WHO/SDE/WSH/05.

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Dichloroacetic Acid in Drinking-water
Background document for development of WHO Guidelines for Drinking-water Quality

© World Health Organization 2005 This document may be freely reviewed, abstracted, reproduced and translated in part or in whole but not for sale or for use in conjunction with commercial purposes. Inquiries should be addressed to: permissions@who.int. The designations employed and the presentation of the material in this document do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use.

Through this process. Sweden. and documentation related to aspects of protection and control of public drinkingwater quality is accordingly prepared and updated. these constituted Volume 2 of the GDWQ. and the first addendum to the third edition was published in 2005. describing the approaches used in deriving guideline values and presenting critical reviews and evaluations of the effects on human health of the substances or contaminants of potential health concern in drinking-water. Under the oversight of a group of coordinators each of whom was responsible for a group of chemicals considered in the GDWQ. Volume 2. Japan. respectively. Comments were taken into consideration by the coordinators and authors. Finland. a lead institution prepared a background document evaluating the risks for human health from exposure to the particular chemical in drinking-water. Denmark. WHO has published information on health criteria and other supporting information to the GDWQ. The third edition of the GDWQ was published in 2004. Health criteria and other supporting information. United Kingdom and United States of America prepared the documents for the third edition and addenda.. and Volume 3. have the right to have access to an adequate supply of safe drinking water. Italy. During the preparation of background documents and at expert meetings. Surveillance and control of community supplies. Institutions from Canada. whatever their stage of development and their social and economic conditions. the first edition of the WHO Guidelines for Drinking-water Quality (GDWQ) was published in three volumes: Volume 1. 1996 and 1997.. they comprise a series of freestanding monographs.” A major WHO function to achieve such goals is the responsibility “to propose . Norway. Since the first edition of the GDWQ. Second editions of these volumes were published in 1993. and to make recommendations with respect to international health matters . Recommendations.. including this one. careful consideration was given to information available in previous risk assessments carried . Since publication of the third edition. the draft health criteria documents were submitted to a number of scientific institutions and selected experts for peer review. For each chemical contaminant or substance considered. The GDWQ are subject to a rolling revision process. It was subsequently revised in 1963 and in 1971 under the same title. In the first and second editions. regulations. Germany.Preface One of the primary goals of WHO and its member states is that “all people. Addenda to Volumes 1 and 2 of the second edition were published on selected chemicals in 1998 and on microbiological aspects in 2002. Poland. Netherlands. microbial.. In 1984–1985.. chemical and radiological aspects of drinking-water are subject to periodic review. The draft documents were also released to the public domain for comment and submitted for final evaluation by expert meetings. France.” The first WHO document dealing specifically with public drinking-water quality was published in 1958 as International Standards for Drinking-water.

nitrate and nitrite. the Joint FAO/WHO Meetings on Pesticide Residues and the Joint FAO/WHO Expert Committee on Food Additives (which evaluates contaminants such as lead.out by the International Programme on Chemical Safety. . cadmium. in addition to food additives). Further up-to-date information on the GDWQ and the process of their development is available on the WHO Internet site and in the current edition of the GDWQ. in its Environmental Health Criteria monographs and Concise International Chemical Assessment Documents. the International Agency for Research on Cancer.

Canada. Many individuals from various countries contributed to the development of the GDWQ. Mr Robert Bos. WHO Headquarters. was prepared by Dr Diana Wong and Dr Joyce Morrissey Donohue. Y. Bartram. WHO Headquarters. United Kingdom (Naturally occurring and industrial contaminants) Ms M. WHO Headquarters. Fawell. USA (Disinfectants and disinfection by-products) The draft text was discussed at the Working Group Meeting for the first addendum to the third edition of the GDWQ. Japan (Analytical achievability) Dr E. The WHO coordinator was Dr J. Environmental Protection Agency. Water Sanitation and Health Programme. to whom special thanks are due. Water Sanitation and Health Programme. Background document for development of WHO Guidelines for Drinking-water Quality. Cotruvo. The final version of the document takes into consideration comments from both peer reviewers and the public.K. The work of the following working group coordinators was crucial in the development of this document and others contributing to the first addendum to the third edition: Dr J. Ms Penny Ward provided invaluable administrative support at the Working Group Meeting and throughout the review and publication process. USA (Materials and chemicals) Mr J. US Environmental Protection Agency. Jackson. provided input on pesticides added to drinking-water for public health purposes. Ohanian. .Acknowledgements The first draft of Dichloroacetic Acid in Drinking-water. J. The input of those who provided comments and of participants in the meeting is gratefully acknowledged. Coordinator. Magara. was responsible for the scientific editing of the document. WRc-NSF. Health Canada (Disinfectants and disinfection by-products) Mr P. Ms Marla Sheffer of Ottawa. Vickers provided a liaison with the International Chemical Safety Programme. The efforts of all who contributed to the preparation of this document and in particular those who provided peer or public domain review comment are greatly appreciated. Hokkaido University. United Kingdom (Chemicals – practical aspects) Prof. Ms C. Giddings. held on 17–21 May 2004. Cotruvo Associates.

Acronyms and abbreviations used in the text BMDL10 CAS DCA DNA EPA FAO GDWQ GSH GST ISO LD50 LOAEL NOAEL PPAR PQL THM USA WHO lower-bound confidence limit on the benchmark dose associated with a 10% increase in response over background Chemical Abstracts Service dichloroacetic acid deoxyribonucleic acid Environmental Protection Agency (USA) Food and Agriculture Organization of the United Nations Guidelines for Drinking-water Quality glutathione glutathione-S-transferase International Organization for Standardization median lethal dose lowest-observed-adverse-effect level no-observed-adverse-effect level peroxisome proliferator activated receptor practical quantification level trihalomethane United States of America World Health Organization .

..........Table of contents 1.........................................................................................................................2 2.3 3...........................................................2 2.........................................................................................................................................1 Analytical methods and analytical achievability ........................13 6......................................1 1..........7 4.................................12 6........ REFERENCES .....................................................5 Genotoxicity and related end-points .............6 Carcinogenicity .........................................................2 Physicochemical properties ............................................ ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE............... PRACTICAL ASPECTS ....4 4......4 Major uses and sources in drinking-water ....... KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS ...................................1 1.....................1 Air .....3 Organoleptic properties.......................................1 1..................................................................................................... GENERAL DESCRIPTION......................1 2..................................................................................1 Acute exposure...................................................14 8.....................................................................................................4 Reproductive and developmental toxicity .....6 4............2 Treatment and control methods and technical achievability........2 2........................... EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS.....................................................................14 7................................1 1.............4 Estimated total exposure and relative contribution of drinking-water...... EFFECTS ON HUMANS.........................................................................3 Long-term exposure ...................................................5 4...................................................3 4.............................................8 4. GUIDELINE VALUE ....................................................................................4 4.......................................2 2.............................................................2 Water..............................................3 Food .....2 Short-term exposure.....................1 Identity .....13 6.................15 ...........................................................................................................9 5.................................................................

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1989.3 0. 2001) Property Boiling point (°C) Melting point (°C) Density (g/cm3) Vapour pressure (Pa) Dissociation constant (pKa) at 25 °C Water solubility (g/litre) Log octanol–water partition coefficient Value 194 13.9 at 25 °C 1. and as a fungicide (Hawley. including dichloroacetic acid. Budavari et al.2 Physicochemical properties1 (Verschueren. as a topical astringent.. 1981. 1. Dichloroacetic acid has been used as a therapeutic agent to treat lactic acidosis. 1977.92 1.4 Major uses and sources in drinking-water Chlorinated acetic acids.5 1. diabetes.56 at 20 °C 23. Weast.1 Identity CAS No. 1988.. 1998a). 1 Conversion factor in air: 1 ppm = 5. 1980. 2000). and familial hyperlipidaemia in humans (Stacpoole et al.27 mg/m3.1. GENERAL DESCRIPTION 1.26 86. 1 . Dichloroacetic acid is used as a chemical intermediate in the synthesis of organic materials. 1. as an ingredient in pharmaceuticals and medicines.3 Organoleptic properties No information is available on the taste or odour threshold of dichloroacetic acid in water. HSDB. are formed from organic material during water chlorination (Coleman et al. HSDB.: Molecular formula: 79-43-6 Cl2CHCOOH Dichloroacetic acid is also known as dichloroacetate. dichloroethanoic acid. IPCS. 2001).. and DCA.

and oxidizing and bleaching in the flour industry.0 to 99 µg/litre in surface water distribution systems and from <1. It is also used in sanitizing equipment and containers and in cooling heat-sterilized foods (US EPA. Reimann et al. 1995). Reimann et al. In a German study of 15 indoor and 3 outdoor swimming pools (Clemens & Scholer.9 and 17 µg/litre. (1996) reported dichloroacetic acid concentrations of 0. Data for drinking-water supplies in the USA indicate that dichloroacetic acid was detected in groundwater and surface water distribution systems at mean concentrations of 6.9 µg/litre in indoor and outdoor pools. processing of seafood. and red meats. The mean concentration of dichloroacetic acid in three indoor pools in the USA was 419 µg/litre (Kim & Weisel. grain.3 Food Chlorine is used in food production and processing.5 and 7. Dichloroacetic acid 2 .5 µg of dichloroacetic acid per litre and that a maximum concentration of 200 µg/litre was found for dichloroacetic acid in chlorinated water in Australia. fruits. dichloroacetic acid concentrations averaged 5. Concentrations ranged from <1.DICHLOROACETIC ACID IN DRINKING-WATER 2. poultry. Dichloroacetic acid is not a volatile compound and is not expected to be present in air unless it is dissolved in atmospheric water vapour. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 2. in revision).1 Air No information is available on the concentrations of dichloroacetic acid in air. sample collection time relative to chlorination of the water. 1998).35 µg of dichloroacetic acid per litre (IARC. 1994). 2. 1992).6 µg/litre and 119. dichloroacetic acid is likely to be found as a disinfection by-product in meat and other food products. Rainwater in Germany contained 1. or addition or exchanges of water in the pools. respectively. (1996) examined the concentrations of dichloroacetic acid in a limited number of samples of several vegetables. including the following: disinfection of chicken in poultry plants. and beer. The formation of dichloroacetic acid (and other haloacetic acids) in pools is discussed in Volume 2 of the WHO Guidelines for Safe Recreational Water Environments (WHO. 2001). The difference between the results of these two studies may be due to differences in the amounts of chlorine used to disinfect swimming pools. 2. respectively. Dichloroacetic acid has also been detected in swimming pool water.0 to 71 µg/litre in groundwater systems (US EPA.05–4 µg/litre measured in rainwater.2 Water IARC (1995) reported that chlorinated drinking-water in Japan contained 4. Therefore.

James et al. the radioactivity present as a percentage of the administered dose was localized in the muscle (11. 1982. Stacpoole et al.19%).. 1999). 1999. urinary excretion of unchanged dichloroacetate was negligible after 8 h.8 µg/kg in flours/breads.. and kidney (0. 1998. bone. and cumulative excretion was less than 1% of the total dose in all subjects (Lukas et al.8. 3.2 µg/litre in beer. liver (6.DICHLOROACETIC ACID IN DRINKING-WATER concentrations ranged from <0. Raymer et al. Transamination of glyoxylate forms glycine and can distribute the label from dichloroacetic acid to urinary glycine conjugates.. Stacpoole et al. gastrointestinal tract (3. James et al. 1998). “Other tissues.. James et al. It was not detected in fruits or tomatoes.4 mg of radiolabelled dichloroacetate per kg of body weight). skin. In young adult rats administered a single radiolabelled gavage dose of 50 mg of sodium dichloroacetate per kg of body weight (42. 1989. 2002) and via both the oral and dermal routes in humans (Kim & Weisel. Dichloroacetic acid is dechlorinated to glyoxylate and then oxidized to oxalate. green beans. average half-lives of the parent compound in plasma were 2. fat (3.97. and testes.53%). all of which are excreted in the urine. Following a single oral dose of 50 mg/kg of body weight in humans..” including plasma.87%). from 0.5 µg/kg in vegetables. Rats administered repeated high doses of dichloroacetic acid also eliminate unmetabolized compound (Gonzalez-Leon et al.. 2. 20. 1998a). However.6 to 11. The apparent dose dependence in plasma clearance suggested that metabolic transformation becomes the rate-limiting step at high doses (Lukas et al. 1998. uptake ranged from 11% for chicken to 85% for pinto beans..3 µg of dichloroacetic acid per litre excreted 2–5% of the dose as unmodified dichloroacetic acid in the urine 3 . 1980).. The data are not adequate to quantify the contributions of each source for an overall assessment of exposure. In rats. Cornett et al.1 µg/kg in grains. and humans given single doses of sodium dichloroacetate intravenously. 1998). 1998a).4 Estimated total exposure and relative contribution of drinking-water The available data are sufficient to demonstrate that food and water are relevant sources for exposure to dichloroacetic acid. spleen. from <0. lung. 1998. two human subjects who ingested drinking-water containing 4 or 6. It is initially distributed to liver and muscle and subsequently to other target organs (Evans. pinto beans.9%). respectively. 1987.46% of the administered dose (James et al. such as hippuric acid (Stacpoole. 1980).9 to 3.. dogs. (2001) found that dichloroacetic acid was stable in water during boiling and was taken up by foods during cooking in water. 1998).8 to 19.. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS Dichloroacetic acid is rapidly absorbed into the bloodstream from the gastrointestinal tract in rats and mice (Stacpoole. Some dichloroacetic acid is also converted to carbon dioxide and eliminated via expired air (James et al. and chicken were tested.. brain. Carrots.43 h. and from 1. 1997.5 to 15. heart. accounted for 9.74%). Schultz et al. and 0..

The most frequent human variant (1c-1c) identified by Blackburn et al... and the dermal LD50 was 0. and 1d-1d variants retained only 3–5% of their original activity. 1951). causing irreversible inhibition (Anderson et al. 1999). 1998a). (2001) identified four variant forms of the enzyme among a group of 128 Caucasian blood donors (GST-zeta 1a-1a. respectively (Woodard et al.1 ml/kg of body weight (about 795 mg/kg of body weight) (Smyth et al. 1000. 1b-1b. releasing glyoxylate as a product. whereas the 1b-1b. (2001) was found to be the least active in the metabolism of dichloroacetic acid (Tzeng et al.3 to 374 min in human volunteers after intravenous administration of five 50 mg/kg of body weight doses (Curry et al. Lantum et al. the lowest dose of 300 mg/kg of body weight was a LOAEL (Moser et al. 1985). 1999)... 1998b). and 1d-1d). suggesting that dichloroacetic acid inhibits its own metabolism (James et al. 1c-1c. the LD50 was 2820 mg/kg of body weight.. with either death or complete recovery within 36 h. Dichloroacetic acid inhibition of GST-zeta appears to be the result of the formation of a covalent complex between GSH and dichloroacetic acid that can either dissociate. or 2000 mg of dichloroacetic acid per kg of body weight exhibited neurobehavioural toxicity 4–24 h following dosing. or covalently bind to a nucleophilic residue in the enzyme.DICHLOROACETIC ACID IN DRINKING-WATER shortly after exposure (Kim et al. whereas the most active variant (1a-1a) had a low distribution in the population. (2002) found that.. Using chlorofluoroacetate as a substrate.. The plasma elimination of dichloroacetic acid by rats was slowed by administration of a single prior dose of the acid. Based on decreased grip strength. There are interspecies and intraspecies differences in the activity of GST-zeta with dichloroacetic acid as a substrate (Tong et al.. 1997). Blackburn et al. 2000). 1941). 300. 1999). GST-zeta is identical to maleylacetoacetate isomerase. as indicated by decreased hind limb grip strength and decreased motor activity. after inhibition. Groups of Long-Evans rats (10 per group) administered a single gavage dose of 0. the 1a-1a variant retained 12% of its initial activity.1 Acute exposure Oral LD50s of 4480 and 5520 mg of dichloroacetic acid per kg of body weight have been reported in rats and mice. an enzyme in the metabolic pathway for tyrosine catabolism (Fernandez-Canon & Penalva.. 1998a. These effects were reversible. The mean plasma half-life increased from 63. 1998). The enzyme that catalyses the GSH-dependent oxygenation of dichloroacetate has been identified as GST-zeta (Tong et al. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS 4.. Acute effects included narcosis. 1c-1c. 4 . 4. In another study on male rats. with recovery occurring 7–14 days after dosing.

. to a lesser extent. Two rats of each sex in the 2000 mg/kg of body weight per day group died during the study. lactate. 12. At 39.5. 75. Lesions included pale and discoloured kidneys. At 12. conjunctivitis. At 72 mg/kg of body weight per day. and decreased erythrocyte count and haemoglobin levels. 39. and adrenals at all dose levels. and no effects on the liver were observed at this dose. an increased incidence of haemosiderinladen Kupffer’s cells in the liver and cystic mucosal hyperplasia in the gall bladder were observed at all dose levels. 125.5 g/litre (approximately 80 mg/kg of body weight per day) and higher (Kato-Weinstein et al. effects included decreased body weight gain in both sexes. Effects included a dose-dependent decrease in body weight and increased relative weights of liver. mild vacuolar change.. and pyruvate levels at all dose levels. were observed in the cerebrum and cerebellum of treated rats of both sexes in all dose groups. Based on organ weight effects and brain lesions. 1981). or 72 mg/kg of body weight per day for 90 days. 50 mg/kg of body weight per day. or 2000 mg/kg of body weight per day for 3 months. the lowest dose tested. 1981). and decreased mean blood glucose. and testes..DICHLOROACETIC ACID IN DRINKING-WATER 4. male B6C3F1 mice were also treated with 0. kidneys. 500.2 Short-term exposure Increased liver weight and localized areas of liver necrosis were reported in male B6C3F1 and male and female Swiss-Webster mice treated with dichloroacetic acid in drinking-water for 14 days at concentrations of 1 or 2 g/litre (250 or 500 mg/kg of body weight per day). effects included increased relative liver weights in males. effects included dyspnoea. or 100 mg/kg of body weight per day for 13 weeks.5 mg/kg of body weight per day and above. Increased cell proliferation in the livers of male B6C3F1 mice occurred at 2 g/litre (500 mg/kg of body weight per day) after 5 but not 14 days (Sanchez & Bull. brain lesions.5. inflammation. was the LOAEL (Katz et al. chronic inflammation 5 . and haemosiderosis in the liver. the lowest dose tested. 1978.5 mg/kg of body weight per day and above. Beagle dogs were given sodium dichloroacetate by capsule at 50. partial paralysis of the hind limbs. In this study. Sprague-Dawley rats (10 per sex per dose) were administered sodium dichloroacetate by gavage at dose levels of 0. 1998). a progressive depression in haematological parameters. brain. in the cerebellum. Beagle dogs (five per sex per dose) received dichloroacetate in capsules at daily doses of 0. 1990). Effects included dose-dependent weight loss. kidney.3 g/litre (75 mg/kg of body weight per day). Male B6C3F1 mice given dichloroacetic acid in drinking-water at concentrations of 0 or 0. 125 mg/kg of body weight per day. 1978. was identified as a LOAEL (Katz et al. pancreas. characterized by vacuolation of the myelinated white tracts resembling oedema. Brain and testes were the principal target organs.1 to 3 g/litre (0 or 16 to 490 mg/kg of body weight per day) for up to 8 weeks showed significant dose-dependent increases in the glycogen content of the liver at concentrations of 0. Histopathological effects included slight to moderate vacuolation of white myelinated tracts in the cerebrum and. The major signs of intoxication were hind limb paralysis and frequent urination. and histopathology in the liver.

low.DICHLOROACETIC ACID IN DRINKING-WATER and acinar degeneration in the pancreas. The neurotoxicity was most severe in F344 rats whose exposure in drinking-water began post-weaning. were observed at daily doses as low as 16 mg/kg of body weight.. over the course of 100 weeks of treatment.. the results of this dose group were excluded from the analysis. No liver necrosis was noted in any of the groups (DeAngelo et al. There was a mild increase in absolute and relative testis weights at 40. described as uncoordinated placement of the hind limbs and hunched posture. 1991). 0. the LOAEL was 16 mg/kg of body weight per day. respectively. the lowest dose tested (Moser et al. The neurobehavioural toxicity of dichloroacetic acid was examined in two age groups of rats (young adult and weanling). the animals were sacrificed at 60 weeks.6.5 mg/kg of body weight per day. Based on gait abnormalities in drinking-water studies of 12–13 weeks’ duration. using two strains of rats (F344 and Long-Evans) and two routes of administration (drinking-water and gavage) for varying lengths of time (8 weeks to 24 months). other effects observed in both F344 and Long-Evans rats included deficits in the righting reflex. 0. The neurotoxicity was progressive with continued exposure and persisted for up to 2 years following high-dose exposures of 6 months. At higher doses. ocular abnormalities and a unique chest-clasping response were observed only in F344 rats. The neuropathy did not reverse or diminish. and. as a result. In the high dose group. 3.2 mg/kg of body weight per day. In general. In a second study using the same experimental protocol. but 6 . and testicular abnormalities.3 Long-term exposure Male F344 rats (60–78 per group) were given dichloroacetic acid in drinking-water at concentrations of 0. The LOAEL for this study was 12. 4. male F344 rats (78 per group) were given 0 or 2. decreased hind limb grip strength. Peripheral neuropathy in the treated group resulted in a sequential lowering of the dichloroacetic acid concentration to 1. Final mean body weights of treated animals were significantly reduced to 73% of control values.05. and mild tremors. the lowest dose tested (Cicmanec et al.5 g of dichloroacetic acid per litre in drinking-water. Treatment at this level was continued to 103 weeks. Time-weighted average daily doses in the control. F344 rats were more sensitive than Long-Evans rats.2 mg/kg of body weight. or 5.0 g/litre at 26 weeks. mild vacuolization of white myelinated tracts in the cerebrum and/or cerebellum. early signs of peripheral neuropathy resulted in a sequential lowering of the drinking-water concentration to 1. Gait abnormalities. Histopathology showed that microscopic effects were limited to the central nervous system and were most severe in the spinal cord. 1996).0 g/litre at 52 weeks. The time-weighted average daily dose was 139 mg/kg of body weight. 1999).0 g/litre for 100 weeks. and weanlings appeared to be somewhat more sensitive than young adults. which showed degeneration of the posterior columns accompanied by gliosis and loss of myelinated axons.5. Absolute testes weights were significantly decreased. Daily doses of dichloroacetic acid ranged from 16 to 308 mg/kg of body weight per day for drinking-water exposures and from 30 to 1000 mg/kg of body weight per day for gavage exposures. and middle dose groups were 0. and 40..

7 . or 1440 mg/kg of body weight per day for 14 days and evaluated for reproductive tract toxicity. At 160 mg/kg of body weight per day and higher. was observed at a dose of 168 mg/kg of body weight per day and higher. At 54 mg/kg of body weight per day and higher. or 5.5. 7.4 Reproductive and developmental toxicity Male Sprague-Dawley rats (eight per group) were given dichloroacetic acid by gavage at doses of 0. or 486 mg/kg of body weight per day) for 60 weeks.05. 410. but only at the two highest dose levels at 100 weeks. At 480 mg/kg of body weight per day and higher. 4. which increased in severity with increasing dose. 1999). and atypical formation and resorption of residual bodies. Hepatic peroxisome proliferation was increased in the highest dose group (DeAngelo et al. and there was a statistically significant decrease in the percentage of motile sperm. water consumption was reduced to 60% of that of controls.DICHLOROACETIC ACID IN DRINKING-WATER there was no change in relative testes weights. 0... Based on these results. the statistical significance of this finding was not reported.6 or 77 mg/kg of body weight per day for 75 weeks.and 75-week studies was 7. 8. 1991).5 g/litre (0. 1. A dose-dependent increase in liver weight was seen at 26 and 52 weeks in all treatment groups evaluated for this end-point (84 mg/kg of body weight per day and higher). or 429 mg/kg of body weight per day) for 90–100 weeks. or 3. 18. 160. At 18 mg/kg of body weight per day. Other groups of mice received dichloroacetate at 7.5. 315. 77. 2. At final sacrifice. Male B6C3F1 mice (30–71 per dose group) were administered dichloroacetic acid in drinking-water at concentrations of 0.6 mg/kg of body weight per day (DeAngelo et al.05. as indicated by a significant increase in alanine aminotransferase and liver necrosis. 0. 1997). The NOAEL for the 60. mean body weights were significantly decreased. rats exhibited clear histopathological effects on spermiation indicative of spermatotoxicity... including retention of Step 19 spermatids. and relative liver weight was increased at the three highest dose levels. the percentage of abnormal cauda sperm was significantly increased. An increase in kidney weight was seen only at 410 mg/kg of body weight per day. and no data on control responses were given. In the highest dose group. Male B6C3F1 mice (50 per dose group) received dichloroacetate in their drinkingwater at 0. and absolute and relative liver weights were significantly increased at 315 mg/kg of body weight per day and higher. A dose-dependent increase in liver toxicity.5. 18 mg/kg of body weight per day was identified as a NOAEL (Linder et al. Effects included altered spermiation. 480. however. 0. No effects were seen on testes or spleen weight. 0. significantly increased alanine aminotransferase activity was also observed with the 84 mg/kg of body weight per day dose.0 g/litre (0. 84. Body weight was decreased at the two highest dose levels. 168. two animals were judged by the authors to have mild increased retention of Step 19 spermatids. 1996). 54. Neither changes in other organ weights nor non-neoplastic liver lesions were observed at final sacrifice (DeAngelo et al.6. epididymis weights were decreased. 3.

(1995) studied groups of 10–20 explanted embryos from SpragueDawley rats cultured for 46 h in dichloroacetic acid solutions (0–10 mmol/litre). and DNA content were seen at 2. 140. Data for teratogenicity of dichloroacetic acid were considered to be equivocal in the frog embryo teratogenesis assay – Xenopus (Bantle et al. dose-dependent decrease in crown–rump length was seen at 3. One report indicated that dichloroacetic acid may increase prophage induction in Escherichia coli (DeMarini et 8 . In this study. 1992). Collectively. Fetal cardiac malformations were reported in the offspring of pregnant dams dosed at 1900 mg/kg of body weight per day on gestation days 9–11 and 12–15. or 2400 mg/kg of body weight per day (first study) or 0.. No treatmentrelated effects were observed for pregnancy rates. at 2400 mg/kg of body weight per day on gestation days 10 or 12. 2003). and the number of live fetuses per litter was significantly reduced. At 900 mg/kg of body weight per day and above. protein content. several structural defects not seen in the control or lowest dose group were increased at the higher doses. Significant dose-related increases in the relative liver weights of the dams were observed at all dose levels.5 mmol/litre and above. This was based on increased relative maternal liver weight and increased soft tissue abnormalities at 140 mg/kg of body weight per day (Smith et al. the maternal and developmental NOAELs were both 14 mg/kg of body weight per day. 14. For example..DICHLOROACETIC ACID IN DRINKING-WATER Pregnant Long-Evans rats (20 per group) received dichloroacetic acid by oral gavage on gestation days 6–15 at doses of 0.5 Genotoxicity and related end-points There have been numerous studies investigating the genotoxicity of dichloroacetic acid (summarized in US EPA. 900. 1992). In addition. or the frequency of pre-implantation losses. post-implantation losses were significantly increased. maternal body weight gain was significantly reduced. 1999). A significant. The results of most in vitro tests have been negative or equivocal. the total number of implants per litter. and at 3500 mg/kg of body weight per day on gestation day 12 (Epstein et al. Reduced fetal body weight was observed in the offspring of dams exposed to 1900 mg/kg of body weight per day on gestation days 6–8. 1400. with or without metabolic activation. Saillenfait et al.. head length.to 3-day periods during gestation in order to examine the effects of treatment during organogenesis. negative or equivocal results were obtained in most reverse mutation tests in Salmonella typhimurium. while significant. 1900. dose-related decreases in yolk sac diameter. dose-related mortality occurred in treated dams. somite (embryonic segment) number. and in most forward mutation tests in mouse lymphoma cells. or 400 mg/kg of body weight per day (second study). 4.5 mmol/litre and above. these studies indicate a developmental LOAEL of 1900 mg/kg of body weight per day. At 140 mg/kg of body weight per day and higher. in tests for DNA strand breakage in mammalian cells. Pregnant rats were administered gavage doses of dichloroacetate ranging from 1900 to 3500 mg/kg of body weight per day on specific 1. Dose-related decreases in fetal growth and increases in total soft tissue malformations occurred at 140 mg/kg of body weight per day and above. At 1400 mg/kg of body weight per day and higher.

410.0 g/litre (0. Male B6C3F1 mice were administered dichloroacetic acid in drinking-water at concentrations of 0. or 5. this finding has not been confirmed by other laboratories and required extremely high dichloroacetic acid concentrations to achieve significance. hepatocellular adenomas in 42% of treated animals. Dichloroacetic acid was reported to induce both gene mutations and gross chromosomal aberrations in L5178Y mouse lymphoma cells in vitro.5.. Male B6C3F1 mice given dichloroacetic acid in drinking-water at a concentration of 0 or 0. base substitutions) was analysed.6 Carcinogenicity Male B6C3F1 mice were given dichloroacetic acid in drinking-water at 0 or 5 g/litre (approximately 0 or 1000 mg/kg of body weight per day) for 61 weeks. An increase in hepatocellular carcinomas was observed in 81% of treated animals (Herren-Freund et al. but the concentrations required to induce these effects were in the millimoles per litre range (Harrington-Brock et al.. 0... 7. and hyperplastic nodules in 8% of treated animals.5 g/litre (approximately 190 or 665 mg/kg of body weight per day) for 60 weeks. compared with 10% in controls. tumours were not observed in male mice administered 1 g/litre (140 mg/kg of body weight per day) for 52 weeks or 2 g/litre (280 mg/kg of body weight per day) for 37 weeks followed by a 15-week recovery period (Bull et al.DICHLOROACETIC ACID IN DRINKING-WATER al. Mutational frequencies in the lacI gene still differed significantly between treated and control mice after this adjustment (Leavitt et al. 1990). The results of in vivo studies have been mixed. 1987). or in assays for DNA adduct formation (Austin et al. An increase in liver adenomas.. 1994). after 60 weeks. 2003). 4. and hyperplastic nodules was observed only in the two highest dose groups (DeAngelo et al. and duplicate identical mutations in each animal were subtracted from the total number of mutations. 1998). Male B6C3F1 mice receiving dichloroacetic acid in drinking-water at 2 g/litre (300 mg/kg of body weight per day) for 52 weeks developed hepatocellular carcinomas. No consistent pattern of positive or negative results for genotoxicity has been observed in the mouse micronucleus assay. 1991). both concentrations induced a significantly elevated mutational frequency at this locus. 1996. or 486 mg/kg of body weight per day) for 60 weeks. carcinomas. 0. In order to account for possible confounding by clonal expansion. US EPA. compared with 5% in controls.. neither concentration induced an increased frequency of mutations in the lacI gene. compared with 0% in controls (Daniel et al. the type of mutation (i.5. Transgenic mice (Big Blue) were exposed to dichloroacetic acid in drinking-water at concentrations of 1 or 3.e. 1996. in assays for DNA strand breaks in mouse or rat cells.5 g/litre (0 or 88 mg/kg of body weight per day) for 104 weeks developed hepatocellular carcinomas in 63% of treated animals.05. 1997). 3. 9 . Parrish et al..6. 77. 1992).... After 4 or 10 weeks of treatment.

with 71%. or 410 mg/kg of body weight per day) for 104 weeks.5. At 52 weeks.0 and 3.DICHLOROACETIC ACID IN DRINKING-WATER Male B6C3F1 mice (35–71 per dose) were given dichloroacetic acid in drinkingwater at concentrations of 0. compared with 26% of controls. and 100% of the animals. The slides were examined independently by two individuals for the presence of altered hepatic foci. 84. 10 . developing these tumours. The authors concluded that neither peroxisome proliferation nor hepatocyte proliferation was associated with the induction of liver cancer in these mice (DeAngelo et al. the incidence of hepatocellular carcinoma was significantly elevated in the three highest dose groups. accumulation of lipid droplets. 0. respectively. At study termination. 1. versus 0% in controls).0. or 3. 95%. 0. Carter et al.. large foci of cellular alteration.5 g/litre groups. Eosinophilic cells seemed to progress from altered hepatic foci to eosinophilic adenomas and carcinomas.5 g/litre (0. No hepatocellular tumours were observed in any group after 26 weeks of exposure. in female B6C3F1 mice given dichloroacetic acid in drinking-water at concentrations of 0. dysplastic.0 g of dichloroacetic acid per litre in drinkingwater for 52 weeks did not develop liver tumours (Bull et al. At 78 weeks. (2003) examined the histology slides from the DeAngelo et al.0. The strongest dose– response correlation was noted for cytomegaly and. Hepatocyte proliferation (as measured by incorporation of radiolabelled thymidine) outside of proliferative lesions was not significantly different from control rates at any of the doses that produced tumours. based on measured water consumption) for 90– 100 weeks. and 78 weeks in all dose groups except the lowest one.05. 315. liver tumours were observed in all animals in the highest dose group (US EPA. glycogen accumulation. and basophilic and/or clear cell. adenomas. 168. and carcinomas.5 g/litre groups. compared with a control rate of 10%. 0. for atypical nuclei. 2003). respectively. (1999) study. or 3. Interim sacrifices were conducted at 26. respectively. 8. 77. 1991). 1999). atypical nuclei.5. Dysplastic cells progressed from altered hepatic foci to carcinomas. 2.0 and 3. Basophilic or clear cells progressed either from altered hepatic foci to large foci of cellular alteration to carcinomas or from large foci of cellular alteration to adenomas and carcinomas. 1990). The investigators were blind to the dose and time of sacrifice of the animals. the incidence of hepatocellular carcinoma was significantly elevated in the two highest dose groups (20% and 50% of animals in the 2. or 429 mg/kg of body weight per day. 52.. Lesions were subcategorized as eosinophilic. cytomegaly. After all of the slides were characterized. they were arrayed by dose and time of sacrifice to determine if there was a pattern in the progression to tumours. to a lesser extent. the tissues were also examined for the relationship between necrosis. the percentage of animals with this tumour had increased to 50% and 70% in the 2. In this same study (Carter et al. Several separate patterns were observed.. Hepatic peroxisome proliferation (as measured by cyanide-insensitive palmitoyl coenzyme A oxidase) was significantly elevated only in the highest dose group after 26 weeks of exposure and was not increased at any time point in other dose groups. and enlarged nuclei and tumours.5 g/litre (0. Female B6C3F1 mice administered 2. On the other hand.

0.5. 89. 0. compared with 11.6 mg/kg of body weight per day (DeAngelo et al.2 mg/kg of body weight per day. and the results of this dose group were excluded from the analysis.1% in controls). or hepatocellular carcinomas) was statistically increased in the high-dose group at 51 weeks (40% compared with 0% in controls) and in the mid. The 296 mg/kg of body weight per day group had 70% hyperplastic nodules. 89. Increased incidences of adenomas and altered hepatocyte foci were observed in the highest dose group after 51 weeks and in the two highest dose groups after 82 weeks.and high-dose groups at 82 weeks (39. 1995). the incidence of combined hepatocellular adenomas and carcinomas was 24.. and the negative control group had only 4% hepatic adenomas. 21% hepatic adenomas. 4.1% in treated animals. hepatocellular adenomas. compared with 4.5% in high-dose group. After 51 weeks at 330 mg/kg of body weight per day. 0. 115. or 330 mg/kg of body weight per day) for 51 or 82 weeks.2 mg/kg of body weight over the course of 100 weeks of treatment. At 40.3% in mid-dose group. In a second study using the same experimental protocol. 1996). these animals were sacrificed at 60 weeks.5. 26% hepatic adenomas.86. Time-weighted average daily doses in the remaining groups were 0. or 5.05. 0. 3. 1996). male F344 rats (78 per group) were given drinking-water containing dichloroacetic acid at concentrations of 11 .6 g/litre (reported to be 0.5% of animals had altered hepatocyte foci and 84. Male Fischer 344 rats were administered time-weighted average concentrations of 0.DICHLOROACETIC ACID IN DRINKING-WATER Female mice (40–90 per dose) were administered dichloroacetic acid in drinkingwater at concentrations of 0. No hepatoproliferative lesions were seen in the 4 mg/kg of body weight per day group. After 82 weeks at 115 mg/kg of body weight per day. 40. Male F344 rats (60–78 per group) were given dichloroacetic acid in drinking-water at concentrations of 0. or 296 mg/kg of body weight per day) in drinking-water. Animals in the highest dose group developed early signs of peripheral neuropathy that were not reversed or diminished by a sequential lowering of the drinking-water concentration of dichloroacetic acid. and 4% hepatocarcinomas at terminal sacrifice at 60 weeks (Richmond et al. compared with 8.9% of animals in this dose group.. No liver histopathology was observed at 3.4 g of dichloroacetic acid per litre (0.4% of controls.7% of controls. 0. followed by sacrifice at intervals for up to 104 weeks.05.6. 40% of animals exhibited altered foci and 35% had adenomas. or 2.3%) was observed only in the highest dose group after 82 weeks of exposure. The 40 mg/kg of body weight per day group had 10% hyperplastic nodules. after 82 weeks at 330 mg/kg of body weight per day. or 2. A statistically significant increase in the percentage of animals with liver carcinoma (26. and 10% hepatocarcinomas after 104 weeks. Total proliferative lesions (combined neoplasms and hyperplastic nodules) were observed in 34. 40.3% of animals showed altered foci and 25% had developed liver adenomas.26. 39. The dose–response relationship between drinking-water concentrations of dichloroacetic acid and the yield of liver tumours and altered hepatocyte foci was described by the author as being suggestive of non-linearity (Pereira.0 g/litre. 0. or 40. The total yield of lesions (altered hepatocyte foci.2% had adenomas.

compared with spontaneously occurring tumours (Anna et al.0 g/litre at 26 weeks. Those that were affected fell into three groupings according to the authors: genes involved with tissue remodelling and/or angiogenesis. It is possible that multiple mechanistic pathways are involved in dichloroacetic acid-induced rodent hepatocarcinogenicity and that these pathways are dose-dependent or species-specific.. Proliferative lesions were observed in 32. marked decreases in plasma lactate and alanine. Stauber & Bull. or repeated dosing regimens. 2003).5 g/litre. and xenobiotic metabolism. Peripheral neuropathy in the treated group resulted in a sequential lowering of the dichloroacetic acid concentration to 1. compared with 3% of controls. 1997. A number of mechanistic bioassays have shown that altered hepatic foci and hepatocellular tumours initiated or promoted by treatment with dichloroacetic acid are eosinophilic and contain GST-pi (Pereira & Phelps. EFFECTS ON HUMANS Dichloroacetic acid has been used as a therapeutic agent to treat lactic acidosis.6% of treated animals. elevated plasma ketone bodies. and familial hyperlipidaemia in humans. compared with 6. The information available on the mechanisms of dichloroacetic acid-induced liver tumorigenesis in rodents is not sufficient to identify a single mode of action leading to cancer. Ferreira-Gonzalez et al. The PPAR-alpha gene was present on one of the gene arrays and was not found to be activated by the dose of dichloroacetic acid used. decreased triglyceride levels. 1996). gene expression was suppressed. 1997). and treatment was continued to 103 weeks. There are two reports of gene array analysis of liver cells from mice treated with 2 g of dichloroacetic acid per litre for 4 weeks (Thai et al. do not show loss of heterozygosity on chromosome 6 (Tao et al.1% of controls (DeAngelo et al... Both reports involve the same tissue samples. combined hepatocellular adenomas and carcinomas were found in 28.. Approximately 50% of patients receiving 25–50 mg/kg of body weight per day experience anxiolytic or sedative effects following oral. Biochemical effects of dichloroacetate treatment include significantly reduced fasting blood glucose levels.1% of treated animals.4% of treated animals.0% of controls. 1996).. diabetes. significantly decreased plasma cholesterol levels. damage response. compared with 3.. Altered hepatic foci and hepatocellular tumours exhibit differences in the mutational spectra of K. In most cases. and elevated serum uric acid levels (Stacpoole et al. 1998a). The three different gene arrays tested displayed differences between control tissues and those from exposed mice. intravenous. The time-weighted average doses were 0 or 139 mg/kg of body weight per day. 1978). 1996). oral or intravenous therapeutic doses are usually in the range of 25–50 mg/kg of body weight per day (Stacpoole et al. 2001.and H-ras proto-oncogenes. Not all of the genes affected were identified. and selectively stimulate the replication rate of different populations of immunoreactive cells (Latendresse & Pereira. These effects usually occur within 60 min of dichloroacetic acid 12 . 1994.DICHLOROACETIC ACID IN DRINKING-WATER 0 or 2. 1995).. Hepatocellular carcinomas were observed in 21. 5.

1992). 1995). PRACTICAL ASPECTS 6. EPA Method 552. dichloroacetic acid is currently being used only in the treatment of lactic acidosis.1. 6. Standard Method 13 . 1998a). 1979). In one of these cases. To date.. the observed peripheral neuropathy had improved. No adverse clinical or laboratory symptoms were detected in one patient. 2001). EPA Method 552. diminished to absent tendon reflexes. and no measurable response was obtained in the peroneal or orbital nerves. at about 20% per year (Stacpoole et al.1 (US EPA. there have been no reports of dichloroacetic acid-induced neoplasia in any human tissue and no reports of gonadal toxicity in humans (Stacpoole et al. age. and mortality among this population is high. although serum cholesterol returned to high levels (Stacpoole et al.DICHLOROACETIC ACID IN DRINKING-WATER treatment. and appear to be unrelated to gender. This increase was reversible after treatment ended (Stacpoole et al. 1998). and decreased strength in all muscle groups of the lower extremities. the haloacetic acids are extracted on a miniature anion exchange column and converted to methyl esters in the eluant prior to analysis (US EPA. 1998b). 1998a). 1998a). In EPA Method 552. 1998a.2 involves a liquid–liquid extraction procedure.2 (US EPA..1 Analytical methods and analytical achievability The chloroacetic acids can be detected in water by EPA Method 552. they showed a 2-fold increase in serum transaminases. suggesting the possibility of preclinical hepatic toxicity.. Both EPA methods use gas chromatography and electron capture detection.. 1998a). Several cases of mild peripheral neuropathy following dichloroacetic acid treatment at 50–100 mg/kg of body weight per day for several months to a year have been reported (Stacpoole et al. Mild slowing of conduction velocity was noted in both posterior tibial nerves.. 1992).. after which the acetic acids are converted to methyl esters (US EPA. dichloroacetic acid was reinstituted at 25 mg/kg of body weight per day following reversal of neurological symptoms. Total serum cholesterol levels decreased significantly in both patients (Moore et al. 1979). However. may last several hours... or Standard Method 6251B (APHA et al. and this dose was maintained for 2 years without further evidence of neuropathy (Stacpoole et al. Physical examination revealed slight decreases in the strength of facial and finger muscles. Six months after discontinuation of the treatment. 1995). Two young males were administered daily oral doses of 50 mg of dichloroacetate per kg of body weight to treat severe familial hypercholesterolaemia. Electromyographic studies showed denervation changes in foot and leg muscles. Two children with congenital lactic acidosis were treated orally with 25– 75 mg of dichloroacetic acid per kg of body weight per day for several months. but the second complained of tingling in his fingers and toes after 16 weeks. providing a limited opportunity to observe the effects of chronic exposures. Spruijt et al. or route of administration (Stacpoole et al. All were completely reversible after cessation of treatment...

Method detection limits range from <0.2 Treatment and control methods and technical achievability Although it is technically feasible to remove dichloroacetic acid (and other disinfection by-products) prior to distribution. however. A subchronic study by Cicmanec et al. personal communication). (1991) found adverse effects on the liver. The hepatic and nervous system effects are consistent with some of the observations from the human clinical reports (Stacpoole et al. 1999).. doserelated decreases in fetal growth and increases in total soft tissue malformations were observed in pregnant Long-Evans rats (Smith et al. accordingly. 2002). Lower dichloroacetic acid concentrations can be achieved by using alternatives to chlorine for disinfection. Increasing the coagulant dose can give enhanced removal of organic precursors (Hartman et al. 1991). The data from humans are primarily the product of the use of dichloroacetic acid in the treatment of patients suffering from hereditary lactic acidosis (Stacpoole et al. Fair. 1998b) and are supported by data from animal studies (Katz et al. GUIDELINE VALUE Dichloroacetic acid exposure is associated with both tumorigenic and nontumorigenic health effects in humans and laboratory animals.. the pH needs to be controlled. this is the least attractive option for controlling dichloroacetic acid concentrations. 1999). At higher doses (≥140 mg/kg of body weight per day). 1998a).. Moser et al.4 µg/litre. Controlling coagulation to remove organic carbon prior to chlorination can reduce dichloroacetic acid concentrations.. but this may lead to increased formation of THMs (Singer et al. Effects on sperm in rats were reported by Linder et al. not suitable for deriving risk-based values for a healthy population. (1997). 1978. 1991). 1991). Nikolaou et al.. Plants using ozone followed by chloramine were found to produce lower dichloroacetic acid concentrations than those using free chlorine (Nissinen et al. 7.. 1981. is unlikely to be the preferred method of control. the lower pH associated with higher coagulant doses can lead to increased dichloroacetic acid concentrations (Dixon & Lee.. However. Granular activated carbon can be used to obtain greater than 80% removal of dichloroacetic acid (Lykins et al. otherwise. 6. 14 . testes. 1998a.. and nervous system in groups of five male and female dogs at doses as low as 12.5 mg/kg of body weight per day. They are.1 to 0. Some control of dichloroacetic acid concentrations can be achieved by increasing the pH at which chlorination is carried out.DICHLOROACETIC ACID IN DRINKING-WATER 6251B uses a micro liquid–liquid extraction procedure combined with gas chromatography and electron capture detection (APHA et al. 1992). 1995.. There is no ISO method for chloroacetic acids. once formed. The PQL for dichloroacetic acid is approximately 1 µg/litre (P.. removal of dichloroacetic acid. 1998)..

and 10-6 are 400.. Chemical Research in Toxicology. Difficulties in meeting a guideline value must never be a reason to compromise adequate disinfection. peroxisome proliferation. REFERENCES Anderson WB et al.0075 (mg/kg of body weight per day)-1 was derived from the BMDL10 using a linear multistage model of the dose–response data. 1990. 1992. If it is assumed that a 60-kg person ingests 2 litres of water per day. However. 1996). 40. It should be possible to achieve a dichloroacetic acid concentration at or below the 50 µg/litre provisional guideline value by appropriate control of the water treatment processes. the concentration of dichloroacetic acid in drinking-water associated with upper-bound excess lifetime cancer risks of 10-4. 84. 15 . Daniel et al. The slope factor of 0. 1999...1. 12: 1144–1149. 1995. and DNA hypomethylation have all been observed following dichloroacetic acid exposure and have been hypothesized to be involved in its carcinogenicity. Recent data from Carter et al. or 429 mg/kg of body weight per day for up to 2 years were plotted using the US EPA’s Benchmark Dose software version 1. 10-5. IARC (2002) recently reclassified dichloroacetic acid as Group 2B (possibly carcinogenic to humans). the available data are not sufficient to establish a cancer mode of action with reasonable certainty. 8. The tumour prevalence data from male mice (DeAngelo et al..DICHLOROACETIC ACID IN DRINKING-WATER Dichloroacetic acid has been observed to be tumorigenic in rats and mice by a number of researchers (Herren-Freund et al. based on the absence of data on human carcinogenicity and sufficient evidence of its carcinogenicity in experimental animals. Richmond et al. The combined data for carcinomas and adenomas in male B6C3F1 mice exposed to doses of 0. However. Pereira. especially at the very low exposure levels expected to apply to humans ingesting chlorinated drinking-water. The concentration associated with a 10-5 upper-bound excess lifetime cancer risk is usually identified as the health-based guideline for drinking-water when the contaminant is a carcinogen. 1999) were used to quantify the cancer risk from dichloroacetic acid. Genotoxicity data are considered to be inconclusive. respectively. since altered hepatic foci from treated mice were found to have three different types of cellular characteristics. DeAngelo et al. (1999) Inactivation of glutathione transferase zeta by dichloroacetic acid and other fluorine-lacking α-haloalkanoic acids. it may not be possible to provide for adequate disinfection treatment of potable water and maintain dichloroacetic acid at levels of 40 µg/litre or less. The guideline value is designated as provisional because the data on treatment are insufficient to ensure that the 40 µg/litre value is technically achievable under a wide range of circumstances. 1996. 1987. 8.. particularly at lower doses. the guideline value is provisionally established as 50 µg/litre. and 4 µg/litre. changes in signal transduction pathways.. 315. (2003) suggest that there may be more than one mechanism leading to tumours. 168. Glycogen deposition. Accordingly. Bull et al.3. This classification replaced an earlier Group 3 classification (not classifiable as to its carcinogenicity in humans) from 1995.

Coleman WE et al. 11: 671–678. Biochemical and Biophysical Research Communications. (1989) The Merck index. Fundamental and Applied Toxicology. 17: 376–389. Budavari S. DC. 63: 341–359. 37: 89–93. NJ. (2003) A 2-year dose–response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F1 mouse given the drinking water chemical dichloroacetic acid. (1992) Hepatocarcinogenicity of chloral hydrate. Environmental Carcinogenesis Program. AWWA. Pharmacogenetics. 19: 159–168. National Institutes of Health. Austin EW et al. 111: 53–64. Journal of Applied Toxicology. (1994) Proto-oncogene activation in dichloroacetic acid-. (1991) The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse. WEF (1998) Standard methods for the examination of water and wastewater. trichloroethylene. Washington. NC.DICHLOROACETIC ACID IN DRINKING-WATER Anna CR et al. An encyclopedia of chemicals. Zentralblatt für Hygiene und Umweltmedizin. Merck. American Public Health Association. (1991) 90-day toxicity study of dichloroacetate in dogs. 262: 752–756. Smith A. Toxicology. (1980) Identification of organic compounds in a mutagenic extract of a surface drinking water by a computerized gas chromatography/mass spectrometry system (GC/MS/COM). Environmental Health Perspectives. 16: 337–347.and tetrachloroethylene-induced liver tumors in B6C3F1 mice. 14: 576–588. FETAX validation using 12 compounds with and without an exogenous metabolic activation system. 11th ed. US Department of Health and Human Services. Scholer HF (1992) Halogenated organic compounds in swimming pool waters. 31: 77–82. 16 . (2001) GSTZ1d: a new allele of glutathione transferase zeta and maleylacetoacetate isomerase. (1996) Lipid peroxidation and formation of 8-hydroxydeoxyguanosine from acute doses of halogenated acetic acids. Blackburn AC et al. 20th ed. and dichloroacetic acid in the male B6C3F1 mouse. 114: 207–221. (1990) Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Bantle JA et al. and biologicals. Daniel FB et al. APHA. Cicmanec JL et al. Curry SH et al. Carter JH et al. Cornett R et al. 19: 447–472. (1996) The carcinogenicity of dichloroacetic acid in the male Fischer 344 rat. and Water Environment Federation. Rahway. (1999) Inhibition of glutathione S-transferase and tyrosine metabolism by dichloroacetate: A potential unifying mechanism for its altered biotransformation and toxicity. Clemens M. (1999) Phase III interlaboratory study of FETAX. Fundamental and Applied Toxicology. DeAngelo AB et al. eds. 2-chloroacetaldehyde. Toxicology. 193(1): 91–98. American Water Works Association. Fundamental and Applied Toxicology. pp. Clinical Pharmacology and Therapeutics. 2255–2261. Environmental Science and Technology. DeAngelo AB et al. Fundamental and Applied Toxicology. Bull RJ et al. Research Triangle Park. drugs. O’Neill M. (1985) Plasma concentrations and metabolic effects of intravenous sodium dichloroacetate. Part 3. National Institute of Environmental Health Sciences.

MD. New York. trichloroacetic acid and dichloroacetic acid. Herren-Freund SL et al.org/). Vol. 413: 265–276. IARC (1995) Dry cleaning.nih. International Agency for Research on Cancer (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Proceedings of the 1991 annual conference of the American Water Works Association.DICHLOROACETIC ACID IN DRINKING-WATER DeAngelo AB. Denver. (1995) Ras oncogene activation during hepatocarcinogenesis in B6C3F1 male mice by dichloroacetic and trichloroacetic acids. 10th ed.inchem. Toxicology and Applied Pharmacology. pp. Epstein DL et al. 16(3): 495–500. Lee RG (1991) Disinfection by-products control: a survey of American system treatment plants. HSDB (2001) Hazardous Substances Data Bank. 84). In: Water research for the new decade. (1991) Controlling by-products precursor removal by GAC and alum coagulation.nlm. 58(8): 485–507. American Water Works Association. Dixon KL. available at http://www. 90: 183–189. Lyon. International Programme on Chemical Safety (Environmental Health Criteria 216. Hartman DJ et al. 241. 4693: 225–235. IPCS (2000) Disinfectants and disinfectant by-products. 9: 429–437. Moore MM (1998) Mutagenicity of three disinfection by-products: diand trichloroacetic acid and chloral hydrate in L5178Y/TK +/. (1987) The carcinogenicity of trichloroethylene and its metabolites. Harrington-Brock K. Bethesda. Proceedings of the 1991 annual conference of the American Water Works Association. 63). Sheldon ML (1994) Dichloroacetic acid and related compounds: Induction of prophage in E. 265–285. coli and mutagenicity and mutation spectra in Salmonella TA 100. American Water Works Association. Lyon. Fernandez-Canon JM. International Agency for Research on Cancer (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.(-)3. George MH. House DE (1999) Hepatocarcinogenicity in the male B6C3F1 mouse following a lifetime exposure to dichloroacetic acid in the drinking water: dose–response determination and modes of action. 193–252.gov/). Doerr CL. 273: 329–337.7. Mutagenesis. Gonzalez-Leon A et al. Perry EP. Geneva. in mouse liver. Toxicology and Applied Pharmacology. 31: 3124–3126. Denver. Vol. pp. some chlorinated solvents and other industrial chemicals. Van Nostrand Reinhold. Penalva MA (1998) Characterization of a fungal maleylacetoacetate isomerase gene and identification of its human homologue. Teratology. 146: 189–195. Evans OB (1982) Dichloroacetate tissue concentration and its relationship to hypolactatemia and pyruvate dehydrogenase activity by dichloroacetate. p. CO. Carcinogenesis. IARC (2002) Some drinking-water disinfectants and contaminants. In: Water research for the new decade. DeMarini DM. Specialized Information Services (available at http://toxnet. 17 . National Library of Medicine. NY. (1997) Pharmacokinetics and metabolism of dichloroacetate in the F344 rat after prior administration in drinking water.2C mouse lymphoma cells. Biochemical Pharmacology. Mutation Research. Journal of Biological Chemistry. World Health Organization. CO. Ferreira-Gonzalez A et al. (1992) Cardiopathic effects of dichloroacetate in the fetal Long-Evans rat. including arsenic. Hawley GG (1981) The condensed chemical dictionary. Journal of Toxicology and Environmental Health.

Proceedings of the 1991 annual conference of the American Water Works Association. Carcinogenesis. Katz R et al. (1978) Dichloroacetate: 90 day oral administration in rats. Chemical Research in Toxicology. (1979) Reduction of serum cholesterol in two patients with homozygous familial hypercholesterolemia by dichloroacetate. Nissinen TK et al. 15: 957–963. (1997) Glutathione-dependent conversion to glyoxylate. Toxicologic Pathology. 48(1): 9– 20. Toxicology and Applied Pharmacology. (1997) Spermatotoxicity of dichloroacetic acid. 80: 187–195. Lykins BW et al. 25(5): 433–440. Identification of glycine conjugates. (1998) Effects of dichloroacetate on glycogen metabolism in B6C3F1 mice. including hippurate. Drug Metabolism and Disposition. sodium: 3-month oral toxicity studies in rats and dogs. Weisel CP (1998) Dermal absorption of dichloro. Lukas G et al. Nikolaou AD. a major pathway of dichloroacetate biotransformation in hepatic cytosol from humans and rats. Latendresse JR. 130: 141–154. Denver. as urinary metabolites of dichloroacetate. Environmental Research.and trichloroacetic acids from chlorinated water. (1980) Biological disposition of sodium dichloroacetate in animals and humans after intravenous administration. Neurotoxicology and Teratology. 25(11): 1223–1227. Journal of Pharmacological Sciences.DICHLOROACETIC ACID IN DRINKING-WATER James MO et al. Reproductive Toxicology. Anders MW (2002) Kinetics of the biotransformation of maleylacetone and chlorofluoroacetic acid by polymorphic variants of human glutathione transferase zeta (hGSTZ1-1). 18 . (2002) Disinfection by-products in Finnish drinking waters. Global Nest. 33: 285–293. (1998) Pharmacokinetics and metabolism of [14C]dichloroacetate in male SpragueDawley rats. 8(4): 555–575. Kostopoulou MN. 26(11): 1134–1143. (1999) Behavioral evaluation of the neurotoxicity produced by dichloroacetic acid in rats. Kim H. (1991) Controlling disinfection by-products with alternative disinfectants. Atherosclerosis. Katz R et al. 1(3): 143–155. Moser VC et al. James MO et al. Lantum HB. 21(6): 719–731. Lekkas TD (1999) Organic by-products of drinking water chlorination. 69(4): 419–421. CO. 18(11): 2101–2106. (1999) Evaluation of biomarkers of environmental exposures: Urinary haloacids associated with ingestion of chlorinated drinking water. Kim H et al. (1981) Dichloroacetate. Drug Metabolism and Disposition. NJ. Board PG. 57: 273–287. Leavitt SA et al. (1997) Assessment of the mutagenicity of dichloroacetic acid in lacI transgenic B6C3F1 mouse liver. Linder RE et al. pp. Summit. 11(5): 681– 688. Journal of Exposure Analysis and Environmental Epidemiology. Toxicology. Moore GW et al. is reduced in dichloroacetate-treated rats. 897–911. In: Water research for the new decade. Ciba-Geigy. Pereira MA (1997) Dissimilar characteristics of N-methyl-N-nitrosourea-initiated foci and tumors promoted by dichloroacetic acid or trichloroacetic acid in the liver of female B6C3F1 mice. American Water Works Association. Chemosphere. Kato-Weinstein J et al.

Raymer JH. Stacpoole PW. Stacpoole PW. Smith MK et al. Archives of Toxicology. Office of Research and Development. Schultz IR et al. 110: 103–111. 158(2): 103–114. 87(2): 212–222. Pellizzari ED. Smyth HF. National Center for Environmental Research. (1999) Comparative toxicokinetics of chlorinated and brominated haloacetates in F344 rats. Cancer Letters. Cancer Letters. Pereira MA (1996) Carcinogenic activity of dichloroacetic acid and trichloroacetic acid in the liver of female B6C3F1 mice. Bull RJ (1990) Early induction of reparative hyperplasia in B6C3F1 mice treated with dichloroacetate and trichloroacetate. 38(11): 1124–1144. Sanchez IM. 64: 33–46. Muscle & Nerve. Kornauser D (1979) Toxicity of chronic dichloroacetate [letter]. Fundamental and Applied Toxicology. Grob K. 173: 229–247. Journal of the American Water Works Association. Phelps JB (1996) Promotion by dichloroacetic acid and trichloroacetic acid of N-methylN-nitrosourea-initiated cancer in the liver of female B6C3F1 mice. Greiner A (1995) DBPs in chlorinated North Carolina drinking waters. 41: 2167–2176. Obolensky A. Metabolic effects and pharmacodynamics in normal rats. Moore GW. Paper presented at the Science to Achieve Results (STAR) Drinking Water Progress Review Meeting. DC. Life Sciences. Teratology. Hu Y (2001) Exposures to water disinfection byproducts via food. Stacpoole PW (1987) Dichloracetate derivatives. (1992) Statistical analysis of a developmental toxicity interaction study. American Medical Association Archives of Industrial Hygiene and Occupational Medicine. Saillenfait AM. US Environmental Protection Agency. Spruijt L et al. 4: 119–122. Toxicology. Toxicology. 87(10): 83–92. Richmond RE et al. New England Journal of Medicine. Reimann S. Singer PC. (2001) Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Mitteilungen Aus Dem Gebiete der Lebensmitteluntersuchung und Hygiene. Frank H (1996) Environmental chloroacetic acids in foods analyzed by GC-ECD. tetrachloroethylene and four of their metabolites in rat whole embryo culture. 22–23 February 2001. Pereira MA. New England Journal of Medicine. Toxicology. Moore GW. 31: 192–199. Langonne I. (2002) Dichloroacetate toxicokinetics and disruption of tyrosine catabolism in B6C3F1 mice: dose–response relationships and age as a modifying factor. Stacpoole PW (1989) The pharmacology of dichloroacetate. Schultz IR et al. Weil CS (1951) Range-finding toxicity data: List IV. Metabolism. Kronauser DM (1978) Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia. 298: 526–530. 19 . (1995) Immunohistochemical analysis of dichloroacetic acid (DCA)-induced hepatocarcinogenesis in male Fischer (F344) rats. Toxicology and Applied Pharmacology. 24: 916–924. 70: 71–82. Sabate JP (1995) Developmental toxicity of trichloroethylene.DICHLOROACETIC ACID IN DRINKING-WATER Parrish JM et al. 300: 72. 92: 67–76. Carpenter CP. (1996) Haloacetate-induced oxidative damage to DNA in the liver of male B6C3F1 mice. Washington. 118: 488–489. 102: 133–141.

Chemical Research in Toxicology. 543(2): 167–180. Revision 1.0. Archives of Disease in Childhood. (1996) Loss of heterozygosity on chromosome 6 in dichloroacetic acid and trichloroacetic acid-induced liver tumors in female B6C3F1 mice. 4): 989–994. In: Methods for the determination of organic compounds in drinking water — Supplement II. DC. US EPA (1994) Final draft for the drinking water criteria document on chlorinated acids/aldehydes/ketones/alcohols. Office of Science and Technology. 22: 1317–1322. (1998a) Clinical pharmacology and toxicology of dichloroacetate. Chemical Research in Toxicology. Office of Research and Development. NC. Biochemistry Journal. New York. 144(2): 235–246. Washington. by-products of the drinking water disinfection process. Cincinnati. DC. (2000) Polymorphism. OH. US Environmental Protection Agency. Verschueren K (1977) Handbook of environmental data on organic chemicals. US Environmental Protection Agency. Health and Ecological Criteria Division (EPA 68-C2-0139). (2003) Altered gene expression in mouse livers after dichloroacetic acid exposure. 108: 257–261. (1998b) Treatment of congenital lactic acidosis with dichloroacetate. NTIS PB92-207703). National Exposure Research Laboratory. US EPA (1995) Method 552. derivatization and gas chromatography with electron capture detection. The comparative carcinogenicity of dichloroacetic and trichloroacetic acid: Implication for risk assessment. In support of summary information on Integrated Risk Information System (IRIS). Tzeng H-F et al. US EPA (1992) EPA Method 552. Stauber AJ. Van Nostrand Reinhold. Toxicology and Applied Pharmacology.1. 77: 535–541. 13: 231–236. Cancer Letters. Stacpoole PW et al. Board PG. US Environmental Protection Agency. Tong Z. Office of Water. US EPA (2001) Stage 2 occurrence assessment for disinfectants and disinfection byproducts (D/DBPs). Thai SF et al. Tao L et al. Board PG. National Center for Environmental Assessment. Determination of haloacetic acids and dalapon in drinking water by liquid–liquid extraction. Carcinogenesis. US Environmental Protection Agency. DC. Tong Z.DICHLOROACETIC ACID IN DRINKING-WATER Stacpoole PW et al. 331(2): 371–374. Anders MW (1998a) Glutathione transferase zeta catalyses the oxygenation of the carcinogen dichloroacetic acid to glyoxylic acid. Thai SF et al. HERL-0820). NY. US Environmental Protection Agency. US EPA (2003) Toxicological review of dichloroacetic acid.and species-dependent inactivation of glutathione transferase zeta by dichloroacetate. US Environmental Protection Agency (EPA 600/R92/129. Environmental Health Perspectives. Mutation Research. Washington. Research Triangle Park. 106(Suppl. Health Effects Research Laboratory (Document No. (2001) Detection of early gene expression changes by differential display in the livers of mice exposed to dichloroacetic acid. Washington. II. Anders MW (1998b) Glutathione transferase zeta-catalyzed biotransformation of dichloroacetic acid and other alpha-haloacids. 20 . US EPA (1991) Toxicology of the chloroacetic acids.2. 11: 1332–1338. Bull RJ (1997) Differences in phenotype and cell replicative behavior of hepatic tumors induced by dichloroacetate (DCA) and trichloroacetate (TCA). Washington. DC.

69th ed. (1941) The acute oral toxicity of acetic. (1988) Handbook of chemistry and physics. dichloroacetic and trichloroacetic acids. Swimming pools and similar recreational water environments.DICHLOROACETIC ACID IN DRINKING-WATER Weast RC. WHO (in revision) Guidelines for safe recreational water environments. World Health Organization. ed. 21 . CRC Press. chloroacetic. Vol. Journal of Industrial Hygiene and Toxicology. Sanitation and Health. Geneva. Cleveland. Woodard G et al. 23: 78–82. 2. Water. OH.

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