The disinfection of drinking water is an important public health service that generates high quality, safe and palatable tap water. The disinfection of drinking water to reduce waterborne disease was ...an outstanding public health achievement of the 20 th century.An unintended consequence is the reaction of disinfectants with natural organic matter,anthropogenic contaminants and bromide/iodide to form disinfection by-products（DBPs）.A large number of DBPs are cytotoxic, neurotoxic, mutagenic, genotoxic, carcinogenic and teratogenic. Epidemiological studies demonstrated low but significant associations between disinfected drinking water and adverse health effects. The distribution of DBPs in disinfected waters has been well defined by advances in high precision analytical chemistry. Progress in the analytical biology and toxicology of DBPs has been forthcoming.The objective of this review was to provide a detailed presentation of the methodology for the quantitative, comparative analyses on the induction of cytotoxicity and genotoxicity of103 DBPs using an identical analytical biological platform and endpoints. A single Chinese hamster ovary cell line was employed in the assays. The data presented are derived from papers published in the literature as well as additional new data and represent the largest direct quantitative comparison on the toxic potency of both regulated and emerging DBPs.These data may form the foundation of novel research to define the major forcing agents of DBP-mediated toxicity in disinfected water and may play an important role in achieving the goal of making safe drinking water better.
The haloacetonitriles (HANs) is an emerging class of nitrogenous-disinfection byproducts (N-DBPs) present in disinfected drinking, recycled, processed wastewaters, and reuse waters. HANs were ...identified as primary forcing agents that accounted for DBP-associated toxicity. We evaluated the toxic characteristics of iodoacetonitrile (IAN), bromoacetonitrile (BAN), dibromoacetonitrile (DBAN), bromochloroacetonitrile (BCAN), tribromoacetonitrile (TBAN), chloroacetonitrile (CAN), dichloroacetonitrile (DCAN), trichloroacetonitrile (TCAN), bromodichloroacetonitrile (BDCAN), and chlorodibromoacetonitrile (CDBAN). This research generated the first quantitative, comparative analyses on the mammalian cell cytotoxicity, genotoxicity and thiol reactivity of these HANs. The descending rank order for HAN cytotoxicity was TBAN ≈ DBAN > BAN ≈ IAN > BCAN ≈ CDBAN > BDCAN > DCAN ≈ CAN ≈ TCAN. The rank order for genotoxicity was IAN ≈ TBAN ≈ DBAN > BAN > CDBAN ≈ BDCAN ≈ BCAN ≈ CAN ≈ TCAN ≈ DCAN. The rank order for thiol reactivity was TBAN > BDCAN ≈ CDBAN > DBAN > BCAN > BAN ≈ IAN > TCAN. These toxicity metrics were associated with membrane permeability and chemical reactivity. Based on their physiochemical parameters and toxicity metrics, we developed optimized, robust quantitative structure activity relationship (QSAR) models for cytotoxicity and for genotoxicity. These models can predict cytotoxicity and genotoxicity of novel HANs prior to analytical biological evaluation.
The disinfection of drinking water is a major public health achievement; however, an unintended consequence of disinfection is the generation of disinfection by-products（DBPs）. Many of the identified ...DBPs exhibit in vitro and in vivo toxicity, generate a diversity of adverse biological effects, and may be hazards to the public health and the environment.Only a few DBPs are regulated by several national and international agencies and it is not clear if these regulated DBPs are the forcing agents that drive the observed toxicity and their associated health effects. In this study, we combine analytical chemical and biological data to resolve the forcing agents associated with mammalian cell cytotoxicity of drinking water samples from three cities. These data suggest that the trihalomethanes（THMs） and haloacetic acids may be a small component of the overall cytotoxicity of the organic material isolated from disinfected drinking water. Chemical classes of nitrogen-containing DBPs, such as the haloacetonitriles and haloacetamides, appear to be the major forcing agents of toxicity in these samples. These findings may have important implications for the design of epidemiological studies that primarily rely on the levels of THMs to define DBP exposure among populations. The TIC-Tox approach constitutes a beginning step in the process of identifying the forcing agents of toxicity in disinfected water.
Recent studies used the sum of the measured concentrations of individual disinfection byproducts (DBPs) weighted by their Chinese hamster ovary (CHO) cell cytotoxicity LC50 values to estimate the ...DBP-associated cytotoxicity of disinfected waters. This approach assumed that cytotoxicity was additive rather than synergistic or antagonistic. In this study, we evaluated whether this assumption was valid for mixtures containing DBPs at the concentration ratios measured in authentic disinfected waters. We examined the CHO cell cytotoxicity of defined DBP mixtures based on the concentrations of 43 regulated and unregulated DBPs measured in eight drinking and potable reuse waters. The hypothesis for additivity was supported using three experimental approaches. First, we demonstrated that the calculated additive toxicity (CAT) and bioassay-based calculated additive toxicity (BCAT) of the DBP mixtures agree within 12% on a median basis. We also found an additive toxicity response (CAT ≈ BCAT) between the regulated and unregulated DBP classes. Finally, the empirical biological cytotoxicity of the DBP subset mixtures, independent of the calculated toxicity, was additive. These results support the validity of using the sum of cytotoxic potency-weighted DBP concentrations as an estimate of the CHO cell cytotoxicity associated with known DBPs in real disinfected waters.
Disinfection by-products (DBPs) are formed when disinfectants (chlorine, ozone, chlorine dioxide, or chloramines) react with naturally occurring organic matter, anthropogenic contaminants, bromide, ...and iodide during the production of drinking water. Here we review 30 years of research on the occurrence, genotoxicity, and carcinogenicity of 85 DBPs, 11 of which are currently regulated by the U.S., and 74 of which are considered emerging DBPs due to their moderate occurrence levels and/or toxicological properties. These 74 include halonitromethanes, iodo-acids and other unregulated halo-acids, iodo-trihalomethanes (THMs), and other unregulated halomethanes, halofuranones (MX 3-chloro-4-(dichloromethyl)-5-hydroxy-2(
5H)-furanone and brominated MX DBPs), haloamides, haloacetonitriles, tribromopyrrole, aldehydes, and
N-nitrosodimethylamine (NDMA) and other nitrosamines. Alternative disinfection practices result in drinking water from which extracted organic material is less mutagenic than extracts of chlorinated water. However, the levels of many emerging DBPs are increased by alternative disinfectants (primarily ozone or chloramines) compared to chlorination, and many emerging DBPs are more genotoxic than some of the regulated DBPs. Our analysis identified three categories of DBPs of particular interest. Category 1 contains eight DBPs with some or all of the toxicologic characteristics of human carcinogens: four regulated (bromodichloromethane, dichloroacetic acid, dibromoacetic acid, and bromate) and four unregulated DBPs (formaldehyde, acetaldehyde, MX, and NDMA). Categories 2 and 3 contain 43 emerging DBPs that are present at moderate levels (sub- to low-μg/L): category 2 contains 29 of these that are genotoxic (including chloral hydrate and chloroacetaldehyde, which are also a rodent carcinogens); category 3 contains the remaining 14 for which little or no toxicological data are available. In general, the brominated DBPs are both more genotoxic and carcinogenic than are chlorinated compounds, and iodinated DBPs were the most genotoxic of all but have not been tested for carcinogenicity. There were toxicological data gaps for even some of the 11 regulated DBPs, as well as for most of the 74 emerging DBPs. A systematic assessment of DBPs for genotoxicity has been performed for ∼60 DBPs for DNA damage in mammalian cells and 16 for mutagenicity in
Salmonella. A recent epidemiologic study found that much of the risk for bladder cancer associated with drinking water was associated with three factors: THM levels, showering/bathing/swimming (i.e., dermal/inhalation exposure), and genotype (having the
GSTT1-1 gene). This finding, along with mechanistic studies, highlights the emerging importance of dermal/inhalation exposure to the THMs, or possibly other DBPs, and the role of genotype for risk for drinking-water-associated bladder cancer. More than 50% of the total organic halogen (TOX) formed by chlorination and more than 50% of the assimilable organic carbon (AOC) formed by ozonation has not been identified chemically. The potential interactions among the 600 identified DBPs in the complex mixture of drinking water to which we are exposed by various routes is not reflected in any of the toxicology studies of individual DBPs. The categories of DBPs described here, the identified data gaps, and the emerging role of dermal/inhalation exposure provide guidance for drinking water and public health research.
Iodinated X-ray contrast media (ICM) were investigated as a source of iodine in the formation of iodo-trihalomethane (iodo-THM) and iodo-acid disinfection byproducts (DBPs), both of which are highly ...genotoxic and/or cytotoxic in mammalian cells. ICM are widely used at medical centers to enable imaging of soft tissues (e.g., organs, veins, blood vessels) and are designed to be inert substances, with 95% eliminated in urine and feces unmetabolized within 24 h. ICM are not well removed in wastewater treatment plants, such that they have been found at elevated concentrations in rivers and streams (up to 100 μg/L). Naturally occurring iodide in source waters is believed to be a primary source of iodine in the formation of iodo-DBPs, but a previous 23-city iodo-DBP occurrence study also revealed appreciable levels of iodo-DBPs in some drinking waters that had very low or no detectable iodide in their source waters. When 10 of the original 23 cities’ source waters were resampled, four ICM were foundiopamidol, iopromide, iohexol, and diatrizoatewith iopamidol most frequently detected, in 6 of the 10 plants sampled, with concentrations up to 2700 ng/L. Subsequent controlled laboratory reactions of iopamidol with aqueous chlorine and monochloramine in the absence of natural organic matter (NOM) produced only trace levels of iodo-DBPs; however, when reacted in real source waters (containing NOM), chlorine and monochloramine produced significant levels of iodo-THMs and iodo-acids, up to 212 nM for dichloroiodomethane and 3.0 nM for iodoacetic acid, respectively, for chlorination. The pH behavior was different for chlorine and monochloramine, such that iodo-DBP concentrations maximized at higher pH (8.5) for chlorine, but at lower pH (6.5) for monochloramine. Extracts from chloraminated source waters with and without iopamidol, as well as from chlorinated source waters with iopamidol, were the most cytotoxic samples in mammalian cells. Source waters with iopamidol but no disinfectant added were the least cytotoxic. While extracts from chlorinated and chloraminated source waters were genotoxic, the addition of iopamidol enhanced their genotoxicity. Therefore, while ICM are not toxic in themselves, their presence in source waters may be a source of concern because of the formation of highly toxic iodo-DBPs in chlorinated and chloraminated drinking water.
This study reveals key disinfection byproduct (DBP) toxicity drivers in drinking water across the United States. DBPs, which are ubiquitous in drinking water, form by the reaction of disinfectants, ...organic matter, bromide, and iodide and are generally present at 100–1000× higher concentrations than other contaminants. DBPs are linked to bladder cancer, miscarriage, and birth defects in human epidemiologic studies, but it is not known as to which DBPs are responsible. We report the most comprehensive investigation of drinking water toxicity to date, with measurements of extracted whole-water mammalian cell chronic cytotoxicity, over 70 regulated and priority unregulated DBPs, and total organic chlorine, bromine, and iodine, revealing a more complete picture of toxicity drivers. A variety of impacted waters were investigated, including those impacted by wastewater, agriculture, and seawater. The results revealed that unregulated haloacetonitriles, particularly dihaloacetonitriles, are important toxicity drivers. In seawater-impacted water treated with chloramine, toxicity was driven by iodinated DBPs, particularly iodoacetic acids. In chlorinated waters, the combined total organic chlorine and bromine was highly and significantly correlated with toxicity (r = 0.94, P < 0.01); in chloraminated waters, total organic iodine was highly and significantly correlated with toxicity (r = 0.80, P < 0.001). These results indicate that haloacetonitriles and iodoacetic acids should be prioritized in future research for potential regulation consideration.
Disinfection of drinking water protects public health against waterborne pathogens. However, during disinfection, toxic disinfection byproducts (DBPs) are formed. Exposure to DBPs was associated with ...increased risk of bladder cancer in humans. DBPs are generated at concentrations below their carcinogenic potencies; it is unclear how exposure leads to adverse health outcomes. We used computational estimates of the energy of the lowest unoccupied molecular orbital (E LUMO) to predict thiol reactivity and additive toxicity among soft electrophile DBPs. Bromoacetic acid (BAA) was identified as non-thiol-reactive, which was supported by in chemico and in vitro data. Bromoacetonitrile (BAN) and bromoacetamide (BAM) were thiol-reactive. Genotoxicity induced by these compounds was reduced by increasing the thiol pool with N-acetyl l-cysteine (NAC), while NAC had little effect on BAA. BAN and BAM shared depletion of glutathione (GSH) or cellular thiols as a molecular initiating event (MIE), whereas BAA induces toxicity through another pathway. Binary mixtures of BAM and BAN expressed a potentiating effect in genotoxicity. We found that soft electrophile DBPs could be an important predictor of common mechanism groups that demonstrated additive toxicity. In silico estimates of E LUMO could be used to identify the most relevant DBPs that are the forcing factors of the toxicity of finished drinking waters.
Drinking water utilities will increasingly rely on alternative water sources in the future, including wastewater reuse. Safety must be assured in the application of advanced oxidation processes ...(AOPs) and supporting treatments for wastewater effluent reuse. This study developed toxicological profiles for source and tap waters, wastewaters, and treated effluents by different processes from four military installation locations. The objective of this study was to evaluate the toxicity of extracted organics from diverse source waters and after reuse treatments. The toxicity analyses included thiol reactivity, mammalian cell cytotoxicity, and genotoxicity. Differences in toxicity between source or tap waters and effluents from wastewater treatment processes supported AOP treatment to reduce risks of potable reuse. An anoxic and aerobic activated sludge process followed by sand filtration controlled toxicity to levels similar to a municipal drinking water. An anaerobic membrane bioreactor process exceeded the toxicity levels of a typical drinking water. Two AOP processes (ultraviolet (UV) + reverse osmosis (RO) + chlorination (NaOCl) or RO + UV–H2O2 + NaOCl) significantly reduced toxicity. The integration of the wastewater systems with ultrafiltration, AOP, and RO was effective to reduce the toxicity to levels comparable to, or better than, tap water samples.
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