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elevated THM4 concentrations and adverse health outcomes,
including bladder cancer,5 children born small for gestational HISTORICAL CHALLENGES: THE CONUNDRUM OF
age,6,7 and miscarriages.8 The most consistent association has NOM
been for bladder cancer. For example, a meta-analysis for
European males indicated that bladder cancer was 47% more Unlike most other drinking water contaminants, DBPs form
prevalent among those consuming water with THM4 > from disinfectant application within the plant, as a result of the
50 μg/L compared to those consuming water with THM4 < final drinking water treatment process (disinfection) and
5 μg/L; additional research has demonstrated an even higher
risk associated with consumption of water featuring high Published: December 28, 2017
Figure 1. Conventional mass basis vs emerging toxicity-weighted basis for evaluating the DBP-associated safety of a disinfected water. In the
conventional 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
commonly used 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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and genotoxicity assays on a Chinese hamster ovary (CHO)
cell platform.34 These results have indicated that unregulated
DBP classes, particularly N-DBPs and their brominated ADVANCES IN ANALYTICAL CHEMISTRY PAINT A
analogues, are orders of magnitude more cytotoxic and DYNAMIC PICTURE OF DBP EVOLUTION
genotoxic than the regulated THM4 and HAA5; iodinated Due to its widespread availability, GC/MS dominated DBP
analogues are even more cytotoxic and genotoxic. However, characterization during the first two decades following their
until recently the focus has remained on meeting specific discovery. Most of the DBP classes that have been identified to
regulatory targets. For example, there is a 10 ng/L Notification date remain low molecular weight, (semi)volatile compounds
Level for NDMA in California,35 and the U.S. EPA has been amenable to GC/MS or compounds rendered suitable for GC/
considering whether to promulgate nationwide regulatory limits MS analysis by derivatization (e.g., HAAs).40,41 While the
on nitrosamines.36 The challenge for utilities practicing increase in concentrations of these DBP classes with chlorine
chlorination as primary disinfection with chloramination as contact time has been recognized, their relative contribution to
secondary disinfection is to optimize these disinfection TOX has generally been considered static, such that THM4
processes to simultaneously meet limits on THM4, HAA5, concentrations should correlate with the production of other
and NDMA. Are these the proper DBP targets to minimize halogenated DBPs. The application of high performance liquid
exposure to toxicity drivers? chromatography (HPLC) and high-resolution mass spectrom-
While DBP chemists frequently cite high toxic potency as a etry technologies is revealing the important contribution of
rationale for focusing on emerging DBP classes, the polar DBPs to the uncharacterized TOX, and is suggesting a
1683 DOI: 10.1021/acs.est.7b05440
Environ. Sci. Technol. 2018, 52, 1681−1689
Environmental Science & Technology Feature
solely on in vivo assays is unlikely to make significant inroads Indeed, researchers have applied bioassays to bulk waters to
into the assessment of >600 DBPs. A scheme for prioritizing optimize disinfection schemes without identification of specific
DBPs for in vivo testing is needed. toxicity drivers,33 but methodological improvements are
As indicated previously, the application of quantitative in needed. Toxicological assays generally require concentration
vitro cytotoxicity and genotoxicity assays based on Chinese of water samples (i.e., >1000-fold) to observe significant effects,
hamster ovary (CHO) cells has generated a database of >100 yet it is precisely the low molecular weight (semi)volatile DBPs
DBPs enabling ranking of their toxicity.34 The database has of current focus that are partially lost during the extraction and
demonstrated that unregulated halogenated DBPs, including concentration procedures employed to prepare samples for
haloacetaldehydes and nitrogen-based haloacetonitriles, haloa- these bioassays. Current methods to surmount this challenge
cetamides and halonitromethanes, are orders of magnitude include spiking back specific volatile DBPs lost during
more cytotoxic and genotoxic than the carbon-based regulated concentration into the extracts, but this assumes that all
THM4 and HAA5. When used to weight measured DBP volatile DBPs have been characterized.61 Alternatively, raw
concentrations, these assays can suggest which DBPs are likely water samples could be concentrated and then disinfected, but
to be toxicity drivers, helping to prioritize DBPs for future in retaining a wide range of organic precursors without
vivo assays (Figure 1). Highlighting the need for in vivo testing, concentrating inorganic components (which could exert
CHO cells lack certain metabolic features that may be toxicity via high salinity, for example) has proven challeng-
important for the activation of DBPs to mutagens. For ing.74,75 Given the focus on volatile DBPs to date, capturing
example, CHO cells do not express the enzyme glutathione and concentrating volatile DBPs is a key challenge that must be
S-transferase (GST) theta-1 (GSTT1), which can activate overcome to measure the DBP-associated toxicity of disinfected
brominated THMs and dibromonitromethane to mutagens.63 bulk waters.
This approach can be expanded with additional cell lines
featuring these metabolic functions or others, including human
stem cell models for developmental effects,64 cells overex-
■ CHALLENGES FOR EPIDEMIOLOGY
While meta-analyses of epidemiological studies have indicated a
pressed with specific membrane proteins to evaluate trans- significant association between consumption of drinking waters
membrane transport,65 and nontransformed (i.e., noncancer- with high levels of THM4 and bladder cancer incidence, the
ous) human uroepithelial cells related to bladder cells.66 Some 95% confidence intervals on their odds ratios hover near the
of the battery of in vitro assays for analysis of water quality border of statistical significance (e.g., an odds ratio of 1.47 with
based on other organisms67 may also be useful. For example, a 95% confidence interval of 1.05−2.05).5 Many of the
the marine polychaete Platynereis dumerilii, which can survive individual studies constituting these meta-analyses do not
the high salinity of water concentrates, has been applied to indicate a significant association.5 Exposure assessment is a
demonstrate the developmental toxicity of more than 20 primary challenge limiting the resolution of epidemiological
halogenated aromatic DBPs.68 studies. Particularly for the bladder cancer end point, the cancer
In vitro assays can also be useful to demonstrate toxic modes would result from the accumulated lifetime exposure to DBPs.
of action, including the identification of enzyme systems Most epidemiological studies have relied on THM4 measure-
associated with DBP metabolism. For example, laboratory ments to quantify exposure because of the widespread
studies have demonstrated that three enzyme systems, GSTT1, availability of THM4 data resulting from their early discovery
GST zeta-1 (GSTZ1), and cytochrome P450 2E1 (CYP2E1), and their collection as part of regulatory compliance. However,
can activate brominated THMs to mutagens (GSTT1), or THM4 concentrations can vary seasonally and even diurnally.
inactivate HAAs and certain other halogenated DBPs (GSTZ1 Furthermore, THM4 measurements are typically infrequent
and CYP2E1).63 DBP research should take advantage of the (e.g., quarterly for compliance in the U.S.). Unlike many other
21st Century ToxCast69,70 Program, a unique program initiated contaminants, DBP concentrations also exhibit significant
by multiple U.S. federal agencies, including the National spatial variability since they continue to form within the
Institutes of Health, the U.S. Environmental Protection Agency, distribution system.49,76 For example, nitrosamine concen-
and the Food and Drug Administration, that has advanced high trations increase with distance from the plant, while HBQ-
throughput in vitro toxicology assays to characterize modes of DBPs are transformed to hydroxy-HBQs throughout the
action. With CRISPR-Cas9 gene-editing technology,71,72 distribution systems.49,76 Even within neighborhoods, DBP
engineered cell models may become available to facilitate concentrations can vary significantly in ways that are difficult to
screening for specific mechanisms of action. Understanding the predict due to inadequate modeling of water age within
mechanisms of action can help prioritize DBPs likely to be distribution systems.
associated with specific end points (e.g., bladder cancer) for It is important to reiterate that THM4 concentrations have
confirmation using in vivo assays. Additionally, characterizing been targeted to measure exposure to DBPs not because they
mechanisms of action can lead to the development of have been demonstrated to be the primary drivers of cancer
biomarkers of DBP exposure for use in epidemiology studies. risk, but because THMs are carcinogens and their concen-
Although DBPs occur within complex mixtures, how trations were assumed to correlate with those of other
individual DBPs interact with respect to the toxicity of the DBPs.10,14,15 This assumption is questionable for two reasons.
mixture has received little attention. The toxicities of DBPs First, the emerging concept of the dynamic transformation of
determined in single compound assays generally are assumed to NOM over time scales relevant to drinking water distribution
be additive when measured DBP concentrations are weighted would suggest that the percentage contribution of THM4 to
by metrics of toxicity to prioritize DBPs.38,39 Because previous TOX is not static (Figure 2). Consumers close to the drinking
research using in vivo assays has demonstrated that the water facility may consume a different array of DBPs (e.g., more
assumption of additivity is not always valid for DBP higher molecular weight polar DBPs) than those at the ends of
mixtures,61,73 research is needed to understand when DBPs the distribution system (e.g., a higher percentage contribution
in mixtures exhibit synergistic or antagonistic interactions. to TOX by low molecular weight (semi)volatile DBPs like
1685 DOI: 10.1021/acs.est.7b05440
Environ. Sci. Technol. 2018, 52, 1681−1689
Environmental Science & Technology Feature
THM4). Second, the shift in disinfection practices from suggest that brominated THMs are drivers of the cancer risk,
chlorination to combinations of alternative primary disinfec- the data are insufficient to draw a conclusion regarding the
tants and chloramination for secondary disinfection can reduce importance of THMs for the cancer risk. Research is needed to
THM4 while promoting nitrosamines, iodinated DBPs and determine whether these genotypes are involved with the
other DBP classes. activation of other DBPs, particularly those that correlate with
Using the primary toxicity drivers to measure exposure would THM4 concentrations in the predominantly chlorinated waters
presumably enhance the resolution of epidemiological studies, evaluated in that epidemiological study. Determining the DBP
highlighting the value of the close collaboration between classes serving as the drivers of the cancer risk will become
chemists and toxicologists needed to identify these forcing increasingly important as changes in disinfection practice alter
agents. Initial efforts weighting measured DBP concentrations the relative proportion of the DBP classes in disinfected
by metrics of toxic potency obtained from in vitro assays have drinking waters.
underscored the potential importance of certain unregulated, Another approach is to identify chemicals excreted in urine
low molecular weight DBPs (e.g., haloacetonitriles).38,39 or exhaled breath that correlate with DBP exposure. For
However, research is needed regarding the bioavailability of example, the exhaled concentrations of brominated THMs in
these compounds. Researchers have evaluated the pharmaco- swimmers were linked to DBP concentrations in a swimming
kinetics of THMs77 and demonstrated that exposure via pool,79 whereas excretion of trichloroacetic acid and TOX have
inhalation and dermal contact may be more important than been measured in urine.80,81 Could byproducts or DBP-
via ingestion.78 Are the unregulated halogenated DBPs biomolecule adducts be identified that are indicative of in vivo
sufficiently volatile such that skin absorption or inhalation exposure to toxicity drivers and that are linked to modes of
during showering is important? Research is needed regarding action associated with cancer development? The formation of
the pharmacokinetics of these other DBP classes. THMs are DNA adducts following GSTT1 activation of brominated
rapidly excreted by exhalation, but is the same true of THMs82 could be expanded to other DBP classes. Could such
haloacetonitriles? If haloacetonitriles are not readily excreted, byproducts or adducts be used as biomarkers to measure
is this because of efficient detoxification? Understanding of exposure in shorter-term epidemiological studies relevant to
adsorption (bioavailability), distribution, metabolism, and bladder cancer? In light of the trend toward combinations of
excretion of different classes of DBPs requires further research disinfectants, toxicity-relevant biomarkers reflecting recent
using advanced approaches. exposure to DBPs could foreshadow the results of future
Even if the toxicity drivers are identified, their incorporation epidemiological studies evaluating these changes in disinfectant
into retrospective cancer epidemiology studies would be practice.
challenging due to the lack of concentration measurements
over the previous decades and the spatiotemporal variations in
concentrations alluded to previously. However, initiating
■ TRANSLATING RESEARCH INTO PRACTICE
Utilities have attempted to optimize the combination of
relevant data collection of toxicologically important DBPs disinfectants to simultaneously meet pathogen reduction goals
would contribute to epidemiological studies focusing on and regulatory limits on DBPs. The identification of toxicity
shorter-term end points, such as developmental toxicity, and drivers will demand close collaboration between chemists,
would lay the groundwork for future cancer epidemiology toxicologists, and epidemiologists, but is critical to ensure that
studies. Another key factor is analytical cost, particularly given efforts toward disinfection optimization do not inadvertently
the number of measurements that might be needed to address increase exposure to toxicity drivers. Given the clear trade-offs
spatiotemporal variability in concentrations. It is noteworthy between pathogen inactivation and DBP formation, it is
that some of the putative toxicity drivers (e.g., haloacetonitriles) imperative to better coordinate research efforts into both
can be measured using essentially the same analytical methods aspects, a harmony which is unfortunately infrequent. This is
employed for THM4. Commercially available THM4 analyzers particularly important in light of the changes occurring in
capable of providing results with roughly half-hour frequencies disinfection practice. For example, recent research has indicated
could be modified to include such potential toxicity drivers. that use of chloramines as a secondary disinfectant may aid
Incorporating consideration of genotypes exhibiting a higher inactivation of Legionella pneumophila in premise plumbing, yet
susceptibility to DBP-associated toxicity would also increase the promote the growth of Mycobacterium avium.83 How should the
statistical significance of the association of bladder cancer with benefits of chloramination associated with DBP reduction be
DBP exposure. For example, an epidemiological study by weighed against the potential promotion of certain opportun-
Cantor et al.63 found an adjusted odds ratio of 1.8 (0.9−3.5 istic pathogens?
95% confidence interval) for bladder cancer for waters with >49 An intriguing opportunity for collaboration between these
μg/L THM4 relative to waters with ≤8 μg/L. However, the disciplines is to better characterize pathogen inactivation. While
adjusted odds ratio for these two THM4 concentration pathogen inactivation kinetics have been determined, the
categories increased to 5.9 (1.8−19.0) when only the detailed mechanisms by which chemical disinfectants inactivate
subpopulation featuring the GSTT1 and GSTZ1 CT/TT pathogens remain poorly understood. Inactivation fundamen-
enzyme systems were considered. Laboratory research had tally involves the chemical transformation of important
demonstrated that these enzyme systems are involved in the biomolecules by the disinfectant. These reactions are essentially
transformation of brominated THMs, HAAs, dibromonitro- the same as those involved with DBP production. The skills
methane, and potentially other halogenated DBPs, in some developed by DBP researchers to characterize such chemical
cases (e.g., GSTT1 activation of brominated THMs and transformations could aid in the understanding of the
dibromonitromethane) forming mutagens.63 The laboratory mechanisms of pathogen inactivation. For example, research
studies suggest one plausible mechanism by which DBPs, such on bacteriophage inactivation has defined the extent to which
as brominated THMs, could cause cancer. While the correlation different disinfectants react with the protein capsid, which
between THM4 concentrations and these genotypes may would inhibit binding of the phage to the host, or the genomic
1686 DOI: 10.1021/acs.est.7b05440
Environ. Sci. Technol. 2018, 52, 1681−1689
Environmental Science & Technology Feature
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needed to justify such expenses.
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AUTHOR INFORMATION (15) National Primary Drinking Water Regulations: Stage 2
Corresponding Authors Disinfectants and Disinfection Byproducts Rule. 40 CFR Parts 9,
*(X.-F.L.) E-mail: xingfang.li@ualberta.ca. 141, and 142. Federal Register 2006, 71, No. 2, 388−493.
*(W.A.M.) Phone: 650-725-9298; fax: 650-723-7058; e-mail: (16) Liang, L.; Singer, P. C. Factors influencing the formation and
wamitch@stanford.edu. relative distribution of haloacetic acids and trihalomethanes in drinking
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ORCID (17) Ged, E. C.; Chadik, P. A.; Boyer, T. H. Predictive capability of
Xing-Fang Li: 0000-0003-1844-7700 chlorination disinfection byproducts models. J. Environ. Manage. 2015,
William A. Mitch: 0000-0002-4917-0938 149, 253−262.
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The authors declare no competing financial interest. water supplies: a review. J. Water Supply: Res. Technol.–AQUA 2002,
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51 (8), 415−448.
ACKNOWLEDGMENTS (19) Shah, A. D.; Mitch, W. A. Halonitroalkanes, halonitriles,
haloamides and N-nitrosamines: A critical review of nitrogenous
We thank Ms. Lindsay Jmaiff Blackstock and Dr. Ping Jiang for disinfection byproduct (N-DBP) formation pathways. Environ. Sci.
their assistance in the preparation of the manuscript.
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Technol. 2012, 46 (1), 119−131.
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