation.org GREY LITERATURE MedNar grey World Health Organisation; www.who.int/water_sanitation_health/dwqn/en ProQuest dissertations & Theses database Trove Conference Proceedings Examples of keywords: Disinfection by-products, disinfection by product*[tw], chlorinat*[tw], chlorine[tw], chlorine/chemistry[mh], purification by product*[tw], water supply[mh], water suppl*[tw], water purification*[tw], drinking water[tw],potable[tw], treated water*[tw], exposure, dermal, inhalation, ingestion, swim*[tw], bath*[tw], shower*[tw], human*[tw], trihalomethanes, haloacetic acids, bromate, chlorite, halonitromethanes, Iodo-acids, halo acids, Iodo-trihalomethanes, halofuranones, halomides, haloacetonitriles, tribromopyrole, nitrosodimethylamine, nitrosamines, aldehydes, chlorate etc Neoplasms, kidney, liver, lung, breast, skin etc. Search modifiers “and” “or” etc. will be applied. Assessment of methodological quality Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardised critical appraisal instruments from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer. Data collection Data will be extracted from papers included in the review using the standardised data extraction tool from JBI-MAStARI (Appendix II). The standardized data extraction tool will be modified as necessary if it does not suit the study requirements for data extraction. The data extracted will include specific details about the exposure, populations, study methods and outcomes of significance to the review question and specific objectives. Data synthesis Quantitative data will, where possible be pooled in statistical meta-analysis using Revman 5.1 (The Cochrane collaboration). All results will be subject to double data entry. Measures of association including odds ratios, rate ratios, standardised incidence ratios, hazard ratio, risk ratios, will be considered relative risk. If required, extracted data will be transformed into Ln (Relative risk) with standard errors calculated from available data using the method described by Greenland53. If effect estimates are not available, they will be calculated from crude data and the 95% confidence limits. Where possible, effect measure adjusted for maximum number of covariates will be extracted. Heterogeneity will be assessed statistically using the standard Chi2 and I2 and also explored using subgroup analyses based on the different study designs, primary cancer site diagnoses and whether or not secondary metastises have been accounted for in mortality records. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate. Conflicts of interest No conflicts of interest are known. Acknowledgements TGB & Associates for an introduction to the element of water. Ed Aromataris and Tim Schultz for help refining the question, although the original question remains, is chlorine disinfected water hydrating? Hao-min Cheng for taking on the critical role of secondary reviewer. As this systematic review forms partial submission for the award of Masters of Clinical Science through the Joanna Briggs Institute, the University of Adelaide, a secondary reviewer will only be used for critical appraisal.

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