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Assessing exposure and health consequences of chemicals in drinking water: current state of knowledge and research needs.

Introduction

The safety of water supplies is of paramount public health importance. An estimated 13% of the world population lacked access to improved drinking-water sources in 2008 [UNICEF and World Health Organization (WHO) 2011], and almost 10% of the total burden of disease worldwide could be prevented by improving drinking-water supply, sanitation, hygiene, and the management of water resources (Pruss-Ustun et al. 2008). Microbiological contamination is the largest cause of waterborne disease at a global scale. However, chemicals in water supplies can be related to health risks, generally when associated with long-term exposures (Thompson et al. 2007).

There are uncertainties about the safety of current standards for some regulated chemicals, and the potential health impacts of unregulated or emerging chemical contaminants are largely unknown. In May 2012, a workshop was held at the Centre for Research of Environmental Epidemiology (CREAL), Barcelona, Spain, with the aim of advancing the field of epidemiology and chemical contaminants in water and to make recommendations for future research. Our aspiration was that the proposed suggestions be useful and applicable to any type of chemical contaminant occurring in drinking water. Chemicals that we discuss as examples in this review are substances whose main pathway of human exposure is through drinking water. Although the chemical universe is broad and most chemicals do not occur exclusively in drinking water, water is essential for life, and exposures to chemicals in drinking water, even at low concentrations, may have important consequences across the entire population. Here we focus on cancer as an example and summarize the main discussion points and conclusions of the workshop.

Occurrence

Regulated chemicals. Drinking-water quality is regulated in most countries, and monitoring is conducted routinely. A complete list of chemicals that are currently regulated in drinking water, and the regulatory limits promulgated for each chemical by the WHO (2011), the U.S. Environmental Protection Agency (EPA 2009), and the European Union (EU) Council (1998) are provided in Table 1. These regulatory guidelines require periodic review to be updated according to new evidence. For example, the U.S. EPA reduced its maximum contaminant level (MCL) for arsenic from 50 [micro]g/L in 1942 to the current level of 10 [micro]g/L in response to growing scientific evidence of its adverse health effects (Smith et al. 2002). Epidemiological studies have reported associations of trihalomethane (THM) levels in drinking water (a surrogate measure of the disinfection by-product mixture) and bladder cancer (Villanueva et al. 2004) at THM levels lower than the current regulations in the United States and the European Union (80 and 100 [micro]g/L, respectively; Table 1). The current MCL for nitrate was set based on methemoglobinemia among infants, but there is uncertainty concerning the safety of this MCL for chronic effects over longer exposure periods (e.g., on cancer) (Ward et al. 2005). Manganese is a neurotoxin associated with learning disabilities and deficits in intellectual function in children (Zoni and Lucchini 2013). The WHO manganese guideline has been fluctuating from the initial 500 [micro]g/L in 1958 (Ljung and Vahter 2007) to its discontinuation in the current (fourth) edition of the WHO guidelines (WHO 2011). This has generated controversy in the scientific community because the last guideline before discontinuation (400 [micro]g/L) was questionable according to some authors (Ljung and Vahter 2007) and the discontinuation of the manganese guidelines has received criticisms (Frisbie et al. 2012). Although many contaminants are monitored and regulated, the adequacy of the MCL approach is open to debate, in part because these limits are often based on toxicological studies of animals because human studies are not available or are inconclusive.

Emerging chemical contaminants. Non-regulated chemicals are of particular concern and constitute a main focus of current research (Richardson and Ternes 2011). Wastewater from human activities may contaminate water supply sources with pharmaceuticals, nanoparticles, consumer products (such as sunscreens), and other contaminants (Table 2), and these chemicals have been identified in drinking water (Ternes 2007). For example, iodinated or nitrogenated disinfection by-products (DBPs) [which are unregulated DBPs that are more toxic than their chlorinated and carbonaceous DBP analogs (Plewa et al. 2008b)] may occur in water supplies at very low concentrations (Plewa et al. 2004, 2008a). Degradation byproducts of pharmaceuticals, which may be more toxic than their parent compounds, also have been identified in drinking water (Shen and Andrews 2011). The contribution of drinking water as a source of exposure to perfluorinated chemicals may be as important as dietary intake (Ericson et al. 2008), and evidence suggests that continued human exposure to even relatively low concentrations of perfluorooctanoic acid (PFOA) in drinking water results in elevated body burdens that may increase the risk of health effects (Post et al. 2012). Although concentrations are generally low (usually in the range of nanograms per liter) and some individual chemicals may pose no appreciable risks to human health (Schriks et al. 2010), there are concerns about potential risks of exposures to mixtures (Silva et al. 2002). The removal efficiency by drinking-water treatment processes has been evaluated for some substances (WHO 2012) but is poorly known for many emerging pollutants.

Global Indicators of Toxicity

Water supplies often include mixtures of chemical contaminants that vary in time and space. In addition, the epidemiological and toxicological evaluation of mixtures involves significant challenges, in many cases beyond the limits of current research methods. In vitro bioassays (or biosensors) developed through toxicological research are promising tools for measuring the global toxicity of chemical mixtures in water samples and may be coupled with more in-depth analysis of specific contaminants when a positive response is detected. For example, Jeong et al. (2012) evaluated in vitro mammalian cell toxicity for a range of DBPs in an attempt to identify specific DBPs responsible for genomic DNA damage. End points that can be measured by in vitro bioassays include mutagenicity (Ames test) (Richardson et al. 2010), genotoxicity (micronuclei, Comet assay) (Plewa et al. 2010), endocrine disruption (DR-CALUX bioassay) (Brand et al. 2013; Sato et al. 2010), and cytotoxicity (Plewa et al. 2010). Although the use of these markers is not without limitations (such as the need for complex and nonstandardized sample pretreatment methods in order to obtain concentrates before laboratory analysis and the uncertain validity for some of the assays, limited throughput development, elevated cost, low sensitivity, and results reflecting only short-term exposure evaluations). Further development of these techniques and their incorporation into epidemiol ogical research may improve our understanding of the effects of mixtures. These efforts will require improved, interdisciplinary communication and collaboration including analytical chemists, toxicologists, and epidemiologists.

Human Exposure

Accurate exposure assessment in human observational studies is essential to obtain valid results and constitutes a main methodological challenge, as summarized in Table 3. Difficulties in identifying and measuring contaminants in water supplies at very low concentrations and substances occurring in mixtures hamper the evaluation of human exposure, requiring new methods in health risk analysis (Schwarzenbach et al. 2006).

DBPs are an example of chemicals occurring in complex mixtures, and this has been addressed in part by using a few compounds as surrogates for the DBP mixture as a whole. For example, observational studies of human DBP exposures and health effects have focused on a small subset of the several hundred DBPs that may occur in public water supplies (Richardson et al. 2007), particularly the THMs and haloacetic acids (HAAs) (Hinckley et al. 2005; Hoffman et al. 2008; Righi et al. 2012). However, although these compounds are often used as a surrogate for other DBPs, the assumption that they correlate with other DBPs is not universally supported, and correlations can vary in time and space (Villanueva et al. 2012).

Methods of exposure assessment are influenced by the specific outcome under study. For instance, for end points with a long latency, such as cancer, long time periods of more than several decades need to be evaluated, whereas for reproductive outcomes, it is very important to accurately capture the temporal variation in exposure over a shorter period covering the relevant time windows before and during gestation.

Chemicals or metabolites have been measured in biological samples in epidemiological studies to estimate exposures [e.g., urinary or toenail arsenic measurements in cancer studies (Karagas et al. 2004)]. Urinary trichloroacetic acid is a promising biomarker of DBPs that requires methodological development before a generalized use in epidemiological studies (Savitz 2012). In addition, among the available biomarkers specific for drinking-water contaminants, many have short half-lives (e.g., urinary trichloroacetic acid) and are thus of limited value to associate with health outcomes that require long-term exposures (Savitz 2012). Consequently, exposure assessment in most instances relies on assessing personal behavior (ascertained through questionnaires) and measuring environmental levels of the chemicals (Hoffman et al. 2008; Levallois et al. 2012).

Inhalation and dermal contact may be relevant exposure routes for volatile or skin-permeable chemicals. In such cases, activities involving different water uses at home (e.g., showering, bathing), in recreation (e.g., swimming in pools), and through occupations involving water contact should be considered.

Alternative methods of exposure assessment may involve statistical modeling; for example, modeling based on known geographic distributions of contaminants (Toledano et al. 2005), hydrological modeling of underground plumes of contaminants (Gallagher et al. 2010), and/or the use of surrogate parameters such as land use (Aschebrook-Kilfoy et al. 2012). Several methods can be used in combination, tailored to the availability of data; for example, in a recent study on the long-term exposure to arsenic and cancer, Nuckols et al. (2011) combined arsenic data from their own measurements in water samples collected at homes of the participants, data from public water utilities, and historical data for aquifers.

Exposure estimates with minimal measurement error are necessary to produce valid effect estimates. Misclassification of exposure is of particular concern at the low exposure range because it tends, under most scenarios, to attenuate associations toward the null (Cantor and Lubin 2007; Waller et al. 2001) or to reduce the precision of associations (Wright and Bateson 2004). Strategies to minimize measurement error are necessary from study design to data analysis, and include, for example, the collection of repeated measures of individual water use over the relevant exposure period (Forssen et al. 2009) and assessing reliability of interviews to exclude unreliable questionnaires (Villanueva et al. 2009).

Health Effects

The following is an overview of epidemiological findings from individual-based studies of chemical contaminants in water and cancer. Table 4 displays a summary of the evidence of carcinogenicity as evaluated and concluded by the WHO International Agency for Research on Cancer (IARC).

There is sufficient evidence in humans that arsenic in drinking water causes cancers of the urinary bladder, lung, and skin (IARC 2004). Studies conducted in areas with lower levels of arsenic in drinking water (i.e., at or below the MCL) have reported inconsistent results, and cancer risks associated with exposure to low arsenic levels over decades remain uncertain.

Bladder cancer has been consistently associated with DBP exposure (Cantor 2010), and pooled analyses combining data from studies conducted in different countries have reported associations between bladder cancer and THM at levels below current MCLs (Costet et al. 2011; Villanueva et al. 2004). Some (Cragle et al. 1985; King et al. 2000; Wilkins and Comstock 1981), but not all (Doyle et al. 1997; Hildesheim et al. 1998; Koivusalo et al. 1997), studies of DBP exposure and colon cancer have reported positive associations. Similarly, positive associations for DBP exposure have been found for rectal cancer (Bove et al. 2007; Doyle et al. 1997; Hildesheim et al. 1998) not replicated in other studies (King et al. 2000; Koivusalo et al. 1997; Wilkins and Comstock 1981).

The epidemiological investigation for nitrate and cancer has been challenging. Drinking water may be a primary source of nitrate exposure when drinking-water concentrations are > 50 mg/L (IARC 2010). Below this threshold, diet is the main exposure route, involving complex mechanisms of action through endogenous formation of 7V-nitroso compounds (IARC 2010). Long-term exposure to nitrate in drinking water has been evaluated in relation to multiple cancer sites including the esophagus, stomach, bladder, and colon (IARC 2010). Although there is inadequate human evidence for carcinogenicity, there is sufficient evidence from experimental animals for the carcinogenicity of nitrite in combination with amines or amides, and ingested nitrate under conditions that result in endogenous nitrosation has been classified as probably carcinogenic to humans (IARC 2010).

Other contaminants have been less extensively investigated in relation to cancer risk. Fluoride is added to drinking water at low concentrations in some countries to prevent dental caries, and naturally occurs in water at higher levels in certain parts of the world such as the Rift Valley in Africa (Malde et al. 2011). The IARC (1987) evaluated fluoride carcinogenicity and concluded that human and animal evidence was inadequate (Table 3). Some epidemiological studies on osteosarcoma have been published after this evaluation (Bassin et al. 2006; Kim et al. 2011), but consistent associations have not been observed.

The liver is a target organ for microcystin-LR (IARC 2010), which are toxins produced by cyanobacteria as a result of algae blooms and the eutrophication of surface waters. Individual-based studies evaluated by IARC (2010) have assessed exposure by comparing water consumed from ponds or ditches versus other sources and no measurements of toxins or bacteria were considered. In consequence, IARC concluded that evidence in humans for the carcinogenicity of microcystin-LR is inadequate (IARC 2010). Other carcinogens such as heavy metals, pesticides, and solvents may occur in drinking water as a consequence of human activities and natural hydrogeochemical processes. However, evidence on the cancer risk on human populations is limited.

Mechanisms and Biomarkers

The elucidation of mechanisms of action to provide biological plausibility and support causality suggested by epidemiological associations is a priority in current research. Biomarkers of early effect can be used in epidemiological studies to provide evidence about subclinical or intermediate effects of exposures (e.g., cytogenetic changes), and effects of very low exposure levels, and they can be used in experimental studies to evaluate the effect of an intervention. For an intermediate biomarker to be informative, it should be associated with both the disease and exposure of interest and reflect an intermediate step in the pathway between exposure and disease. For example, a suggested mechanism of action for arsenic is through epigenetic dysregulation, although there are limited human studies available (Ren et al. 2011). In addition, the evaluation of genetic variants may be used to identify susceptible populations underlying the biological mechanisms of action. For example, the evaluation of genetic variants of DBP-metabolizing enzymes in an epidemiological study on bladder cancer and THM exposure has shown that polymorphisms in key metabolizing enzymes modified DBP-associated bladder cancer risk (Cantor et al. 2010). In addition, the consistency of these findings with experimental observations of GSTT1 (glutathione S-transferase theta 1), GSTZ1 (glutathione S-transferase zeta 1), and CYP2E1 (cytochrome P450, family 2, subfamily E, polypeptide 1) enzymatic activity strengthens the hypothesis that DBPs cause bladder cancer and suggests possible mechanisms, as well as the classes of compounds likely to be implicated (Cantor et al. 2010).

There are few validated biomarkers specific for chemical contaminants in drinking water. However, the availability of prospective studies with biobanked samples and biotechnological development allowing large numbers of compounds to be measured in small amounts of biological samples (e.g., urine, plasma, serum) is encouraging. These technologies include genomics, epigenomics, transcriptomics, adductomics, proteomics, and metabolomics (Rappaport and Smith 2010; Wild 2005). Application of these techniques will facilitate a comprehensive approach to identify perturbations in biological systems and associated mechanisms of action (Moore et al. 2013). These technologies have not been widely applied in water research but have shown promising results in other areas of environmental research.

Future Challenges

A significant and growing body of evidence suggests that climate change will have a detrimental effect on the quality of water available for human consumption in the future. For example, increasing temperatures may enhance conditions for the proliferation of cyanobacteria and algae (Joehnk et al. 2008; Newcombe et al. 2012; Paerl and Huisman 2008). Cyanobacteria are of particular concern for human populations because they can produce cyanotoxins such as microcystin that have carcinogenic effects (IARC 2010). The frequency of extreme weather events is expected to increase as a consequence of climate change, and the concentrations of chemical contaminants may be affected by extreme precipitation events. For example, tests conducted in models of different types of soils showed that certain mobile pharmaceuticals occur at higher concentrations in soil and groundwater during and directly after intense precipitation events (Oppel et al. 2004). Simulation studies have shown that pesticide concentrations fluctuate with changes in precipitation intensity and seasonality (Bloomfield et al. 2006; Probst et al. 2005). Evidence concerning the effect of drought is mixed. For example, concentrations of heavy metals (e.g., chrome, mercury, lead, cadmium) introduced primarily from anthropogenic activities in the Rhine River basin are higher during drought years (Zwolsman and van Bokhoven 2007). In contrast, no significant changes during drought conditions, but significant variability between seasons, has been described in the Dommel River, a tributary of the Meuse river in the Netherlands where increased groundwater flow in winter led to increased metal concentrations (Wilbers et al. 2009). In summary, it is expected that climate change could adversely affect drinking-water quality, but there is limited knowledge concerning the magnitude and distribution of the impact at different scales (global, regional, local).

Final Remarks and Recommendations

General aspects. Although microbiological contamination is the largest contribution to waterborne disease and mortality at a global scale, chemical contaminants in water supplies also can cause disease, sometimes after long periods of exposure. The concentrations in drinking water, the prevalence of human exposure in the population, and the level of toxicity can be used to prioritize chemicals for further research. These characteristics may vary geographically and, therefore, further research should be designed to local-, region-, or country-specific circumstances as appropriate. Finally, exposures and risks affecting vulnerable populations (e.g., children and pregnant women) require special attention and are of particular interest.

Arsenic is a unique example of a substance in drinking water with conclusive evidence from human epidemiological studies. There is no doubt that arsenic is a human carcinogen at high concentrations (IARC 2004); however, there is inadequate information to determine the carcinogenic potential of other chemicals that occur in drinking water (Table 4). Arsenic has several unique characteristics--including the fact that drinking water represents the predominant source of exposure in humans; the levels in water, and thus the magnitude of the exposure, is very high in certain areas (e.g., Bangladesh); the availability of measurements in drinking water has allowed the development of epidemiological studies; the wide variability in exposures facilitates the detection of risks; the occurrence as an isolated substance rather than in mixtures allows the direct measurement of the putative agent; the magnitude of the risks are high compared with other chemicals; and the existence of biomarkers--all of which have helped to improve exposure assessment and elucidation of mechanisms of action of arsenic.

Recommendations on occurrence and exposure assessment. Improved exposure assessment to water contaminants is essential to derive valid exposure-response curves and useful knowledge for risk assessment and regulation, and here we provide some suggestions.

* The research need concerning regulated chemicals is to clarify the effects at or below their MCLs, which are suspected for some contaminants. Access to water utility monitoring data, which is necessary to conduct such studies, should be encouraged and facilitated. Access to large databases would facilitate improved exposure assessment in epidemiological studies, if the data are reliable and sufficient to evaluate temporal and geographical variations applicable to study areas.

* The measurement of emerging contaminants needs advanced and specialized analytical methods, and close collaboration between epidemiologists and analytical chemists is required to provide contaminant occurrence data suitable in format and quantity for epidemiological research. Better communication between epidemiologists and environmental analytical chemists would facilitate human health studies in this area. A mechanism to converge interests might be to collect water samples for analytical chemistry method development alongside ongoing epidemiological studies, or training analytical chemists in exposure assessment procedures.

* The evaluation of mixtures requires some attention in future studies because this remains a challenge beyond current methods. New developments may contribute to understand the health effects of chemical contaminants in drinking water.

* Some in vitro assays as indicators of water toxicity are promising tools deserving incorporation in future studies to complement exposure assessment and health risk analyses. These bioassays may be especially effective to evaluate the global effect of chemical mixtures and identify "hot spots" of toxicity. Such findings can be useful in generating hypotheses for more in-depth and resource-intensive analysis of specific contaminants and health outcomes. Incorporating these methods in epidemiological research should be encouraged, and further validation should be conducted when necessary.

* Epidemiological research generally requires large numbers of measurements and data. This may constitute a challenge in the collaboration with analytical chemists and toxicologists if experimental methods are manual or laborious but should be overcome in the future with, for example, the development of high-throughput techniques able to analyze large amounts of water samples.

* Ongoing cohort studies should be encouraged to incorporate a water dimension because retrospective assessment is challenging, particularly for outcomes with a long latency such as cancer. This would require water sample collection, measurements, and personal questionnaires in ongoing cohort studies, and new or reinforced collaborations between research groups. New cohorts (or data collections in existing cohorts) should be also encouraged to implement environmental sampling and storage of such samples (envirobanking) for use in future nested case-control studies.

* Methods developed for environmental and geospatial sciences, including geographical information systems and fate/transport modeling of chemicals, have been demonstrated to be useful in exposure assessment for risk analysis for waterborne chemical contaminants. Consequently, greater emphasis on incorporating these methodologies into environmental epidemiological studies should be made.

* Climate change is likely to affect water quality with uncertain implications for human health. Research to evaluate these impacts and the potential human health consequences at different regional scales and in different climates is necessary.

Recommendations on epidemiological methods. Epidemiological studies based on rigorous study design are essential to properly evaluate the human health risks associated with chemical contaminants in drinking water. Here we summarize some suggestions in this direction.

* There is a need to investigate the potential health outcomes of emerging (i.e., non-regulated) contaminants because current knowledge on health effects is mainly limited to regulated chemicals. However, there are still uncertainties and further research is needed to evaluate potential effects below MCLs for certain regulated chemicals.

* Studies capturing widely contrasting exposure levels are particularly useful to estimate risks. Therefore, environmental epidemiologists should influence the decision as to the location of study sites on this basis.

* Large studies with sufficient statistical power are necessary when the expected health risks are small in magnitude. It is advisable to know contaminant levels and exposure prevalence before undertaking an epidemiological study to allow the estimation of sample size to reach sufficient statistical power.

* The incorporation of biomarkers of exposure, effect, and genetic susceptibility in epidemiological studies is encouraged to identify molecular mechanisms of action and to contribute to the assessment of causality. Studies evaluating biomarkers could be companion studies within ongoing larger or small- to medium-sized experimental studies. In particular, -omic technologies can add to the current understanding of biological mechanisms and generate new hypotheses, requiring advanced and complex statistical tools to deal with the large amounts of data generated. However, biomarkers must be validated and biomarker studies generally require large numbers of observations and replication in multiple populations. Additional drawbacks of biomarker studies are the relatively high cost, the limitation of biomarkers with regard to capturing past exposures, their invasiveness, and the possibility for reverse causation (i.e., in cross-sectional or case-control studies).

General conclusions. Assessing the health impacts of chemical contaminants in drinking water is a challenge that requires improved methodologies and enhanced inter-disciplinarity in future epidemiological studies. Useful and valuable knowledge will increase if future studies successfully integrate existing and new developments from analytical chemistry, toxicology, exposure science, molecular epidemiology, statistics, environmental epidemiology, environmental sciences, engineering, and geospatial sciences. Improved cooperation and collaboration with stakeholders such as the water industry, regulatory, and public health agencies and affected communities would serve to produce higher-quality risk analyses, as well as to improve the likelihood of implementing effective and early intervention measures. Institutional support promoting access to reliable routine monitoring data at all levels and collaboration with stakeholders (e.g., water utilities, regulators, and consumer groups) would be beneficial. Finally, research efforts in this area are frequently hampered by the lack of specific funding for this research field, and the availability of stable and substantial financial support is needed, either from governmental or nongovernmental sources.

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Cristina M. Villanueva, (1,2,3) Manolis Kogevinas, (1,2,3,4) Sylvaine Cordier, (5) Michael R. Templeton, (6) Roel Vermeulen, (7) John R. Nuckols, (8) Mark J. Nieuwenhuijsen, (1,2) and Patrick Levallois (9,10,11)

(1) Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; (2) IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain; (3) CIBER Epidemiologfa y Salud Publica (CIBERESP), Madrid, Spain; (4) National Institute of Public Health, Athens, Greece; (5) Inserm (Institut National de la Sante et de la Recherche Medicale) UMR 1085, IRSET (Institut de Recherche Sante Environnement et Travail), Universite de Rennes 1, Rennes, France; (6) Imperial College London, Department of Civil and Environmental Engineering, London, United Kingdom; (7) Environmental Epidemiology Division, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands; (8) Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, USA; (9) Universite Laval, Quebec, Quebec, Canada; (10) Institut National de Sante Publique du Quebec, Quebec, Canada; (11) Centre de recherche du Centre hospitalier universitaire (CHU) de Quebec, Quebec, Canada

Address correspondence to C.M. Villanueva, CREAL-Centre for Research in Environmental Epidemiology, Barcelona Biomedical Research Park, Doctor Aiguader, 88, 08003-Barcelona (Spain). Telephone: (34) 93 214 73 44. E-mail: cvillanueva@creal.cat

This review is based on a meeting funded by the European Science Foundation (EW11-006) with the collaboration of B-DEBATE (International Center for Scientific Debate, Barcelona, Spain). Participants of the workshop included the authors and A. Bernard (Catholic University of Louvain, Belgium), T. De Kok (Maastricht University, the Netherlands), J. Fawell (independent consultancy and advisory services on drinking water and environment, United Kingdom), A. Gomez (Public Health Agency of Barcelona, Spain), J. Grimalt [Institute of Environmental Assessment and Water Research (ID^EA), Spanish Council for Scientific Research (CSIC), Spain], T. Grummt (Federal Environment Agency, Germany), M. Heringa (KWR Watercycle Research Institute, the Netherlands), P. Hunter (University of East Anglia, United Kingdom), G. Lindstrom (Orebro University, Sweden), P. Marsden (Drinking Water Inspectorate, United Kingdom), M. Pedersen (CREAL, Spain), M. Plewa (University of Illinois at Urbana-Champaign, USA), E. Righi (Universita degli Studi di Modena e Reggio Emilia, Italy), M. Schriks (KWR Watercycle Research Institute, the Netherlands), L. Stayner (University of Illinois, USA), F. Valero (Aigues Ter-Llobregat, Spain), E.D. Wagner (University of Illinois at Urbana-Champaign, USA), E. Zuccato (Mario Negri Institute for Pharmacological Research, Italy).

The authors declare they have no actual or potential competing financial interests.

Received: 5 November 2012; Accepted: 24 December 2013; Advance Publication: 3 January 2014; Final Publication: 1 March 2014.
Table 1. Regulatory limits [[micro]g/L (except for asbestos)] for
chemicals in drinking water established by the WHO (2011), the U.S.
EPA (2009), and the EU Council (1998).

Chemical                                          WHO   U.S. EPA

Acrylamide                                        0.5        (a)
Alachlor                                           20          2
Aldicarb                                           10         --
Aldrin + dieldrin                                0.03         --
Antimony                                           20          6
Arsenic                                            10         10
Asbestos (million fibers                           --          7
  >10 [micro]m per liter)
Atrazine                                      100 (b)          3
Barium                                            700      2,000
Benzene                                            10          5
Benzo[a]pyrene                                    0.7        0.2
Berylium                                           --          4
Boron                                           2,400         --
Bromate                                            10         10
Bromodichloromethane                               60         --
Bromoform                                         100         --
Cadmium                                             3          5
Carbofuran                                          7         40
Carbon tetrachloride                                4          5
Chloramines (as [Cl.sub.2])                        --      4,000
Chlorate                                          700         --
Chlordane                                         0.2          2
Chlorine                                        5,000      4,000
Chlorine dioxide                                   --        800
Chlorite                                          700      1,000
Chlorobenzene                                      --        100
Chloroform                                        300         --
Chlorotoluron                                      30         --
Chlorpyrifos                                       30         --
Chromium (total)                                   50        100
Copper                                          2,000     13,000
Cyanazine                                         0.6         --
Cyanide                                            --        200
2,4-D (dichlorophenoxyacetic acid)                 30         70
Dalapon                                            --        200
2,4-DB (dichlorofenoxybutyric acid)                90         --
DDT (dichlorodiphenyltrichloroethane)               1         --
  and metabolites
Dibromochloromethane                              100         --
1,2-Dibromo-3-chloropropane (DBCP)                  1        0.2
1,2-Dibromoethane                                 0.4         --
Dichloroacetate                                    50         --
Dichloroacetonitrile                               20         --
1,2-Dichlorobenzene (o-dichlorobenzene)         1,000        600
1,4-Dichlorobenzene (p-dichlorobenzene)           300         75
1,2-Dichloroethane                                 30          5
1,2-Dichloroethene                                 50         --
1,1-Dichloroethylene                               --          7
c/s-1,2-Dichloroethylene                           --         70
frans-1,2-Dichloroethylene                         --        100
Dichloromethane                                    20          5
1,2-Dichloropropane                                40          5
1,3-Dichloropropene                                20         --
Dichlorprop                                       100         --
Di(2-ethylhexyl) adipate                           --        400
Di(2-ethylhexyl) phtalate                           8          6
Dimethoate                                          6         --
Dinoseb                                            --          7
1,4-Dioxane                                        50         --
Dioxin (2,3,7,8-TCDD)                              --    0.00003
Diquat                                             --         20
Edetic acid                                       600         --
Endothall                                          --        100
Endrin                                            0.6          2
Epichlorohydrin                                   0.4        (a)
Ethylbenzene                                      300        700
Ethylene dibromide                                 --       0.05
Fenoprop/Silvex/2,4,5-TP/2-(2,4,5-                  9         50
  trichlorophenoxy)propionic acid
Fluoride                                        1,500      4,000
Glyphosate                                         --        700
Haloacetic acids (HAAs) (c)                        --         60
Heptachlor                                         --        0.4
Heptachlor epoxide                                 --        0.2
Hexachlorobenzene                                  --          1
Hexachlorobutadiene                               0.6         --
Hexachlorocyclopentadiene                          --         50
Hydroxyatrazine                                   200         --
Isoproturon                                         9         --
Lead                                               10         15
Lindane                                             2        0.2
Mecoprop                                           10         --
Mercury                                             6          2
4-(2-Methyl-4-chlorophenoxy) acetic acid            2         --
  (MCPA)
Methoxyclor                                        20         40
Metolachlor                                        10         --
Microcystin-LR                                      1         --
Molinate                                            6         --
Monochloramine                                  3,000         --
Monochloroacetate                                  20         --
Nickel                                             70         --
Nitrate                                        50,000     45,000
Nitrilotriacetic acid                             200         --
Nitrite                                         3,000      4,500
W-Nitrosodimethylamine (NDMA)                     0.1         --
Oxamyl (Vydate[R])                                 --        200
Pendimethalin                                      20         --
Pentachlorophenol                                   9          1
Pesticides                                         --         --
Pesticides (total)                                 --         --
Picloram                                           --        500
Polychlorinated biphenyls (PCBs)                   --        0.5
Polycyclic aromatic hydrocarbons                   --         --
Selenium                                           40         50
Simazine                                            2          4
Sodium dichloroisocyanurate/                 50,000/-         --
  cyanuric acid                                40,000
Styrene                                            20        100
Tertbutylazine                                      7         --
Tetrachloroethene (tetrachloroethylene)            40          5
Tetrachloroethylene + trichloroethylene            --         --
Thallium                                           --          2
Toluene                                           700      1,000
Toxaphene                                          --          3
Trichloroacetate                                  200         --
1,2,4-Trichlorobenzene                             --         70
1,1,1-Trichloroethane                              --        200
1,1,2-Trichloroethane                              --          5
Trichloroethene/trichloroethylene                  20          5
2,4,6-Trichlorophenol                             200         --
2,4,5-T (2,4,5-trichlorophenoxyacetic acid)         9         --
Trifluralin                                        20         --
Trihalomethanes (total)                            --         80
Vinyl chloride                                    0.3          2
Xylenes                                           500     10,000

                                                         Chemical
Chemical                                         EU       group

Acrylamide                                      0.1      Organic
Alachlor                                         --      Organic
Aldicarb                                         --      Organic
Aldrin + dieldrin                                --      Organic
Antimony                                        5.0     Inorganic
Arsenic                                          10     Inorganic
Asbestos (million fibers                         --     Inorganic
  >10 [micro]m per liter)
Atrazine                                         --      Organic
Barium                                           --     Inorganic
Benzene                                         1.0      Organic
Benzo[a]pyrene                                0.010      Organic
Berylium                                         --     Inorganic
Boron                                         1,000     Inorganic
Bromate                                          10        DBP
Bromodichloromethane                             --        DBP
Bromoform                                        --        DBP
Cadmium                                         5.0     Inorganic
Carbofuran                                       --      Organic
Carbon tetrachloride                             --      Organic
Chloramines (as [Cl.sub.2])                      --    Disinfectant
Chlorate                                         --        DBP
Chlordane                                        --      Organic
Chlorine                                         --    Disinfectant
Chlorine dioxide                                 --    Disinfectant
Chlorite                                         --        DBP
Chlorobenzene                                    --      Organic
Chloroform                                       --        DBP
Chlorotoluron                                    --      Organic
Chlorpyrifos                                     --      Organic
Chromium (total)                                 50     Inorganic
Copper                                        2,000     Inorganic
Cyanazine                                        --      Organic
Cyanide                                          50     Inorganic
2,4-D (dichlorophenoxyacetic acid)               --      Organic
Dalapon                                          --      Organic
2,4-DB (dichlorofenoxybutyric acid)              --      Organic
DDT (dichlorodiphenyltrichloroethane)            --      Organic
  and metabolites
Dibromochloromethane                             --        DBP
1,2-Dibromo-3-chloropropane (DBCP)               --      Organic
1,2-Dibromoethane                                --      Organic
Dichloroacetate                                  --        DBP
Dichloroacetonitrile                             --        DBP
1,2-Dichlorobenzene (o-dichlorobenzene)          --      Organic
1,4-Dichlorobenzene (p-dichlorobenzene)          --      Organic
1,2-Dichloroethane                              3.0      Organic
1,2-Dichloroethene                               --      Organic
1,1-Dichloroethylene                             --      Organic
c/s-1,2-Dichloroethylene                         --      Organic
frans-1,2-Dichloroethylene                       --      Organic
Dichloromethane                                  --      Organic
1,2-Dichloropropane                              --      Organic
1,3-Dichloropropene                              --      Organic
Dichlorprop                                      --      Organic
Di(2-ethylhexyl) adipate                         --      Organic
Di(2-ethylhexyl) phtalate                        --      Organic
Dimethoate                                       --      Organic
Dinoseb                                          --      Organic
1,4-Dioxane                                      --      Organic
Dioxin (2,3,7,8-TCDD)                            --      Organic
Diquat                                           --      Organic
Edetic acid                                      --      Organic
Endothall                                        --      Organic
Endrin                                           --      Organic
Epichlorohydrin                                0.10      Organic
Ethylbenzene                                     --      Organic
Ethylene dibromide                               --      Organic
Fenoprop/Silvex/2,4,5-TP/2-(2,4,5-               --      Organic
  trichlorophenoxy)propionic acid
Fluoride                                      1,500     Inorganic
Glyphosate                                       --      Organic
Haloacetic acids (HAAs) (c)                      --        DBP
Heptachlor                                       --      Organic
Heptachlor epoxide                               --      Organic
Hexachlorobenzene                                --      Organic
Hexachlorobutadiene                              --      Organic
Hexachlorocyclopentadiene                        --      Organic
Hydroxyatrazine                                  --      Organic
Isoproturon                                      --      Organic
Lead                                             10     Inorganic
Lindane                                          --      Organic
Mecoprop                                         --      Organic
Mercury                                         1.0     Inorganic
4-(2-Methyl-4-chlorophenoxy) acetic acid         --      Organic
  (MCPA)
Methoxyclor                                      --      Organic
Metolachlor                                      --      Organic
Microcystin-LR                                   --    Algal toxin
Molinate                                         --      Organic
Monochloramine                                   --    Disinfectant
Monochloroacetate                                --        DBP
Nickel                                           20     Inorganic
Nitrate                                      50,000     Inorganic
Nitrilotriacetic acid                            --      Organic
Nitrite                                         500     Inorganic
W-Nitrosodimethylamine (NDMA)                    --        DBP
Oxamyl (Vydate[R])                               --      Organic
Pendimethalin                                    --      Organic
Pentachlorophenol                                --      Organic
Pesticides                                     0.10      Organic
Pesticides (total)                             0.50      Organic
Picloram                                         --      Organic
Polychlorinated biphenyls (PCBs)                 --      Organic
Polycyclic aromatic hydrocarbons               0.10      Organic
Selenium                                         10     Inorganic
Simazine                                         --      Organic
Sodium dichloroisocyanurate/                     --    Disinfectant
cyanuric acid
Styrene                                          --      Organic
Tertbutylazine                                   --      Organic
Tetrachloroethene (tetrachloroethylene)          --      Organic
Tetrachloroethylene + trichloroethylene          10      Organic
Thallium                                         --     Inorganic
Toluene                                          --      Organic
Toxaphene                                        --      Organic
Trichloroacetate                                 --        DBP
1,2,4-Trichlorobenzene                           --      Organic
1,1,1-Trichloroethane                            --      Organic
1,1,2-Trichloroethane                            --      Organic
Trichloroethene/trichloroethylene                --      Organic
2,4,6-Trichlorophenol                            --      Organic
2,4,5-T (2,4,5-trichlorophenoxyacetic acid)      --      Organic
Trifluralin                                      --      Organic
Trihalomethanes (total)                         100        DBP
Vinyl chloride                                 0.50      Organic
Xylenes                                          --      Organic

DBP, disinfection by-product.

(a) Each water system must certify annually that when it uses
acrylamide and-or epichlorohydrin to treat water, the combination of
dose and monomer level does not exceed the levels specified, as
follows: acrylamide = 0.05% dosed at 1 mg/L (or equivalent);
epichlorohydrin = 0.01% dosed at 20 mg/L (or equivalent). (b)
Includes its chloro-s-triazine metabolites. (c) Includes the sum of
monochloroacetic acid, dichloroacetic acid, trichloroacetic acid,
monobromoacetic acid, and dibromoacetic acid.

Table 2. Emerging chemical contaminants that may occur in water
sources or treated drinking water [data from Richardson and Ternes
(2011)], with the current state of information regarding their health
effects.

Chemical group                               Source

Algal toxins               Produced by algal blooms from an excess of
                           nutrients (in agricultural runoff and
                           wastewater discharges).

Artificial sweeteners      Consumers > urban wastewater > natural
                           waters > drinking-water source.

Brominated flame           Used during many years in commercial
retardants                 products such as children's sleepwear,
                           foam cushions in chairs, computers,
                           plastics, and electronics. Diet is a
                           source of exposure because some are
                           persistent and accumulate in fish, eggs,
                           milk, and meat.

Benzotriazoles             Complexing agents widely used as
                           anticorrosives and for silver protection
                           in dishwashing liquids.

DBPs                       Generated through chemical reaction
                           between organic matter and a disinfectant
                           (e.g., chlorine, chloramine, chlorine
                           dioxide) in the treatment of drinking
                           water and swimming pools.

Ionic liquids              Organic salts with low melting point
                           (< 100[degrees]C) promoted as "green
                           chemistry" replacements to traditional
                           solvents in industry. They exhibit some
                           unique properties, including tunable
                           viscosity, miscibility, and electrolytic
                           conductivity, which make them useful for
                           many applications, including organic
                           synthesis and catalysis, production of
                           fuel cells, batteries, coatings, oils, and
                           nanoparticles, as well as other chemical
                           engineering and biotechnology
                           applications.

Illicit drugs              Found in surface waters, but generally
                           removed by treatment in water utilities
                           (Huerta-Fontela et al. 2008).

Musks                      Highly lipophilic chemicals widely used as
                           fragrance additives in many consumer
                           products including perfumes, lotions,
                           sunscreens, deodorants, and laundry
                           detergents.

Naphtenic acids            Result from petroleum extraction. Occur
                           naturally in crude oil deposits across the
                           world (up to 4% by weight) and in coal.

Nanomaterials              Heterogeneous group of chemicals sized 1-
                           100 nm, highly stable, strong, conductors,
                           and with low permeability.

Perfluorinated compounds   Used to make stain repellents (such as
(PFCs)                     Teflon), and in the manufacture of paints,
                           adhesives, waxes, polishes, metals,
                           electronics, fire-fighting foams, and
                           caulks as well as grease-proof coatings
                           for packaging. Diet is the main route of
                           exposure, followed by drinking water,
                           house dust, and air.

Pesticide transformation   Result from the hydrolysis, oxidation,
by-products                biodegration, or photolysis of pesticides.
                           Can be present at higher levels than the
                           parent compound and can be as toxic or
                           more toxic. Diet is a source of exposure.

Pharmaceuticals            Human consumption > excretion > urban
                           wastewater > natural waters > drinking-
                           water source.

Siloxanes                  Used in cosmetics, deodorants, soaps, hair
                           conditioners, hair dyes, car waxes, baby
                           pacifiers, cookware, cleaners, furniture
                           polishes, and water-repellent windshield
                           coatings.

Sunscreens/ultraviolet     Personal care products > urban wastewater
filters                    > natural waters > drinking-water source.
                           Identified in drinking water (in
                           Barcelona, Spain) with average
                           concentrations up to 295 ng-L (Diaz-Cruz
                           et al. 2012).

Single chemicals

Dioxane                    High-production chemical used as a solvent
                           stabilizer in the manufacture and
                           processing of paper, cotton, textile
                           products, automotive coolants, cosmetics,
                           and shampoos and as a stabilizer of
                           1,1,1-trichloroethane (a degreasing
                           agent).

Perchlorate                Highly stable and soluble chemical used in
                           solid propellants in rockets, missiles,
                           and fireworks as well as in highway
                           flares. Can be found as a contaminant in
                           sodium hypochlorite. Perchlorate can
                           accumulate in plants and has been found in
                           biological samples.

Chemical group                             Chemicals

Algal toxins               Microcystins (e.g., microcystin-LR),
                           nodularins, anatoxins, cylindrospermopsin,
                           and saxitoxins.

Artificial sweeteners      Sucralose (Splenda[R], SucraPlus[TM]),
                           acesulfame, saccharin, cyclamate, etc.

Brominated flame           Several chemicals classified in different
retardants                 groups such as polybrominated diphenyl
                           ethers (PBDEs), polybrominated biphenyl
                           (PBB), hexabromocyclododecane (HBCD).

Benzotriazoles             The two most common forms are
                           benzotriazole and tolytriazole.

DBPs                       More than 700 compounds identified to
                           date, which together are estimated to
                           account for ~ 50% of the total organic
                           halogen content.

Ionic liquids              The chemical structures typically involve
                           a cationic or anionic polar head group
                           with accompanying alkyl side chains.
                           Cationic head groups include imidazolium,
                           pyridinium, pyrrolidinium, morpholinium,
                           piperidium, quinolinium, quaternary
                           ammonium, and quaternary phosphonium
                           moieties; anionic head groups include
                           tetrafluoroborate (B[F.sub.4.sup.-]),
                           hexafluorophosphate (P[F.sub.6.sup.-]),
                           bis(trifluoromethylsulfonyl)-imide
                           [[(C[F.sub.3]S[O.sub.2]).sub.2][N.sup.-]],
                           dicyanamide [[(CN).sub.2][N.sup.-]],
                           chloride, and bromide.

Illicit drugs              Several chemicals, including amphetamine-
                           like compounds, benzodiazepines,
                           cannabinoids, cocainics, lysergic acid
                           diethylamine (LSD), opioids, and
                           metabolites (Valcarcel et al. 2012).

Musks                      Several chemicals. May have nitroaromatic
                           structures [as in the case of musk xylene
                           (1-ferf-butyl-3,5-dimethyl-2,4,6-
                           trinitrobenzene) or musk ketone
                           (4-ferf-butyl-2,6-dimethyl-3,5-
                           dinitroacetophenone)] or polycyclic
                           structures [as in the case of
                           7-acetyl-1,1,3,4,4,6-hexamethyl-
                           1,2,3,4-tetrahydronaphthalene (AHTN;
                           trade name, tonalide), 1,3,4,6,7,8-
                           hexahydro4,6,6,7,8,8-
                           hexamethylcyclopenta-(g)-2-
                           benzopyran(HHCB; trade name,
                           galaxolide), 4-acetyl-6-ferf-butyl1,
                           1-dimethylindan (ADBI; trade name,
                           celestolide),
                           dihydropentamethylindanone (DPMI;
                           trade name, cashmeran), or 5-acetyl
                           -1,1,2,3,3,6-examethylindan (AHMI,
                           tradename phantolide)].

Naphtenic acids            Complex mixture of alkyl-substituted
                           acyclic and cyclo-aliphatic carboxylic
                           acids that dissolve in water at neutral or
                           alkaline pH and have surfactant-like
                           properties.

Nanomaterials              Several chemical groups and structures
                           including fullerenes, nanotubes, quantum
                           dots, metal oxanes, titanium dioxide,
                           nanoparticles, nanosilver, and zerovalent
                           iron nanoparticles.

Perfluorinated compounds   Different types. The most common are
(PFCs)                     perfluorooctanoic acid (PFOA) and
                           perfluorooctanesulfonic acid (PFOS).

Pesticide transformation   Several chemicals, such as alachlor
by-products                ethanesulfonic acid (ESA), alachlor
                           oxanilic acid (OA), acetochlor ESA,
                           acetochlor OA, metolachlor ESA,
                           metolachlor OA, 3-hydroxycarbofuran, and
                           terbufos sulfone.

Pharmaceuticals            Several chemicals, including
                           antidepressants, antiviral drugs,
                           glucocorticoids, antimycotics,
                           antibiotics, beta-blockers.

Siloxanes                  Cyclic siloxanes
                           [octamethylcyclotetrasiloxane (D4),
                           decamethylcyclopentasiloxane (D5),
                           dodecamethylcyclohexasiloxane (D6), and
                           tetradecamethylcycloheptasiloxane (D7)]
                           and linear siloxanes.

Sunscreens/ultraviolet     Several chemicals. The ones identified in
filters                    drinking water are benzophenone-3 (BP3),
                           octocrylene (OC), 2-ethylhexyl
                           4-methoxycinnamate (EHMC),
                           3-(4-methylbenzylidene) camphor (4-MBC),
                           and 2-ethylhexyl 4-(dimethylamino)
                           benzoate (OD-PABA).

Single chemicals

Dioxane                    1,4/Dioxane. Regulated by U.S. EPA
                           (50 mg/L).

Perchlorate                Perchlorate

                                       Suspected or known
Chemical group                           health effects

Algal toxins               Microscystin-LR is hepatotoxic, genotoxic,
                           and carcinogenic (IARC 2010).

Artificial sweeteners      Unknown. Sucralose is a persistent
                           chemical in the environment (half-life up
                           to several years).

Brominated flame           Neurotoxicity and thyroid disruption
retardants                 (Dingemans et al. 2011).

Benzotriazoles             Unknown. Soluble in water, resistant to
                           biodegradation, and only partly removed in
                           wastewater treatment.

DBPs                       Genotoxic, carcinogenic, reprotoxic.

Ionic liquids              Different toxicity in animals (Pham et al.
                           2010). No human studies.

Illicit drugs              The effect of the mixture is unknown.

Musks                      Endocrine disruption, according to animal
                           evidence (Schreurs et al. 2004).

Naphtenic acids            Liver toxicity in mammals (Rogers et al.
                           2002). No human studies.

Nanomaterials              Unknown.

Perfluorinated compounds   Liver, pancreatic, and testicular tumor in
(PFCs)                     animals. Inmunotoxicity (DeWitt et al.
                           2012), thyroid function disruption (Boas
                           et al. 2012; Melzer et al. 2010).

Pesticide transformation   Unknown.
by-products

Pharmaceuticals            The effect of the mixture is unknown.

Siloxanes                  Unknown.

Sunscreens/ultraviolet     Unknown.
filters

Single chemicals

Dioxane                    Unknown.

Perchlorate                Unknown. Perchlorate can cross the
                           placenta.

Table 3. Challenges of exposure assessment for chemical contaminants
in drinking water.

Challenge                                   Comments

Low exposure levels        Accuracy of analytical measurements in
                           water is particularly important at the low
                           range of exposure. In addition, detailed
                           personal information of water use behavior
                           is convenient.

Chemicals occurring in     Examples include pharmaceutical residues
mixtures                   and disinfection by-products. Depending on
                           the individual constituents of the
                           mixture, chemical-by-chemical exposure
                           assessment may not be feasible or could
                           result in simplistic exposure estimates.

Time-space variability     Repeated measurements and distribution of
                           sampling points covering different water
                           zones is necessary to evaluate
                           geographical and temporal variation during
                           the relevant exposure period.

Long-term exposure         Longer exposure periods are likely to
windows                    result in greater exposure
                           misclassification. In the case of chronic
                           diseases such as cancer, data collection
                           must include accurate location of study
                           participants (residence and workplace) and
                           water use over the duration of an exposure
                           period relevant to disease etiology.
                           Combined with environmental levels,
                           quantitative estimation of exposure can be
                           conducted. An added challenge is the lack
                           of historical monitoring data.

Lack of monitoring data    This is particularly problematic to
                           evaluate some exposures (such as emerging
                           contaminants) and some outcomes (such as
                           cancer because historical records are
                           frequently unavailable). More research is
                           needed to develop validated simulation
                           models that can be used to estimate levels
                           and exposure over the relevant time
                           period.

Lack of validated          Currently available validated biomarkers
biomarkers of exposure     typically reflect recent exposures and
                           thus may not be useful for outcomes with
                           latency periods longer than the half-life
                           of the biomarker compound. Exceptions may
                           occur if the time between consecutive
                           exposure events is shorter than the
                           elimination half-life or exposure can be
                           regarded as constant within the relevant
                           time window (such as for trichloroacetic
                           acid).

Multiple exposure routes   Exposure to a number of water contaminants
(ingestion, inhalation,    can occur through multiple routes. For
dermal absorption)         example, some DBPs can be incorporated
                           through inhalation, dermal absorption and
                           ingestion. For other waterborne
                           contaminants, such as nitrate (at levels
                           in water < 50 mg-L) and per-and
                           polyfluorinated compounds, diet is the
                           main source of exposure (Ericson Jogsten
                           2011; IARC 2010). For such contaminants,
                           exposure by all plausible routes should be
                           assessed in order to produce the most
                           accurate estimate of disease risk.

Table 4. Evidence of carcinogenicity as concluded by the IARC for
some chemicals whose main pathway of human exposure is through
drinking water [modified from the General Remarks to IARC Monograph,
Volume 101 (IARC 2012b)].

Agent                                Human evidence   Animal evidence

Elements
  Arsenic                              Sufficient       Sufficient

  Fluoride                             Inadequate       Inadequate

Nitrate                                Inadequate       Inadequate/
                                                      sufficient (b)
Microcystin-LR                         Inadequate       Inadequate
DBPs: Trihalomethanes
  Chloroform                           Inadequate       Sufficient

  Bromodichloromethane                 Inadequate       Sufficient

  Dibromochloromethane                 Inadequate         Limited

  Bromoform                            Inadequate         Limited
DBPs: Haloacetic acids
  Dichloroacetic acid                  Inadequate       Sufficient

  Trichloroacetic acid                 Inadequate       Sufficient

  Bromochloroacetic acid               Inadequate       Sufficient

  Dibromoacetic acid                   Inadequate       Sufficient
DBPs: Halogenated acetonitriles
  Bromochloroacetonitrile               No data         Inadequate

  Chloroacetonitrile                    No data         Inadequate

  Dibromoacetonitrile                   No data         Inadequate

  Dichloroacetonitrile                  No data         Inadequate

  Trichloroacetonitrile                 No data         Inadequate

  Dibromoacetonitrile                   No data         Sufficient

Chloral hydrate                        Inadequate       Sufficient

MX (3-chloro-4-(dichloromethyl)        Inadequate         Limited
  -5-hydroxy-2(5H)-furanone)
Bromate                                Inadequate       Sufficient
  (evaluated as potassium bromate)
Chlorite                                No data         Inadequate
  (evaluated as sodium chlorite)
  Chlorinated drinking water           Inadequate       Inadequate
Chemicals used in the disinfection
  of drinking water
Hypochlorite salts                      No data         Inadequate

Chloramine                             Inadequate       Inadequate

                                        Overall
Agent                                evaluation (a)        IARC
                                        (group)         Monograph

Elements
  Arsenic                                  1          Vol. 100 C
                                                        (IARC 2012a)
  Fluoride                                 3          Suppl. 7
                                                        (IARC 1987)
Nitrate                                  2A (c)       Vol. 94
                                                        (IARC 2010)
Microcystin-LR                             2B         Vol. 94
DBPs: Trihalomethanes                                   (IARC 2010)
  Chloroform                               2B         Vol. 73
                                                        (IARC 1999)
  Bromodichloromethane                     2B         Vol. 52
                                                        (IARC 1991)
  Dibromochloromethane                     3          Vol. 52
                                                        (IARC 1991)
  Bromoform                                3          Vol. 52
DBPs: Haloacetic acids                                  (IARC 1991)
  Dichloroacetic acid                      2B         Vol. 106
                                                        (IARC 2013)
  Trichloroacetic acid                     2B         Vol. 106
                                                        (IARC 2013)
  Bromochloroacetic acid                   2B         Vol. 101
                                                        (IARC 2012b)
  Dibromoacetic acid                       2B         Vol. 101
DBPs: Halogenated acetonitriles                         (IARC 2012b)
  Bromochloroacetonitrile                  3          Vol. 52
                                                        (IARC 1991)
  Chloroacetonitrile                       3          Vol. 52
                                                        (IARC 1991)
  Dibromoacetonitrile                      3          Vol. 52
                                                        (IARC 1991)
  Dichloroacetonitrile                     3          Vol. 52
                                                        (IARC 1991)
  Trichloroacetonitrile                    3          Vol. 52
                                                        (IARC 1991)
  Dibromoacetonitrile                      2B         Vol. 101
                                                        (IARC 2012b)
Chloral hydrate                            2A         Vol. 106
                                                        (IARC 2013)
MX (3-chloro-4-(dichloromethyl)          2B (d)       Vol. 84
  -5-hydroxy-2(5H)-furanone)                            (IARC 2004)
Bromate                                    2B         Vol. 73
  (evaluated as potassium bromate)                      (IARC 1999)
Chlorite                                   3          Vol. 52
  (evaluated as sodium chlorite)                        (IARC 1991)
  Chlorinated drinking water               3          Vol. 52
Chemicals used in the disinfection                      (IARC 1991)
  of drinking water
Hypochlorite salts                         3          Vol. 52
                                                        (IARC 1991)
Chloramine                                 3          Vol. 84
                                                        (IARC 2004)

(a) Group 1 (the agent is carcinogenic to humans), 2A (the agent is
probably carcinogenic to humans), 2B (the agent is possibly
carcinogenic to humans), 3 (the agent is not classifiable as to its
carcinogenicity to humans). (b) There is sufficient evidence in
experimental animals for the carcinogenicity of nitrite in
combination with amines or amides.(c) (c) Ingested nitrate or nitrite
under conditions that result in endogenous nitrosation is probably
carcinogenic to humans. (d) Other relevant data were used to upgrade
the evaluation.
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Author:Villanueva, Cristina M.; Kogevinas, Manolis; Cordier, Sylvaine; Templeton, Michael R.; Vermeulen, Ro
Publication:Environmental Health Perspectives
Article Type:Report
Geographic Code:4EUSP
Date:Mar 1, 2014
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