Do Iodine Contrast Media Compounds Used for Medical Imaging Contribute to the Formation of Iodinated Disinfection By-Products in Drinking Water?

Susan D. Richardson, Stephen Duirk, Cristal Lindell, Chris Cornelison U.S. EPA, National Exposure Research Laboratory, Athens, GA

Thomas Ternes and Guido Fink Federal Institute of Hydrology, Koblenz, Germany.

U.S. Environmental Protection Agency Office of Research & Development Drinking Water DBPs

• Formed by the reaction of disinfectants with natural organic matter Concern over possible human health risk:

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

• Recent concerns about possible reproductive & developmental effects (from epi studies) Iodo-THMs

THM4 Iodinated THMs

12 CHCl 2I

CHCl 2Br 10

8 g/L)

μ CHClBr 6 CHCl 3 2 THM ( 4 CHClBrI CHClI 2

CHBr 2I 2 CHBrI 2

0 1 Iodinated THMs 3 Cl 2 CHBr 3 2 Cl 3 THM4 4 1 Cl 5 0 Cl 6

Nationwide Occurrence Study: Krasner, Weinberg, Richardson, et al., Environ. Sci. Technol. 2006, 40, 7175-7185. Iodo-acids

Regulated HAAs vs. Unregulated Iodo-Acids (Plant 19) 2

1.5

L 1

/

g

µ 0.5

0

A

A

A

A A A Z

A

E

A

d

A

A

i

A A

A

A

I

I

c

C

B

C

B

C

B

a

i

D

D

T

D Regulated Unregulated

Iodo-DBP Occurrence Study: Richardson et al., Environ. Sci. Technol. 2008, 40, 7175-7185. GC/NCI-MS (SIM m/z 127). Genotoxicity of Iodoacetic acid

Plewa et al., Environ. Sci. Technol. 2004 IA also caused developmental effects in mouse embryos (Hunter et al., 1995) Induction of Genomic DNA Damage in Normal, Non-Transformed Human Fetal Intestinal Cells

100 Iodoacetic Acid

80

Bromoacetic Chloroacetic Acid Acid 60

40

20

0 Human FHs Cell Genomic DNA Damage as Damage DNA Human FHs Cell Genomic Average Median SCGE Tail Moment Values Tail Moment SCGE Median Average 1 10 100 1000 10000 Monohaloacetic Acid Concentration (µM)

New data courtesy of Michael Plewa, Univ. Illinois (9/11/08) Iodo-DBPs Maximized with Chloramines Chlorine: fast fast fast I- + HOCl HOI IO - IO - HOCl 2 HOCl 3 fast iodite iodate NOM NOM Sink for iodide Cl-DBPs iodo-DBPs HOCl also competes for rxn with NOM, so much lower iodo-DBPs with chlorine

Chloramines: HOI also has longer half-life slow in chloraminated waters fast - - - I + NH2Cl HOI X IO2 IO3 iodite iodate fast NOM NOM

Cl-DBPs iodo-DBPs Adapted from Bichsel and von Gunten 1999 and 2000 Something curious

Iodide (µg/L) Sum iodo- Sum iodo- acids (µg/L) THMs (µg/L) Plant 2 1.0 0.37 4.9

Plant 4 ND 0.10 1.2

Plant 11 1.5 0.21 2.3

Plant 15 ND 0.17 2.4

Detection limit = 0.13 µg/L Something curious

Iodide (µg/L) Sum iodo- Sum iodo- acids (µg/L) THMs (µg/L) Plant 2 1.0 0.37 4.9

Plant 4 ND 0.10 1.2

Plant 11 1.5 0.21 2.3

Plant 15 ND 0.17 2.4

Detection limit = 0.13 µg/L What about other sources of iodine? Iodine Contrast Media

O O O HN HN I OH I I I I HN I HN OH HN OH HO O O O O I HN I O I O Ioxithalamic acid Iothalamic acid Diatrizoate

I OH O HN OH CH3 OH NH O NOH O I I I I O OH O NH H3CO NH OH NH I O Iopamidol Iopromide + NH2Cl Iodo-DBPs ??

Iopamidol Iodine Contrast Media: rivers, creeks and ground water unplanned indirect potable reuse conc. 100 (> 100 µg/L) Diatrizoate in µg/L Iopamidol ( 21 µg/L) Iopromid Ioxitalamic acid (10 µg/L) 10 Iothalamic acid ( ): Sum (2.8 µg/L) (1.0 µg/L) 1 (0.6 µg/L)

0.1

0.01 Rhine Mühlbach Mittelgraben Winkelbach groundwater groundwater

Ternes & Hirsch, Environ. Sci. Techn. (2000) 34, 2741-2748 Selected Pharmaceuticals in German Drinking Waters

LOQ Number Number Median 90-Percentile Maximum in samples samples Substances µg/L > LOQ > 0.010 µg/L in µg/L in µg/L in µg/L

Clofibric acid 0.001 16 of 30 6 0.001 0.024 0.070 Ibuprofen 0.001 3 of 30 0

Thomas Ternes, Federal Institute of Hydrology, Germany Iodine Contrast Media in Raw Source Waters from U.S.

Iopamidol Iomeprol Iopromide Iohexol Diatrizoate

Plant 1 11 ND ND ND ND Plant 2 510 ND 24 120 93 Plant 4 110 ND 6 49 ND Plant 10 ND ND ND ND ND Plant 11 100 ND ND 85 ND Plant 12 280 ND ND 120 ND Plant 13 ND ND ND ND ND Plant 15 2700 ND 25 ND ND Plant 17 ND ND ND ND ND Plant 19 ND ND ND ND ND

LC/ESI-MS/MS; LOQ = 5-20 ng/L Method for Iodine Contrast Media

Filtration of 100 mL sample with < 1 μm glass fiber filter Adjust sample to pH 2.8 with 3.5 M H2SO4

Addition of Surrogate standards: Spike internal standard to each sample

Solid phase extraction Cartridge : Isolute ENV+ 200 mg, 3mL

Dry cartridges: completely by a nitrogen stream for 1 h

Elution: 4 x 1 mL of methanol

Evaporation to dryness with nitrogen

Dissolve the residue in 500 μL phosphate-buffer

Measure with LC/ESI-MS/MS LC/ESI-MS/MS

• 2 MRMs per analyte • Gradient elution (ammonium acetate buffer / acetonitrile)

XIC of +MRM (14 pairs): 777.8/558.7 amu from Sample 20 (200 ng/l) of 10.11.08 RKM Iso 2 a, b 2.5e4 6.7 Max. 2.5e4 cps. 2.4e4 Iopamidol 2.3e4 I OH 2.2e4 O HN OH 2.1e4 NH 2.0e4 O I I 1.9e4 1.8e4 O NH 1.7e4 1.6e4 1.5e4 1.4e4 1.3e4 12.7 1.2e4 Iomeprol Intensity, cps Intensity, 1.1e4 OH 1.0e4 ONH OH 9000.0 8000.0 I I O OH 7000.0 HONH OH 6000.0 N 5000.0 I O 4000.0 3000.0 2000.0 1000.0 12.39 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Time, min Reactions with Chlorine and Chloramine Experimental Reaction Conditions: • Filtered Athens, GA source water (w/NOM & traces of Br-) • pH adjusted to 6.5 or 8.5 (10mM buffer) • Spiked with 20uM Iopamidol • With or without 2uM Br- spike

• Treated 24, 48, 72, or 96 hrs w/ either HOCl or NH2Cl

Extraction (similar to EPA Method 552): • 100mL sample

• +30g Na2SO4 & pH dropped to <1.5 • liq/liq extraction w/3mL MTBE (conc. to 1ml) • Half retained for Iodo-THM analysis • Half methylated with diazomethane for Iodo-Acid analysis • GC/EI-MS We see Iodo-DBPs formed!

Iodo-THMs Iodo-Acids

HClO Experiments Cl2-I Br-Cl-I Br2-I Cl-I2 Br-I2 I3 IodoAcetic pH 6.5 √ √ √ √ √ pH 6.5, 2uM Br- pH 8.5 √ √ √ √ √ pH 8.5, 2uM Br- √ √ √ √ √ √

NH2Cl Experiments pH 6.5 √ √ √ √ √ √ pH 6.5, 2uM Br- √ √ √ √ pH 8.5 √ √ √ pH 8.5, 2uM Br-

• Start to see DBPs at 24 and 48 hrs • pH 8.5: More iodo-DBPs with HOCl (Chlorine)

• pH 6.5: More iodo-DBPs with NH2Cl (Chloramine) Preliminary Results

• Iodo-THMs and Iodo-acids observed! (Start to see DBPs at 24 and 48 hrs)

• See mostly ones with Cl & I (no added Br at this point)

• pH 8.5: More iodo-DBPs with HOCl (Chlorine)

• pH 6.5: More iodo-DBPs with NH2Cl (Chloramine) Preliminary Results

HOCl (pH 8.5)

1,000 900 800 700 600 Dichloroiodomethane 500 400 Chlorodiiodomethane 300 Iodo-THM (nM) 200 100 0 0 5 10 15 20 25 Iopamidol (mM) Preliminary Results

Chloramine (pH 6.5)

350

300

250

200 Dichloroiodomethane 150 Chlorodiiiodomethane Iodoacetic acid 100 Iodo-THM (nM)

50

0 0 5 10 15 20 25 Iopamidol (mM) What’s Next

• Further experiments (more replicates)

• Extend to other Iodine Contrast Media

• Look for the decay of the parent compound with LC/ESI-MS/MS (after reaction with chlorine or chloramine)

• Identify potential high MW reaction products (using LC/ESI-MS/MS) • From parent compounds • From microbial degradation products of parent compounds