Drinking Water Disinfection Byproducts - ACS Publications - American

Dec 28, 2017 - cloud the resolving power of epidemiological studies? Using the ..... and their collection as part of regulatory compliance. However,...
0 downloads 0 Views 551KB Size
Subscriber access provided by the University of Exeter

Feature

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Environmental Science & Technology is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 22

Environmental Science & Technology

1 2

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

3

Xing-Fang Li1* and William A. Mitch2*

4 5 6 7 8

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.

9 10

Abstract

11

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

12

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

13

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

14

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

15

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

16

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

17

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

18

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

19

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

20

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

21

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

22

other DBP classes in addition to THMs.

23 24 25

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

26

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

27

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

28

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

29

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

30

greatest achievements in public health.

31

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

32

bromodichloromethane, dibromochloromethane and bromoform) forming as byproducts of chlorine

33

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

Environmental Science & Technology

Page 2 of 22

34

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

35

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

36

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

37

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

38

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

39

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

40

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

41

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

42

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

43

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

44

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

45

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

46

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

48

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

49

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

50

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

51

approaches enabling researchers to surmount these impediments.

52

Historical Challenges: the Conundrum of NOM

53

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

54

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

55

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

56

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

57

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

58

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

59

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

60

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

61

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

62

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

63

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

64

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

65

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

2 ACS Paragon Plus Environment

Page 3 of 22

Environmental Science & Technology

66

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

67

highlighting the challenge of closing the TOX mass balance.

68

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

69

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

70

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

71

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

72

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

73

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

74

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

75

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

76

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

77

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

78

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

79

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

80

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

81

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

82

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

83

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

84

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

85

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

86

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

87

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

88

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

89

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

90

these efforts misplaced?

91

Changing Disinfection Practices Raise Difficult Questions

92

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

93

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

94

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

95

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

96

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

97

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

98

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

Environmental Science & Technology

99

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

100

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

101

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

102

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

103

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

104

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

105

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

106

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

107

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

108

toward their brominated and iodinated analogues.23,24

109

Page 4 of 22

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

110

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

111

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

112

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

113

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

114

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

115

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

116

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

117

haloacetaldehydes30 and halonitromethanes.31

118

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

119

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

120

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

121

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

122

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

123

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

124

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

125

Disinfection Optimization and Toxicity Drivers

126

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

127

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

128

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

129

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

130

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

4 ACS Paragon Plus Environment

Page 5 of 22

Environmental Science & Technology

131

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

132

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

133

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

134

chlorination or chloramination.19

135

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

136

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

137

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

138

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

139

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

140

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

141

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

142

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

143

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

144

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

145

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

146

proper DBP targets to minimize exposure to toxicity drivers?

147

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

148

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

149

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

150

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

151

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

152

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

153

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

154

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

155

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

156

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

157

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

158

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

159

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

160

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

161

discussed below.

162

Advances in Analytical Chemistry Paint a Dynamic Picture of DBP Evolution

5 ACS Paragon Plus Environment

Environmental Science & Technology

Page 6 of 22

163

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

164

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

165

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

166

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

167

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

168

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

169

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

170

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

171

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

172

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

173

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

232

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

233

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

234

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

235

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

236

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

237

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

238

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

239

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

240

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

241

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

242

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

243

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

244

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

245

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

246

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

247

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

248

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

249

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

250

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

251

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

252

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

253

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

254

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

255

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

256

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

257

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

258

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

259

biomarkers of DBP exposure for use in epidemiology studies.

8 ACS Paragon Plus Environment

Page 9 of 22

260

Environmental Science & Technology

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

261

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

262

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

263

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

264

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

265

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

266

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

267

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

268

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

269

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

270

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

271

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

272

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

273

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

274

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

275

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

276

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

277

Challenges for Epidemiology

278

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

279

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

280

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

281

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

282

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

283

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

284

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

285

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

286

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

287

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

288

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

289

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

290

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

291

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

9 ACS Paragon Plus Environment

Environmental Science & Technology

292

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

293

inadequate modeling of water age within distribution systems.

294

Page 10 of 22

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

295

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

296

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

297

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

298

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

299

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

300

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

301

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

302

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

303

chlorination to combinations of alternative primary disinfectants and chloramines for secondary

304

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

305

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

306

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

307

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

308

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

309

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

310

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

311

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

312

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

313

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

314

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

315

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

316

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

317

different classes of DBPs requires further research using advanced approaches.

318

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

319

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

320

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

321

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

322

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

323

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

324

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

Page 11 of 22

Environmental Science & Technology

325

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

326

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

327

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

328

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

329 330

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

331

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

332

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

333

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

334

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

335

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

336

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

337

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

338

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

339

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

340

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

341

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

342

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

343

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

344

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

345

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

346

waters.

347

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

348

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

349

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

350

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

351

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

352

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

353

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

354

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

355

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

356

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

357

Translating research into practice 11 ACS Paragon Plus Environment

Environmental Science & Technology

358

Page 12 of 22

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

359

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

360

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

361

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

362

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

363

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

364

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

365

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

366

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

367

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

368

promotion of certain opportunistic pathogens?

369

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

370

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

371

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

372

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

373

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

374

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

375

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

376

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

377

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

378

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

379

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

380

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

381

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

Environmental Science & Technology

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

REFERENCES

411 412 413

(1) Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. World Health Organization. WHO Press, Geneva, Switzerland, 2009. http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf

414 415 416

(2) History of Drinking Water Treatment. A Century of U.S. Water Chlorination and Treatment: One of the Ten Greatest Public Health Achievements of the 20th Century. Centers for Disease Control and Prevention. https://www.cdc.gov/healthywater/drinking/history.html (retrieved September 5, 2017).

417 418

(3) Rook, J. J. Formation of haloforms during chlorination of natural water. Water Treat. Exam. 1974, 23(2), 234–243.

419 420

(4) Bellar, T. A.; Lichtenberg, J. J.; Kroner, R. C. The occurrence of organohalides in chlorinated drinking waters. J. Am. Water Works Assoc. 1974, 66 (12), 703-706.

421 422 423 424

(5) Costet, N.; Villanueva, C. M.; Jaakkola, J. J. K.; Kogevinas, M.; Cantor, K. P.; King, W. D.; Lynch, C. F.; Nieuwenhuijsen, M. J.; Cordier, S. Water disinfection by-products and bladder cancer: is there a European specificity? A pooled and meta-analysis of European case-control studies. Occup. Environ. Med. 2011, 68 (5), 379–85. 13 ACS Paragon Plus Environment

Environmental Science & Technology

Page 14 of 22

425 426

(6) Wright J. M.; Evans A.; Kaufman J. A.; Rivera-Núñez Z.; Narotsky M.G. Disinfection by-product exposures and the risk of specific cardiac birth defects. Environ Health Perspect. 2017,125(2), 269–277.

427 428 429

(7) Grellier, J.; Bennett, J.; Patelarou, E.; Smith, R .B.; Toledano, M. B.; Rushton, L.; Briggs, D. J.; Nieuwenhuijsen, M. J. Exposure to disinfection by-products, fetal growth, and prematurity. Epidemiology. 2010, 21 (3), 300–13.

430 431

(8) Waller, K.; Swan, S. H.; DeLorenze, G.; Hopkins, B. Trihalomethanes in drinking water and spontaneous abortion. Epidemiology. 1998, 9 (2), 134-140.

432 433

(9) Key Statistics for Bladder Cancer. American Cancer Society. https://www.cancer.org/cancer/bladdercancer/about/key-statistics.html (retrieved September 5, 2017).

434 435

(10) National Primary Drinking Water Regulations: Disinfectants and Disinfection Byproducts. 40 CFR Parts 9, 141, and 142. Federal Register 1998, 63, No.241, 69390-69476.

436 437

(11) McGuire, M. J.; Meadows, R. G. AWWARF trihalomethane survey. J. Am. Water Works Assoc. 1988, 80 (1), 61-68.

438 439

(12) Richardson, S. D. Disinfection by-products: formation and occurrence in drinking water. In Encyclopedia of Environmental Health, Ed. J.O. Nriagu, Elsevier, Inc. Press: 2011; pp110-136.

440 441 442

(13) Krasner, S. W.; Weinberg. H. S.; Richardson, S. D.; Pastor, S. J.; Chinn, R.; Sclimenti, M. J.; Onstad, G. D. Thruston, A. D. Occurrence of a new generation of disinfection byproducts. Environ. Sci. Technol. 2006, 40(23), 7175-7185.

443 444 445

(14) National Primary Drinking Water Regulations. U.S. Environmental Protection Agency. https://www.epa.gov/ground-water-and-drinking-water/national-primary-drinking-water-regulations (retrieved September 6, 2017).

446 447

(15) National Primary Drinking Water Regulations: Stage 2 Disinfectants and Disinfection Byproducts Rule. 40 CFR Parts 9, 141, and 142. Federal Register 2006, 71, No. 2, 388-493.

448 449

(16) Liang, L.; Singer. P. C. Factors influencing the formation and relative distribution of haloacetic acids and trihalomethanes in drinking water. Environ. Sci. Technol. 2003, 37(13), 2920-2928.

450 451

(17) Ged, E. C., Chadik, P. A., Boyer, T. H. Predictive capability of chlorination disinfection byproducts models. J. Environ. Manage. 2015,149, 253-262.

452 453

(18) Westerhoff, P.; Mash, H. Dissolved organic nitrogen in drinking water supplies: a review. J. Water Supply: Res. Technol.--AQUA 2002, 51(8), 415–448.

454 455 456

(19) Shah, A. D.; Mitch, W. A. Halonitroalkanes, halonitriles, haloamides and N-nitrosamines: A critical review of nitrogenous disinfection byproduct (N-DBP) formation pathways. Environ. Sci. Technol., 2012, 46(1), 119-131.

457 458

(20) Integrated Risk Information System. U.S. Environmental Protection Agency. https://www.epa.gov/iris (retrieved September 7, 2017).

459 460

(21) Dai, N.; Mitch, W. A. Relative importance of N-nitrosodimethylamine compared to total Nnitrosamines in drinking waters. Environ. Sci. Technol. 2013, 47(8), 3648-3656.

14 ACS Paragon Plus Environment

Page 15 of 22

Environmental Science & Technology

461 462 463

(22) Zeng, T.; Glover, C.M.; Marti, E.; Woods, G.; Karanfil, T.; Mitch, W.A.; Dickenson, E.R.V. Relative importance of different water categories as sources of N-nitrosamine precursors. Environ. Sci. Technol., 2016, 50(24),13239-13248.

464 465 466

(23) Zhao, Y.; Qin, F.; Boyd, J. M.; Anichina, J.; Li, X.-F. Characterization and determination of chloroand bromo-benzoquinones as new chlorination disinfection byproducts in drinking water. Anal. Chem. 2010, 82(11), 4599-4605.

467 468

(24) Hua, G., Reckhow, D. A., Kim, J. Effect of bromide and iodide ions on the formation and speciation of disinfection byproducts during chlorination. Environ.Sci. Technol. 2006, 40 (9), 3050-3056.

469 470

(25) Dotson, A. D.; Rodriguez, C. E.; Linden, K. G. UV disinfection implementation status in US water treatment plants. J. Am. Water Works Assoc. 2012, 104(5), E318-E324.

471 472

(26) Seidel, C. J.; McGuire, M. J.; Summers, R. S.; Via, S. Have utilities switched to chloramines? J. Am. Water Works Assoc. 2005, 97 (10), 87−97.

473 474 475

(27) Zhao Y-Y.; Boyd J. M.; Woodbeck M.; Andrews R. C.; Qin F.; Hrudey S. E.; Li X-F. Formation of N-nitrosamines from eleven disinfection treatments of seven different surface waters. Environ. Sci. Technol. 2008, 42 (13), 4857–4862.

476 477

(28) Schreiber, I.M.; Mitch, W.A. Nitrosamine formation pathway revisited: the importance of dichloramine and dissolved oxygen. Environ. Sci. Technol. 2006, 40 (19), 6007-6014.

478 479

(29) Bichsel, Y., von Gunten, U. Formation of iodo-trihalomethanes during disinfection and oxidation of iodide-containing waters. Environ. Sci. Technol. 2000, 34(13), 2784-2791.

480 481 482

(30) Shah, A. D.; Krasner, S. W.; Chen, T., C.-F.; von Gunten, U.; Mitch, W .A. Tradeoffs in disinfection byproduct formation associated with precursor pre-oxidation for control of nitrosamine formation. Environ. Sci. Technol. 2012, 46(9), 4809-4818.

483 484

(31) McCurry, D. L.; Quay, A. N.; Mitch, W. A. Ozone promotes chloropicrin formation by oxidizing amines to nitro compounds. Environ. Sci. Technol. 2016, 50(3), 1209-1217.

485 486 487

(32) McCurry, D.L.; Krasner, S.W.; Mitch, W.A. Control of nitrosamines during non-potable and de facto wastewater reuse with medium pressure ultraviolet light and preformed monochloramine. Environ. Sci.: Water Res. Technol. 2016, 2, 502-510.

488 489 490

(33) Yang, Y.; Komaki, Y.; Kimura, S. Y.; Hu, H. Y.; Wagner, E. D.; Marinas, B. J.; Plewa, M. J. Toxic impact of bromide and iodide on drinking water disinfected with chlorine or chloramines. Environ. Sci. Technol. 2014, 48 (20), 12362-12369.

491 492

(34) Wagner, E. D.; Plewa, M. J. CHO cytotoxicity and genotoxicity analyses of disinfection by-products: an updated review. J. Environ. Sci. 2017, 58, 64-76.

493 494 495

(35) California Department of Public Health. NDMA and Other Nitrosamines - Drinking Water Issues. http://www.waterboards.ca.gov/drinking_water/certlic/drinkingwater/NDMA.shtml (accessed August 15, 2015)

496 497

(36) A New Approach to Protecting Drinking Water and Public Health. U.S. Environmental Protection Agency, Office of Water. EPA 815F10001 (accessed August 15, 2015)

498 499

(37) Plewa, M. J.; Wagner, E. D.; Richardson, S. D. TIC-Tox: a preliminary discussion on identifying the forcing agents of DBP-mediated toxicity of disinfected water. J. Environ. Sci. 2017, 58, 208-216. 15 ACS Paragon Plus Environment

Environmental Science & Technology

Page 16 of 22

500 501 502

(38) Szczuka A.; Parker K. M.; Harvey C.; Hayes E.; Vengosh A.; Mitch W.A. Regulated and unregulated halogenated disinfection byproduct formation from chlorination of saline groundwater. Water Res. 2017, 122, 633-644.

503 504

(39) Zeng, T.; Plewa, M. J.; Mitch, W. A. N-nitrosamines and halogenated disinfection byproducts in u.s. full advanced treatment trains for potable reuse. Water Res., 2016, 101, 176-186

505 506 507 508

(40) Daiber, E. J.; DeMarini D. M.; Ravuri S. A.; Liberatore H. K.; Cuthbertson A. A.; ThompsonKlemish A.; Byer J. D.; Schmid J. E.; Afifi M. Z.; Blatchley, III E. R.; Richardson S. D. Progressive increase in disinfection byproducts and mutagenicity from source to tap to swimming pool and spa water: impacts of human inputs. Environ. Sci. Technol., 2016. 50 (13), 6652–6662.

509 510 511 512

(41) Jeong, C. H.; Anduri, S.; Richardson S. D.; Daiber E. J.; McKague A. B.; Nieuwenhuijsen M. J.; Kogevinas M.; Villanueva C. M.; Goslan E. H.; Luo W.; Isabelle L. M.; Pankow J. F.; Wagner E. D.; Plewa M. J. The occurrence and toxicity of disinfection by-products in european drinking waters: correlations with the hiwate epidemiological program. Environ. Sci. Technol., 2012, 46: 12120-12128.

513 514 515

(42) Lavonen, E. E.; Gonsior, M.; Tranvik, L. J.; Schmitt-Kopplin, P.; Kohler, S. J. Selective chlorination of natural organic matter: identification of previously unknown disinfection byproducts. Environ. Sci. Technol. 2013, 47(5), 2264-2271.

516 517 518 519

(43) Gonsior, M.; Schmitt-Kopplin, P.; Stavklint, H.; Richardson, S. D.; Hertkorn, N.; Bastviken, D. Changes in dissolved organic matter during the treatment processes of a drinking water treatment plant in Sweden and formation of previously unknown disinfection byproducts. Environ. Sci. Technol. 2014, 48(21), 12714-12722.

520 521

(44) Zhai, H.; Zhang, X. Formation and decomposition of new and unknown polar brominated disinfection byproducts during chlorination. Environ. Sci. Technol. 2011, 45(6), 2194-2201.

522 523 524

(45) Pan, Y.; Zhang, X. Four groups of new aromatic halogenated disinfection byproducts: effect of bromide concentration on their formation and speciation in chlorinated drinking water. Environ. Sci. Technol. 2013, 47(3), 1265-1273.

525 526 527

(46) Wang, W.; Qian, Y.; Jmaiff, L. K.; Hrudey, S.E.; Krasner, S.; Li, X.-F. Precursors of halobenzoquinones and their removal during drinking water treatment processes. Environ. Sci. Technol. 2015, 49(16), 9898-9904.

528 529 530

(47) Chuang, Y.-H.; McCurry, D. L.; Tung, H.-H.; Mitch, W.A. Formation pathways and tradeoffs between haloacetamides and haloacetaldehydes during combined chlorination and chloramination of lignin phenols and natural waters. Environ. Sci. Technol., 2015, 49(24), 14432-14440

531 532

(48) Qian, Y.; Wang, W.; Boyd, J. M.; Wu, M.; Hrudey, S. E.; Li, X. F. UV-induced transformation of four halobenzoquinones in drinking water. Environ. Sci. Technol. 2013, 47(9), 4426-4433.

533 534 535

(49) Wang, W.; Qian, Y.; Li, J.; Moe, B.; Huang, R.; Zhang, H.; Hrudey, S. E.; Li, X.-F. Analytical and toxicity characterization of halo-hydroxyl-benzoquinones as stable haloquinone disinfection byproducts in treated water. Anal. Chem. 2014, 86(10), 4982–4988.

536 537

(50) Roux, J. L.; Gallard, H.; Croué, J.-P.; Papot, S.; Deborde, M. NDMA formation by chloramination of ranitidine: Kinetics and mechanism. Environ. Sci. Technol. 2012, 46 (20), 11095−11103.

16 ACS Paragon Plus Environment

Page 17 of 22

Environmental Science & Technology

538 539 540

(51) Hanigan, D.; Thurman, E. M.; Ferrer, I.; Zhao, Y.; Andrews, S.; Zhang, J.; Herckes, P.; Westerhoff, P. Methadone contributes to N-nitrosodimethylamine formation in surface waters and wastewaters during chloramination. Environ. Sci. Technol. Lett. 2015, 2 (6), 151−157.

541 542

(52) Dai, N.; Zeng, T.; Mitch, W. A. Predicting N-Nitrosamines: N-Nitrosodiethanolamine as a significant component of total N-nitrosamines in recycled wastewater. Environ Sci Technol. Let. 2015, 2 (3), 54-58.

543 544

(53) Rule, K. L.; Ebbett, V. R.; Vikesland, P. J. Formation of chloroform and chlorinated organics by free-chlorine-mediated oxidation of triclosan. Environ. Sci. Technol. 2005, 39 (9), 3176-3185.

545 546

(54) Dotson, A.; Westerhoff, P. Occurrence and removal of amino acids during drinking water treatment. J. Am. Water Works Assoc. 2009, 101(9), 101–115.

547 548 549

(55) Sivey, J. D.; Howell, S. C.; Bean, D .J.; McCurry, D. L.; Mitch, W. A.; Wilson, C.J. Dual role for lysine during protein modification by HOCl and HOBr: lysine nitrile as a putative biomarker for oxidative stress. Biochemistry 2013, 52(7), 1260-1271.

550 551 552

(56) Choe, J. K.; Richards. D. H.; Wilson, C .J.; Mitch, W. A. Degradation of amino acids and structure in model proteins and bacteriophage MS2 by chlorine, bromine and ozone. Environ. Sci. Technol. 2015, 49(22), 13331-13339.

553 554 555

(57) Walse, S. S.; Plewa, M. J.; Mitch, W. A. Exploring amino acid side chain decomposition using enzymatic digestion and HPLC-MS: combined lysine transformations in chlorinated waters. Anal. Chem. 2009, 81 (18), 7650-7659.

556 557

(58) Tang, Y. N.; Xu, Y.; Li, F.; Jmaiff, L. K.; Hrudey, S. E.; Li, X.-F. Non-targeted analysis of peptides and disinfection byproducts in water. J. Environ. Sci. 2016, 42, 259−266.

558 559

(59) Huang, G.; Jiang, P.; Li, X.-F. Mass spectrometry identification of N-chlorinated dipeptides in drinking water. Anal. Chem. 2017, 89(7), 4204−4209.

560 561 562 563

(60) Schroter, J.; Griesinger, H.; Reuss, E.; Schulz, M.; Riemer, T.; Suss, R. Schiller, J.; Fuchs, B. Unexpected products of the hypochlorous acid-induced oxidation of oleic acid: a study using high performance thin-layer chromatography-electrospray ionization mass spectrometry. J. Chromatogr. A 2016, 1439, 89-96.

564 565 566

(61) Boorman G. A.; Dellarco V.; Dunnick J. K.; Chapin R. E.; Hunter S., Hauchman F., Gardner H.; Cox M.; Sills R. C. Drinking water disinfection byproducts: review and approach to toxicity evaluation. Environmental Health Perspect. 1999, 107, 207-217.

567 568 569

(62) Richardson, S.D.; Plewa, M.J.; Wagner, E.D.; Schoeny, R.; DeMarini, D.M. Occurrence, genotoxicity, and carcinogenicity of regulated and emerging disinfection by-products in drinking water: a review and roadmap for research. Mutat. Res. 2007, 636, 178-242.

570 571 572 573 574

(63) Cantor, K.P.; Villanueva, C.M.; Silverman, D.T.; Figueroa, J.D.; Real, F.X.; Garcia-Closas, M.; Malats, N.; Chanock, S.; Yeager, M.; Tardon, A.; Garcia-Closas, R.; Serra, C.; Carrato, A.; CastanoVinyals, G.; Samanic, C.; Rothman, N.; Kogevinas, M. Polymorphisms in GSTT1, GSTZ1, and CYP2E1, disinfection by-products, and risk of bladder cancer in Spain. Environ. Health Perspect. 2010, 118, 15451550.

17 ACS Paragon Plus Environment

Environmental Science & Technology

Page 18 of 22

575 576

(64) Fu K.Z.; Li J.H.; Vemula S.; Moe B. Effects of halobenzoquinone and haloacetic acid water disinfection byproducts on human neural stem cells. J. Environ. Sci. 2017, 58, 239-249.

577 578 579

(65) Li, J.; Bauer, M.; Moe, B.; Leslie, E.M.; and Li, X.-F. Multidrug resistance protein 4 (MRP4/ABCC4) protects cells from the toxic effects of halobenzoquinones. Chem. Res. Toxicol. 2017,30(10),1815-1822.

580 581 582

(66) Li, J.; Wang, W.; Moe, B.; Wang, H.; Li, X.-F. Chemical and toxicological characterization of halobenzoquinones, an emerging class of disinfection byproducts. Chem. Res. Toxicol. 2015, 28(3), 306– 318.

583 584 585 586 587

(67) Neale P. A.; Altenburger R.; Aït-Aïssa S.; Brion F.; Busch W.; de Aragão Umbuzeiro G.; Denison M.S.; Du Pasquier D.; Hilscherová K.; Hollert H. Morales D.A.; Novák J.; Schlichting R.; Seiler T.; Serra H.; Shao Y.; Tindall A. J.; Tollefsen K. E.; Williams T. D.; Escher B. I. Development of a bioanalytical test battery for water quality monitoring: Fingerprinting identified micropollutants and their contribution to effects in surface water. Water Res. 2017, 123, 734-750.

588 589 590

(68) Yang M.; Zhang, X. Comparative developmental toxicity of new aromatic halogenated dbps in a chlorinated saline sewage effluent to the marine polychaete Platynereis dumerilii. Environ. Sci. Technol. 2013, 47(19), 10868-10876.

591 592

(69) Toxicity ForeCaster (ToxCast™) Data. U.S. Environmental Protection Agency. https://www.epa.gov/chemical-research/toxicity-forecaster-toxcasttm-data (retrieved Oct 18, 2015)

593 594

(70) A National Toxicology Program for the 21st Century Roadmap to Achieve the NTP Vision. U.S. Department of Health and Human Services. https://ntp.niehs.nih.gov/results/tox21/index.html

595 596

(71) Doudna, J. A.; Charpentier, E. The new frontier of genome engineering with CRISPR-Cas 9. Science 2014, 346(6213), 1258096 (1-9).

597 598 599

(72) Cong, L.; Ran, F. A.; Cox, D.; Barretto, R.; Habib, N.; Hsu, P. D.; Wu, X.; Jiang, W.; Marraffini, L. A.; Zhang, F. Multiplex genome egineering using CRISPR-Cas 9 systems. Science 2013, 339(6162), 819823.

600 601 602 603

(73) Narotsky M. G.; Klinefelter G. R.; Goldman J. M.; De Angelo A. B.; Best D. S.;McDonald A.; Strader L. F.; Murr A. S.; Suarez J. D.; George M. H.; E. Hunter III S.; Simmons J. E. Reproductive toxicity of a mixture of regulated drinking-water disinfection by-products in a multigenerational rat bioassay. Environmental Health Perspect. 2015,123(6), 564-570.

604 605 606 607 608

(74) Pressman, J. G.; Richardson S. D.; Speth T. F.; Miltner R. J.; Narotsky M. G.; Hunter III E. S.; Rice G. E.; Teuschler L. E.; McDonald A.; Parvez S.; Krasner S. K.; Weinberg H. S.; McKague A. B.; Parrett C. J.; Bodin N.; Chinn R.; Lee C.-F. T.; Simmons J. E. Concentration, chlorination, and chemical analysis of drinking water disinfection byproduct mixtures health effects research: U.S. EPA’s Four Lab Study. 2010. Environ. Sci. Technol., 2010, 44 (19): 7184-7192.

609 610 611

(75) Simmons, J. E.; Richardson S. D.; Speth T.F.; Miltner R. J.; Rice G.; Schenck K. M.; Hunter, III E. S.; Teuschler L. K. Research issues underlying the four-lab study: integrated disinfection byproducts mixtures research. J. Toxicol. Environ. Health, Pt. A, 2008, 71,1125-1132.

612 613 614

(76) Zhao, Y.-Y.; Boyd, J.; Hrudey, S. E.; Li, X.-F. Characterization of new nitrosamines in drinking water using liquid chromatography tandem mass spectrometry. Environ. Sci. & Technol. 2006, 40(24), 7636-7641.

18 ACS Paragon Plus Environment

Page 19 of 22

Environmental Science & Technology

615 616 617

(77) Kenyon, E.M.; Eklund, C.; Leavens, T.; Pegram, R.A. Development and application of a human PBPK model for bromodichloromethane to investigate the impacts of multi-route exposure. J Appl Toxicol. 2016, 36, 1095-111.

618 619 620

(78) Leavens, T. L.; Blount, B. C.; DeMarini, D. M.; Madden, M. C.; Valentine, J. L.; Case, M. W.; Silva, L. K.; Warren, S. H.; Hanley, N. M.; Pegram, R. A. Disposition of bromodichloromethane in humans following oral and dermal exposure. Toxicol. Sci. 2007, 99, 432−445.

621 622 623 624

(79) Font-Ribera, L.; Kogevinas, M.; Schmalz, C.; Zwiener, C.; Marco, E.; Grimalt, J. O.; Liu, J.; Zhang, X.; Mitch, W.; Critelli, R.; Naccarati, A.; Heederik, D.; Spithoven, J.; Arjona, L.; de Bont, J.; GraciaLavedan, E.; Villanueva, C. M. Environmental and personal determinants of the uptake of disinfection by-products during swimming. Environ. Res., 2016, 149, 206-215.

625 626 627

(80) Bader, E.L.; Hrudey, S.E.; Froese, K.L. Urinary excretion half-life of trichloroacetic acid as a biomarker of exposure to chlorinated drinking water disinfection by-products. Occup. Environ. Med. 2004, 61, 715–716.

628 629

(81) Kimura, S.Y.; Zheng, W.; Hipp, T.N.; Allen, J.M.; Richardson, S.D. Total organic halogen (TOX) in human urine: A halogen-specific method for human exposure studies. J. Environ. Sci. 2017, 58, 285-295.

630 631 632

(82) Ross, K.M.; Pegram, R.A. In vitro biotransformation and genotoxicity of the drinking water disinfection byproduct bromodichloromethane: DNA binding mediated by glutathione transferase theta 11. Toxicol Appl Pharmacol. 2004, 195, 166-81.

633 634

(83) Rhoads, W. J.; Pruden, A.; Edwards, M. K. Interactive effects of corrosion, copper and chloramines on Legionella and Mycobacteria in hot water plumbing. Environ. Sci. Technol. 2017, 51(12), 7065-7075.

635 636 637

(84) Wigginton, K. R.; Pecson, B. M.; Sigstam, T.; Bosshard, F.; Kohn, T. Virus inactivation mechanisms: impact of disinfectants on virus function and structural integrity. Environ. Sci. Technol. 2012, 46 (21), 12069−12078.

638 639

(85) Smeets, P.W.M.H.; Medema, G.J.; van Dijk, J.C. The Dutch secret: safe drinking water without chlorine in the Netherlands. Drink. Water Eng. Sci. Discuss. 2008, 1, 173-212.

640 641

19 ACS Paragon Plus Environment

Environmental Science & Technology

Page 20 of 22

642 643 644 645 646 647 648 649

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.

650 651

20 ACS Paragon Plus Environment

Page 21 of 22

Environmental Science & Technology

652 653 654 655 656 657 658

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.

659

21 ACS Paragon Plus Environment

Environmental Science & Technology

Page 22 of 22

660 661

TOC Art

662 663 664 665 666 667 668

22 ACS Paragon Plus Environment