Carcinogenic risk of N-Nitrosamines in Shanghai Drinking Water

May 14, 2019 - N-Nitrosamines are drinking water disinfection byproducts that pose a high carcinogenic risk. We hypothesized that raw water treatment ...
1 downloads 0 Views 1MB Size
Download PDF
Article pubs.acs.org/est

Cite This: Environ. Sci. Technol. 2019, 53, 7007−7018

Carcinogenic risk of N‑Nitrosamines in Shanghai Drinking Water: Indications for the Use of Ozone Pretreatment Zhiyuan Chen,†,⊥ Lan Yang,†,⊥ Yu Huang,† Peter Spencer,‡ Weiwei Zheng,† Ying Zhou,† Songhui Jiang,† Weimin Ye,§ Yuxin Zheng,|| and Weidong Qu*,†

Downloaded via UNIV OF SOUTHERN INDIANA on July 31, 2019 at 08:22:47 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Centers for Water and Health, Key Laboratory of Health Technology Assessment, National Health Commission of the People’s Republic of China, Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University, Shanghai, 200032, China ‡ Oregon Institute of Occupational Health Sciences, and Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, Oregon 97239, United States § Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 171 77, Sweden || School of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China S Supporting Information *

ABSTRACT: N-Nitrosamines are drinking water disinfection byproducts that pose a high carcinogenic risk. We hypothesized that raw water treatment processes influence the types and concentrations of nitrosamines in drinking water, thereby posing differential health risks. We compared the finished water of two water treatment plants (WTP-A, WTP-B) serving Shanghai, China. Both plants use the Qingcaosha reservoir as a water source to generate drinking water with conventional but distinct treatment processes, namely preoxidation with sodium hypochlorite (WTP-A) vs ozone (WTP-B). Average nitrosamine concentrations, especially that of the probable human carcinogen (2A) Nnitrosodimethylamine, were higher in finished (drinking) water from WTP-A (35.83 ng/L) than from WTP-B (5.07 ng/L). Other differences in mean nitrosamines in drinking water included N-nitrosodipropylamine (42.62 ng/L) and N-nitrosomethylethylamine (26.73 ng/L) in WTP-A in contrast to Nnitrosodiethylamine (7.26 ng/L) and N-nitrosopyrrolidine (59.12 ng/L) in WTP-B. The estimated adult cancer risk from exposure to mixed nitrosamines was 1.83 times higher from WTP-A than from WTP-B drinking water. Children exposed to nitrosamines had a significantly higher cancer risk than adults (p < 0.05). Disease burden exceeded 106 person-years. Taken together, these data suggest that use of ozone in the preoxidation step can reduce nitrosamine formation in drinking water and thereby lower the population cancer health risk.

■

carcinogens” (Group B2).8 Exposure to NDMA in drinking water, the most potentially harmful nitrosamine in drinking water, has an estimated specified cancer risk level of 10−6 at 0.7 ng/L,8 and a World Health Organization guideline value of 100 ng/L based on carcinogenicity and risk assessment.9 Six nitrosamines, namely NDEA, NDMA, NPYR, N-nitrosodibutylamine (NDBA), N-nitrosodipropylamine (NDPA), and Nnitrosomethylethylamine (NMEA), are included in EPA’s Second Unregulated Contaminant Monitoring Rule,10 and five nitrosamines, including NDEA, NDMA, NDPA, NPYR, NNitrosodiphenylamine (NDPhA), appear on EPA’s Fourth Contaminant Candidate List.11 The occurrence of nitros-

INTRODUCTION N-Nitrosamines (R1−(R2−)N−N = O) are emerging nitrogenous disinfection byproducts (DBPs) that are largely formed during chloramine disinfection of water.1,2 Public health concerns arise from their genotoxic, cytotoxic, and carcinogenic potential.3−5 Genotoxic nitrogenous DBPs, such as Nnitrosodiethylamine (NDEA) and N-nitrosopyrrolidine (NPYR), produce dose-dependent experimental liver cancer in rats.5 Epidemiologic investigation has suggested that exposure to N-nitrosodimethylamine (NDMA) in food is associated with a higher risk of colorectal cancer, especially rectal carcinoma.6 NDMA and NDEA are both classified as “probably carcinogenic to humans” (Group 2A) by the International Agency for Research on Cancer (IARC),7 and the Integrated Risk Information System (IRIS) of the United States Environmental Protection Agency (U.S. EPA) proposed that seven nitrosamines are classifiable as “probable human © 2019 American Chemical Society

Received: Revised: Accepted: Published: 7007

December 31, 2018 May 8, 2019 May 14, 2019 May 14, 2019 DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology

Water Samples. Raw water and finished drinking water samples were collected in February, 2017. Raw water was collected from the input to WTP-A, located ∼25 km from the Qingcaosha river and separately from the input to WTP-B, located ∼15 km from the same source. WTP-A and WTP-B are separated by ∼13 km. Both WTPs employ conventional processes (i.e., preoxidation, coagulation, sedimentation, sand filtration, biological-activated carbon, chlorination) to produce drinking water. The main difference in water treatment is the preoxidation step, which employs either sodium hypochlorite (WTP-A) or ozone (WTP-B) as the preoxidant. We collected water samples using the methods recommended by the China national standard for water sample collection, 26 this emphasizes the need to collect water samples in rain-free days to avoid interference from rain and runoff. Water samples were taken for three rain-free consecutive days, with three replicates per location; thus, confounding factors, such as pollutants and precursors from the fluctuation of runoff following raining, were excluded. Samples were collected in one-liter brown glass bottles, placed in coolers with ice-packs, and transported to the laboratory within 4 h. Solid-Phase Extraction and GC/MS Analysis. According to U.S. EPA Method 521,27 water samples were extracted by passing the water over activated charcoal at 5 mL/min, followed by 20 mL of acetone, n-hexane (v/v, 1:1) rinse, and activation by methanol. After loading, samples were eluted with 10 mL of acetonitrile, methanol, and acetone, one after another. The eluate was allowed to evaporate, and the residue was redissolved in 10 mL of methanol. The solution was concentrated to 1 mL by nitrogen evaporation. Eight nitrosamines were determined by gas chromatograph−mass spectrometry (GC/MS, Shimadzu, Japan). The detection method was performed as described previously.28 Analytical methods for determination of nitrosamines underwent strict quality assurance/quality control as recommended by the U.S. EPA, including determination of recovery, relative standard deviation, and method detection limit (Supporting Information (SI) Table S1). Cancer Risk Assessment. Human health risk assessment was conducted to evaluate the carcinogenic risk of nitrosamines in drinking water according to Risk Assessment Guidance for Superfund, Parts A, E, and F.29−31 Based on the occurrence levels of individual nitrosamine in finished drinking water from WTP-A and WTP-B, the lifetime average daily dose (LADD) was calculated from multiple exposure routes, including ingestion, inhalation, and dermal absorption. This value was multiplied by the specific-chemical cancer slope factor (SF) or inhalation unit risk (IUR) to calculate the estimated lifetime cancer risk (ELCR). Concentrations of nitrosamines in finished water (Cw) were transformed to equivalent-concentrations in air (Cair) according to eq 1.31 The LADD for adults exposed to each of the eight water-borne nitrosamines via ingestion, dermal absorption, and inhalation was calculated according to eqs 2, 3, and 4, respectively. A simple additive model was applied to calculate risk from mixed nitrosamine exposure, and age-dependent adjustment factors (ADAF) were introduced to assess the nitrosamine cancer risk for children.

amines in drinking water and their potential risks for human health are also of great concern in Canada,12 the UK,13 and Japan.14 The presence of nitrosamines in drinking water varies with both the source water and water treatment process.15,16 Raw water with ammonia nitrogen, algae, and organic precursors, such as dimethylamine and trimethylamine, favors the formation of nitrosamines.2,16 The raw-water disinfectant is a critical variable, such that chloramine minimizes formation of some regulated DBPs and increases generation of some emerging nitrogenous and iodinated DBPs.17,18 To meet requirements of the U.S. Safe Drinking Water Act and to accord with the National Standards for Drinking Water Quality in China, most water-treatment plants (WTPs) employ chloramine as the disinfectant to control regulated DBPs,2,18 such that nitrosamines are ubiquitous in the drinking water of both countries.19,20 Although nitrosamines pose greater health hazards than the regulated trihalomethanes and haloacetic acids,4 little has been done to assess the health risks of exposure to nitrosamines in drinking water. While health risk assessments have been conducted for adult exposures to a single nitrosamine (NMDA) via one exposure route (ingestion),21 the impact of oral, respiratory, and dermal exposure to multiple semivolatile nitrosamines in water used by children and adults for drinking or bathing is still unknown. Although children have a relatively large body surface area,22 water intake,23 and are often more sensitive to pollutants than adults,24 these factors are insufficiently considered in traditional risk assessments. To lay a solid foundation to protect the public from harmful effects of nitrosamines, risk assessment should consider their diverse chemical species and differential cytotoxic and carcinogenic potential. This will guide the choice of raw water treatment methods that minimize nitrosamineassociated health risks. Based on the foregoing considerations, we measured nitrosamines in the finished water of two treatment plants both supplied by the Yangtze River-fed Qingcaosha reservoir, the biggest shallow estuary reservoir in the world and new water source for Shanghai. With a capacity of 430 million m3 and an area of 70 km2, the Qingcaosha reservoir is designed to provide Shanghai’s 24 million residents with 68 days of water without refilling from the Yangtze River.25 Water treatment plant A (WTP-A) employes preoxidation with sodium hypochlorite plus chlorination, while plant B (WTP-B) uses preoxidation with ozone plus chlorination processing. We sought (i) to compare the types and amounts of nitrosamines in finished water from the two plants, (ii) to estimate the cancer risk and disease burden based on children and adults exposure to nitrosamines via multiple routes under actual environmental concentrations, and (iii) to provide scientific support for decision-making to control the health risks arising from nitrosamines in drinking water.

■

MATERIALS AND METHODS Reagents. All chemicals were purchased from Sigma unless specified otherwise. A mixed standard solution of eight Nnitrosamines (2000 mg/L in methanol), containing NDBA, NDEA, NDMA, NDPA, NMEA, NPYR, N-nitrosomorpholine (NMOR), and N-nitrosopiperidine (NPIP), was obtained together with activated carbon (Cat. No. A1978) from Supelco, Ltd. (St. Louis, MO). Distilled water meeting European Union Declaration of Conformity standards was made by Millipore Sigma-Aldrich Co. Ltd. (St. Louis, MO).

Cair =

Cw × HLC R × (T + 273.16)

LADDing = 7008

(1)

Cw × IR × EF × ED × CFing BW × LT

(2) DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology

percentile value for exposure variables were used to estimate the RME scenario. Burden of Disease. The burden of cancer associated with nitrosamines was measured in disability-adjusted life years (DALYs). As recommended by The Global Burden of Disease Study, DALYs are comprised of the years of life lost (YLLs) and the years lost due to disabilities (YLDs).37 DALYs were calculated according to eq8.

LADDder = 2FA × K p × Cw ×

6τevent × tevent π

× EV × ED × EF × SA × CFder

BW × LT

(3)

LADDinh =

Cair × InhR × EF × ET × ED × CFinh BW × LT

(4)

Where Cw and Cair are the concentrations of nitrosamines in water and air, respectively, HLC the Henry’s law constant, R the gas constant, T the temperature, IR the ingestion rate, InhR the inhalation rate, CF the conversion factor, FA the fraction of absorbed water, Kp the specific-chemical dermal permeability coefficient, τevent the lag time per event (showering or bathing), tevent the event duration, SA the skin surface area available for absorption, and EV the event frequency. The values of exposure factors such as exposure frequency (EF), exposure duration (ED), exposure time (ET), body weight (BW), and lifetime (LT) were recommended by Exposure Factors Handbook of Chinese Population and China Statistical Yearbook.32,33 Detailed information about the parameters values and reference is provided in SI Table S2 and Table S3. The estimated lifetime cancer risk (ELCR) via ingestion and dermal absorption was calculated using eqs 5 and 6, while the ELCR for inhaled nitrosamines in air was determined according to the updated U.S. EPA approach using eq 7.31 ELCR ing = LADDing × SF × ADAF

(6)

ELCR inh =

Cair × EF × ET × ED × IUR × ADAF LT

(7)

∫x=a

DCxe−βx e−r(x − a)dx

(8)

Where D is disability weight, C the age-weighting factor, β the age-weighting function parameter, r the annual discount rate, and L the duration of disability. The average life expectancy (a +L) and population data refer to the 2015 Chinese National Census.33 Detailed information is provided in SI Table S4. Statistical Analysis. All graphics productions were performed with Graphpad Prism 7.0 (GraphPad Software, San Diego, CA). The Wilcoxon signed-ranks test and t test were performed to conduct statistical analysis, with p < 0.05 taken as significant.

■

RESULTS Preoxidation and the Formation of N-Nitrosamines: O3 vs NaClO. To compare the influence of raw water treatment processes on the formation of nitrosamine disinfection byproducts, we selected two water treatment plants, namely WTP-A and WTP-B as research objects. Both of them receive raw water from the Qingcaosha Reservoir but employ different preoxidation processes that can influence the species and concentrations of nitrosamines in finished drinking water. For WTP-A, NDMA, NDPA, and NMEA were found in finished water, whereas NDEA, NDMA, and NPYR were identified in WTP-B finished water. The concentrations of nitrosamines in finished water from WTP-A and WTP-B ranged from not detectable (ND) to dozens of nanograms per liter. Importantly, NDMA was detected in the finished water of both WTP-A and WTP-B. The NDMA concentration (35.83 ± 19.57 ng/L) in the finished drinking water of WTP-A, which used sodium hypochlorite preoxidation combined with chlorination disinfection, was approximately seven times higher than that in WTP-B (5.07 ± 2.01 ng/L), which used ozone preoxidation with chlorination. Addtionally, the NDMA concentration increased ∼3.5 times during the transition from raw (10.28 ± 3.62 ng/L) to finished water in WTP-A. NDPA showed the highest concentration (42.62 ± 10.15 ng/ L) among nitrosamines in WTP-A finished water, and the concentration of NPYR (59.12 ± 3.00 ng/L) was highest in WTP-B. NDEA was not detected in raw water of WTP-B but was present (7.26 ± 1.20 ng/L) in its finished water (Table 1). Multiroutes Estimation of Cancer Risks Based on Actual Exposure Concentrations. We referred to “Risk Assessment Guidance for Superf und” recommended by U.S. EPA to evaluate the LADD and ELCR induced by nitrosamines based on measured concentrations in finished drinking water derived from the two different treatment processes. Since the concentration of nitrosamine species in finished water is directly related to population health, we calculated the carcinogenic risk based on the concentration of nitrosamines in finished water. Qualitative and quantitative differences in measured nitrosamine content of water sampled from WTP-A and WTP-B were reflected in distinct population LADD and ELCR estimates. For instance, the oral LADD value for the

(5)

SF × ADAF ABSGI

ELCR der = LADDder ×

x=a+L

DALY =

Where SF is the oral cancer slope factor, IUR the inhalation unit risk, ABGGI the fraction of contaminant absorbed in the gastrointestinal tract, and ADAF the age-dependent adjustment factor. SF was defined as an upper-bound estimate of the increase in cancer risk per unit dose by extrapolating toxicologically equivalent doses from rats to humans.34 IUR was defined as an upper-bound excess lifetime cancer risk estimated to result from continuous lifetime exposure to an agent at a concentration of 1 μg/m3 in air.35 For carcinogenic chemicals operating by a mutagenic mode of action, early life susceptibility should be assumed. Therefore, instead of treating children as a subgroup, ADAF and agespecific exposure factors were applied in the evaluation of risk from early life exposures.36 The formula for calculating risk associated with exposure of children was similar to that used for adults (vide supra), except that ADAF was added to assess the additional risk, and average time (AT) was substituted for lifetime (LT) exposure. Exposure Scenario Analysis. The central tendency exposure (CTE) scenario was used to estimate the current general condition of exposure, and the mean concentrations of nitrosamines and the 50th percentile values of exposure parameters were employed to estimate the CTE scenario. The reasonable maximum exposure (RME) scenario was defined as the highest exposure that is reasonably expected to occur at a site and still within the range of possible exposures, which can be used to estimate the maximum potential risk.35 The 95th percentile concentration of nitrosamines and the 95th 7009

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

39.18−49.25 56.88−63.70

45.97 59.12

47.65 61.92

WTP-A individual nitrosamine ranged from 8.16 × 10−7 (NMEA) to 1.36 × 10−6 (NDPA), while the oral ELCR value ranged from 9.11 × 10 −6 (NDPA) to 5.58 × 10−5 (NDMA) in a CTE scenario. Whereas, for WTP-B, the oral LADD value for the individual nitrosamine ranged from 1.54 × 10−7 (NDMA) to 1.81 × 10−6 (NPYR), and the oral ELCR value ranged from 3.76 × 10−6 (NPYR) to 3.32 × 10−5 (NDEA). Due to differences in the concentration of NDMA in drinking water, the oral ELCR for NDMA in WTP-A was 7.07 times that of WTP-B (Table 2). Estimates for lifetime average daily dose and cancer risk through ingestion, dermal absorption, and inhalation are shown in Table 2. Each nitrosamine species with respect to different exposure routes generated a unique LADD and ELCR with a difference ranging from 1 to 4 orders of magnitude. The cancer risk through ingestion was much higher than that for dermal and inhalation exposure routes, and the risk from dermal and inhalation was equivalent. In the CTE scenario, the cancer risk levels for oral exposure to NDPA, NMEA, NDEA, NPYR, and NDMA in either WTP-A or WTP-B were higher than 10−6, the negligible risk level defined by the U.S. EPA. Since exposure to multiple nitrosamines may result in additive effects, the lifetime oral cancer risk for total nitrosamines was 8.29 × 10−5 for WTP-A, and 4.49 × 10−5 for WTP-B. Thus, the lifetime cancer risks for total nitrosamines exceeded 10−5. NDMA made the highest percentage contribution (67.3%) to total oral lifetime cancer risk in WTP-A finished drinking wtaer, followed by NMEA (21.7%), and NDPA (11.0%). For WTP-B, NDEA made the highest percentage contribution (74.0%) to total oral risks, followed by NDMA (17.6%), and NPYR (8.4%). In the CTE scenario, the lifetime dermal cancer risk for total nitrosamines was 2.60 × 10−7 for WTP-A and 1.94 × 10−7 for WTP-B. The highest dermal cancer risk for WTP-A and WTPB was from NDPA (1.53 × 10−7) and NDEA (1.79 × 10−7), respectively. As for inhalation, NDMA (1.09 × 10−7) and NDEA (3.90 × 10−7) posed the highest cancer risk for WTP-A and WTP-B, respectively. The health risks from other nitrosamines through dermal absorption and inhalation were negligible (10−4 cancer risk for children, respectively. For exposure to NDMA, the cancer risk translates to one tumor per thousand infants per lifetime. DALYs Based on Actual Exposure. Estimated DALYs from exposure to nitrosamines comported with the magnitude of the respective carcinogenic risk. The total cancer-related DALYs associated with nitrosamines ranged from 101 to 107 (Table3). In the CTE scenario, DALYs from every single DBP are added directly, such that synergistic, antagonistic, potentiating, or inverse potentiating effects of the varied nitrosamine species are assumed not to exist. Under this assumption, the DALYs for nitrosamines in WTP-A finished water were 6.31 × 106 person-years, while the corresponding value for WTP-B was 3.47 × 106 person-years. NDMA in WTP-A contributed the highest DALYs, as compared to other nitrosamines. The sum of DALYs via ingestion, inhalation and dermal exposure to NDMA was 4.23 × 106 person-years, which accounted for 67.0% of the DALYs associated with total nitrosamines. This showed that NDMA in finished water raised the maximum cancer risk among nitrosamines formed in the process of disinfection.

■

DISCUSSION The cancer risk posed by exposure to mixed nitrosamines in drinking water is a public health concern.38 N-Nitrosamines are found in drinking water that has been disinfected with chloramine, chlorine dioxide, and ozone.39,40 The present study of drinking water generated by two WTPs in Shanghai reveals significant qualitative and quantitative differences in nitrosamine content and associated cancer risk. The divergent results can be traced to the different methods of disinfecting raw water employed by the two plants.

a

10−06 10−08 10−10 10−06 × × × × 1.18 5.46 9.06 1.24 10−09 10−09 10−10 10−09 × × × × 7.13 1.01 3.85 8.53 10−07 10−08 10−08 10−07 × × × × 4.01 2.27 1.24 4.37 10−09 10−10 10−09 10−09 × × × × 2.67 4.45 5.92 9.04 10−04 10−05 10−05 10−04 × × × × 1.10 3.04 1.12 1.52 10−07 10−07 10−06 10−06 × × × × 7.36 5.96 5.31 6.65 10−07 10−08 10−10 10−07 × × × × 3.90 1.54 3.36 4.06 10−09 10−10 10−10 10−09 × × × × 2.35 2.87 1.43 2.78 10−07 10−09 10−09 10−07 × × × × 1.79 8.70 6.24 1.94 10−09 10−10 10−09 10−09 1.19 1.71 2.97 4.33 × × × × 3.32 7.89 3.79 4.49 10−07 10−07 10−06 10−06 × × × × 2.22 1.54 1.81 2.18

10−05 10−06 10−06 10−05

× × × ×

10−07 10−07 10−07 10−07 × × × × 3.37 2.70 1.71 7.78 10−09 10−08 10−09 10−08 × × × × 6.24 3.50 7.03 4.83 10−07 10−07 10−07 10−07 × × × × 1.40 3.50 1.18 6.08 10−09 10−08 10−09 10−08 × × × × 2.75 4.99 5.35 5.80 10−04 10−05 10−05 10−04 × × × × 1.88 3.07 6.85 2.87 10−06 10−06 10−06 10−05 × × × × 3.68 4.39 3.12 1.12 10−07 10−08 10−08 10−07 × × × × 1.09 8.75 4.89 2.45 10−09 10−08 10−09 10−08 × × × × 2.03 1.14 2.01 1.54 10−08 10−07 10−08 10−07 × × × × 6.15 1.53 4.55 2.60 10−09 10−08 10−09 10−08 × × × × 1.21 2.19 2.08 2.52 10−05 10−06 10−05 10−05 × × × × 5.58 9.11 1.80 8.29 10−06 10−06 10−07 10−06 × × × × 1.09 1.30 8.16 3.21

ELCR LADD ELCR ingestion LADD ELCR inhalation LADD ELCR LADD ELCR ingestion LADD nitrosamines

WTP-A NDMA NDPA NMEA Total WTP-B NDEA NDMA NPYR total

inhalation LADD dermal dermal

ELCR

reasonable maximum exposureb central tendency exposurea

Table 2. Lifetime Average Daily Dose (LADD, in mg/kg/day) and Estimated Lifetime Cancer Risk (ELCR) of Adults Exposed to Nitrosamines from Two Water Treatment Plants under Central Tendency Exposure (CTE) and Reasonable Maximum Exposure (RME) Scenarios

Environmental Science & Technology

7011

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology

Figure 1. Estimated lifetime cancer risk associated with ingestion, dermal absorption, inhalation, and total exposure to nitrosamine-contaminated drinking water from two WTPs by age groups. The risk in this figure is estimated under central tendency exposure scenario.

depends on the types and number of raw-water contaminants, such as organic amines and ammonia.48,49 Given the common raw water source (Qingcaosha reservoir) of the two WTPs, the presence of different species and concentrations of nitrosamines in the finished water from WTP-A and WTP-B shows the disinfection process is of paramount importance in determining the quality of finished water with respect to nitrosamine content. While the probable human carcinogen NDMA was commonly detected in both WTP-A and WTP-B finished water, the mean concentration of NDMA in WTP-A exceeded the notification level of 10 ng/L defined by California Department of Health, while the concentration of NDMA in WTP-B was lower than 10 ng/L.50 The highest concentration of nitrosamines formed in WTP-A was the potential human carcinogen NDPA at 42.62 ng/L, a level that far exceeded the notification level (10 ng/L) defined by California. The water source of the two water treatment plants is located in the lower reaches of the Yangtze River. There are many cities and enterprises along the Yangtze River. With the emissions of industrial and domestic wastewater into the Yangtze River, the levels of ammonia nitrogen and other nitrogenous organic matter in raw water is very high;51 these serve as important precursors of disinfection byproducts. The WTP-A uses the preoxidant sodium hypochlorite, which can directly react with organic precursors in raw water to form DBPs.2 Liberated chlorine presumably reacted with organic ammonia in raw water to form chloramine, which generated

While the concentration of NDMA in raw water supplying the water treatment plants WTP-A and WTP-B was comparable, its concentration in WTP-A finished water was much higher than that of WTP-B. Estimated cancer risks for total nitrosamines in drinking water varied by exposure route and by subject age. The cancer risk for adults from mixed nitrosamines in WTP-A drinking water was 1.83 times higher than that of WTP-B. Children exposed to nitrosamines were found to have a significantly higher cancer risk than that for comparably exposed adults (p < 0.05). Thus, selecting the appropriate water treatment process can efficiently reduce the formation of high-risk nitrosamines and associated risk to human health. The relevance of these findings extends beyond drinking water and cancer risk since nitrosamines (notably NDMA) are also contaminants of food,41 beverages,38 tobacco,42 personal care products,43 and their possible role as neurotoxins in the etiology of sporadic neurodegenerative disease has also been raised.44 Maximum daily total nitrosamine exposure in the U.S. in units of ng/d is estimated at 25 000 ± 4950, driven by consumption of tobacco products (22 000 ± 4350), food (1900 ± 380), alcohol (1000 ± 200), and drinking water (120 ± 24).45 The Formation of N-Nitrosamines. The formation of water-borne N-nitrosamine DBPs is related to the chemical composition of raw water treated by disinfection,15,17 to treatment processes and,46 in particular, the types of disinfectants and the amount of disinfectants.47 When treatment processes are stable, the formation of DBPs generally 7012

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

ingestion 0−3 3−9 9−18 18−60 60−80 ⩾80 total mixed exposure dermal 0−3 3−9 9−18 18−60 60−80 ⩾80 total mixed exposure Inhalation 0−3 3−9 9−18 18−60 60−80 ⩾80 total mixed exposure

ages

1006 1005 1005 1006 1004 1001 1006 1006

1002 1002 1002 1002 1000 10−03 1002 1004

1002 1002 1002 1002 1000 10−03 1003 1004

× × × × × × × ×

× × × × × × × ×

× × × × × × × ×

1.43 7.89 8.34 1.15 3.00 4.20 4.23 6.28

1.91 1.37 1.94 1.87 4.45 6.30 7.14 1.69

1.98 1.83 3.63 3.51 7.21 9.10 1.10 1.08

NDMA

7013

1.12 1.03 2.05 1.98 4.06 5.12 6.22

3.36 2.40 3.41 3.29 7.80 1.11 1.25

2.33 1.29 1.36 1.88 4.90 6.87 6.91

× × × × × × ×

× × × × × × ×

× × × × × × ×

1003 1003 1003 1003 1001 10−02 1003

1003 1003 1003 1003 1001 10−01 1004

1005 1005 1005 1005 1003 1000 1005

NDPA

WTP-A

6.26 5.79 1.15 1.11 2.28 2.87 3.49

9.99 7.14 1.01 9.80 2.33 3.30 3.73

4.60 2.54 2.68 3.72 9.70 1.35 1.36

× × × × × × ×

× × × × × × ×

× × × × × × ×

1002 1002 1003 1003 1001 10−02 1003

1002 1002 1003 1002 1001 10−02 1003

1005 1005 1005 1005 1003 1001 1006

NMEA

4.98 4.60 9.14 8.86 1.82 2.29 2.78 3.56

4.53 3.25 4.61 4.45 1.06 1.50 1.70 2.26

8.53 4.70 4.97 6.87 1.79 2.51 2.53 3.41

× × × × × × × ×

× × × × × × × ×

× × × × × × × ×

1003 1003 1003 1003 1002 10−01 1004 1004

1003 1003 1003 1003 1002 10−01 1004 1004

1005 1005 1005 1005 1004 1001 1006 1006

NDEA

central tendency exposure

1.40 1.29 2.56 2.48 5.08 6.41 7.79

1.35 9.66 1.37 1.32 3.15 4.46 5.04

1.99 1.10 1.16 1.61 4.18 5.86 5.90

× × × × × × ×

× × × × × × ×

× × × × × × ×

1003 1003 1003 1003 1001 10−02 1003

1003 1002 1003 1003 1001 10−02 1003

1005 1005 1005 1005 1003 1000 1005

NDMA

WTP-B

4.30 3.98 7.91 7.65 1.56 1.98 2.40

1.37 9.79 1.39 1.34 3.19 4.52 5.12

9.70 5.37 5.67 7.83 2.04 2.85 2.88

× × × × × × ×

× × × × × × ×

× × × × × × ×

1000 1000 1000 1000 10−01 10−04 1001

1002 1001 1002 1002 1000 10−03 1002

1004 1004 1004 1004 1003 1000 1005

NPYR

6.50 5.39 1.19 1.16 2.47 3.97 3.57 3.24

4.79 3.34 5.05 4.74 1.15 1.86 1.80 3.89

6.98 2.96 3.25 6.28 1.57 2.41 1.96 8.36

× × × × × × × ×

× × × × × × × ×

× × × × × × × ×

1002 1002 1003 1003 1001 10−02 1003 1004

1002 1002 1002 1002 1001 10−02 1003 1004

1005 1005 1005 1005 1004 1001 1006 1006

NDMA

3.22 2.67 5.89 5.75 1.22 1.97 1.77

7.39 5.14 7.78 7.28 1.77 2.86 2.78

7.05 3.00 3.29 6.34 1.59 2.43 1.98

× × × × × × ×

× × × × × × ×

× × × × × × ×

1003 1003 1003 1003 1002 10−01 1004

1003 1003 1003 1003 1002 10−01 1004

1005 1005 1005 1005 1004 1001 1006

NDPA

WTP-A

2.03 1.69 3.73 3.62 7.75 1.25 1.11

2.48 1.73 2.62 2.44 5.96 9.59 9.33

1.57 6.69 7.33 1.41 3.53 5.42 4.42

× × × × × × ×

× × × × × × ×

× × × × × × ×

1003 1003 1003 1003 1001 10−01 1004

1003 1003 1003 1003 1001 10−02 1003

1006 1005 1005 1006 1004 1001 1006

NMEA

1.41 1.17 2.58 2.51 5.35 8.61 7.73 9.94

8.47 5.90 8.92 8.34 2.02 3.27 3.18 4.39

2.53 1.07 1.18 2.27 5.69 8.69 7.11 1.99

× × × × × × × ×

× × × × × × × ×

× × × × × × × ×

1004 1004 1004 1004 1002 10−01 1004 1004

1003 1003 1003 1003 1002 10−01 1004 1004

1006 1006 1006 1006 1004 1001 1006 1007

NDEA

reasonable maximum exposure

4.01 3.34 7.34 7.16 1.52 2.46 2.20

2.96 2.06 3.11 2.91 7.10 1.15 1.11

4.31 1.83 2.01 3.89 9.70 1.48 1.21

× × × × × × ×

× × × × × × ×

× × × × × × ×

1003 1003 1003 1003 1002 10−01 1004

1003 1003 1003 1003 1001 10−01 1004

1006 1006 1006 1006 1004 1002 1007

NDMA

WTP-B

1.08 8.94 1.98 1.93 4.10 6.60 5.92

2.63 1.83 2.76 2.59 6.23 1.02 9.87

2.55 1.09 1.19 2.29 5.74 8.85 7.18

× × × × × × ×

× × × × × × ×

× × × × × × ×

1001 1000 1001 1001 10−01 10−04 1001

1002 1002 1002 1002 1000 10−02 1002

1005 1005 1005 1005 1003 1000 1005

NPYR

Table 3. Disability-Adjusted of Life Years (DALYs, in Person-Years) by Age Groups Exposed to Nitrosamines from Two Water Treatment Plants Under the CTE and RME Scenarios

Environmental Science & Technology Article

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology

nitrosamines.30 The boiling point of five types of nitrosamines in this study are lower than 250 °C (SI Table S6), and can thus be regarded as volatile organic compounds. Given that bathing and showering are considered to contribute significantly to exposure to volatile DBPs via inhalation,62 the attributable carcinogenic risk via inhalation can be estimated with an updated U.S. EPA method. However, we employed a traditional method to calculate the LADD for exposure to total nitrosamines (NDMA, NDEA, NDPA, NMEA, NPYR) through inhalation to facilitate comparison of the daily average dose among other routes. The Risk Analysis in Mixed Exposure Model. Since disinfection byproducts can pose hazards to human health via a variety of exposure routes, the cumulative risk from different exposure routes must be considered. Cancer risk levels in adults exposed to total nitrosamines in finished drinking water generated from WTP-A or WTP-B exceeded 10−5, and the carcinogenic risk from exposure to every detected single nitrosamine alone also exceeded 10−6, which represents a negligible risk level as defined by U.S. EPA. Exposure to water-borne nitrosamines by the oral route posed the highest estimated cancer risk. Nitrosamines have a low dermal permeability coefficient,35 so the amount of absorption is not high. In this study, estimates for dermal entry of NDPA and NDEA accounted for 1.68% and 0.54% of oral exposure, respectively. The cancer risk for total nitrosamines through inhalation exposure, respectively, accounted for 0.30% (WTP-A) and 0.90% (WTP-B) of oral exposure; this is equivalent to an estimated proportion of the dose from inhalation exposure of haloacetic acids and haloketones during showering that represent less than 1% of the ingestion dose.63 The 10−4 risk-specific screening levels of NDMA and NMEA for residential exposure to drinking water correspond to 11 ng/ L and 71 ng/L, respectively, which are lower than those for other nitrosamines (SI Table S5).64 Thus, the high cancer risk for drinking water produced by WTP-A resulted from the combination of high exposure levels and relative toxicity of three nitrosamines (NDMA, NMEA, and NDPA). The cancer risk of NDMA in drinking water of WTP-B is lower than that for WTP-A, which coincides with the fact that ozone preoxidation generates lower levels of NDMA.48 There are some difference in exposure parameter values, and hence cancer risk, between men and women. We compared the difference between exposure and cancer risk by gender and found that dermal cancer risk for females was 1.13 times greater than the male dermal risk. (SI Figure S1) Children consume more food and water per unit of body weight than adults, so the relative amount of exposure from these sources to nitrosamines and other DBPs is higher than that of adults.23 Additionally, differences in metabolism, detoxication, and excretion may alter the chemical risks for children relative to adults.65 Moreover, DNA-damaging agents would be expected to have greater impacts on early life stages because substantial levels of body growth-related cell replication increases the likelihood that a cell will undergo division before DNA damage has been repaired.36 Several studies have demonstrated an increase in tumors in the offspring of pregnant animals treated with NDMA by oral exposure,66,67 and health risks induced by exposure to harmful agents in early life may be an order of magnitude greater than for comparable exposures occurring in adulthood.68 We found that children exposed to nitrosamines have a significantly higher estimated cancer risk than adults (p < 0.05) over their

unregulated nitrosamines.2,52,53 By contrast, in WTP-B, where ozone is used as the preoxidant, there is reduced formation of nitrosamines as ozone can deactivate precursors effectively at the low exposures relevant to disinfection.48,54 Ozone preoxidation is thus preferred over sodium hypochlorite for minimizing the generation of nitrosamines, especially for NDMA. The main mechanism for forming NDMA involves a nucleophilic displacement reaction between the secondary amine precursor containing the N,N-dimethylamino group and dichloramine.16,55,56 Therefore, the high organic precursors in raw water together with chlorine-based disinfection promote the formation of NDMA. In most cases, NMEA together with NDMA and other nitrosamines were founded in source water due to upstream industrial or domestic wastewater discharges,19,46,57,58 while NMEA formed in the disinfection process can be effectively absorbed by subsequent granular activated carbon, which accounts for the low concentrations of NMEA in finished water. The granular activated carbon is a nonpolar adsorbent, and its adsorption capacity of nonpolar compounds in water is greater than that of polar compounds. According to the molecular structure of NDMA and NMEA and their solubility difference (NDMA is infinitely soluble in water, and NMEA is soluble in water),59 it can be seen that the polarity of NDMA is greater than NMEA, therefore NMEA can be absorbed more easily by the granular activated carbon, which resulting in the reduction of NEMA. The increase in the concentration of NPYR in WTP-B finished water may be due to the reaction of ozone with organic amine precursors during ozone oxidation, and continued reaction of ammonia and residual organic matter in subsequent chlorine disinfection.46,60 The results indicated that NPYR can be present in the raw water, as well as being formed in the treatment process. In addition, NPYR has been detected in Yangtze River water in a nationwide survey, with the maximum NPYR formation potential (FP) in source water (lake/reservoir) recorded as 44.9 ng/L.19 The Selection of Risk Assessment Parameters for a Mixed Exposure Model. The health risks from chemicals reflect the integrated effect of exposure to all exogenous compounds, with consideration given to differences in exposure routes and absorption characteristics.61 The effect of mixed exposure to chemicals has always been a difficult issue in the evaluation of toxicological effects. From the perspective of risk assessment, the risk evaluation method should be able to predict the potential maximum risk, so the risk of mixed exposure is usually evaluated by effect addition. A simple additive model was used to calculate the effects of mixed exposure to multiple nitrosamines, because the U.S. EPA indicates that the difference between accurate results and results from a simple additive model is quite small for total carcinogenic risks less than 0.1.29 Therefore, it is reasonable to estimate the carcinogenic risk of nitrosamines in Shanghai’s Qingcaosha-derived drinking water using a simple additive model. The selection of carcinogenic parameters influences the results on suitability, accuracy, and reliability of the risk assessment. For the present study, the U.S. EPA recommendation is to use the gastrointestinal absorption fraction to obtain the dermal slope factor from the oral slope factor for exposure via a dermal route. The absorption rate of organic compounds in the gastrointestinal tract is usually >50%, and a 100% gastrointestinal absorption fraction is recommended for those substances lacking a specific absorption fraction, such as 7014

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology

cancer and other diseases. Here we show that use of sodium hypochlorite for the pretreatment of raw water is linked with nitrosamine contamination of finished water. By contrast, ozone pretreatment yields finished water that, while not totally free of nitrosamines, has a substantially lower carcinogenic risk and disease burden. Although the choice of the preferred water treatment method is apparent in the control of nitrosamines, especially for NDMA, bromate can be formed when ozone is employed to disinfect drinking water, which provides an additional important risk factor for cancer.76 Recently, a synergistic effect was also found between bromate and organic halo-DBPs in ozonated water, and such an effect substantially enhanced the toxicity of bromate.77 Fortunately, the Qingcaosha Reservoir was brought on line to reduce the influence of seawater intrusion during winter periods when a number of halides enter the Yangtze River. The dam of the Qingcaosha Reservoir resists seawater intrusion and keeps the low halide concentration across the seasons.

lifetime exposure. This demonstrates the pressing need for more effective measures for water treatment to reduce health hazards and risks induced by nitrosamines. Disease Burden Analysis. The burden of disease provides a critical measure for development of public health policy. For example, if ischemic heart disease and cerebrovascular disease are key causes of health loss and life-expectancy reduction,69 then steps are needed to address these specific issues to reduce disease burden and increase life expectancy. In the present study of drinking water DBPs, the average DALYs for exposure to finished water from WTP-A were 1.83 times higher than those for WTP-B. The DALYs linked to nitrosamines from WTP-A accounted for 1.50% of the total disease burden of malignant tumors in China (2010), ∼4150/100 000 persons, a number deemed high enough for remedial action.70 In the CTE scenario, the total DALYs for NDMA in WTP-A were 4.23 × 106 person-years or 42.3/100 000 persons. NDMA comprised 67.1% of the total DALYs in WTP-A, a result that demonstrates the urgent need for better control of this potent carcinogen. Since most nitrosamines are genotoxic and listed as Group 2A or 2B carcinogens according to the IARC classification, the potential health risk of exposure to individual and mixed nitrosamines via drinking water demands prompt remedy. The total amount and toxic equivalent quantity provide scientific data that can be used to reduce population cancer risks from nitrosamines in drinking water.71 Implementation of improved water purification systems can draw on these data in addition to economic, technical and other considerations to develop improved drinking water quality for the protection of population health. Selection of an ozone preoxidation step appears to be the best route to follow to minimize nitrosamine contamination of drinking water for Shanghai and beyond. Treatment of contaminated water with nanoscale zerovalent iron or granular activated carbon composites holds the promise of essentially complete removal of nitrosamine contaminants.72 Uncertainties. The cancer slope factor is generally derived by linear low-dose extrapolation from laboratory animals to humans based on physiologically based toxicokinetic modeling (PBTK) in adults,73 a method that lacks lifestage-specific evalution of the dose metric applicable to children.35 Another uncertainty arises from differences in behavioral patterns with respect to the use of drinking water at different temperatures, including hot tea and coffee.74 Boiling water can change the concentration of nitrosamines in relation to thermal stability, water evaporation, and nitrosamine volatilization.21 As noted above, food is another potential source of nitrosamines because these compounds are generated from amines and nitrates in plants and from nitrites used to preserve meats.41 Additionally, simple additive models provide only approximate risks from real-world mixed exposures to nitrosamines. The generalizability of the present results is also restricted to the Chinese population, such that a “racial calibrating factor” is needed to adjust for differences in metabolism and physique for nonChinese populations.75 The massive Qingcaosha Reservoir was brought on line in 2012 to increase Shanghai’s drought-threatened water supply and to replace the Huangpu River source, which has been affected by severe chemical pollution. While the Qingcaosha Reservoir is a major investment in the provision of clean water for the population of Shanghai, the present study shows that downstream raw water treatment can impair water purity through the generation of genotoxic nitrosamines linked to

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.est.8b07363. Details on quality control, exposure, and physicochemical parameters values of nitrosamines (Table S1−S8). The concentration data of other DBPs in raw water are presented in Table S9. The detailed cancer risk is shown in Tables S10−S19. The cancer risk by gender (Figure S1) and by age group under RME (Figure S2) and treatment scheme of two WTPs (Figure S3) are included (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*Phone: 86-21-54237203; fax: 86-21-64045165; e-mail: [email protected]. ORCID

Ying Zhou: 0000-0002-2010-7601 Weidong Qu: 0000-0002-8863-9671 Author Contributions ⊥

Z.C. and L.Y. contributed equally to this work.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This project was supported by the Chinese National Natural Science Foundation (No. 81630088 & 81273035), grant for Chang Jiang Scholars Program, Shanghai Outstanding Academic Leaders Plan, and a grant from the Key Project from the Chinese Ministry of Science (2017YFC1600200). We appreciate Dr. Zhijie Zhang (Department of Statistics & Epidemiology, Fudan University) for assistance with statistics. The suggestions and critical reviews of three anonymous reviewers are greatly appreciated.

■

ABBREVIATIONS ADAF age-dependent adjustment factors ADD average daily dose BW body weight CTE central tendency exposure DALY disability-adjusted life year 7015

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology DBPs ED EF ELCR ET EV GC/MS IARC InhR IR IRIS IUR LADD LT ND NDBA NDEA NDMA NDPA NDPhA NMEA NMOR NPIP NPYR RME SF U.S. EPA WTP YLDs YLLs

■

(9) WHO (World Health Organization). Guidelines for DrinkingWater Quality; World Health Organization: Geneva, 2011. (10) U.S. EPA (Environmental Protection Agency). Unregulated Contaminant Monitoring Rule 2 (UCMR 2). https://www.epa.gov/ dwucmr/second-unregulated-contaminant-monitoring-rule (accessed March 18, 2018). (11) U.S. EPA (Environmental Protection Agency). Contaminant Candidate List 4 (CCL4). https://www.epa.gov/ccl/contaminantcandidate-list-4-ccl-4-0 (accessed March 18, 2018). (12) Charrois, J. W. A.; Boyd, J. M.; Froese, K. L.; Hrudey, S. E. Occurrence of N-nitrosamines in Alberta public drinking-water distribution systems. J. Environ. Eng. Sci. 2007, 6 (1), 103−114. (13) Templeton, M. R.; Chen, Z. NDMA and seven other nitrosamines in selected UK drinking water supply systems. Aqua 2010, 59 (4), 277. (14) Asami, M.; Oya, M.; Kosaka, K. A nationwide survey of NDMA in raw and drinking water in Japan. Sci. Total Environ. 2009, 407 (11), 3540−3545. (15) Krasner, S. W.; Templeton, M. R.; Graham, N.; Voulvoulis, N. The formation and control of emerging disinfection by-products of health concern. Philos. Trans. R. Soc., A 2009, 367 (1904), 4077− 4095. (16) Mitch, W. A.; Sedlak, D. L. Formation of N-nitrosodimethylamine (NDMA) from dimethylamine during chlorination. Environ. Sci. Technol. 2002, 36 (4), 588−95. (17) Schreiber, I. M.; Mitch, W. A. Nitrosamine formation pathway revisited: the importance of chloramine speciation and dissolved oxygen. Environ. Sci. Technol. 2006, 40 (19), 6007−14. (18) Wei, X.; Chen, X.; Wang, X.; Zheng, W.; Zhang, D.; Tian, D.; Jiang, S.; Ong, C. N.; He, G.; Qu, W. Occurrence of Regulated and Emerging Iodinated DBPs in the Shanghai Drinking Water. PLoS One 2013, 8 (3), No. e59677. (19) Bei, E.; Shu, Y.; Li, S.; Liao, X.; Wang, J.; Zhang, X.; Chen, C.; Krasner, S. Occurrence of nitrosamines and their precursors in drinking water systems around mainland China. Water Res. 2016, 98, 168−175. (20) Russell, C. G.; Blute, N. K.; Via, S.; Wu, X.; Chowdhury, Z. Nationwide assessment of nitrosamine occurrence and trends. J. - Am. Water Works Assoc. 2012, 104 (3), E205−E217. (21) Kim, H.; Han, K. Ingestion Exposure to Nitrosamines in Chlorinated Drinking Water. Environ. Health Toxicol. 2011, 26, e2011003−7. (22) Guzelian, P. S.; Henry, C. J.; Olin, S. S. Similarities and differences between children and adults. Cancer Res. 1992, 39 (9), 3628−3637. (23) Landrigan, P. J.; Kimmel, C. A.; Correa, A.; Eskenazi, B. Children’s Health and the Environment: Public Health Issues and Challenges for Risk Assessment. Environ. Health Perspect. 2004, 112 (2), 257−265. (24) Sly, P. D.; Flack, F. Susceptibility of Children to Environmental Pollutants. Ann. N. Y. Acad. Sci. 2010, 1140 (1), 163−183. (25) China Daily Wedsite; http://www.chinadaily.com.cn/china/ 2011-05/26/content_12581749.htm. (26) Standard Examination Methods for Drinking Water: Collection and Preservation of Water Samples (GB/T 5750−1985); Ministry of Health of the People’s Republic of China: Beijing, 2007. (27) United States Environmental Protection Agency (EPA). Method 521: Determination of Nitrosamines in Drinking Water by Solid Phase Extraction and Capillary Column Gas Chromatography with Large Volume Injection and Chemical Ionization Tandem Mass Spectrometry (MS/MS); National Exposure Research Laboratory Office of Research and Development: Cincinnati, OH, 2004. (28) Liu, X. L.; Zheng, W. W.; Wei, X.; Chen, H. Y.; Wang, X.; Zhang, H. M.; Jiang, S. H.; He, G. S.; Qu, W. D. Investigation on the levels of carbon-, nitrogen-, iodine-containing disinfection byproducts in a water plant in Jiangsu province, China. Chin. J. Prev. Med. 2012, 46 (2), 133−138 (In Chinese) . (29) U.S. EPA (Environmental Protection Agency). Risk Assessment Guidance for Superfund: Vol. I Human Health Evaluation Manual (Part

disinfection byproducts exposure duration exposure frequency estimated lifetime cancer risk exposure time event frequency gas chromatography−mass spectrometry International Agency for Research on Cancer inhalation rate ingestion rate Integrated Risk Information System inhalation unit rate lifetime average daily dose lifetime not detectable N-nitrosodibutylamine N-nitrosodiethylamine N-nitrosodimethylamine N-nitrosodipropylamine N-nitrosodiphenylamine N-nitrosomethylethylamine N-nitrosomorpholine N-nitrosopiperidine N-nitrosopyrrolidine reasonable maximum exposure slope factor the United States Environmental Protection Agency water treatment plant years lost due to disabilities years of life lost

REFERENCES

(1) Bond, T.; Huang, J.; Templeton, M. R.; Graham, N. Occurrence and control of nitrogenous disinfection by-products in drinking water–a review. Water Res. 2011, 45 (15), 4341−54. (2) Krasner, S. W.; Mitch, W. A.; Mccurry, D. L.; Hanigan, D.; Westerhoff, P. Formation, precursors, control, and occurrence of nitrosamines in drinking water: a review. Water Res. 2013, 47 (13), 4433−4450. (3) Ooka, M.; Takazawa, H.; Takeda, S.; Hirota, K. Cytotoxic and genotoxic profiles of benzo[a]pyrene and N-nitrosodimethylamine demonstrated using DNA repair deficient DT40 cells with metabolic activation. Chemosphere 2016, 144, 1901−1907. (4) Plewa, M. J.; Wagner, E. D.; Muellner, M. G.; Hsu, K.-M.; Richardson, S. D., Comparative Mammalian Cell Toxicity of N-DBPs and C-DBPs. In Occurrence, Formation, Health Effects and Control of Disinfection By-Products in Drinking Water; Karanfil, T., Krasner, S. W., Westerhoff, P., Xie, Y., Eds.; ACS Publications: Washington, DC, 2008; Vol. 995, pp 36−50. (5) Berger, M. R.; Schmähl, D.; Zerban, H. Combination experiments with very low doses of three genotoxic N-nitrosamines with similar organotropic carcinogenicity in rats. Carcinogenesis 1987, 8 (11), 1635−43. (6) Zhu, Y.; Wang, P. P.; Zhao, J.; Green, R.; Sun, Z.; Roebothan, B.; Squires, J.; Buehler, S.; Dicks, E.; Zhao, J.; Cotterchio, M.; Campbell, P. T.; Jain, M.; Parfrey, P. S.; McLaughlin, J. R. Dietary N-nitroso compounds and risk of colorectal cancer: a case-control study in Newfoundland and Labrador and Ontario, Canada. Br. J. Nutr. 2014, 111 (6), 1109−17. (7) IARC (International Agency for Research on Cancer). Agents Classified by the IARC Monographs. http://monographs.iarc.fr/ ENG/Classification/ClassificationsAlphaOrder.pdf (accessed March 18, 2018). (8) Integrated Risk Information System. United States Environmental Protection Agency. https://www.epa.gov/iris (accessed March 18, 2018). 7016

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology A); Office of Emergency and Remedial Response: Washington, DC, 1989. (30) U.S. EPA (Environmental Protection Agency). Risk Assessment Guidance for Superfund Vol. I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment); Office of Superfund Remediation and Technology Innovation: Washington, DC, 2004. (31) U.S. EPA (Environmental Protection Agency). Risk Assessment Guidance for Superfund Vol. I: Human Health Evaluation Manual (Part F, Supplemental Guidance for Inhalation Risk Assessment); Office of Superfund Remediation and Technology Innovation: Washington, DC, 2009. (32) Ministry of Environmental Protection. Exposure Factors Handbook of Chinese Population; China Environmental Science Press: Beijing, 2016. (33) National Bureau of Statistics of China. China Statistical Yearbook; China Statistics Press: Beijing, 2015. (34) U.S. EPA (Environmental Protection Agency). Guidelines for Carcinogen Risk Assessment; Risk Assessment Forum: Washington, DC, 2005. (35) U.S. EPA (Environmental Protection Agency). Exposure Factors Handbook: 2011 ed.. EPA/600/R-09/052F; Office of Research and Development: Washington, DC, 2011. (36) U.S. EPA (United States Environmental Protection Agency). Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens; Risk Assessment Forum: Washington, DC, 2005. (37) Lopez, A. D.; Mathers, C. D.; Ezzati, M.; Jamison, D. T.; Murray, C. J. L. The Global Burden of Disease and Risk Factors; Oxford University Press; World Bank, 2006; Vol. 369 (5), pp 1−475. (38) Fan, C. C.; Lin, T. F. N-nitrosamines in drinking water and beer: Detection and risk assessment. Chemosphere 2018, 200, 48. (39) Richardson, S. D.; Postigo, C. Drinking Water Disinfection Byproducts. Springer: Berlin Heidelberg, 2011; p 93−137. (40) Pozzi, R.; Bocchini, P.; Pinelli, F.; Galletti, G. C. Determination of nitrosamines in water by gas chromatography/chemical ionization/ selective ion trapping mass spectrometry. J. Chromatogr. A 2011, 1218 (14), 1808−14. (41) Park, J.; Seo, J.; Lee, J.; Kwon, H. Distribution of Seven NNitrosamines in Food. Toxicol. Res. 2015, 31 (3), 279−288. (42) Ramírez, N.; Ö zel, M. Z.; Lewis, A. C.; Marcé, R. M.; Borrull, F.; Hamilton, J. F. Exposure to nitrosamines in thirdhand tobacco smoke increases cancer risk in non-smokers. Environ. Int. 2014, 71 (C), 139−147. (43) Schothorst, R. C.; Somers, H. H. Determination of Nnitrosodiethanolamine in cosmetic products by LC-MS-MS. Anal. Bioanal. Chem. 2005, 381 (3), 681−5. (44) de la Monte, S. M.; Tong, M. Mechanisms of nitrosaminemediated neurodegeneration: potential relevance to sporadic Alzheimer’s disease. J. Alzheimer's Dis. 2009, 17 (4), 817−25. (45) Gushgari, A. J.; Halden, R. U. Critical review of major sources of human exposure to N-nitrosamines. Chemosphere 2018, 210, 1124−1136. (46) Chen, W. H.; Wang, C. Y.; Huang, T. H. Formation and fates of nitrosamines and their formation potentials from a surface water source to drinking water treatment plants in Southern Taiwan. Chemosphere 2016, 161, 546−554. (47) Singer, P. C. Formation and Control of Disinfection ByProducts in Drinking Water. J. Environ. Eng. 1994, 120 (4), 1056− 1061. (48) Shah, A. D.; Krasner, S. W.; Lee, C. F.; von Gunten, U.; Mitch, W. A. Trade-offs in disinfection byproduct formation associated with precursor preoxidation for control of N-nitrosodimethylamine formation. Environ. Sci. Technol. 2012, 46 (9), 4809−18. (49) Mitch, W. A.; Gerecke, A. C.; Sedlak, D. L. A NNitrosodimethylamine (NDMA) precursor analysis for chlorination of water and wastewater. Water Res. 2003, 37 (15), 3733−3741.

(50) California Department of Public Health. NDMA and Other Nitrosamines - Drinking Water Issues. http://www.cdph.ca.gov/ certlic/drinkingwater/Pages/NDMA.aspx (accessed March 18, 2019). (51) Tong, Y.; Zhao, Y.; Zhen, G.; Chi, J.; Liu, X.; Lu, Y.; Wang, X.; Yao, R.; Chen, J.; Zhang, W. Nutrient Loads Flowing into Coastal Waters from the Main Rivers of China (2006−2012). Sci. Rep. 2015, 5, 16678. (52) National Research Council (US) Safe Drinking Water Committee. Drinking Water and Health; National Academies Press: Washington, DC, 1980. (53) 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., Rev. Mutat. Res. 2007, 636 (1−3), 178−242. (54) Song, Y.; Breider, F.; Ma, J.; von Gunten, U. Nitrate formation during ozonation as a surrogate parameter for abatement of micropollutants and the N-nitrosodimethylamine (NDMA) formation potential. Water Res. 2017, 122, 246−257. (55) Choi, J.; Valentine, R. L. Formation of N-nitrosodimethylamine (NDMA) from reaction of monochloramine: a new disinfection byproduct. Water Res. 2002, 36 (4), 817−24. (56) Lee, C.; Schmidt, C.; Yoon, J.; von Gunten, U. Oxidation of Nnitrosodimethylamine (NDMA) precursors with ozone and chlorine dioxide: kinetics and effect on NDMA formation potential. Environ. Sci. Technol. 2007, 41 (6), 2056−63. (57) Rice, J.; Wutich, A.; Westerhoff, P. Assessment of De Facto Wastewater Reuse across the US: trends between 1980 and 2008. Environ. Sci. Technol. 2013, 47 (19), 11099−105. (58) Liao, X.; Wang, C.; Wang, J.; Zhang, X.; Chen, C.; Krasner, S. W.; Suffet, I. H. Nitrosamine precursor and DOM control in an effluent-affected drinking water. J. - Am. Water Works Assoc. 2014, 106 (7), E307−318. (59) U.S. National Library of Medicine. Hazardous Substances Data Bank (HSDB). https://toxnet.nlm.nih.gov/newtoxnet/hsdb.htm (accessed by March 18, 2019). (60) West, D. M.; Wu, Q.; Donovan, A.; Shi, H.; Ma, Y.; Jiang, H.; Wang, J. N-nitrosamine formation by monochloramine, free chlorine, and peracetic acid disinfection with presence of amine precursors in drinking water system. Chemosphere 2016, 153, 521−7. (61) U.S. EPA (Environmental Protection Agency). Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures. EPA/630/R-00/002; Risk Assessment Forum: Washington, DC, 2000. (62) Wilkes, C. R.; Small, M. J.; Andelman, J. B.; Giardino, N. J.; Marshall, J. Inhalation exposure model for volatile chemicals from indoor uses of water. Atmos. Environ., Part A 1992, 26 (12), 2227− 2236. (63) Xu, X.; Weisel, C. P. Inhalation Exposure to Haloacetic Acids and Haloketones during Showering. Environ. Sci. Technol. 2003, 37 (3), 569. (64) U.S. EPA (Environmental Protection Agency). Regional Removal Management Level (RML) Resident Tapwater Table. https://semspub.epa.gov/work/HQ/197278.pdf (accessed March 18, 2019). (65) SP, S. Anticonvulsant adverse drug reactions: age dependent and age independent. In Similarities and Differences between Children and Adults; Implications for Risk Assessment; International Life Sciences Institute Press: Washington, DC, 1992. (66) Anderson, L. M.; Priest, L. J.; Budinger, J. M. Lung tumorigenesis in mice after chronic exposure in early life to a low dose of dimethylnitrosamine. J. Natl. Cancer Inst. 1979, 62 (6), 1553− 5. (67) Althoff, J.; Grandjean, C.; Marsh, S.; Pour, P.; Takahashi, M. Transplacental effects of nitrosamines in Syrian hamsters. II. Nitrosopiperidine. Z. Krebsforsch. Klin. Onkol. 1977, 90 (1), 71−7. (68) Ginsberg, G. L. Assessing cancer risks from short-term exposures in children. Risk Anal. 2003, 23 (1), 19−34. (69) Fan, J.; Li, G. Q.; Liu, J.; Wang, W.; Wang, M.; Qi, Y.; Xie, W. X.; Liu, J.; Zhao, F.; Li, Y.; Zhao, D. Impact of cardiovascular disease 7017

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018

Article

Environmental Science & Technology deaths on life expectancy in Chinese population. Biomed. Environ. Sci. 2014, 27 (3), 162−8. (70) Liu, Y.; Liu, J.; Yin, P.; Liu, S.; Cai, Y.; You, J.; Zeng, X.; Wang, L.; Zhou, M. The disease burden of malignant tumor in China, 1990 and 2010. Chin. J. Prev. Med. 2015, 49 (4), 309−314 (In Chinese) . (71) Meng, W.; Zhang, N.; Zhang, Y.; Zheng, B. H. The study on technique of basin water quality target management I: Pollutant total amount control technique in control unit. Res. Environ. Sci. 2007, 20 (4), 1−8. (72) Wang, W.; Wang, J.; Guo, Y.; Zhu, C.; Pan, F.; Wu, R.; Wang, C. Removal of multiple nitrosamines from aqueous solution by nanoscale zero-valent iron supported on granular activated carbon: Influencing factors and reaction mechanism. Sci. Total Environ. 2018, 639, 934−943. (73) Gray, R.; Peto, R.; Brantom, P.; Grasso, P. Chronic Nitrosamine ingestion in 1040 rodents: The effect of the choice of nitrosamine, the species studied, and the age of starting exposure. Cancer Res. 1991, 51 (23 Pt 2), 6470. (74) Chen, H.; Zhang, Y.; Ma, L.; Liu, F.; Zheng, W.; Shen, Q.; Zhang, H.; Wei, X.; Tian, D.; He, G. Change of water consumption and its potential influential factors in Shanghai: A cross-sectional study. BMC Public Health 2012, 12 (1), 1−9. (75) Mage, D. T.; Allen, R. H.; Kodali, A. Creatinine corrections for estimating children’s and adult’s pesticide intake doses in equilibrium with urinary pesticide and creatinine concentrations. J. Exposure Sci. Environ. Epidemiol. 2008, 18 (4), 360−368. (76) Lv, X.; Lu, Y.; Yang, X.; Dong, X.; Ma, K.; Xiao, S.; Wang, Y.; Tang, F. Mutagenicity of drinking water sampled from the Yangtze River and Hanshui River (Wuhan section) and correlations with water quality parameters. Sci. Rep. 2015, 5, 9572. (77) Han, J.; Zhang, X. Evaluating the Comparative Toxicity of DBP Mixtures from Different Disinfection Scenarios: A New Approach by Combining Freeze-Drying or Rotoevaporation with a Marine Polychaete Bioassay. Environ. Sci. Technol. 2018, 52 (18), 10552− 10561.

7018

DOI: 10.1021/acs.est.8b07363 Environ. Sci. Technol. 2019, 53, 7007−7018