Search tips
Search criteria 


Logo of envhperEnvironmental Health PerspectivesBrowse ArticlesAbout EHPGeneral InformationAuthorsMediaProgramsPartnerships
Environ Health Perspect. 1999 February; 107(Suppl 1): 207–217.
PMCID: PMC1566350
Research Article

Drinking water disinfection byproducts: review and approach to toxicity evaluation.


There is widespread potential for human exposure to disinfection byproducts (DBPs) in drinking water because everyone drinks, bathes, cooks, and cleans with water. The need for clean and safe water led the U.S. Congress to pass the Safe Drinking Water Act more than 20 years ago in 1974. In 1976, chloroform, a trihalomethane (THM) and a principal DBP, was shown to be carcinogenic in rodents. This prompted the U.S. Environmental Protection Agency (U.S. EPA) in 1979 to develop a drinking water rule that would provide guidance on the levels of THMs allowed in drinking water. Further concern was raised by epidemiology studies suggesting a weak association between the consumption of chlorinated drinking water and the occurrence of bladder, colon, and rectal cancer. In 1992 the U.S. EPA initiated a negotiated rulemaking to evaluate the need for additional controls for microbial pathogens and DBPs. The goal was to develop an approach that would reduce the level of exposure from disinfectants and DBPs without undermining the control of microbial pathogens. The product of these deliberations was a proposed stage 1 DBP rule. It was agreed that additional information was necessary on how to optimize the use of disinfectants while maintaining control of pathogens before further controls to reduce exposure beyond stage 1 were warranted. In response to this need, the U.S. EPA developed a 5-year research plan to support the development of the longer term rules to control microbial pathogens and DBPs. A considerable body of toxicologic data has been developed on DBPs that occur in the drinking water, but the main emphasis has been on THMs. Given the complexity of the problem and the need for additional data to support the drinking water DBP rules, the U.S. EPA, the National Institute of Environmental Health Sciences, and the U.S. Army are working together to develop a comprehensive biologic and mechanistic DBP database. Selected DBPs will be tested using 2-year toxicity and carcinogenicity studies in standard rodent models; transgenic mouse models and small fish models; in vitro mechanistic and toxicokinetic studies; and reproductive, immunotoxicity, and developmental studies. The goal is to create a toxicity database that reflects a wide range of DBPs resulting from different disinfection practices. This paper describes the approach developed by these agencies to provide the information needed to make scientifically based regulatory decisions.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.1M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Mughal FH. Chlorination of drinking water and cancer: a review. J Environ Pathol Toxicol Oncol. 1992 Sep-Oct;11(5-6):287–292. [PubMed]
  • Melnick RL, Dunnick JK, Sandler DP, Elwell MR, Barrett JC. Trihalomethanes and Other Environmental Factors That Contribute to Colorectal Cancer. Environ Health Perspect. 1994 Jun;102(6-7):586–588. [PMC free article] [PubMed]
  • Dunnick JK, Haseman JK, Lilja HS, Wyand S. Toxicity and carcinogenicity of chlorodibromomethane in Fischer 344/N rats and B6C3F1 mice. Fundam Appl Toxicol. 1985 Dec;5(6 Pt 1):1128–1136. [PubMed]
  • Bull RJ, Sanchez IM, Nelson MA, Larson JL, Lansing AJ. Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology. 1990 Sep;63(3):341–359. [PubMed]
  • King WD, Marrett LD. Case-control study of bladder cancer and chlorination by-products in treated water (Ontario, Canada). Cancer Causes Control. 1996 Nov;7(6):596–604. [PubMed]
  • Morris RD. Drinking water and cancer. Environ Health Perspect. 1995 Nov;103 (Suppl 8):225–231. [PMC free article] [PubMed]
  • Doyle TJ, Zheng W, Cerhan JR, Hong CP, Sellers TA, Kushi LH, Folsom AR. The association of drinking water source and chlorination by-products with cancer incidence among postmenopausal women in Iowa: a prospective cohort study. Am J Public Health. 1997 Jul;87(7):1168–1176. [PubMed]
  • Koivusalo M, Pukkala E, Vartiainen T, Jaakkola JJ, Hakulinen T. Drinking water chlorination and cancer-a historical cohort study in Finland. Cancer Causes Control. 1997 Mar;8(2):192–200. [PubMed]
  • Hildesheim ME, Cantor KP, Lynch CF, Dosemeci M, Lubin J, Alavanja M, Craun G. Drinking water source and chlorination byproducts. II. Risk of colon and rectal cancers. Epidemiology. 1998 Jan;9(1):29–35. [PubMed]
  • Cantor KP, Lynch CF, Hildesheim ME, Dosemeci M, Lubin J, Alavanja M, Craun G. Drinking water source and chlorination byproducts. I. Risk of bladder cancer. Epidemiology. 1998 Jan;9(1):21–28. [PubMed]
  • Kurokawa Y, Hayashi Y, Maekawa A, Takahashi M, Kokubo T, Odashima S. Carcinogenicity of potassium bromate administered orally to F344 rats. J Natl Cancer Inst. 1983 Nov;71(5):965–972. [PubMed]
  • Ballmaier D, Epe B. Oxidative DNA damage induced by potassium bromate under cell-free conditions and in mammalian cells. Carcinogenesis. 1995 Feb;16(2):335–342. [PubMed]
  • Waller K, Swan SH, DeLorenze G, Hopkins B. Trihalomethanes in drinking water and spontaneous abortion. Epidemiology. 1998 Mar;9(2):134–140. [PubMed]
  • Kramer MD, Lynch CF, Isacson P, Hanson JW. The association of waterborne chloroform with intrauterine growth retardation. Epidemiology. 1992 Sep;3(5):407–413. [PubMed]
  • Gallagher MD, Nuckols JR, Stallones L, Savitz DA. Exposure to trihalomethanes and adverse pregnancy outcomes. Epidemiology. 1998 Sep;9(5):484–489. [PubMed]
  • Savitz DA, Andrews KW, Pastore LM. Drinking water and pregnancy outcome in central North Carolina: source, amount, and trihalomethane levels. Environ Health Perspect. 1995 Jun;103(6):592–596. [PMC free article] [PubMed]
  • Bove FJ, Fulcomer MC, Klotz JB, Esmart J, Dufficy EM, Savrin JE. Public drinking water contamination and birth outcomes. Am J Epidemiol. 1995 May 1;141(9):850–862. [PubMed]
  • Reif JS, Hatch MC, Bracken M, Holmes LB, Schwetz BA, Singer PC. Reproductive and developmental effects of disinfection by-products in drinking water. Environ Health Perspect. 1996 Oct;104(10):1056–1061. [PMC free article] [PubMed]
  • Jorgenson TA, Meierhenry EF, Rushbrook CJ, Bull RJ, Robinson M. Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice. Fundam Appl Toxicol. 1985 Aug;5(4):760–769. [PubMed]
  • Melnick RL, Kohn MC, Dunnick JK, Leininger JR. Regenerative hyperplasia is not required for liver tumor induction in female B6C3F1 mice exposed to trihalomethanes. Toxicol Appl Pharmacol. 1998 Jan;148(1):137–147. [PubMed]
  • Dunnick JK, Eustis SL, Lilja HS. Bromodichloromethane, a trihalomethane that produces neoplasms in rodents. Cancer Res. 1987 Oct 1;47(19):5189–5193. [PubMed]
  • Dunnick JK, Melnick RL. Assessment of the carcinogenic potential of chlorinated water: experimental studies of chlorine, chloramine, and trihalomethanes. J Natl Cancer Inst. 1993 May 19;85(10):817–822. [PubMed]
  • Daniel FB, DeAngelo AB, Stober JA, Olson GR, Page NP. Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse. Fundam Appl Toxicol. 1992 Aug;19(2):159–168. [PubMed]
  • DeAngelo AB, Daniel FB, Stober JA, Olson GR. The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse. Fundam Appl Toxicol. 1991 Feb;16(2):337–347. [PubMed]
  • Herren-Freund SL, Pereira MA, Khoury MD, Olson G. The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol Appl Pharmacol. 1987 Sep 15;90(2):183–189. [PubMed]
  • DeAngelo AB, Daniel FB, Most BM, Olson GR. The carcinogenicity of dichloroacetic acid in the male Fischer 344 rat. Toxicology. 1996 Dec 18;114(3):207–221. [PubMed]
  • DeAngelo AB, Daniel FB, Most BM, Olson GR. Failure of monochloroacetic acid and trichloroacetic acid administered in the drinking water to produce liver cancer in male F344/N rats. J Toxicol Environ Health. 1997 Dec 12;52(5):425–445. [PubMed]
  • Richmond RE, Carter JH, Carter HW, Daniel FB, DeAngelo AB. Immunohistochemical analysis of dichloroacetic acid (DCA)-induced hepatocarcinogenesis in male Fischer (F344) rats. Cancer Lett. 1995 May 25;92(1):67–76. [PubMed]
  • Austin EW, Parrish JM, Kinder DH, Bull RJ. Lipid peroxidation and formation of 8-hydroxydeoxyguanosine from acute doses of halogenated acetic acids. Fundam Appl Toxicol. 1996 May;31(1):77–82. [PubMed]
  • Ferreira-Gonzalez A, DeAngelo AB, Nasim S, Garrett CT. Ras oncogene activation during hepatocarcinogenesis in B6C3F1 male mice by dichloroacetic and trichloroacetic acids. Carcinogenesis. 1995 Mar;16(3):495–500. [PubMed]
  • Snyder RD, Pullman J, Carter JH, Carter HW, DeAngelo AB. In vivo administration of dichloroacetic acid suppresses spontaneous apoptosis in murine hepatocytes. Cancer Res. 1995 Sep 1;55(17):3702–3705. [PubMed]
  • Austin EW, Okita JR, Okita RT, Larson JL, Bull RJ. Modification of lipoperoxidative effects of dichloroacetate and trichloroacetate is associated with peroxisome proliferation. Toxicology. 1995 Mar 31;97(1-3):59–69. [PubMed]
  • Daniel FB, Schenck KM, Mattox JK, Lin EL, Haas DL, Pereira MA. Genotoxic properties of haloacetonitriles: drinking water by-products of chlorine disinfection. Fundam Appl Toxicol. 1986 Apr;6(3):447–453. [PubMed]
  • Le Curieux F, Giller S, Gauthier L, Erb F, Marzin D. Study of the genotoxic activity of six halogenated acetonitriles, using the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test. Mutat Res. 1995 Feb;341(4):289–302. [PubMed]
  • Bull RJ, Meier JR, Robinson M, Ringhand HP, Laurie RD, Stober JA. Evaluation of mutagenic and carcinogenic properties of brominated and chlorinated acetonitriles: by-products of chlorination. Fundam Appl Toxicol. 1985 Dec;5(6 Pt 1):1065–1074. [PubMed]
  • Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, Zeiger E. Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ Mutagen. 1986;8 (Suppl 7):1–119. [PubMed]
  • Komulainen H, Kosma VM, Vaittinen SL, Vartiainen T, Kaliste-Korhonen E, Lötjönen S, Tuominen RK, Tuomisto J. Carcinogenicity of the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone in the rat. J Natl Cancer Inst. 1997 Jun 18;89(12):848–856. [PubMed]
  • Koga M, Akiyama T, Glaze WH. Analysis of ozonation by-products produced in drinking water treatment. Toxicol Ind Health. 1991 Sep-Nov;7(5-6):423–432. [PubMed]
  • Til HP, Woutersen RA, Feron VJ, Hollanders VH, Falke HE, Clary JJ. Two-year drinking-water study of formaldehyde in rats. Food Chem Toxicol. 1989 Feb;27(2):77–87. [PubMed]
  • Tobe M, Naito K, Kurokawa Y. Chronic toxicity study on formaldehyde administered orally to rats. Toxicology. 1989 May 31;56(1):79–86. [PubMed]
  • DeAngelo AB, George MH, Kilburn SR, Moore TM, Wolf DC. Carcinogenicity of potassium bromate administered in the drinking water to male B6C3F1 mice and F344/N rats. Toxicol Pathol. 1998 Sep-Oct;26(5):587–594. [PubMed]
  • Dunnick JK, Heath JE, Farnell DR, Prejean JD, Haseman JK, Elwell MR. Carcinogenic activity of the flame retardant, 2,2-bis(bromomethyl)-1,3-propanediol in rodents, and comparison with the carcinogenicity of other NTP brominated chemicals. Toxicol Pathol. 1997 Nov-Dec;25(6):541–548. [PubMed]
  • Hard GC. Mechanisms of chemically induced renal carcinogenesis in the laboratory rodent. Toxicol Pathol. 1998 Jan-Feb;26(1):104–112. [PubMed]
  • Kasai H, Nishimura S, Kurokawa Y, Hayashi Y. Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNA. Carcinogenesis. 1987 Dec;8(12):1959–1961. [PubMed]
  • Sai K, Takagi A, Umemura T, Hasegawa R, Kurokawa Y. Relation of 8-hydroxydeoxyguanosine formation in rat kidney to lipid peroxidation, glutathione level and relative organ weight after a single administration of potassium bromate. Jpn J Cancer Res. 1991 Feb;82(2):165–169. [PubMed]
  • Umemura T, Sai K, Takagi A, Hasegawa R, Kurokawa Y. A possible role for oxidative stress in potassium bromate (KBrO3) carcinogenesis. Carcinogenesis. 1995 Mar;16(3):593–597. [PubMed]
  • Bull RJ, Birnbaum LS, Cantor KP, Rose JB, Butterworth BE, Pegram R, Tuomisto J. Water chlorination: essential process or cancer hazard? Fundam Appl Toxicol. 1995 Dec;28(2):155–166. [PubMed]
  • Larson JL, Wolf DC, Butterworth BE. Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B6C3F1 mice: comparison of administration by gavage in corn oil vs ad libitum in drinking water. Fundam Appl Toxicol. 1994 Jan;22(1):90–102. [PubMed]
  • Tennant RW, French JE, Spalding JW. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect. 1995 Oct;103(10):942–950. [PMC free article] [PubMed]
  • Morris RD, Audet AM, Angelillo IF, Chalmers TC, Mosteller F. Chlorination, chlorination by-products, and cancer: a meta-analysis. Am J Public Health. 1992 Jul;82(7):955–963. [PubMed]
  • McGeehin MA, Reif JS, Becher JC, Mangione EJ. Case-control study of bladder cancer and water disinfection methods in Colorado. Am J Epidemiol. 1993 Oct 1;138(7):492–501. [PubMed]
  • Moser AR, Luongo C, Gould KA, McNeley MK, Shoemaker AR, Dove WF. ApcMin: a mouse model for intestinal and mammary tumorigenesis. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1061–1064. [PubMed]
  • Sørensen IK, Kristiansen E, Mortensen A, van Kranen H, van Kreijl C, Fodde R, Thorgeirsson SS. Short-term carcinogenicity testing of a potent murine intestinal mutagen, 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), in Apc1638N transgenic mice. Carcinogenesis. 1997 Apr;18(4):777–781. [PubMed]
  • Pritchard JB. Aquatic toxicology: past, present, and prospects. Environ Health Perspect. 1993 Apr;100:249–257. [PMC free article] [PubMed]
  • Hawkins WE, Overstreet RM, Fournie JW, Walker WW. Development of aquarium fish models for environmental carcinogenesis: tumor induction in seven species. J Appl Toxicol. 1985 Aug;5(4):261–264. [PubMed]
  • Boorman GA, Botts S, Bunton TE, Fournie JW, Harshbarger JC, Hawkins WE, Hinton DE, Jokinen MP, Okihiro MS, Wolfe MJ. Diagnostic criteria for degenerative, inflammatory, proliferative nonneoplastic and neoplastic liver lesions in medaka (Oryzias latipes): consensus of a National Toxicology Program Pathology Working Group. Toxicol Pathol. 1997 Mar-Apr;25(2):202–210. [PubMed]
  • Walker WW, Manning CS, Overstreet RM, Hawkins WE. Development of aquarium fish models for environmental carcinogenesis: an intermittent-flow exposure system for volatile, hydrophobic chemicals. J Appl Toxicol. 1985 Aug;5(4):255–260. [PubMed]
  • Hendriks AJ. Modeling response of species to microcontaminants: comparative ecotoxicology by (sub)lethal body burdens as a function of species size and partition ratio of chemicals. Ecotoxicol Environ Saf. 1995 Nov;32(2):103–130. [PubMed]
  • Ishikawa T, Shimamine T, Takayama S. Histologic and electron microscopy observations on diethylnitrosamine-induced hepatomas in small aquarium fish (Oryzias latipes). J Natl Cancer Inst. 1975 Oct;55(4):909–916. [PubMed]
  • Stone R. A molecular approach to cancer risk. Science. 1995 Apr 21;268(5209):356–357. [PubMed]
  • Pitot HC, Goldsworthy TL, Moran S, Kennan W, Glauert HP, Maronpot RR, Campbell HA. A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci. Carcinogenesis. 1987 Oct;8(10):1491–1499. [PubMed]
  • Lijinsky W, Reuber MD, Riggs CW. Dose response studies of carcinogenesis in rats by nitrosodiethylamine. Cancer Res. 1981 Dec;41(12 Pt 1):4997–5003. [PubMed]
  • Laurén DJ, Teh SJ, Hinton DE. Cytotoxicity phase of diethylnitrosamine-induced hepatic neoplasia in medaka. Cancer Res. 1990 Sep 1;50(17):5504–5514. [PubMed]
  • Bjerknes M, Cheng H, Kim H, Schnitzler M, Gallinger S. Clonality of dysplastic epithelium in colorectal adenomas from familial adenomatous polyposis patients. Cancer Res. 1997 Feb 1;57(3):355–361. [PubMed]
  • Harris MW, Chapin RE, Lockhart AC, Jokinen MP. Assessment of a short-term reproductive and developmental toxicity screen. Fundam Appl Toxicol. 1992 Aug;19(2):186–196. [PubMed]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Science