emerging drinking water disinfection by-products

Emerging Drinking Water Disinfection By-Products

Susan D. Richardson

U.S. Environmental Protection Agency, National Exposure Research Laboratory, Athens, GA

U.S. Environmental Protection AgencyOffice of Research & Development

Drinking Water DBPs—What are the Issues?

Concern over possible humanhealth risk:

• Epidemiologic studies: risk of bladder cancer; some cause cancer in laboratory animals

• Recent concerns about possiblereproductive & developmentaleffects (from epi studies)

Goal: Comprehensively identify DBPs formed from different disinfectants, test for toxicity, understand their formation, minimize or eliminate in drinking water

Drinking Water DBPs: How are they formed?

DBPs discovered in 1974

Jon Rook Tom Bellar

>600 DBPs Identified

Halogenated DBPs• Halomethanes• Haloacids• Haloaldehydes• Haloketones• Halonitriles• Haloamides• Halonitromethanes• Halofuranones (e.g., MX)• Oxyhalides (e.g., bromate)• Many others

Non-halogenated DBPs• Nitrosamines• Aldehydes• Ketones• Carboxylic acids• Others

>600 DBPs Identified

Halogenated DBPs• Halomethanes• Haloacids• Haloaldehydes• Haloketones• Halonitriles• Haloamides• Halonitromethanes• Halofuranones (e.g., MX)• Oxyhalides (e.g., bromate)• Many others

Non-halogenated DBPs• Nitrosamines• Aldehydes• Ketones• Carboxylic acids• Others

N-DBPs

~50% of TOX >1000 Da: Khiari, et al., Proc. 1996 AWWA Water Quality Technology Conference

But, more than 50% still not known….

Unknown 69.9%

THMs 13.5%

HAAs 11.8%

Halofuranones 0.1%IodoTHMs 0.2%

HANs 0.8%HALDs 1.8%HKs 0.9%HACEs 0.5%HNMs 0.5%

Nationwide Occurrence Study, Krasner et al., Environ. Sci. Technol. 2006, 40, 7175-7185.

Only 11 DBPs Regulated in U.S.

DBP MCL (µg/L)

Total THMs 805 Haloacetic acids 60Bromate 10Chlorite 1000

Little known about occurrence, toxicity of unregulated DBPsRegulated DBPs do not cause bladder cancer in animals!

Only 11 DBPs Regulated in U.S.

DBP MCL (µg/L)

Total THMs 805 Haloacetic acids 60Bromate 10Chlorite 1000

One regulated DBP never tested for cancer- Two unregulated DBPs are carcinogens- Many unregulated DBPs more genotoxic than regulated ones

Richardson, Plewa, Wagner, Schoeny, and DeMarini. Occurrence, genotoxicity, and carcinogenicity of regulated and emergingdisinfection by-products in drinking water: A review and roadmap for research. Mutation Research 2007, 636, 178-242.

Bladder cancer and drinking water: Pooled analysis

OR adjusted by (sex), study, age, smoking status, ever worked in high-risk occupations, heavy coffee consumption and total fluid intake

0

0,5

1

1,5

2

Men Women Both

OR

(95%

CI)

0-1ug/L

>1-5 ug/L

>5-25ug/L

>25-50ug/L

>50ug/L

Villanueva et al., Epidemiology 2004, 15, 357-367.

Exposure routes

TOTAL INTERNAL DOSE

Ingestion(water, coffee, tea,

water-based food and beverages)

All disinfection by-products

Inhalation(shower, swimming

pool, etc.)Volatile DBP

e.g. THMs

Dermal absorption(swimming pool,

bath, etc.)

Permeable DBPs e.g. THMs,

haloketones, …

Slide courtesy of Manolis Kogevinas, Centre for Research in Environmental Epidemiology/IMIM, Barcelona

Unlike other contaminants that may or may not be present in drinking water…

DBPsare ubiquitous

DibromonitromethaneDibromonitromethane——DNA Adducts DNA Adducts

Data courtesy of Tony DeAngelo & Leon King, U.S. EPA, NHEERL, RTP, NC

Retention Time (min)

0

200

400

600P-

32 D

isin

tigra

tions

per

Min

ute

(DPM

)

0

200

400

600

800

1000

1200

0

100

200

300

400

500

600

0

100

200

300

400

500

600

0 10 20 30 40 50 60 700

100

200

300

400

500

600

0 10 20 30 40 50 60 700

200

400

600

800

1000

1200

Control #10 Rat Liver DNA

Butanol Extracted (0.32 *10 )9

Male

High Dose # 58 DNBM Liver DNA Butanol Extracted (7.7 * 10 )9

Male


Male

Control # 70 Rat Liver DNA

Butanol Extracted (0.24 * 10 ) 9

Female


Female


Female

500

300

100

1.491.26 1.

37 1.49

1.16

1.26

1.49

1.37

0.88

1.26

1.16 0.

88

1.16

0.88 0.

951.

12 1.26 9

1.26

8

7

91

1.4

0.8

1.3

0.5 1.

2

DBNM produces DNA adducts in the livers of rats after only 30 days of exposure

(in vivo, male and female rats)

Tony also now seeing effects in normal human colon cells

Iodo-THMs

12

34

56

THM4

Iodinated THMs

CHCl 2I

CHClI 2 CHClBrI

CHBrI 2

CHBr 2I

CHCl 3

CHCl 2Br

CHClBr 2

CHBr 3

0

2

4

6

8

10

12

THM

(μ

g/L)

THM4 Iodinated THMs

3 Cl 2 Cl1 Cl

0 Cl

Krasner, Weinberg, Richardson, et al., Environ. Sci. Technol. 2006, 40, 7175-7185.

Chlorine:

I- + HOCl HOI IO2- IO3

-fast fast

Sink for iodide

iodateiodite

fast

HOCl also competes for rxn with NOM, so much lower iodo-DBPs with chlorine

NOM

iodo-DBPsNOM

Cl-DBPs

fast

HOCl HOCl

Iodo-DBPs Maximized with Chloramines

Chloramines:

I- + NH2Cl HOI IO2- IO3

-

iodateiodite

fast slow

NOM

iodo-DBPs

NOM

Cl-DBPs

Xfast

HOI also has longer half-life in chloraminated waters

Adapted from Bichsel and von Gunten, 1999 and 2000

Plewa et al., Environ. Sci. Technol. 2004IA also caused developmental effects in mouse embryos (Hunter et al., 1995)

Genotoxicity of Iodoacetic acid

Haloamides

• New class of DBP recently identified

• Nationwide DBP Occurrence Study: up to 14 ug/L; NH2Cl may increase their formation

• Highly genotoxic, cytotoxic

• New iodoamide DBP: Bromoiodoacetamide- Found in drinking water from 6 states H

I

Br

NH2

O

C C

C

O

NH2C

H

H

Cl

Cl

C

O

NH2C

H

Br

Chloroacetamide

Bromochloroacetamide

Br

H

H

C NH2C

O

Cl

H

C NH2C

O

Cl

Br

H

C NH2C

O

Br Cl

C

O

NH2CCl

Cl

Bromoacetamide Dichloroacetamide

Dibromoacetamide Trichloroacetamide

Plewa et al., Environ. Sci. Technol. 2008, 42, 955-961.

Haloamides--Cytotoxicity

Data courtesy of Michael Plewa, University of Illinois

CHO Cell Cytotoxicity as % C½ Values (~LC50)Log Molar Concentration (72 h Exposure)

10-6 10-5 10-4 10-3 10-2

IAA

BAA TB

AA

DB

CAA

DB

AA

BDC

AA

BCA

AC

AA

TCAA

DC

AA

DB

NM

BN

MTB

NM

BDC

NM

BC

NM

DC

NM

CN

MTC

NM

DB

CN

M

Trib

rom

opyr

role

MX

Bro

mat

e

EMS

+Con

trol

3,3-

Dib

rom

o-4-

oxop

enta

noic

Aci

d

3-Io

do-3

-bro

mop

rope

noic

Aci

d

3,3-

Dib

rom

opro

peno

ic A

cid

Trib

rom

opro

peno

ic A

cid

2-B

rom

obut

ened

ioic

Aci

d2,

3-D

ibro

mop

rope

noic

Aci

d

2-B

rom

o-3-

met

hylb

uten

edio

ic A

cid

DIA

A

Bro

moa

ceta

mid

e

Dib

rom

oace

tam

ide

Chl

oroa

ceta

mid

e

Dic

hlor

oace

tam

ide

Haloacetic Acids

Halo Acids

Halonitromethanes

Other DBPs

Haloacetam ides

DBP Chemical Class

December 2006BI

AA2-

Iodo

-3-b

rom

opro

peno

ic A

cid Tr

ichl

oroa

ceta

mid

e

Iodo

acet

amid

e

Haloacetonitriles

Dib

rom

oace

toni

trile

Bro

moa

ceto

nitri

le

Bro

moc

hlor

oace

toni

trile

Chl

oroa

ceto

nitri

le

3,3-

Bro

moc

hlor

o-4-

oxop

enta

noic

Aci

d

Iodo

acet

onitr

ile

Dic

hlor

oace

toni

trile

Tric

hlor

oace

toni

trile

HalomethanesIo

dofo

rm

Bro

mof

orm

Chl

orod

ibro

mom

etha

ne

Chl

orof

orm

Diio

doac

etam

ide

Bro

moc

hlor

oace

tam

ide

Trib

rom

oace

tam

ide

Bro

moi

odoa

ceta

mid

eD

ibro

moc

hlor

oace

tam

ide

Chl

oroi

odoa

ceta

mid

e

Haloamides--Genotoxicity


S ing le C e ll G e l E lectrophores is G eno tox ic ity P o tencyLog M o la r C oncen tra tion (4 h E xposure )

10 -6 10 -5 10 -4 10 -3 10 -2

IAA

BA

A

CA

A

DIA

A

TBA

A

DBA

A3,3-

Dib

rom

o-4-

oxop

enta

noic

Aci

d

2-B

rom

obut

ened

ioic

Aci

d

2-Io

do-3

-bro

mop

rope

noic

Aci

d2,

3-D

ibro

mop

rope

noic

Aci

d

DB

NM

BDC

NM

TBN

M

TCN

M

BN

M

BC

NM

DB

CN

M

DC

NM

CN

M

Bro

moa

ceta

mid

e

Dib

rom

oace

tam

ide

Trib

rom

opyr

role

MX

Bro

mat

e

EMS

+Con

trol

H aloace tic A c ids

H a lo A c ids

H a loace tam ides

H a lon itrom ethanes

O ther D B P s

D B P C hem ica l C lass

N ot G enotox ic : D C A A , TC A A , B D C A A , D ich lo roace tam ide , C h lo ro form C h lo rod ib rom om ethane, 3 ,3 -D ib rom opropeno ic A c id , 3 -Iodo-3-brom opropeno ic A c id , 2 ,3 ,3 ,T rib rom opropeno ic A c id D ecem ber 2006

Chl

oroa

ceta

mid

e

Tric

hlor

oace

tam

ide

Iodo

acet

amid

e

H a loace ton itriles Bro

moa

ceto

nitri

le

Dib

rom

oace

toni

trile

Bro

moc

hlor

oace

toni

trile

Chl

oroa

ceto

nitri

le

3,3-

Bro

moc

hlor

o-4-

oxop

enta

noic

Aci

d

Iodo

acet

onitr

ile

Tric

hlor

oace

toni

trile

Dic

hlor

oace

toni

trile

BIA

A

CD

BA

A

BC

AA

Diio

doac

etam

ide

Bro

moc

hlor

oace

tam

ide

Chl

oroi

odoa

ceta

mid

e

Trib

rom

oace

tam

ide

Dib

rom

chlo

rooa

ceta

mid

eB

rom

oiod

oace

tam

ide

Bromo/iodo amides

Genotoxicity of Other DBPs


S ing le C e ll G e l E lectrophores is G eno tox ic ity P o tencyLog M o la r C oncen tra tion (4 h E xposure )

10 -6 10 -5 10 -4 10 -3 10 -2

IAA

BA

A

CA

A

DIA

A

TBA

A

DBA

A3,3-

Dib

rom

o-4-

oxop

enta

noic

Aci

d

2-B

rom

obut

ened

ioic

Aci

d

2-Io

do-3

-bro

mop

rope

noic

Aci

d2,

3-D

ibro

mop

rope

noic

Aci

d

DB

NM

BDC

NM

TBN

M

TCN

M

BN

M

BC

NM

DB

CN

M

DC

NM

CN

M

Bro

moa

ceta

mid

e

Dib

rom

oace

tam

ide

Trib

rom

opyr

role

MX

Bro

mat

e

EMS

+Con

trol

H aloace tic A c ids

H a lo A c ids

H a loace tam ides

H a lon itrom ethanes

O ther D B P s

D B P C hem ica l C lass

N ot G enotox ic : D C A A , TC A A , B D C A A , D ich lo roace tam ide , C h lo ro form C h lo rod ib rom om ethane, 3 ,3 -D ib rom opropeno ic A c id , 3 -Iodo-3-brom opropeno ic A c id , 2 ,3 ,3 ,T rib rom opropeno ic A c id D ecem ber 2006

Chl

oroa

ceta

mid

e

Tric

hlor

oace

tam

ide

Iodo

acet

amid

e

H a loace ton itriles Bro

moa

ceto

nitri

le

Dib

rom

oace

toni

trile

Bro

moc

hlor

oace

toni

trile

Chl

oroa

ceto

nitri

le

3,3-

Bro

moc

hlor

o-4-

oxop

enta

noic

Aci

d

Iodo

acet

onitr

ile

Tric

hlor

oace

toni

trile

Dic

hlor

oace

toni

trile

BIA

A

CD

BA

A

BC

AA

Diio

doac

etam

ide

Bro

moc

hlor

oace

tam

ide

Chl

oroi

odoa

ceta

mid

e

Trib

rom

oace

tam

ide

Dib

rom

chlo

rooa

ceta

mid

eB

rom

oiod

oace

tam

ide

Bromo/iodo acetonitriles

Bromo-nitromethanes

IAA

But, all of this toxicity testing is for separate, individual DBPs…

DBPsare really present as MIXTURES

>300 DBPs probably present in glass of water

Four Lab Study

Integrated Disinfection By-products Mixtures Research: Toxicological and Chemical Evaluation of Alternative Disinfection Treatment ScenariosA collaborative effort between:NHEERL (National Health and Environmental Effects Research Laboratory), RTPNERL (National Exposure Research Laboratory), AthensNRMRL (National Risk Management Research Laboratory), CincinnatiNCEA (National Center for Environmental Assessment), Cincinnati

Purpose:To address concerns related to potential health effects from exposure to DBPs that cannot be addressed directly from toxicological studies of individual DBPs or simple DBP mixtures

In Vitro and In Vivo Toxicological Assays

• Reproductive/developmental• Mutagenicity• Carcinogenicity• Neurotoxicity• Metabolism

In vitro:

In vivo:• Reproductive/developmental• Mutagenicity/carcinogenicity• Immunotoxicity• Hepatic/renal toxicity• Neurotoxicity/developmental neurotoxicity• Kinetics/metabolism

600 ga l.C W 200

ga l.

500 ga l.

100 gal.14 gal.

P erm eate to W aste

Ion E xchange

R O C oncentration of D B Ps

F ro m P lant (0 .5 gpm )

Water is concentrated by RO to maintain the water matrix for rats to be able to drink (can’t give organic solvents to rats!)

600 gal.CW 200

gal.

500 gal.

100 gal.14 gal.

Permeate to Waste

Ion Exchange

RO Concentration of DBPs

From Plant (0.5 gpm)

1st Phase (1999-2001):Cl2 & O3; treated water firstConcentrated after

1st Phase of study published: Richardson et al., J. Toxicol. Environ. Health 2008, 71, 1165-1186.Other 4-Lab papers also in this special issue

Full Study Concentration

ION EXCHANGECOLUMNS

PERMEATE

CONCENTRATEIONEXCHANGECOLUMNS

FLOWEQUALIZATION

ULTRAFILTRATIONMEMBRANES

RAW SURFACE WATER

BAGFILTER

REVERSE OSMOSIS

MEMBRAMES

IONEXCHANGECOLUMNS

FLOWEQUALIZATION

ULTRAFILTRATIONMEMBRANES

RAW SURFACE WATER

BAGFILTER

REVERSE OSMOSIS

MEMBRAMES

Full Study (2006-2008):Concentrated NOM firstTreated with Cl2 after

General Timeline for Animal Experiments

GD0

PND0

PND21

P0

F1

F2

Gestation Lactation

Born Wean Mate Parturition

Born

Gestation Lact’n

Gestation LengthParturition

Litter ExamsPostnatal Day 0ViabilityPup weightAnogenital distance• 12 litters/group

Litter ExamsPostnatal Day 6ViabilityPup weightReduce litter size to 8

(4 males, 4 females)

Litter ExamsDay 13ViabilityEye openingNipple retention

Litter ExamsDay 21ViabilityPup weightWeanAssign fate

ExposureStartsGD 2

Results

• Good mix of Cl/Br DBPs produced

• Most DBPs fairly consistently produced among chlorination events

• Most DBPs are stable over time on the rats’ cages

Toxicity Results

No effects for:• Gestation length• Prenatal viability• Postnatal viability• Pup Weight• Eye opening• Nipple retention• Organ weights

Effects for:• Delayed puberty in F1 females (<1 day)

• Delayed puberty also seen with regulated DBP mixtures

• Subtle puberty effect (at 136x) that appears consistent with dose-response curve of regulated DBPs at 500x, 1000x, 2000x

• Increased anogenital distance (AGD) in F1 males

• Males: Sperm counts down 50%

• Total litter loss (postnatal) in one F2 litter

• Vaginal prolapse in one P0 dam

• Dental malocclusion in one F1 litter

• Small neurotoxicity effects (motor activity, grip strength)

• Inhibited differentiation of human placental trophoblast cells and hCG secretion (both with chlorinated concentrate and regulated DBPs)

• Small increase in mutagenicity in chlorinated concentrate

• Mammary tumors (regulated DBP mixture)

Conclusions

• A thorough examination of reproductive/developmental and other endpoints was predominantly negative

• Some small, subtle effects for chlorinated water concentrate (136x concentration factor may be “on the edge” of ability to see effects)

• Concentration offered by RO a bonus for detecting DBPs present at very low levels (e.g., MX, which is present in drinking water at ng/L levels)

• Combination of comprehensive, qualitative identification work and quantification of 75 DBPs allowed comprehensive assessment of DBPs present in water

• Most DBPs stable on rats’ cages and chlorination events were reproducible

Want to determine the statistical power in this study for detection of the subtle effects noted and do a follow-up study that includes Chlorine vs. Chloramines

Richardson, Duirk, Lindell, Cornelison, Ternes, presented at Micropol Conference, June 2009

Formation of iodo-DBPs from X-ray contrast media

Iopamidol

HOCl

NH2ClIodo-DBPs+ NOM

Iodo-DBP Occurrence Study

2.42.40.170.17ND ND Plant 15Plant 15

2.32.30.210.211.51.5Plant 11Plant 11

1.21.20.100.10ND ND Plant 4Plant 4

4.94.90.370.371.01.0Plant 2Plant 2

Sum iodoSum iodo--THMs THMs ((µµg/L)g/L)

Sum iodoSum iodo--acids acids ((µµg/L)g/L)

Iodide (Iodide (µµg/L)g/L)

Detection limit = 0.13 µg/L

Richardson et al., Environ. Sci. Technol. 2008, 42, 8330-8338.

Iodo-DBP Occurrence Study

2.42.40.170.17ND ND Plant 15Plant 15

2.32.30.210.211.51.5Plant 11Plant 11

1.21.20.100.10ND ND Plant 4Plant 4

4.94.90.370.371.01.0Plant 2Plant 2

Sum iodoSum iodo--THMs THMs ((µµg/L)g/L)

Sum iodoSum iodo--acids acids ((µµg/L)g/L)

Iodide (Iodide (µµg/L)g/L)

Detection limit = 0.13 µg/L

What about other sources of iodine?

Iodinated X-ray Contrast Media (ICM)

Iopromide

O H

I

C H3

N H

I

N H O HH3CO

IO

O

N O HO H

O

Iohexol

Iopamidol

Ternes & Hirsch, Environ. Sci. Technol. (2000) 34, 2741-2748

0.01

0.1

1

10

100

Rhine Mühlbach Mittelgraben

( 21 µg/L)

(0.6 µg/L)

Winkelbach

(> 100 µg/L)

(10 µg/L)

groundwater

(1.0 µg/L)

(2.8 µg/L)

groundwater

µg/L

ICM concentrations: rivers, creeks and ground water

Diatrizoate Iopamidol Iopromide Ioxitalamic acidIothalamic acid

( ) Sum

NDNDNDNDNDPlant 19NDNDNDNDNDPlant 17NDND25ND2700Plant 15NDNDNDNDNDPlant 13ND120NDND280Plant 12ND85NDND100Plant 11NDNDNDNDNDPlant 10ND496ND110Plant 49312024ND510Plant 2NDNDNDND11Plant 1

DiatrizoateIohexolIopromideIomeprolIopamidol

Courtesy of Thomas Ternes, Federal Institute of Hydrology, GermanyICM measured using LC/ESI-MS/MS; DLs = 5-20 ng/L

ICM in U.S. Drinking Water Sources (ng/L)

NDNDNDNDNDPlant 19NDNDNDNDNDPlant 17NDND25ND2700Plant 15NDNDNDNDNDPlant 13ND120NDND280Plant 12ND85NDND100Plant 11NDNDNDNDNDPlant 10ND496ND110Plant 49312024ND510Plant 2NDNDNDND11Plant 1

DiatrizoateIohexolIopromideIomeprolIopamidol

ICM in U.S. Drinking Water Sources (ng/L)

Courtesy of Thomas Ternes, Federal Institute of Hydrology, GermanyICM measured using LC/ESI-MS/MS; DLs = 5-20 ng/L

Do iodinated X-ray contrast media form iodo-DBPs?

Iopamidol

HOCl

NH2ClIodo-DBPs

??

Controlled Laboratory Reactions

ExperimentsExperiments•• React ICM with HOCl, NHReact ICM with HOCl, NH22Cl (with and without NOM)Cl (with and without NOM)•• 3 pHs3 pHs•• Follow formation of iodoFollow formation of iodo--DBPsDBPs•• Identify reaction products and intermediatesIdentify reaction products and intermediates•• Measure genotoxicity Measure genotoxicity

MethodsMethods•• IodoIodo--THMs: GC/EITHMs: GC/EI--MSMS•• IodoIodo--Acids: GC/NCIAcids: GC/NCI--MS (with derivatization)MS (with derivatization)•• Iopamidol (and other ICM): LC, LC/MS/MSIopamidol (and other ICM): LC, LC/MS/MS•• Larger MW products and intermediates: LC/MS/MSLarger MW products and intermediates: LC/MS/MS•• Genotoxicity: Chinese hamster ovary cells, single cell gel Genotoxicity: Chinese hamster ovary cells, single cell gel

electrophoresiselectrophoresis

Cristal and Steve

Results

Iopamidol

HOCl

NH2ClIodo-DBPs

Iopamidol

HOCl

NH2ClIodo-DBPs+ NOM

X

Iodo-THMs &

Iodo-Acids

42

Genotoxicity: Comet Assay

The tail moment is the integrated value of DNA density multiplied by the migration distance. The % tail DNA is the amount of DNA that has migrated into the gel from the nucleus.

Organic Extracts from Water Samples (Concentration Fold)

0 200 400 600

CH

O C

ells

Gen

omic

DN

A D

amag

e as

the

Ave

rage

Mea

n S

CG

E %

Tail

DN

A V

alue

0

20

40

60

ACC + Iopamidol

ACC +HOCl

ACC + Iopamidol +HOCl

Genotoxicity of Chlorinated Waters Containing Iopamidol

• Human health effects not solved yet—need more toxicity studies

• Studies on route of exposureHave we been looking at the wrong route of exposure?

• DBPs are present as complex mixtures—need toxicity studies addressing this

• What is in the unidentified fraction—anything of concern?

• What about ‘pollutant’ DBPs?

• What about DBPs from alternative disinfectants—do we know everything we need to know before plants switch?

• Chloramination? UV disinfection? Membrane disinfection?

• What about other respiratory/skin effects reported for chloraminated water? Need showering and dermal exposure studies

Roadmap—Where do we go from here?

Serious skin rash issues….

“Before”

Showering with chloraminated water “After”

Showering with chlorinated water at the YMCA in another town

Acknowledgments

Michael Plewa

Jane Ellen Simmons

Tony DeAngelo

David DeMarini

A few fabulous toxicologists who have helped push this field forward….

Also, Mike Narotsky, Sid Hunter, Rex Pegram, ….

In closing…

Ever wonder what happens when you have to scale things up for toxicity testing?

(Especially when working with Michael Plewa)

The Land of Extraordinarily Large Lab Equipment

Toxicity?20 L → 1 mL

Chris

Steve

Cristal

emerging drinking water disinfection by-products

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