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Drinking Water Disinfection Byproducts (DBPs) and Human Health Effects: Multidisciplinary Challenges and Opportunities Xing-Fang Li, and William A. Mitch Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.7b05440 • Publication Date (Web): 28 Dec 2017 Downloaded from http://pubs.acs.org on December 29, 2017

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Environmental Science & Technology

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Drinking Water Disinfection Byproducts (DBPs) and Human Health Effects: Multidisciplinary Challenges and Opportunities

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Xing-Fang Li1* and William A. Mitch2*

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1. Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6R 2G3 Canada 2. Department of Civil and Environmental Engineering, Stanford University, 473 Via Ortega, Stanford, California 94305, United States.

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Abstract

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While drinking water disinfection has effectively prevented water-borne diseases, an unintended

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consequence is the generation of disinfection byproducts (DBPs). Epidemiological studies have

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consistently observed an association between consumption of chlorinated drinking water with an

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increased risk of bladder cancer. Out of the >600 DBPs identified, regulations focus on a few classes,

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such as trihalomethanes (THMs), whose concentrations were hypothesized to correlate with the DBPs

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driving the toxicity of disinfected waters, but the DBPs responsible for the bladder cancer association

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remain unclear. Utilities are switching away from a reliance on chlorination of pristine drinking water

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supplies to the application of new disinfectant combinations to waters impaired by wastewater effluents

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and algal blooms. In light of these changes in disinfection practice, this article discusses new approaches

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being taken by analytical chemists, engineers, toxicologists and epidemiologists to characterize the DBP

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classes driving disinfected water toxicity, and suggests that DBP exposure should be measured using

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other DBP classes in addition to THMs.

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Disinfection vs. Disinfection Byproducts (DBPs): a Complex Balancing Act Diarrheal diseases associated with poor water sanitation remain a leading cause of death in the

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developing world, particularly among children.1 Starting just after 1900, chlorine disinfection of

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municipal drinking waters largely vanquished the outbreaks of cholera, typhoid and other waterborne

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diseases in the developed world by the 1940s.2 Importantly, these gains from chlorine disinfection

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predated the development of vaccines and antibiotics. Chlorination of drinking water represents one of the

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greatest achievements in public health.

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In 1974 analytical chemists discovered that trihalomethanes (THM4; chloroform,

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bromodichloromethane, dibromochloromethane and bromoform) forming as byproducts of chlorine

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reactions with natural organic matter (NOM) reached concentrations up to ~160 µg/L in finished drinking 1 ACS Paragon Plus Environment


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waters.3,4 Since then, epidemiology studies have suggested associations between consumption of

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chlorinated tap water featuring elevated THM4 concentrations and adverse health outcomes, including

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bladder cancer,5 children born small for gestational age,6,7 and miscarriages.8 The most consistent

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association has been for bladder cancer. For example, a meta-analysis for European males indicated that

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bladder cancer was 47% more prevalent among those consuming water with THM4 > 50 µg/L compared

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to those consuming water with THM4 < 5 µg/L; additional research has demonstrated an even higher risk

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associated with consumption of water featuring high THM4 levels for individuals featuring particular

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genetic polymorphisms (discussed below). With estimates of about 60,000 new cases per year, bladder

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cancer is the fourth most common cancer among U.S. males (lifetime odds are ~4%).9

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These results spurred the optimization of disinfection strategies to balance the acute risk posed by

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pathogens against the chronic risk posed by lifetime exposure to potentially carcinogenic DBPs. The

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implementation of regulatory limits on DBPs has helped to curb the highest DBP exposures. The 1979

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Total Trihalomethane Rule limiting THM4 in US drinking waters to 100 µg/L from ~30% to ~3% by 1988.11 Given that pathogen

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inactivation is the primary goal of water treatment and that DBPs represent a widespread environmental

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exposure route to carcinogens, striking this balance is a difficult, but important challenge. This feature

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article discusses factors that have historically hindered progress in DBP research and showcases the new

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approaches enabling researchers to surmount these impediments.

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Historical Challenges: the Conundrum of NOM

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Unlike most other drinking water contaminants, DBPs form from disinfectant application within

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the plant, as a result of the final drinking water treatment process (disinfection) and continue to form

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throughout the distribution system, such that control strategies necessarily focus on minimizing their

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formation. Considered to be the primary organic precursors for DBPs, humic substances in NOM are

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derived from natural biopolymers, including humic and fulvic acids, but their extensive degradation

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fosters a diversity of structures that prevents clear characterization. Their poor structural characterization

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has driven two of the historical challenges in DBP research. First, without the ability to predict DBPs

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likely to form at high yield by applying chlorine reaction pathways to well-characterized precursor

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structures, DBP identification has been largely the domain of analytical chemists. Over 600 DBPs have

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been characterized;12 most being low molecular weight semi-volatile or volatile compounds, due to the

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availability of gas chromatography-based instrumentation. Yet the subset that has been quantified

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constitutes only ~30% of the total organic halogen (TOX) in chlorinated waters on a median basis, with

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THM4 and haloacetic acids (HAAs) each accounting for ~10% of TOX.13 Given the diversity of

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precursors, the total number of DBPs likely will far exceed 1,000 in chlorinated drinking waters,

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highlighting the challenge of closing the TOX mass balance.

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Second, this diversity of DBPs has hindered the identification of those that drive the correlation

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between consumption of chlorinated drinking waters and bladder cancer (hereafter referred to a “toxicity

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drivers”). Regulatory agencies have focused on a limited array of DBPs. In the U.S., regulatory limits

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have been established for 11 DBPs: THM4, 5 haloacetic acids (HAA5; chloroacetic acid, bromoacetic

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acid, dichloroacetic acid, dibromoacetic acid, trichloroacetic acid), bromate and chlorite.14 With minor

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differences, the DBPs targeted for regulation are similar in other countries.12 Importantly, THM4 and

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HAA5 were not targeted for regulation because they were known to be the sole toxicity drivers, but

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because they served as indicators of exposure to the complex mixture of DBPs in chlorinated drinking

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waters.15 While the assumption that THM4 and HAA5 should correlate with the toxicity drivers in

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chlorinated water appears reasonable, the regulatory focus on THM4 and HAA5 has driven a

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corresponding focus among DBP researchers, which may be risky. Are research and regulatory efforts

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targeting the right compounds? For example, epidemiology studies continue to rely on THM4 to measure

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exposure, yet the associations with bladder cancer frequently hover near the boundaries of statistical

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significance.5 Might imperfect correlations between THM4 and the toxicity drivers cloud the resolving

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power of epidemiological studies? Using the primary toxicity drivers to monitor exposure should increase

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the significance of the bladder cancer risk attributable to DBPs, particularly when coupled with

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considerations of genotypes conducive to DBP-associated toxicity (discussed below). Similarly,

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considerable efforts by environmental chemists have focused on limiting THM4 and HAA5 formation.

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Due to inadequate precursor characterization, these efforts have historically relied on empirical models

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correlating THM4 or HAA5 formation with bulk precursor properties (e.g., specific UV absorbance at

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254 nm or the tendency to sorb to XAD resins),16,17 and the development of treatment technologies to

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remove these precursors. If the precursors for toxicity drivers differ from those of THM4 and HAA5, are

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these efforts misplaced?

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Changing Disinfection Practices Raise Difficult Questions

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Two changes in drinking water practice have key implications for DBP research. To meet the

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demands of growing populations, utilities are increasingly exploring a variety of impaired water supplies

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featuring precursor pools fundamentally different from the NOM that has been the focus of prior research.

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These different precursor pools should alter the array of DBPs formed. Compared to NOM, water

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supplies impacted by upstream wastewater discharges or algal blooms tend to feature organic matter with

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lower aromaticity, which should reduce THMs. However, they also exhibit higher organic nitrogen,18

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which should promote the formation of nitrogen-based DBPs (N-DBPs).19 Among N-DBPs, nitrosamines 3 ACS Paragon Plus Environment


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(e.g., N-nitrosodimethylamine (NDMA)) have received significant attention because low ng/L levels in

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drinking water are associated with 10-6 lifetime excess cancer risks.20 Recognizing the fundamental

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differences with NOM, researchers have labeled these precursor pools effluent organic matter (EfOM)

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and algal organic matter (AOM). Highlighting implications for DBP formation, precursors for total

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nitrosamines are more associated with EfOM and AOM than NOM,21 while NDMA is strongly linked to

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EfOM.22 Indeed, NDMA is a key focus for the potable reuse of wastewater, the ultimate example of an

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EfOM-impacted water supply. Utilities are also exploiting higher salinity source waters, including

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freshwaters impacted by sea-level rise, or brackish groundwater and seawater reclaimed by desalination.

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The higher concentrations of bromide and iodide in these waters may change the speciation of DBPs

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toward their brominated and iodinated analogues.23,24

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Concurrently, utilities are switching away from a sole reliance on chlorine disinfection to

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combinations of primary disinfectants (ozone, UV or chlorine) with chloramines as secondary

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disinfectants,25,26 changes driven at least in part by more stringent limits on regulated DBPs. In the U.S.,

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the Stage 1 and 2 Disinfectants and Disinfection Byproducts Rules reduced the regulatory limits on

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THM4 to 80 µg/L and regulated HAA5 at 60 µg/L for the first time.15 Because THM4 and HAA5 form

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predominantly from chlorine reactions with humic substances, these new disinfectant combinations limit

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THM4 and HAA5 formation. However, each disinfectant promotes different DBP classes. For example,

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chloramination promotes nitrosamines27,28 and iodinated DBPs,29 while ozone forms bromate,

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haloacetaldehydes30 and halonitromethanes.31

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These effects on DBP formation can be synergistic. For example, chloramination drives NDMA

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formation in wastewater-impacted drinking waters, particularly during potable reuse,32 and promotes the

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production of iodinated DBPs in higher salinity waters. Together, these alterations in disinfection practice

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suggest that the assumed correlation between THM4 and the toxicity drivers in disinfected waters may no

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longer hold. Could alterations in disinfection practice intended to reduce THM4 ultimately increase the

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toxicity of disinfected water? For example, one laboratory study indicated that the cytotoxicity of a

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drinking water with elevated bromide and iodide was higher when chloraminated than when chlorinated.33

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Disinfection Optimization and Toxicity Drivers

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An initial response to this challenge is to target a more complex optimization of the disinfectant

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combinations to simultaneously control pathogens, the traditional regulated DBPs and the emerging DBPs

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of interest (e.g., N-DBPs and iodinated DBPs). For example, combining ozone for primary disinfection

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with chloramines to maintain a residual in the distribution system can effectively inactivate pathogens and

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reduce formation of regulated THM4 and HAA5. Ozone can also deactivate NDMA precursors, reducing


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NDMA formation during subsequent chloramination. However, the ozone exposure must be optimized

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because the benefits of increasing ozone exposure in terms of reducing pathogens and NDMA come at the

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expense of enhanced production of bromate, halonitromethanes and haloacetaldehydes when followed by

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chlorination or chloramination.19

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This optimization necessitates that we prioritize which DBPs to control, and re-emphasizes the need

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to identify toxicity drivers. The DBP field has been blessed with strong collaborations between chemists

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and toxicologists. For example, over 100 DBPs have been subjected to quantitative cytotoxicity and

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genotoxicity assays on a Chinese hamster ovary (CHO) cell platform.34 These results have indicated that

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unregulated DBP classes, particularly N-DBPs and their brominated analogues, are orders of magnitude

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more cytotoxic and genotoxic than the regulated THM4 and HAA5; iodinated analogues are even more

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cytotoxic and genotoxic. However, until recently the focus has remained on meeting specific regulatory

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targets. For example, NDMA features a 10 ng/L Notification Level in California,35 and the US EPA has

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been considering whether to promulgate nationwide regulatory limits on nitrosamines.36 The challenge for

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utilities practicing chlorine primary disinfection with chloramine secondary disinfection is to optimize

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these disinfection processes to simultaneously meet limits on THM4, HAA5, and NDMA. Are these the

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proper DBP targets to minimize exposure to toxicity drivers?

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While DBP chemists frequently cite high toxic potency as a rationale to focus on emerging DBP

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classes, the contribution of a DBP to toxicity is really a function of both their concentrations and toxic

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potency. To prioritize DBP classes, DBP researchers are beginning to compare measured DBP

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concentrations weighted by metrics of toxic potency (e.g., CHO cytotoxicity). By these calculations, a

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water featuring higher concentrations of some of the more toxic unregulated DBPs but lower

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concentrations of regulated DBPs may be considered to represent a higher risk, provided the sum of the

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toxicity-weighted concentrations of DBPs in the complex mixture is greater (Figure 1). When applied to

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conventional European drinking waters,37 chlorinated or chloraminated high salinity groundwaters,38 or

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chloraminated potable reuse effluents,39 these calculations indicate that unregulated halogenated DBP

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classes, particularly haloacetonitriles, may be greater contributors to the DBP-associated toxicity of

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disinfected waters than the THM4, HAA5 and nitrosamines of current regulatory interest.

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These calculations suggest the need to re-focus DBP research, yet they still consider predominantly

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the low molecular weight, (semi-)volatile DBP classes that constitute only ~30% of TOX. Identifying the

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toxicity drivers requires advances in analytical chemistry and toxicology. Frontiers in these areas are

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discussed below.

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Advances in Analytical Chemistry Paint a Dynamic Picture of DBP Evolution



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Due to its widespread availability, GC/MS dominated DBP characterization during the first two

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decades following their discovery. Most of the DBP classes that have been identified to date remain low

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molecular weight, (semi-)volatile compounds amenable to GC/MS or compounds rendered suitable for

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GC/MS and GC/GC/MS analysis by derivatization (e.g., HAAs).40,41 While the increase in concentrations

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of these DBP classes with chlorine contact time has been recognized, their relative contribution to TOX

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has generally been considered static, such that THM4 concentrations should correlate with the production

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of other halogenated DBPs. The application of high performance liquid chromatography and high-

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resolution mass spectrometry technologies is revealing the important contribution of polar DBPs to the

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uncharacterized TOX, and is suggesting a dynamic transformation of the TOX pool over timescales

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relevant to drinking water distribution. Fourier transform ion cyclotron resonance mass spectrometry (FT-

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ICR-MS) is a high-resolution MS technique (resolution ~1 million with 100 DBPs enabling

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ranking of their toxicity.34 The database has demonstrated that unregulated halogenated DBPs, including

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haloacetaldehydes and nitrogen-based haloacetonitriles, haloacetamides and halonitromethanes, are orders

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of magnitude more cytotoxic and genotoxic than the carbon-based regulated THM4 and HAA5. When

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used to weight measured DBP concentrations, these assays can suggest which DBPs are likely to be

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toxicity drivers, helping to prioritize DBPs for future in vivo assays (Figure 1). Highlighting the need for

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in vivo testing, CHO cells lack certain metabolic features that may be important for the activation of

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DBPs to mutagens. For example, CHO cells do not express the enzyme, glutathione S-transferase (GST)

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theta-1 (GSTT1), which can activate brominated THMs and dibromonitromethane to mutagens.63 This

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approach can be expanded with additional cell lines featuring these metabolic functions or others,

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including human stem cell models for developmental effects,64 cells over-expressed with specific

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membrane proteins to evaluate transmembrane transport,65 and non-transformed (i.e., non-cancerous)

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human uroepithelial cells related to bladder cells.66 Some of the battery of in vitro assays for analysis of

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water quality based on other organisms67 may also be useful. For example, the marine polychaete,

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Platynereis dumerilii, which can survive the high salinity of water concentrates, has been applied to

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demonstrate the developmental toxicity of more than 20 halogenated aromatic DBPs.68

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In vitro assays can also be useful to demonstrate toxic modes of action, including the

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identification of enzyme systems associated with DBP metabolism. For example, laboratory studies have

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demonstrated that three enzyme systems, GSTT1, GST zeta-1 (GSTZ1) and cytochrome P450 2E1

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(CYP2E1) can activate brominated THMs to mutagens (GSTT1), or inactivate HAAs and certain other

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halogenated DBPs (GSTZ1 and CYP2E1)..63 DBP research should take advantage of the 21th Century

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ToxCast69,70 Program, a unique program initiated by multiple U.S. federal agencies, including the

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National Institutes of Health, the U.S. Environmental Protection Agency, and the Food and Drug

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Administration, that has advanced high throughput in vitro toxicology assays to characterize modes of

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action. With CRISPR-Cas9 gene-editing technology,71,72 engineered cell models may become available to

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facilitate screening for specific mechanisms of action. Understanding the mechanisms of action can help

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prioritize DBPs likely to be associated with specific endpoints (e.g., bladder cancer) for confirmation

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using in vivo assays. Additionally, characterizing mechanisms of action can lead to the development of

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biomarkers of DBP exposure for use in epidemiology studies.


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Although DBPs occur within complex mixtures, how individual DBPs interact with respect to the

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toxicity of the mixture has received little attention. The toxicity of DBPs determined in single compound

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assays generally are assumed to be additive when measured DBP concentrations are weighted by metrics

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of toxicity to prioritize DBPs.38,39 Because previous research using in vivo assays has demonstrated that

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the assumption of additivity is not always valid for DBP mixtures,61,73 research is needed to understand

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when DBPs in mixtures exhibit synergistic or antagonistic interactions. Indeed, research has applied

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bioassays to bulk waters to optimize disinfection schemes without identification of specific toxicity

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drivers,33 but methodological improvements are needed. Toxicological assays generally require

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concentration of water samples (i.e., >1000-fold) to observe significant effects, yet it is precisely the low

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molecular weight (semi-)volatile DBPs of current focus that are partially lost during the extraction and

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concentration procedures employed to prepare samples for these bioassays. Current methods to surmount

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this challenge include spiking back specific volatile DBPs lost during concentration into the extracts, but

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this assumes that all volatile DBPs have been characterized.61 Alternatively, raw water samples could be

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concentrated and then disinfected, but retaining a wide range of organic precursors without concentrating

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inorganic components (which could exert toxicity via high salinity, for example) has proven

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challenging.74,75 Given the focus on volatile DBPs to date, capturing and concentrating volatile DBPs is a

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key challenge that must be overcome to measure the DBP-associated toxicity of disinfected bulk waters.

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Challenges for Epidemiology

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While meta-analyses of epidemiology studies have indicated a significant association between

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consumption of drinking waters with high levels of THM4 and bladder cancer incidence, the 95%

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confidence intervals on their odds ratios hover near the border of statistical significance (e.g., an odds

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ratio of 1.47 with a 95% confidence interval of 1.05-2.05).5 Many of the individual studies constituting

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these meta-analyses do not indicate a significant association.5 Exposure assessment is a primary challenge

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limiting the resolution of epidemiology studies. Particularly for the bladder cancer endpoint, the cancer

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would result from the accumulated lifetime exposure to DBPs. Most epidemiology studies have relied on

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THM4 measurements to quantify exposure because of the widespread availability of THM4 data resulting

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from their early discovery and their collection as part of regulatory compliance. However, THM4

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concentrations can vary seasonally and even diurnally. Furthermore, THM4 measurements are typically

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infrequent (e.g., quarterly for compliance in the U.S.). Unlike many other contaminants, DBP

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concentrations also exhibit significant spatial variability since they continue to form within the

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distribution system.49,76 For example, nitrosamine concentrations increase with distance from the plant,

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while HBQ-DBPs are transformed to hydroxy-HBQs throughout the distribution systems.49,76 Even within



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neighborhoods, DBP concentrations can vary significantly in ways that are difficult to predict due to

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inadequate modeling of water age within distribution systems.

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It is important to reiterate that THM4 concentrations have been targeted to measure exposure to

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DBPs not because they have been demonstrated to be the primary drivers of cancer risk, but because

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THMs are carcinogens and their concentrations were assumed to correlate with those of other DBPs.10,14,15

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This assumption is questionable for two reasons. First, the emerging concept of the dynamic

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transformation of NOM over timescales relevant to drinking water distribution would suggest that the

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percentage contribution of THM4 to TOX is not static (Figure 2). Consumers close to the drinking water

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facility may consume a different array of DBPs (e.g., more higher molecular weight, polar DBPs) than

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those at the ends of the distribution system (e.g., a higher percentage contribution to TOX by low

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molecular weight (semi-)volatile DBPs like THM4). Second, the shift in disinfection practices from

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chlorination to combinations of alternative primary disinfectants and chloramines for secondary

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disinfection can reduce THM4 while promoting nitrosamines, iodinated DBPs and other DBP classes.

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Using the primary toxicity drivers to measure exposure would presumably enhance the resolution

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of epidemiology studies, highlighting the value of the close collaboration between chemists and

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toxicologists needed to identify these forcing agents. Initial efforts weighting measured DBP

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concentrations by metrics of toxic potency obtained in in vitro assays have underscored the potential

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importance of certain unregulated, low molecular weight DBPs (e.g., haloacetonitriles).38,39 However,

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research is needed regarding the bioavailability of these compounds. Research has evaluated the

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pharmacokinetics of THMs77 and demonstrated that exposure via inhalation and dermal contact may be

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more important than via ingestion.78 Are the unregulated halogenated DBPs sufficiently volatile such that

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skin absorption or inhalation during showering is important? Research is needed regarding the

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pharmacokinetics of these other DBP classes. THMs are rapidly excreted by exhalation, but is the same

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true of haloacetonitriles? If haloacetonitriles are not readily excreted, is this because of efficient

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detoxification? Understanding of adsorption (bioavailability), distribution, metabolism and excretion of

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different classes of DBPs requires further research using advanced approaches.

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Even if the toxicity drivers are identified, their incorporation into retrospective cancer

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epidemiology studies would be challenging due to the lack of concentration measurements over the

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previous decades and the spatiotemporal variations in concentrations alluded to previously. However,

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initiating relevant data collection of toxicologically important DBPs would contribute to epidemiology

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studies focusing on shorter-term endpoints, such as developmental toxicity, and would lay the

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groundwork for future cancer epidemiology studies. Another key factor is analytical cost, particularly

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given the number of measurements that might be needed to address spatiotemporal variability in 10 ACS Paragon Plus Environment

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concentrations. It is noteworthy that some of the putative toxicity drivers (e.g., haloacetonitriles) can be

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measured using essentially the same analytical methods employed for THM4. Commercially available

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THM4 analyzers capable of providing results with roughly half-hour frequencies could be modified to

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include such potential toxicity drivers. Incorporating consideration of genotypes exhibiting a higher susceptibility to DBP-associated

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toxicity would also increase the statistical significance of the association of bladder cancer with DBP

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exposure. For example, an epidemiology study by Cantor et al.63 found an adjusted odds ratio of 1.8 (0.9-

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3.5 95% confidence interval) for bladder cancer for waters with >49 µg/L THM4 relative to waters with

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≤8 µg/L. However, the adjusted odds ratio for these two THM4 concentration categories increased to 5.9

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(1.8-19.0) when only the subpopulation featuring the GSTT1 and GSTZ1 CT/TT enzyme systems were

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considered. Laboratory research had demonstrated that these enzyme systems are involved in the

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transformation of brominated THMs, HAAs, dibromonitromethane, and potentially other halogenated

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DBPs, in some cases (e.g., GSTT1 activation of brominated THMs and dibromonitromethane) forming

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mutagens.63 The laboratory studies suggest one plausible mechanism by which DBPs, such as brominated

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THMs, could cause cancer. While the correlation between THM4 concentrations and these genotypes

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may suggest that brominated THMs are drivers of the cancer risk, the data are insufficient to draw a

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conclusion regarding the importance of THMs for the cancer risk. Research is needed to determine

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whether these genotypes are involved with the activation of other DBPs, particularly those that correlate

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with THM4 concentrations in the predominantly chlorinated waters evaluated in that epidemiology study.

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Determining the DBP classes serving as the drivers of the cancer risk will become increasingly important

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as changes in disinfection practice alter the relative proportion of the DBP classes in disinfected drinking

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waters.

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Another approach is to identify chemicals excreted in urine or exhaled breath that correlate with

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DBP exposure. For example, the exhaled concentrations of brominated THMs in swimmers were linked

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to DBP concentrations in a swimming pool,79 while excretion of trichloroacetic acid and TOX have been

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measured in urine.80,81 Could byproducts or DBP-biomolecule adducts be identified that are indicative of

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in vivo exposure to toxicity drivers and that are linked to modes of action associated with cancer

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development? The formation of DNA adducts following GSTT1 activation of brominated THMs82 could

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be expanded to other DBP classes. Could such byproducts or adducts be used as biomarkers to measure

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exposure in shorter-term epidemiology studies relevant to bladder cancer? In light of the trend towards

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combinations of disinfectants, toxicity-relevant biomarkers reflecting recent exposure to DBPs could

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foreshadow the results of future epidemiology studies evaluating these changes in disinfectant practice.

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Translating research into practice 11 ACS Paragon Plus Environment


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Utilities have attempted to optimize the combination of disinfectants to simultaneously meet

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pathogen reduction goals and regulatory limits on DBPs. The identification of toxicity drivers will

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demand close collaboration between chemists, toxicologists and epidemiologists, but is critical to ensure

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that efforts towards disinfection optimization do not inadvertently increase exposure to toxicity drivers.

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Given the clear tradeoffs between pathogen inactivation and DBP formation, it is imperative to better

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coordinate research efforts into both aspects, a harmony which is unfortunately infrequent. This is

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particularly important in light of the changes occurring in disinfection practice. For example, recent

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research has indicated that use of chloramines as a secondary disinfectant may aid inactivation of

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Legionella pneumophila in premise plumbing, yet promote the growth of Mycobacterium avium.83 How

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should the benefits of chloramination associated with DBP reduction be weighed against the potential

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promotion of certain opportunistic pathogens?

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An intriguing opportunity for collaboration between these disciplines is to better characterize

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pathogen inactivation. While pathogen inactivation kinetics have been determined, the detailed

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mechanisms by which chemical disinfectants inactivate pathogens remain poorly understood. Inactivation

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fundamentally involves the chemical transformation of important biomolecules by the disinfectant. These

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reactions are essentially the same as those involved with DBP production. The skills developed by DBP

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researchers to characterize such chemical transformations could aid in the understanding of the

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mechanisms of pathogen inactivation. For example, research on bacteriophage inactivation has defined

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the extent to which different disinfectants react with the protein capsid, which would inhibit binding of

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the phage to the host, or the genomic material, hindering replication.84 Additional research has

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characterized the modifications to amino acid side chains within the protein capsid of MS2 bacteriophage

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caused by application of chlorine, bromine or ozone.54 Understanding how these side chain modifications

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alter capsid protein structure and thereby hinder binding to host cells might reveal how altered amino acid

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sequences in viral capsid proteins resulting from mutations could promote resistance to inactivation by

382

disinfectants.

383

Lastly, optimization of combination disinfection has been favored as a low-cost option to balance

384

the acute risk posed by pathogens against the chronic risk associated with DBPs. Yet this balance is

385

extremely complex. A higher cost alternative is to pursue physical treatment processes (e.g., activated

386

carbon, nanofiltration) to remove organic precursors prior to disinfectant application. In addition to

387

removing the organic precursors, such techniques could reduce the applied disinfectant dose by reducing

388

the oxidant demand. In its ultimate manifestation, precursor removal could achieve a bio-stable water,

389

obviating the need to maintain significant disinfectant residuals in distribution systems to prevent the

390

growth of opportunistic pathogens. This practice is applied to various degrees in certain northern 12 ACS Paragon Plus Environment

Page 13 of 22


391

European countries. The Netherlands is an extreme case, with no disinfectants applied for the distribution

392

system.85 In addition to the physical treatment processes, this practice also requires significant capital

393

costs associated with maintenance of the distribution system. Given the widespread nature of disinfected

394

drinking water as an exposure route to carcinogens, such outlays may be justified. However, the

395

collaborations between chemists, toxicologists, and epidemiologists discussed herein will be crucial for

396

defining the toxicity drivers and developing the epidemiological data required for the cost-benefit

397

analyses needed to justify such expenses.

398

Acknowledgement

399 400

We would like to thank Ms. Lindsay Jmaiff Blackstock and Dr. Ping Jiang for their assistance in the preparation of the manuscript.

401 402

*Corresponding Authors

403

E-mail: [email protected]

404

ORCID: Xing-Fang Li: 0000-0003-1844-7700

405

Email: [email protected], Phone: 650-725-9298, Fax: 650-723-7058

406

ORCID: William A. Mitch: 0000-0002-4917-0938

407

Notes

408

The authors declare no competing financial interest.

409 410

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Figure 1: Conventional mass basis vs. emerging toxicity-weighted basis for evaluating the DBPassociated safety of a disinfected water. In the convention view, Water 1 is considered less safe than Water 2, because the THM4 concentration exceeds the MCL, and because it features higher cumulative DBP concentrations on a mass basis. LC50, the concentration of a DBP that kills 50% of the exposed cells or animals, is a metric used commonly to assess toxicity potency. . On a toxicity-weighted basis, Water 1 is considered safer, because it features lower concentrations of the toxicity drivers.

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Figure 2: Evolving understanding of the constitution of total organic halogen (TOX). Previously, the TOX concentration was considered to increase with disinfectant contact time in the distribution system, but the percentage contribution of DBP classes, including THM4, to the total was considered static. The emerging dynamic vision considers an evolution of DBP speciation from high molecular weight DBPs through polar DBPs to low molecular weight, (semi-)volatile DBPs as end products.

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