Genotoxicity and carcinogenicity of disinfection by products in drinking water
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Genotoxicity and Carcinogenicity of Disinfection By-products in Drinking Water. Outline. Health Effects of Chlorinated Drinking Water Review of 30 years of DBP research on occurrence, genotoxicity, and carcinogenicity Dermal/inhalation exposure, genotype, and health risks Research needs.

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Outline
Outline in Drinking Water

  • Health Effects of Chlorinated Drinking Water

  • Review of 30 years of DBP research on occurrence, genotoxicity, and carcinogenicity

  • Dermal/inhalation exposure, genotype, and health risks

  • Research needs


Adverse health effects associated with chlorinated drinking water
Adverse Health Effects Associated with Chlorinated Drinking Water

  • Cancer

    • Colorectal

    • Bladder

  • Reproductive Effects

    • Spontaneous abortion

    • Still birth

    • Low-birth weight

    • Neural tube defects


Occurrence, Genotoxicity, and Carcinogenicity of Regulated and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for ResearchSD Richardson, MJ Plewa, ED Wagner,R Schoeny, DM DeMariniMutation Research 636:178-242, 2007


Genotoxicity of regulated dbps
Genotoxicity of and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for ResearchRegulated DBPs


Carcinogenicity of regulated dbps
Carcinogenicity of Regulated DBPs and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for Research


Features of IARC-Declared Human Carcinogens and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for Research[RW Tennant, Mutat Res 286:111, 1993][MD Shelby, E Zeiger, Mutat Res 234:257, 1990]

  • Are trans-species carcinogens, e.g, they cause tumors in both rats and mice.

  • Frequently cause tumors at multiple organs.

  • Are generally mutagenic across a variety of genotoxic endpoints, e.g., gene and chromosomal mutation.


5 regulated dbps with features of human carcinogens
5 Regulated DBPs with Features and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for Researchof Human Carcinogens

aIARC 2B = possible/EPA B2 = probable human carcinogen.


76 unregulated dbps at ng g l

9 Halonitromethanes and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for Research

5 Iodo-acids

4 Other halo-acids

9 Iodo- & other THMs

12 MX compounds

13 Haloamides

10 Haloacetonitriles

1 Tribromopyrrole

5 Nitrosamines

7 Aldehydes

1 Chlorate

76 Unregulated DBPs at ng-μg/L


Carcinogenicity of unregulated dbps
Carcinogenicity of Unregulated DBPs and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for Research


Unregulated dbps with some features of human carcinogens
Unregulated DBPs with Some Features and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for Researchof Human Carcinogens


Mutagenicity of pool water
Mutagenicity of Pool Water and Emerging Disinfection By-products in Drinking Water: A Review and Roadmap for Research


Review of chemistry and health effects of swimming pool water c zwiener et al es t 41 363 2007
Review of Chemistry and Health Effects of Swimming Pool Water[C Zwiener et al., ES&T 41:363, 2007]

  • Swimming may be a model system for analyzing effects of dermal/inhalation exposure to DPBs.

  • Swimmers have 1.6-fold increased risk of bladder cancer.

  • Molecular epidemiology study of swimmers is currently underway in Barcelona, Spain; pool water is mutagenic


PISCINA Water

Projecte d’Investigació Sobre Compostos Irritants en Natació

Research Project on Irritants in Swimming Pools

http://www.creal.cat/piscina/index.htm


Mutagenicity of xad ethyl acetate extract from chlorinated pool in salmonella ta100
Mutagenicity of XAD/Ethyl Acetate Extract Waterfrom Chlorinated Pool in Salmonella TA100




Ozonation/Chlorination < Mutagenic Than Chlorination WaterLD Claxton et al. (2008) J Toxicol Environ Health A 71:1187



What about alternative disinfection
What about Alternative Disinfection? Waters

  • In the 1990s, alternative disinfection methods (ozonation or chloramination) were promoted to replace chlorination to reduce the levels of THMs.

  • An EPA survey in 2004 showed that the new methods reduce levels of THMs, but they promote formation of new compounds, such as iodo-THMs, iodo-acids, and bromonitromethanes.


Mechanistic issues
Mechanistic Issues Waters

  • Activation of brominated halomethanes by GSTT1-1, leading to bladder cancer

  • Dermal/inhalation exposure may be more important than oral exposure for risk for bladder cancer associated with chlorinated drinking water


Activation of Halomethanes, Watersbut Not Chloroform, to Mutagens by GSTT1-1RA Pegram et al.Toxicol Appl Pharmacol 144:183, 1997


First pharmacokinetic study of a dbp in humans
First Pharmacokinetic Study Watersof a DBP in Humans

Disposition of Bromodichloromethane in Humans Following Oral and

Dermal Exposure

TL Leavens et al., Toxicol Sci 99:432, 2007


Subject’s arm was in water for 1 h with bromodichloromethane(~50 ppm or 50 ng/kg), or subject drank water giving 50 ng/kg exposure. BDCM was metabolized much faster by the oral route than dermal route of exposure.


First cancer epidemiology study of drinking water that assessed route of exposure
First Cancer Epidemiology Study of Drinking Water That Assessed Route of Exposure

Bladder Cancer and Exposure to Water Disinfection By-products Through Ingestion, Bathing, Showering and Swimming in Pools

[CM Villanueva et al.

Am J Epidemiol 165:148, 2007]


Model for br thm induced bladder cancer mk ross ra pegram tox appl pharmacol 195 166 2004
Model for Br-THM-Induced Bladder Cancer Assessed Route of Exposure[MK Ross & RA Pegram,Tox Appl Pharmacol 195:166, 2004]

Dermal

Oral

↑ Blood

Human (BDCM)

Liver

(↓ Blood)

Rodent (BDCM)

Inactivated

by CYP2E1

Activated by GSTT1-1

in kidney & intestine

Salmonella/GSTT1-1

CYP2E1/GSTT1-1

(rodent sites)

Human Mol Epi

↑ Bladder cancer

in GSTT1-1+

↓ Bladder cancer

in GSTT1-1-


Global Gene Expression (Microarray) Studies May Provide More Insight into the Mechanisms by Which DBPs Cause Health Effects


Global Gene Expression Changes by Insight into the Mechanisms by Which DBPs Cause Health Effects MX (Cl-furanone) in Salmonella TA100W.O. Ward et al., BMC Bioinformatics, 8:378, 2007

  • MX altered expression of 448 genes

  • Pathways altered included

    • Heme, porphyrin, & cobalamin biosynthesis

    • Oxidative phosphorylation

    • Protein section and trafficking

    • Nitrogen, sulfur, and pyruvate metabolism

    • DNA replication, recombination, and repair

    • Cell division

  • MX homologues altered expression of other genes and pathways (Ward et al., in press)


Structural Homologues of MX Alter Expression of Unique Genes and PathwaysWO Ward (2009) Environ Mol Mutagen, in press.

Homologues altered

expression of only

2 genes and no

pathways in common


Changes in Global Gene Expression by Water Extracts in Liver Cells in vitroL.M. Crosby et al., J. Toxicol. Environ. Health 71:1195, 2008

  • Water from Miami River, Ohio, USA had iodide and bromide added, then was either chlorinated or ozonated/chlorinated, concentrated ~130X by reverse osmosis, volatile DBPs added back.

  • Rat liver cells were exposed for 24 h

  • Concentrates altered expression of 547 genes

  • Pathways altered included

    • Oxidative stress and cell-cycle arrest

    • Suppression of apoptosis and reduction in DNA repair

    • Inflammation/immune response

    • Increased expression of neurotransmission genes


Research needs
Research Needs Cells in vitro

  • Prioritize DBPs for testing

    ● 6 regulated DBPs still have significant

    genotoxicity data gaps, and 1 has never

    been tested for carcinogenicity.

    ● 14 unregulated DBPs have no

    genotoxicity toxicology data, but 2 are

    carcinogens.

    ● 29 unregulated DBPs at μg/L levels are

    genotoxic.


  • Systematic generation of quantitative genotoxicity data Cells in vitro

    ● ~70 DBPs studied systematically and quantitatively for DNA damage (comet assay) in CHO cells (M. Plewa, U. of IL)

    ● ~20 DBPs studied similarly in Salmonella (D. DeMarini, EPA)

    3. Studies on route of exposure & genotype

    ● Rodent studies (dermal-bladder/colon)

    ● Human studies (experimental & epi)


  • Chemical identification of unknown fraction of drinking water

    ● >50% of total organic halide (TOX) and assimilable organic carbon (AOC) have not been identified as specific compounds. Savitz et al. (2006) epi study on chloraminated water showed correlation between TOX and pregnancy loss.

    ● Additional analytical studies should be conducted in concert with toxicological studies.


  • Evaluate DBPs from alternative disinfection methods water

    ● chloramine, ozone, and chlorine dioxide

    ● UV and membrane technologies

  • Evaluate use of bioassays for assessing source-water and drinking water quality

    ● Salmonella assay used already in a region of Brazil for source-water assessment and regulation

    ● Salmonella assay literature on drinking water mutagenicity is extensive but not linked well to chemical analysis.


  • Complex mixture studies water

    ● >600 identified DBPs, many are toxic, exposed via oral, dermal, and inhalation.

    ● This complexity is not reflected in any of the toxicology studies of individual DBPs.

    ● Need for bioassay-directed fractionation of water extracts for genotoxicity, from different source waters and treatment methods.

  • Review of reproductive and developmental studies

    ● Merge with current review to permit a sound, scientific assessment of current regulations and directions for future research.


Is chlorinated water really a health risk se hrudey 2009 water res 43 2057
Is Chlorinated Water Really a Health Risk? waterSE Hrudey (2009) Water Res 43:2057

  • No DBP causes bladder cancer in rodents.

  • The epidemiology may be biased due to use of small/rural well water supplies instead of large/urban supplies using only ozonation or no disinfection to obtain populations exposed to low levels of DBPs.


The challenge of water disinfection
The Challenge of Water Disinfection water

Bathing

Drinking

Swimming


The collective enterprise of creative thinking and skeptical thinking, working together, keeps the field on track.

Carl Sagan, 1996


Acknowledgments

US EPA thinking, working together, keeps the field on track.

Larry Claxton

Anthony DeAngelo

Susan Richardson

Rex Pegram

Ann Richard

Mike Madden

Lance Brooks

Sarah Warren

Melissa Shelton

Nancy Hanley

William Ward

Doug Wolf

Rita Schoeny

Acknowledgments

UNC

Bijit Kundu

Dan Shaughnessy

Courtney Granville

Postdocs

Amal Abu-Shakra

Matthew Ross

Stefano Landi

Carol Swartz

Collaborators

Robert Franzen

Leif Kronberg

Michael Plewa

Elizabeth Wagner


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