PUBLIC NOTICE: Initiation of Risk Assessments for Chemicals in Drinking Water
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The Calderon-Sher California Safe Drinking Water Act of 1996 (Health and Safety Code Sections 116270 et seq.) requires the Office of Environmental Health Hazard Assessment (OEHHA) to post notices on its Web site of water contaminants for which it is initiating work to develop public health goals (PHGs) for chemicals in drinking water. These are chemicals with existing state Maximum Contaminant Levels (MCLs), or those subject to new regulation. The law also describes the intent and general context of the PHGs (Health and Safety Code Section 116365). PHGs are concentrations of chemicals in drinking water that are not anticipated to produce adverse health effects following long-term exposures. These goals are advisory but must be used as the health basis to update the state's primary drinking water standards (MCLs) by the California Department of Health Services (DHS) (Health and Safety Code Section 116365(b)(1).
There are approximately 85 chemicals for which state MCLs are presently available, and the Act requires review and update of the risk assessments at least every five years (Health and Safety Code Section 116365(e)(1). Chemicals may also be reviewed by OEHHA if requested by DHS or required by legislative mandate. Opportunities for public comment and peer review are provided as required by statute.
OEHHA has published 71 PHGs as of July 2004, although one of these evaluations, that for total chromium, has been rescinded. The technical support documents for the published PHGs are posted on the OEHHA Web site at www.oehha.ca.gov.
PHGs for all the other chemicals that have state MCLs are currently in preparation, and the final group of PHGs with existing MCLs is planned to be released for public review this year. A 45-day public comment period will be provided after posting, followed by a public workshop. Scientific peer reviews are arranged through the University of California. The overall PHG process includes time for OEHHA to prepare revisions, for further public comment, and for OEHHA to prepare responses to comments. The final group of PHGs are planned for publication in 2005.
OEHHA has also prepared scientific memoranda for DHS on the MCLs for “Gross alpha” and “Gross beta.” These MCLs are screening levels for radionuclides in drinking water, rather than regulatory standards for specific chemical entities. The memoranda discuss the relative risk from exposure to radioactivity derived from the various isotopes in the above categories. These documents are also posted on our Web site.
OEHHA is initiating evaluation for several chemicals for which new MCLs have been promulgated by U.S. EPA, which triggers a requirement that OEHHA prepare a PHG. In addition, re-review, as required by Health and Safety Code Section 116365(e)(1), is being initiated for chemicals for which initial PHGs were published in 1997 and 1999, as described in section C below.
C. Initiation of risk assessments
Risk assessments are being initiated for the chemicals listed below, which are newly regulated:
Of the chemicals above, NDMA is being evaluated at the request of DHS, because of a pattern of increasing detections in California groundwater. The other three chemicals or chemical classes are the subject of new MCLs promulgated by the U.S. EPA, therefore requiring development of a PHG.
In addition, reviews are being updated for chemicals for which PHGs were prepared in the first years of our program, prioritized on the basis of availability of new data and significance as a drinking water contaminant. Chemicals that have currently been assigned for review include:
A brief description of these chemicals is provided below. OEHHA requests the submission of pertinent information on these contaminants that could assist our office in preparing or updating the risk assessment and deriving a PHG.
Generally, information submitted to OEHHA in response to this request should not be proprietary in nature, because all information submitted is a matter of public record. In the event that proprietary information is to be submitted, please contact OEHHA general counsel, Carol Monahan at (916) 322-0493 or email@example.com in advance of the submission. Information must be submitted no later than August 31, 2004 to:
Pesticide and Environmental Toxicology Section
Office of Environmental Health Hazard Assessment
P.O. Box 4010
Sacramento, California 95812-4010
Attn: PHG Project
All data timely submitted will be considered in the development of the PHG for these chemicals. The draft documents will be available for discussion at a public workshop and public comments will be solicited as described above in Section B. The final risk assessments will be utilized by DHS in potential revisions to the MCLs for the chemical in drinking water, as described in more detail on the DHS Web site at http://www.dhs.ca.gov/ps/ddwem/chemicals/chemindex.htm.
E. Descriptions of chemicals or substances for review initiation
Bromate is the BrO3- ion, a combination of bromine and oxygen. Bromate is listed as a B2 probable human carcinogen by the U.S. EPA (IRIS, 2004). The U.S. EPA oral reference dose (RfD) for noncancer effects is 0.004 mg/kg-day of bromate, based on kidney effects in rats in the chronic study of DeAngelo et al. (1998). In 1998, the U.S. EPA promulgated an MCL of 0.010 mg/L (10 ppb), and an MCLG of zero for bromate in drinking water, based on a weight of evidence evaluation of both cancer (multiple sites, both sexes, rats) and noncancer effects. Bromate, as the potassium salt, is listed as a group 2b possible human carcinogen by the International Agency for Research on Cancer (IARC, 1999). Bromate has been shown to be mutagenic via in vitro and in vivo scientific studies. In rats, long-term exposure to bromate in drinking water yielded adverse effects on liver and kidney and inhibited body weight gain. Multiple toxic effects have also been observed in humans. The principal concern for human exposure to bromate appears to be as a drinking water contaminant, formed as a byproduct from the ozonation disinfection process. Exposure may also occur from some commercially bottled drinking water. In the past, bromate was sometimes used as a food additive for beer, cheese, and bread.
Allen JW, Collins BW, Lori A, Afshari AJ, George MH, DeAngelo AB, Fuscoe JC (2000). Erythrocyte and spermatid micronucleus analyses in mice chronically exposed to potassium bromate in drinking water. Environ Mol Mutagen 36(3):250-3.
Chipman JK, Davies JE, Parsons JL, Nair J, O'Neill G, Fawell JK (1998). DNA oxidation by potassium bromate; a direct mechanism or linked to lipid peroxidation? Toxicology 126(2):93-102.
Crosby LM, Morgan KT, Gaskill B, Wolf DC, DeAngelo AB (2000). Origin and distribution of potassium bromate-induced testicular and peritoneal mesotheliomas in rats. Toxicol Pathol 28(2):253-66.
DeAngelo AB, George MH, Kilburn SR, Moore TM, Wolf DC (1998). Carcinogenicity of potassium bromate administered in the drinking water to male B6C3F1 mice and F344/N rats. Toxicol Pathol 26(5):587-94.
Fisher N, Hutchinson JB, Berry R, Hardy J, Ginocchio AV, Waite V (1979). Long-term toxicity and carcinogenicity studies of the bread improver potassium bromate 1. Studies in rats. Food Cosmet Toxicol 17(1):33-9.
Fujie K, Shimazu H, Matsuda M, Sugiyama T (1988). Acute cytogenetic effects of potassium bromate on rat bone marrow cells in vivo. Mutat Res 206(4):455-8.
Ginocchio AV, Waite V, Hardy J, Fisher N, Hutchinson JB, Berry R (1979). Long-term toxicity and carcinogenicity studies of the bread improver potassium bromate 2. Studies in mice. Food Cosmet Toxicol 17(1):41-7.
Giri U, Iqbal M, Athar M (1999). Potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress. Cancer Lett 135(2):181-8.
Gradus D, Rhoads M, Bergstrom LB, Jordan SC (1984). Acute bromate poisoning associated with renal failure and deafness presenting as hemolytic uremic syndrome. Am J Nephrol 4(3):188-91.
Guo TL, McCay JA, Karrow NA, Brown RD, Musgrove DL, Luebke RW, Germolec DR, White KL Jr (2001). Immunotoxicity of sodium bromate in female B6C3F1 mice: a 28-day drinking water study. Drug Chem Toxicol 24(2):129-49.
Hard GC (1998). Mechanisms of chemically induced renal carcinogenesis in the laboratory rodent. Toxicol Pathol 26(1):104-12.
Hayashi M, Kishi M, Sofuni T, Ishidate M Jr (1988). Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals. Food Chem Toxicol 26(6):487-500.
IARC (1999). Potassium bromate. IARC Monogr Eval Carcinog Risks Hum 73:481-96.
IRIS (2004). Bromate (last updated on 06/06/2001). Integrated Risk Information System, U.S. Environmental Protection Agency, Washington, DC. Available at: http://www.epa.gov/iris.
Kargalioglu Y, McMillan BJ, Minear RA, Plewa MJ (2002). Analysis of the cytotoxicity and mutagenicity of drinking water disinfection by-products in Salmonella typhimurium. Teratog Carcinog Mutagen 22(2):113-28.
Kurata Y, Diwan BA, Ward JM (1992). Lack of renal tumour-initiating activity of a single dose of potassium bromate, a genotoxic renal carcinogen in male F344/NCr rats. Food Chem Toxicol 30(3):251-9.
Kurokawa Y, Aoki S, Matsushima Y, Takamura N, Imazawa T, Hayashi Y (1986). Dose-response studies on the carcinogenicity of potassium bromate in F344 rats after long-term oral administration. J Natl Cancer Inst 77(4):977-82.
Kurokawa Y, Hayashi Y, Maekawa A, Takahashi M, Kokubo T, Odashima S (1983). Carcinogenicity of potassium bromate administered orally to F344 rats. J Natl Cancer Inst 71(5):965-72.
Kurokawa Y, Maekawa A, Takahashi M, Hayashi Y (1990). Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen. Environ Health Perspect 87:309-35.
Kurokawa Y, Matsushima Y, Takamura N, Imazawa T, Hayashi Y (1987). Relationship between the duration of treatment and the incidence of renal cell tumors in male F344 rats administered potassium bromate. Jpn J Cancer Res 78(4):358-64.
Kutom A, Bazilinski NG, Magana L, Dunea G (1990). Bromate intoxication: hairdressers' anuria. Am J Kidney Dis 15(1):84-5.
Lichtenberg R, Zeller WP, Gatson R, Hurley RM (1989). Bromate poisoning. J Pediatr 114(5):891-4.
Matsumoto I, Morizono T, Paparella MM (1980). Hearing loss following potassium bromate: two case reports. Otolaryngol Head Neck Surg 88(5):625-9.
McLaren J, Boulikas T, Vamvakas S (1994). Induction of poly(ADP-ribosyl)ation in the kidney after in vivo application of renal carcinogens. Toxicology 88(1-3):101-12.
Oh SH, Lee HY, Chung SH, Kim CJ, Choi IJ (1980). Acute renal failure due to potassium bromate poisoning. Yonsei Med J 21(2):106-9.
Ohashi T, Yoshie N, Koide F (1982). [A case of profound sensorineural hearing loss caused by the sodium bromate poisoning (author's transl)]. Nippon Jibiinkoka Gakkai Kaiho 85(1):41-5.
Paul AH (1966). Chemical food poisoning by potassium bromate. Report of an outbreak. N Z Med J 65(401):33-6.
Plewa MJ, Kargalioglu Y, Vankerk D, Minear RA, Wagner ED (2002). Mammalian cell cytotoxicity and genotoxicity analysis of drinking water disinfection by-products. Environ Mol Mutagen 40(2):134-42.
Quick CA, Chole RA, Mauer M (1975). Deafness and renal failure due to potassium bromate poisoning. Arch Otolaryngol 101(8):494-5.
Robbiano L, Carrozzino R, Puglia CP, Corbu C, Brambilla G (1999). Correlation between induction of DNA fragmentation and micronuclei formation in kidney cells from rats and humans and tissue-specific carcinogenic activity. Toxicol Appl Pharmacol 161(2):153-9.
Sato S (1990). Mutagens and carcinogens in the diet. Regulatory perspective: Japan. Prog Clin Biol Res 347:295-306.
Speit G, Haupter S, Schutz P, Kreis P (1999). Comparative evaluation of the genotoxic properties of potassium bromate and potassium superoxide in V79 Chinese hamster cells. Mutat Res 439(2):213-21.
Takamura N, Kurokawa Y, Matsushima Y, Imazawa T, Onodera H, Hayashi Y (1985). Long-term oral administration of potassium bromate in male Syrian golden hamsters. Sci Rep Res Inst Tohoku Univ [Med] 32(1-4):43-6.
Umemura T, Sai K, Takagi A, Hasegawa R, Kurokawa Y (2003). A possible role for cell proliferation in potassium bromate (KBrO3) carcinogenesis. J Cancer Res Clin Oncol 119(8):463-9.
Umemura T; Sai K; Takagi A; Hasegawa R, Kurokawa Y (1995). A possible role for oxidative stress in potassium bromate (KBrO3) carcinogenesis. Carcinogenesis 16(3):593-7.
Umemura T; Takagi A; Sai K; Hasegawa R, Kurokawa Y (1998). Oxidative DNA damage and cell proliferation in kidneys of male and female rats during 13-weeks exposure to potassium bromate (KBrO3). Arch Toxicol 72(5):264-9.
von Gunten U (2003). Ozonation of drinking water: part II. Disinfection and by-product formation in presence of bromide, iodide or chlorine. Water Res 37(7):1469-87.
Wang V, Lin KP, Tsai CP, Kao KP (1995). Bromate intoxication with polyneuropathy. J Neurol Neurosurg Psychiatry 58(4):516-7.
Wolf DC, Crosby LM, George MH, Kilburn SR, Moore TM, Miller RT, DeAngelo AB (1998). Time- and dose-dependent development of potassium bromate-induced tumors in male Fischer 344 rats. Toxicol Pathol 26(6):724-9.
WHO (1995) Evaluation of certain food additives and contaminants. World Health Organization Tech Rep Ser. 859:1-54.
Young YH, Chuu JJ, Liu SH, Lin-Shiau SY (2001). Toxic effects of potassium bromate and thioglycolate on vestibuloocular reflex systems of Guinea pigs and humans. Toxicol Appl Pharmacol 177(2):103-11.
The PHG of 0.07 ppb for cadmium was published by OEHHA in 1999. Cadmium is a natural element in the earth’s crust, and is usually found as a mineral combined with other elements such as oxygen (cadmium oxide), chlorine (cadmium chloride), or sulfur (cadmium sulfate, cadmium sulfide). All soils and rocks contain some cadmium, which may leach into groundwater. Cadmium has many uses, including batteries, pigments, metal coatings, and plastics. It enters water from waste disposal and spills or leaks at hazardous waste sites.
Exposure to high levels of cadmium severely damages the lungs and can cause death. Eating food or drinking water with very high levels severely irritates the digestive tract, and can cause kidney disease. Animals given cadmium in drinking water had high blood pressure, iron-poor blood, liver disease, and nerve or brain damage (ATSDR, 1999). IARC concluded that, based on inhalation data, there is sufficient evidence in humans for the carcinogenicity of cadmium and cadmium compounds. However, the PHG is based on nephrotoxicity derived from an epidemiological study of a cross-sectional sample of the adult Belgian population. The U.S. EPA MCL for cadmium in drinking water is 5 ppb; the California MCL is also 5 ppb. The World Health Organization set a provisional tolerable daily intake of 60-70 µg of cadmium per day. DHS reported 570/11,736 detections of cadmium in drinking water in 1984-2001 (above the DLR of 1 ppb), and 119 MCL exceedances in 1984-2000. DHS has reviewed the cadmium MCL to determine whether it is feasible to lower the MCL substantially closer to the PHG value, and decided that this is not feasible, based on the relatively high DLR (DHS, 2004).
Pertinent findings since PHG development
Dozens of new studies may be relevant to various aspects of the PHG document, including exposure, in vitro toxic effects on a variety of tissues and endpoints, and epidemiological investigations. However, no new cancer studies were found. The reports on associations of cadmium with various effects in humans and in animals should at least reinforce the prior assessment and assumptions. The study in rats of nerve changes after pre- and postnatal cadmium exposures (Yargicoglu et al., 2000) may provide a more sensitive endpoint than used earlier. The study of cadmium effects on the rat prostate (Martin et al., 2001) may be relevant to mechanisms of human prostate carcinogenesis, and evaluation of cadmium effects on mouse heart (Skowerski et al., 2000) may be relevant to human cardiovascular effects. It is not clear whether any of the new studies might lead to a change in the PHG, but the large number of studies and variety of endpoints warrant further examination.
ATSDR (1999). Toxicological profile for cadmium. Agency for Toxic Substances and Disease Registry.
DHS (2004). Status of MCL reviews in response to PHGs; March 2004 update. Accessed 3/30/2004 at: www.dhs.ca.gov/ps/ddwem/chemicals/PHGs/reviewstatus.htm.
Ozcaglar HU, Agirdir B, Dinc O, Turhan M, Kilincarslan S, Oner G (2001). Effects of cadmium on the hearing system. Acta Otolaryngol 121(3):393-7.
Satoh M, Koyama H, Kaji T, Kito H, Tohyama C (2002). Perspectives on cadmium toxicity research. Tohoku J Exp Med 196(1):23-32. Review.
Skowerski M, Jasik K, Konecki J (2000). Effects of interaction between cadmium and selenium on heart metabolism in mice: the study of RNA, protein, ANP synthesis activities and ultrastructure in mouse heart. Med Sci Monit 6(2):258-265.
Verougstraete V, Lison D, Hotz P (2002). A systematic review of cytogenetic studies conducted in human populations exposed to cadmium compounds. Mutat Res 511(1):15-43.
Watanabe Y, Kobayashi E, Okubo Y, Suwazono Y, Kido T, Nogawa K (2002). Relationship between cadmium concentration in rice and renal dysfunction in individual subjects of the Jinzu River basin determined using a logistic regression analysis. Toxicology 172(2):93-101.
Yargicoglu A, Izgut-Uysal V, et al. (2000). The effect of pre-and postnatal cadmium exposure on somatosensory evoked potentials: relation to lipid peroxidation. Int J Neurosci 101:45-56.
Chlorite is a byproduct formed when drinking water is disinfected with chlorine dioxide gas. Drinking water treated in this manner constitutes the primary human exposure source for chlorite. In water, chlorite is a colorless anion with strong oxidizing properties and has a bitter, unpleasant taste at high levels.
The U.S. EPA and DHS have established an MCL of 1.0 mg/L for chlorite (DHS, 2003). The federal standard became effective nationwide on January 1, 2002 for any drinking water system serving 10,000 or more people. All drinking water systems must comply with this MCL beginning January 1, 2004 (U.S. EPA, 2002).
The federal MCL is based on neurodevelopmental delays and altered liver weights reported in two generations of rats exposed to chlorite in utero, via lactation and in drinking water (CMA, 1996). ATSDR used the same toxicological endpoints for their proposed intermediate-exposure maximum residue level (MRL) of 0.1 mg/kg-day for chlorite ingestion (ATSDR, 2002). Sodium chlorite - the compound used in toxicological studies on chlorite - currently is not considered to be a potential carcinogen. The U.S. EPA has classified sodium chlorite as a Group D compound, and IARC lists it as Group 3 (U.S. EPA, 2000a, b; IARC, 1997).
Pharmacokinetics studies conducted on Sprague-Dawley rats indicate that chlorite is rapidly absorbed from the gastrointestinal tract (Abdel-Rahman et al., 1984). Once absorbed, it is widely distributed throughout the body with the highest concentrations being detected in the blood, stomach, testes, skin, lung, kidneys, small intestine, spleen, brain, bone marrow and liver. Elimination occurs relatively slowly via urinary excretion, with a half-life of over 35 hours (Abdel-Rahman et al., 1982, 1984).
Toxicological studies reveal that oral exposure to chlorite can result in significant reproductive, hematological, endocrine and gastrointestinal effects. Reproductive effects include altered sperm morphology and decreased progressive movement (Carlton and Smith, 1985; Carlton et al., 1987). Hematological effects reported are significant decreases in hematocrit and hemoglobin levels, increases in methemoglobin and neutrophil levels, decreases in mean erythrocyte counts, morphological changes in erythrocytes (Harrington et al., 1995) and osmotic fragility (Couri and Abdel-Rahman, 1980) in rats; and decreases in erythrocyte levels and cell indices, decreases in hemoglobin levels, increases in reticulocyte count and methemoglobin levels in monkeys (Bercz et al., 1982).
Abdel-Rahman MS, Couri D, Bull RJ (1982). Metabolism and pharmacokinetics of alternate drinking water disinfectants. Environ Health Perspect 46:19-23.
Abdel-Rahman MS, Couri D, Bull RJ (1984a). The kinetics of chlorite and chlorate in the rat. J Am Coll Toxicol 3:261-267.
ATSDR (2002). Toxicological Profile for Chlorine Dioxide. Draft for Public Comment. Agency for Toxic Substances and Disease Registry, Department of Health and Human Services. September, 2002.
Bercz JP, Jones LL, Garner L, et al. (1982). Subchronic toxicity of chlorine dioxide and related compounds in drinking water in the nonhuman primate. Environ Health Perspect 46:47-55.
Carlton BD, Habash DL, Barsaran AH, et al. (1987). Sodium chlorite administration in Long-Evans rats: reproductive and endocrine effects. Environ Res 42:238-245.
Carlton BD, Smith MK (1985). Reproductive effects of alternate disinfectants and their byproducts. In: Jolley RL, et al., eds. Water chlorination: environmental impact and health effects, vol. 5. Lewis Publications, Chelsea, MI, pp. 295-305.
CMA (1996). Chemical Manufacturers Association. Sodium chlorite: drinking water rat two-generation reproductive toxicity study. Quintiles Report Ref. CMA/17/96.
Couri D, Abdel-Rahman MS, Bull RJ (1982a). Toxicological effects of chlorine dioxide, chlorite and chlorate. Environ Health Perspect 46:13-17.
Couri D, Miller CH, Bull RJ, et al. (1982b). Assessment of maternal toxicity, embryotoxicity and teratogenic potential of sodium chlorite in Sprague-Dawley rats. Environ Health Perspect 46:25-29.
DHS (2003). California Department of Health Services. Comparison of Federal and State MCLs: Maximum Contaminant Levels and Regulation Dates for Drinking Water Contaminants. U.S. EPA vs. CDHS. September 2003. Accessed online at: http://www.dhs.ca.gov/ps/ddwem/
Gill MW, Swanson MS, Murphy SR, et al. (2000). Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat. J Appl Toxicol 20:291-303.
Harrington RM, Romano RR, Gates D, et al. (1995). Subchronic toxicity of sodium chlorite in the rat. J Am Coll Toxicol 14:21-33.
Heffernan WP, Guion C, Bull RJ (1979a). Oxidative damage to the erythrocyte induced by sodium chlorite, in vivo. J Environ Pathol Toxicol 2(6):1478-1499.
Heffernan WP, Guion C, Bull RJ (1979b). Oxidative damage to the erythrocyte induced by sodium chlorite, in vitro. J Environ Pathol Toxicol 2(6):1501-1510.
IARC (1997). Sodium Chlorite (Group 3). Vol 52. International Agency for Research on Cancer, Lyon, France. Last update: November 1997. Accessed online at http://www-cie.iarc.fr/htdocs/monographs/
Mobley SA, Taylor DH, Laurie RD, et al. (1990). Chlorine dioxide depresses T3 uptake and delays development of locomotor activity in young rats. In: Water Chlorination: Chemistry, Environmental Impact and Health Effects, Vol. 6. Jolley RL, et al., eds. Lewis Publications, Chelsea, MI, pp. 347-358.
Moore GS, Calabrese EJ (1980b). The effects of chlorine dioxide and sodium chlorite on erythrocytes of A/J and C57L/J mice. Environ Pathol Toxicol 4(2-3):513-524.
Moore GS, Calabrese EJ, Leonard DA (1980). Effects of chlorite exposure on conception rate and litters of A/J strain mice. Bull Environ Contam Toxicol 25:689-696.
U.S. EPA (2000). Toxicological review of chlorine dioxide and chlorite, in support of summary information on the Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency, Washington, DC.
U.S. EPA (2002). National Primary Drinking Water Regulations. Maximum Contaminant Levels for Disinfection Byproducts. US Environmental Protection Agency. Code of Federal Regulations 40CFR 141.64. April 24, 2002.
U.S. EPA (2004). Chlorite (sodium salt) (CASRN 77758-19-2). Integrated Risk Information System, U.S. Environmental Protection Agency. Updated last on October 12, 2000. Accessed online at: http://www.epa.gov/iris/subst/0648.htm
The PHG of 170 ppb for copper was published by OEHHA in 1997. Copper is a reddish metal that occurs naturally in rocks, soil, water, and air. It also occurs naturally in plants and animals, and is a required mineral for human nutrition. Copper is found as a salt in combination with other compounds. Metallic copper can be found in the U.S. penny, electrical wiring, and some water pipes. Copper compounds are commonly used in agriculture to treat plant diseases like mildew, for water treatment, and as preservatives for wood, leather, and fabrics. Exposure to copper results mostly from the ingestion of food and water. High concentrations of this metal in drinking water may occur if the water is corrosive and there are copper plumbing and brass water fixtures in the home. Drinking or swimming in lakes or reservoirs recently treated with copper to control algae or that receive cooling water from a power plant may lead to high copper exposures. Home garden products that contain copper (e.g. fungicides) to control plant diseases are another potential source of exposure to copper.
Long-term exposure to copper dust can irritate the nose, mouth, and eyes, and cause headaches, dizziness, nausea, and diarrhea. Drinking water with higher than normal levels of copper may cause vomiting, diarrhea, stomach cramps, and nausea. High doses of copper, sometimes taken intentionally, can cause liver and kidney damage, and even death. Data are considered inadequate to establish a recommended dietary allowance of copper, but “safe and adequate levels” were estimated by the NRC as 0.5 to 1 mg/day for infants, and 2 to 3 mg/day for adults and adolescents. Average dietary intakes are about 1 to 2 mg/day; infant formula contains about 0.5 mg/L copper when reconstituted with water. The U.S. EPA has determined that copper is not classifiable as to carcinogenicity (IRIS, 2004); epidemiological studies of potential carcinogenic effects in humans are inconclusive. The PHG is based on a case report of gastrointestinal effects in children, the sensitive group for stomach irritation (Spitalny et al., 1984). U.S. EPA has adopted an Action Level and MCLG of 1.3 mg/L for copper in drinking water, and a secondary maximum contaminant level (SMCL) of 1.0 mg/L. The California Action Level is also 1.3 mg/L, with a secondary MCL of 1.0 mg/L. Copper was detected 1044 times out of 11,645 analyses in public drinking water supplies in the DHS reports for 1984-2001, and found 8 times above the Action Level in sampling from 1994-2001. DHS has not scheduled copper for possible reevaluation despite the fairly large difference between the PHG and the Action Level (DHS, 2004).
Pertinent findings since PHG development
A drinking water study in rats (250 mg/L copper for 9 wks) finds that copper causes changes in both the protein content of the erythrocyte membrane and heme synthesis (Ozcelik et al., 2002). There appears to be only one study (in animals) in the PHG pertaining to reproductive effects following exposure to copper. A study in rats reports that exposure to the salt copper chloride has adverse effects on sexual behavior, territorial aggression, fertility and the reproductive system of the adult male rat (Bataineh et al., 1998).
Since the publication of the PHG, a number of studies using human subjects have reported LOAELs and/or NOAELs that are lower than the one used to derive the PHG. One study in adult humans (n=45) reported gastrointestinal effects associated with drinking tap water containing 5 mg/L copper or soluble copper (Pizarro et al., 2001). In another study using human subjects, the acute NOAEL for copper in drinking water was determined to be 4 mg Cu/L (Araya et al., 2001). Olivares et al. (2001) have identified the lowest thresholds for GI effects (nausea, vomiting, diarrhea, abdominal pain) in healthy adult human volunteers to date; the NOEL is 2 mg Cu/L and the LOAEL is 4 mg Cu/L. Children have been shown to be more susceptible than adults to copper, so one may presume the LOAEL in children may be even lower. However, Pizarro et al. (1999) report that a concentration of 2 mg Cu/L of potable water does not produce an increase in GI symptoms in infants, and that only concentrations greater than 3 mg Cu/L increase the number of episodes of nausea, vomiting and abdominal pain in women. Stenhammar (1999) provides a case report in children with symptoms similar to those in the study used to derive the PHG, with exposure to copper via drinking water. An examination of the science behind the EU and U.S. EPA guidelines concluded that these public-health protective values (2.0 and 1.3 mg/L, respectively) do not have “a firm scientific basis” and that “this is worrying in both health and public policy terms” (Fewtrell et al., 2001). The new studies appear credible and compelling. The PHG must be re-evaluated and perhaps recalculated to reflect the new information. This is a difficult issue because of balancing nutritional requirements versus acute toxic effects at moderately higher exposures, the use of copper in household plumbing, and the complicated regulatory status of copper (an Action Level, not an MCL).
Araya M, McGoldrick M, Klevay L, Strain J, et al. (2001). Determination of an acute no-observed-adverse-effect level (NOAEL) for copper in water. Regul Toxicol Pharmacol 34(2):137-45.
Bataineh H, Al-Hamood M, Elbetieha A (1998). Assessment of aggression, sexual behavior and fertility in adult male rat following long-term ingestion of four industrial metals salts. Hum Exp Toxicol 17(10):570-6.
DHS (2004). Status of MCL Reviews in Response to PHGs. March 2004 Update. http://www.dhs.ca.gov/ps/ddwem/
Fewtrell L, Kay D, MacGill S (2001). A review of the science behind drinking water standards for copper. Int J Environ Health Res 11(2):161-7.
IRIS (2004). Health Hazard Assessment for Copper. U.S. Environmental Protection Agency. www.epa.gov/iris/subst/0368.htm.
Olivares M, Araya M, Pizarro F, et al. (2001). Nausea threshold in apparently healthy individuals who drank fluids containing graded concentrations of copper. Regul Toxicol Pharmacol 33(3):271-5.
Ozcelik D, Toplan S, et al. (2002). Effects of excessive copper intake on hematological and hemorheological parameters. Biol Trace Elem Res 89(1):35-42.
Pizarro F, Olivares M, et al. (2001). Gastrointestinal effects associated with soluble and insoluble copper in drinking water. Environ Health Perspect 109(9):949-52.
Pizarro F, Olivares M. et al. (1999). Acute gastrointestinal effects of graded levels of copper in drinking water. Environ Health Perspect 107(2):117-21.
Spitalny K, Brondum J, Vogf R, et al. (1984). Drinking water induced copper intoxication in a Vermont family. Pediatrics 74:1103-1106.
Stenhammar L (1999). Diarrhoea following contamination of drinking water with copper. Eur J Med Res 4(6):217-8.
The PHG of 1000 ppb for glyphosate (Roundup) was published by OEHHA in 1997. Glyphosate is a widely used nonselective herbicide with agricultural and nonagricultural uses. It has relatively low toxicity in experimental animals and in humans. The PHG is based on a NOAEL of 175 mg/kg-day derived from a rabbit teratology study, where the critical effect observed was maternal mortality and diarrhea. The heavy use of glyphosate has resulted in the evaluation of its association with acute or chronic illnesses in a relatively large number of studies since the development of the PHG.
The PHG differs from the U.S. EPA’s MCL of 700 ppb, developed in 1991, because it is based on a different study and uses different assumptions. The California MCL is also 700 ppb, established in September 1994. No detections of glyphosate were reported by DHS in the recent analyses (1984-01) of public drinking water supplies.
Pertinent findings since PHG development
New toxicity information is available on glyphosate since the publication of the PHG, which could have some impact on the existing toxicology and risk assessment sections of the PHG. Since glyphosate is a very heavily used pesticide, it represents a potential human exposure concern. Therefore the PHG update should be given priority, although there is no indication that the new information will change the PHG value.
Acquavella JF, Weber JA, Cullen MR, Cruz OA, Martens MA, Holden LR, Riordan S, Thompson M, Farmer D (1999). Human ocular effects from self-reported exposures to Roundup herbicides. Hum Exp Toxicol 18(8):479-86.
Arbuckle TE, Lin Z, Mery LS (2001). An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population. Environ Health Perspect 109(8):851-7.
Barbosa ER, Leiros da Costa MD, Bacheschi LA, Scaff M, Leite CC (2001). Parkinsonism after glycine-derivate exposure. Mov Disord 16(3):565-8.
Chang CY, Peng YC, Hung DZ, Hu WH, Yang DY, Lin TJ (1999). Clinical impact of upper gastrointestinal tract injuries in glyphosate-surfactant oral intoxication. Hum Exp Toxicol 18(8):475-8.
Daruich J, Zirulnik F, Gimenez MS (2001). Effect of the herbicide glyphosate on enzymatic activity in pregnant rats and their fetuses. Environ Res 85(3):226-31.
Garry VF, Harkins ME, Erickson LL, Long-Simpson LK, Holland SE, Burroughs BL (2002). Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA. Environ Health Perspect 110, Suppl 3:441-9.
Goldstein DA, Johnson G, Farmer DR, Martens MA, Ford JE, Cullen MR (1999). Pneumonitis and herbicide exposure. Chest 116(4):1139-40.
Hardell L, Eriksson M, Nordstrom M (2002). Exposure to pesticides as risk factor for non-Hodgkin's lymphoma and hairy cell leukemia: pooled analysis of two Swedish case-control studies. Leuk Lymphoma 43(5):1043-9.
Hung DZ, Deng JF, Wu TC (1997). Laryngeal survey in glyphosate intoxication: a pathophysiological investigation. Hum Exp Toxicol 16(10):596-9.
Lin CM, Lai CP, Fang TC, Lin CL (1999). Cardiogenic shock in a patient with glyphosate-surfactant poisoning. J Formos Med Assoc 98(10):698-700.
Nakashima K, Yoshimura T, Mori H, Kawaguchi M, Adachi S, Nakao T, Yamazaki F (2002). [Effects of pesticides on cytokines production by human peripheral blood mononuclear cells -- fenitrothion and glyphosate] Chudoku Kenkyu 15(2):159-65.
Savitz DA, Arbuckle T, Kaczor D, Curtis KM (1997). Male pesticide exposure and pregnancy outcome. Am J Epidemiol 146(12):1025-36.
Sorensen FW, Gregersen M (1999). Rapid lethal intoxication caused by the herbicide glyphosate-trimesium (Touchdown). Hum Exp Toxicol 18(12):735-7.
Walsh LP, McCormick C, Martin C, Stocco DM (2000). Roundup inhibits steroidogenesis by disrupting steroidogenic acute regulatory (StAR) protein expression. Environ Health Perspect 108(8):769-76.
Williams GM, Kroes R, Munro IC (2000). Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans. Regul Toxicol Pharmacol 31(2 Pt 1):117-65. Review.
Haloacetic acids (HAAs) are a group of chemicals that are formed along with other drinking water disinfection byproducts (DBPs) when chlorine or other disinfectants used to control microbial contaminants in the water react with naturally occurring organic and inorganic matter in water, e.g., fulvates from decaying vegetation. HAAs are one of four regulated DBPs under the federal Safe Drinking Water Act. Among the major families of the DBPs, HAAs represent the second largest group detected, on a weight basis, next to the most prevalent group of trihalomethanes (THMs). The water solubility of HAAs is in general much higher than THMs (U.S. EPA, 1994).
Depending on the amount of bromide in the source water as well as the amount of chlorinated disinfectants added, varying amounts of chlorinated, brominated, and mixed bromochloro haloacetic acids are produced. The nine HAAs that have been identified in drinking water include monochloroacetic acid (MCA or CH2ClCOOH), dichloroacetic acid (DCA or CHCl2COOH), trichloroacetic acid (TCA or CCl3COOH), monobromoacetic acid (MBA or CH2BrCOOH), dibromoacetic acid (DBA or CHBr2COOH), bromochloroacetic acid (BCA or CHBrClCOOH), bromodichloroacetic acid (BDCA or CBrCl2COOH), dibromochloroacetic acid (DBCA or CBr2ClCOOH), and tribromoacetic acid (TBA or CBr3COOH). Among the nine HAAs, five chemicals, which are known as HAA5, including MCA, DCA, TCA, MBA, and DBA, have been regulated by the U.S. EPA (U.S. EPA, 1998a). HAA5 is the sum of measured concentrations of MCA, DCA, TCA, MBA, and DBA. HAA6 refers to the sum of HAA5 and BCA concentrations. HAAs are solids or liquids at room temperature and are soluble in water. Unlike the volatile THMs, these halogenated organic chemicals have relatively low vapor pressure and are not expected to volatilize from drinking water or contaminated environmental media to any appreciable extent.
Human consumption of chlorinated drinking water has been epidemiologically linked to bladder, kidney, and rectal cancers (Bull and Kopfler, 1991; IARC, 1991). The U.S. EPA (1998b) has published the Stage 1 Disinfectants/Disinfection Byproducts Rule to regulate HAA5 at a MCL of 0.06 mg/L or 60 ppb annual average. This MCL standard became effective for large surface water public water systems in December 2001 and for small surface water and all ground water public water systems in December 2003. In addition, the U.S. EPA has established an MCLG of zero for DCA based on sufficient evidence of carcinogenicity in animals, and a MCLG of 0.3 mg/L for TCA based on developmental toxicity and possible carcinogenicity (U.S. EPA, 1998b).
Monochloroacetic acid (MCA)
U.S. EPA (1998b) has determined that MCA is a Group D chemical, not classifiable as to human carcinogenicity. In a NTP (1992) study, no statistically significant increases in tumor incidences were reported in rats and mice exposed to MCA via gavage.
Dichloroacetic acid (DCA)
U.S. EPA has classified DCA as a probable human carcinogen, Group B2, and derived an oral slope factor of 0.05 (mg/kg-d)-1 based on liver adenoma and carcinomas in male B6C3F1 mice (Bull and Stauber, 1999; Daniel et al., 1992; U.S. EPA, 2003, 2004a). DCA is a hepatocarcinogen in Fischer 344 rats and B6C3F1 mice (Bull and Stauber, 1999; DeAngelo et al., 1999; Nelson et al., 1990; Sanchez and Bull, 1990). DCA is also known as a peroxisome proliferator and produces tumors at doses less than required for peroxisome proliferation (DeAngelo et al., 1989; Xu et al., 1995). Genotoxicity, reproductive toxicity, embryotoxicity, neurotoxicity, and immunotoxicity of DCA have also been reported (Chang et al., 1992). U.S. EPA has derived a drinking water concentration of 0.0007 mg/L at the one in 1,000,000 risk level for DCA (U.S. EPA, 2004a). U.S. EPA has derived an oral RfD of 0.0004 mg/kg-d for DCA based on lesions observed in the testes, cerebrum, cerebellum and liver in a subchronic dog oral bioassay (Cicmanec et al., 1991; U.S. EPA, 2004a). U.S. EPA (1998b) has also promulgated an MCLG of zero for DCA in drinking water based on carcinogenicity. IARC (1995) concluded that there was inadequate evidence for the carcinogenicity of DCA in humans and limited evidence for its carcinogenicity in experimental animals, and gave DCA an overall classification of Group 3, not classifiable as to its carcinogenicity to humans. DCA is listed as a chemical known to the State to cause cancer under the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65).
Trichloroacetic acid (TCA)
U.S. EPA has classified TCA as a possible human carcinogen, Group C, based on a lack of human carcinogenicity data and limited evidence of an increased incidence of liver neoplasms in both sexes of one strain of mice (Bull et al., 1990; Bull and Stauber, 1999; DeAngelo, 1991; DeAngelo and Daniel, 1990; Herren-Freund et al., 1987; Pereira, 1996; Pereira and Phelps, 1996; Sanchez and Bull, 1990). No evidence of carcinogenicity was found in rats (DeAngelo, 1991; DeAngelo and Daniel, 1992; DeAngelo et al., 1997). TCA has been observed to act as a liver tumor promoter in rats or mice treated with an initiating dose of a carcinogen followed by chronic exposure to TCA in the drinking water (Herren-Freund et al., 1987; Latendresse and Pereira, 1997; Parnell et al., 1988; Pereira and Phelps, 1996; Pereira et al., 1997). TCA is also known as a peroxisome proliferator (DeAngelo et al., 1989; Xu et al., 1995). Results from genotoxicity studies are mixed; TCA does not appear to be a point mutagen (OEHHA, 1999; U.S. EPA, 2004b). Developmental, reproductive, and systemic toxicity of TCA have also been reported (Smith et al., 1989). U.S. EPA (1998b) has promulgated an MCLG of 0.3 mg/L for TCA in drinking water based on developmental toxicity and possible carcinogenicity. IARC (1995) concluded that there was inadequate evidence for the carcinogenicity of TCA in humans and limited evidence for its carcinogenicity in experimental animals, and gave TCA an overall classification of Group 3, not classifiable as to its carcinogenicity to humans. TCA has been evaluated, and was not listed as a chemical known to the State to cause cancer under the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65) (OEHHA, 1999, 2003).
Monobromoacetic acid (MBA)
Limited acute spermatotoxicity of MBA has been reported in adult male rats (Linder et al., 1994).
Dibromoacetic acid (DBA)
DBA has been reported to cause testicular damages in adult male rats (Klinefelter et al., 2002; Linder et al., 1994). In rats dosed with DBA, serum testosterone and sperm motion decreased, degenerative flagellar changes in cauda sperm and abnormal sperm head shapes were present. It has been shown to impair sexual function and fertility in male rabbits exposed to DBA in drinking water in a 25-week lifetime study (Veeramachaneni et al., 2000). The results of both in vivo and in vitro exposure studies indicate that DBA is capable of altering spermatogenesis in adult male rats directly (Holmes et al., 2001). DBA in the drinking water altered intestinal metabolism in Fischer 344 rats, which could influence bioactivation of promutagens and procarcinogens in the drinking water. Limited information on genotoxicity, reproductive toxicity, neurotoxicity, and immunotoxicity of DBA has also been reported. Some studies have indicated that acute doses of the brominated acetic acids are more potent inducers of oxidative stress and increase the 8-hydroxydeoxyguanosine (8-OH-dG) content of the nuclear DNA in the liver. The findings by Parrish et al. (1996) suggest that oxidative damage to DNA may play a more important role in the chronic toxicology of brominated compared to the chlorinated acetic acids.
Bull RJ, Kopfler FC (1991). Health Effects of Disinfectants and Disinfection Byproducts. AWWA Research Foundation and American Water Works Association (AWWA), Denver, Colorado. 192 pp.
Bull RJ, Sanchez IM, Nelson MA, Larson JL, Lansing AJ (1990). Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology 63(3):341-359.
Bull RJ, Stauber AJ (1999). Mechanisms of Carcinogenesis by Dichloroacetate (DCA) and Trichloroacetate (TCA). AWWA Research Foundation and American Water Works Association (AWWA), Denver, Colorado. 93 pp.
Chang LW, Daniel FB, DeAngelo AB (1992). Analysis of DNA strand breaks induced in rodent liver in vivo, hepatocytes in primary culture, and a human cell line by chlorinated acetic acids and chlorinated acetaldehydes. Environ Mol Mutagen 20(4):277-288.
Cicmanec JL, Condie LW, Olson GR, Wang SR (1991). 90-day toxicity study of dichloroacetate in dogs. Fundam Appl Toxicol 17(2):376-389.
Daniel FB, DeAngelo AB, Stober JA, Olson GR, Page NP (1992). Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse. Fundam Appl Toxicol 19(2):159-68.
DeAngelo AB, Daniel FB (1990). Comparative carcinogenicity of dichloroacetic (DCA)and trichloroacetic acid in the B6C3F1 mouse. Toxicologist 10:148, abstract.
DeAngelo AB (1991). Toxicology of the Chloroacetic Acids, By-Products of the Drinking Water Disinfection Process. II. The Comparative Carcinogenicity of Dichloroacetic and Trichloroacetic Acid: Implication for Risk Assessment. U.S. EPA, Deliverable No. 3101, HERL-0820, Research Park Triangle, North Carolina.
DeAngelo AB, Daniel FB (1992). An evaluation of the carcinogenicity of the chloroacetic acids in the male F344 rat. Toxicologist 12:206, abstract.
DeAngelo AB, Daniel FB, McMillan L, Wernsing P, Savage RE Jr (1989). Species and strain sensitivity to the induction of peroxisome proliferation by chloroacetic acids.
Toxicol Appl Pharmacol 101(2):285-98.
DeAngelo AB, Daniel FB, Most BM, Olson GR (1997). 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 52(5):425-445.
Herren-Freund SL, Pereira MA, Khoury MD, Olson G (1987). The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol Appl Pharmacol 90(2):183-189.
Holmes M, Suarez JD, Roberts NL, Mole ML, Murr AS, Klinefelter GR (2001). Dibromoacetic acid, a prevalent disinfection byproduct of drinking water disinfection, compromises the synthesis of specific seminiferous tubule proteins following both in vivo and in vitro exposures. J Androl 22(5):878-890.
IARC (1995). Trichloroacetic Acid. In: International Agency for Research on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risk to Humans: Dry Cleaning, Some Chlorinated Solvents and Other Industrial Chemicals, Vol 63. IARC, Lyon, France, pp. 291-314.
IARC (1991). IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, Vol 52, Chlorinated Drinking Water; Chlorination By-Products; Some Other Halogenated Compounds; Cobalt and Cobalt Compounds. IARC, Lyon, France, pp. 179-268.
Klinefelter GR, Strader LF, Suarez JD, Roberts NL (2002). Bromochloroacetic acid exerts qualitative effects on rat sperm: implications for a novel biomarker. Toxicol Sci. 68(1):164-73.
Latendresse JR, 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. Toxicologic Pathology 25(5):433-40.
Linder RE, Klinefelter GR, Strader LF, Suarez JD, Dyer CJ (1994). Acute spermatogenic effects of bromoacetic acids. Fundam Appl Toxicol 22(3):422-30.
NTP (1992). Toxicity and carcinogenicity studies of monochloroacetic acid (CAS no. 79-11-8) in F/344N rats and B6C3F1 mice (gavage studies). Technical report series no. 396, NIH publication no. 90-2851. National Toxicology Program, Research Triangle Park, North Carolina.
OEHHA (1999). Evidence on the carcinogenicity of trichloroacetic acid and its salts, final report. Office of Environmental Health Hazard Assessment, Cal/EPA, Sacramento, California. 28 pp.
OEHHA (2003). Proposition 65 list of carcinogens. Office of Environmental Health Hazard Assessment, Cal/EPA, Sacramento, California.
Parnell MJ, Exon JH, Koller LD (1988). Assessment of hepatic initiation-promotion properties of trichloroacetic acid. Arch Environ Contam Toxicol 17(4):429-436.
Parrish JM, Austin EW, Stevens DK, Kinder DH, Bull RJ (1996). Haloacetate-induced oxidative damage to DNA in the liver of male B6C3F1 mice. Toxicology 110(1-3):103-11.
Pereira MA (1996). Carcinogenic activity of dichloroacetic acid and trichloroacetic acid in the liver of female B6C3F1 mice. Fund Appl Toxicol 31(2):192-199.
Pereira MA, Phelps JB (1996). Promotion by dichloroacetic acid and trichloroacetic acid of N-methyl-N-nitrosourea-initiated cancer in the liver of female B6C3F1 mice. Cancer Lett 102(1-2):133-141.
Pereira MA, Li K, Kramer PM (1997). Promotion by mixtures of dichloroacetic acid and trichloroacetic acid of N-methyl-N-nitrosourea-initiated cancer in the liver of female B6C3F1 mice. Cancer Lett 115(1):15-23.
Sanchez IM, Bull RJ (1990). Early induction of reparative hyperplasia in the liver of mice treated with dichloroacetate and trichloroacetate. Toxicology 64(1):33-46.
Smith MK, Randall JL, Read EJ, Stober JA (1989). Teratogenic activity of trichloroacetic acid in the rat. Teratology 40(5):445-51.
U.S. EPA (1994). National Primary Drinking Water Regulations: Disinfectants and Disinfection By-Products in Drinking Water; Proposed Rule. Fed Reg 59:38668. July 29.
U.S. EPA (1998a). National Primary Drinking Water Regulations: Disinfectants and Disinfection By-Products; Notice of Data Availability; Proposed Rule. Fed Reg 63:15673-92. March 31.
U.S. EPA (1998b). National Primary Drinking Water Regulations: Disinfectants and Disinfection By-Products; Notice of Data Availability; Final Rule. Fed Reg 63:69390-476. December 16. Stage 1 Disinfectants and Disinfection By-Products Rule, EPA 815-F-98-010. Available at: http://www.epa.gov/safewater/mdbp/dbp1.html.
U.S. EPA (2003). Toxicological review of dichloroacetic acid (CAS No. 79-43-6), in support of summary information on the Integrated Risk Information System (IRIS). National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, D.C. EPA 635/R-03/007. Available at: http://www.epa.gov/iris.
U.S. EPA (2004a). Dichloroacetic acid. In: Integrated Risk Information System (IRIS), U.S. Environmental Protection Agency, Washington, D.C., carcinogenicity update Sept 11, 2003. Available at: http://www.epa.gov/iris/subst/0654.htm.
U.S. EPA (2004b). Trichloroacetic acid. In: Integrated Risk Information System (IRIS), U.S. Environmental Protection Agency, Washington, D.C., carcinogenicity update March 1, 1996. Available at: http://www.epa.gov/iris/subst/0655htm.
Veeramachaneni DNR, Higuchi TT, Palmer JS, Kane CM (2000). Dibromoacetic acid, a disinfection byproducts in water, impairs sexual function and fertility in male rabbits. Biol Reprod 62(Suppl 1):246, Abstract 354, DNR-4-34-32, SSR.
Xu G, Stevens DK, Bull RJ (1995). Metabolism of bromodichloroacetate in B6C3F1 mice. Drug Metab Dispos 23(12):1412-6.
The PHG of 3.2x10-5 mg/L (0.032 ppb) for lindane was published by OEHHA in February 1999. Lindane, the gamma isomer of hexachlorocyclohexane, has been used as an insecticide and as a therapeutic scabicide, pediculicide, and ectoparasiticide for humans and animals. Most pesticide uses have been cancelled, and lindane was not detected in any of the Department of Health Services drinking water sample reports from 1984-2001. Lindane is semivolatile and lipophilic, and has been found in human tissues and breast milk. The PHG is based on liver tumors in mice, with a human equivalent potency value of 1.1 (mg/kg-day)-1 calculated from a 1973 study. The U.S. EPA MCL is 0.0002 mg/L (0.2 ppb), established in 1991, and the California MCL is the same, established in 1994.
Pertinent findings since PHG development
Additional data are available on mechanism of endocrinological effects of lindane, including potentially relevant basic toxicity studies and some largely negative epidemiology evaluations. Also, several recent publications are available on the (declining) levels of lindane in tissues and environmental media. However, no new cancer bioassays were found. Although most uses of lindane have been cancelled, it can still be used in humans for treatment of head lice. Therefore a health risk reassessment is relevant despite the lack of lindane detections in drinking water. Both cancer and non-cancer endpoints are appropriate to review.
Beard AP, Bartlewski PM, Chandolia RK, Honaramooz A, Rawlings NC (1999). Reproductive and endocrine function in rams exposed to the organochlorine pesticides lindane and pentachlorophenol from conception. J Reprod Fertil 115(2):303-14.
Beard AP, Bartlewski PM, Rawlings NC (1999). Endocrine and reproductive function in ewes exposed to the organochlorine pesticides lindane or pentachlorophenol. J Toxicol Environ Health A 56(1):23-46.
Beard AP, Rawlings NC (1999). Thyroid function and effects on reproduction in ewes exposed to the organochlorine pesticides lindane or pentachlorophenol (PCP) from conception. J Toxicol Environ Health A 58(8):509-30.
De Jong FM, De Snoo GR (2001). Pesticide residues in human food and wildlife in The Netherlands. Meded Rijksuniv Gent Fak Landbouwkd Toegep Biol Wet 66(2b):815-22.
Enrique MO, Morales V, Ngoumgna E, Prescilla R, Tan E, Hernandez E, Ramirez GB, Cifra HL, Manlapaz ML (2002A). Prevalence of fetal exposure to environmental toxins as determined by meconium analysis. Neurotoxicology 23(3):329-39.
Fausto AM, Morera P, Margarit R, Taddei AR (2001). Sperm quality and reproductive traits in male offspring of female rabbits exposed to lindane (gamma-HCH) during pregnancy and lactation. Reprod Nutr Dev 41(3):217-25.
Gerhard I, Daniel V, Link S, Monga B, Runnebaum B (1998). Chlorinated hydrocarbons in women with repeated miscarriages. Environ Health Perspect 106(10):675-81.
Hall RC, Hall RC (1999). Long-term psychological and neurological complications of lindane poisoning. Psychosomatics 40(6):513-7.
Konishi Y, Kuwabara K, Hori S (2001). Continuous surveillance of organochlorine compounds in human breast milk from 1972 to 1998 in Osaka, Japan. Arch Environ Contam Toxicol 40(4):571-8.
Koppen G, Covaci A, Van Cleuvenbergen R, Schepens P, Winneke G, Nelen V, van Larebeke N, Vlietinck R, Schoeters G (2002). Persistent organochlorine pollutants in human serum of 50-65 years old women in the Flanders Environmental and Health Study (FLEHS). Part 1: Concentrations and regional differences. Chemosphere 48(8):811-25.
Lopez-Carrillo L, Lopez-Cervantes M, Torres-Sanchez L, Blair A, Cebrian ME, Garcia RM (2002). Serum levels of beta-hexachlorocyclohexane, hexachlorobenzene and polychlorinated biphenyls and breast cancer in Mexican women. Eur J Cancer Prev 11(2):129-35.
McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, Robson D, Skinnider LF, Choi NW (2001). Non-Hodgkin's lymphoma and specific pesticide exposures in men: cross-Canada study of pesticides and health. Cancer Epidemiol Biomarkers Prev 10(11):1155-63.
Peper M, Ertl M, Gerhard I (1999). Long-term exposure to wood-preserving chemicals containing pentachlorophenol and lindane is related to neurobehavioral performance in women. Am J Ind Med 35(6):632-41.
Sahoo A, Samanta L, Das A, Patra SK, Chainy GB (1999). Hexachlorocyclohexane-induced behavioural and neurochemical changes in rat. J Appl Toxicol 19(1):13-8.
Samanta L, Roy A, Chainy GB (1999). Changes in rat testicular antioxidant defence profile as a function of age and its impairment by hexachlorocyclohexane during critical stages of maturation. Andrologia 31(2):83-90.
Samanta L, Sahoo A, Chainy GB (1999). Age-related changes in rat testicular oxidative stress parameters by hexachlorocyclohexane. Arch Toxicol 73(2):96-107.
Schroeder JC, Olshan AF, Baric R, Dent GA, Weinberg CR, Yount B, Cerhan JR, Lynch CF, Schuman LM, Tolbert PE, Rothman N, Cantor KP, Blair A (2001). Agricultural risk factors for t(14;18) subtypes of non-Hodgkin's lymphoma. Epidemiology 12(6):701-9.
Srivastava MK, Raizada RB (2000). A limited three-generation reproduction study on hexachlorocyclohexane (HCH) in rats. Food Chem Toxicol 38(2-3):195-201.
Sujatha R, Chitra KC, Latchoumycandane C, Mathur PP (2001). Effect of lindane on testicular antioxidant system and steroidogenic enzymes in adult rats. Asian J Androl 3(2):135-8.
Traina ME, Rescia M, Urbani E, Mantovani A, Macri; C, Ricciardi C, Stazi AV, Fazzi P, Cordelli E, Eleuteri P, Leter G, Spano M (2003). Long-lasting effects of lindane on mouse spermatogenesis induced by in utero exposure. Reprod Toxicol 17(1):25-35.
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Walsh LP, Stocco DM (2000). Effects of lindane on steroidogenesis and steroidogenic acute regulatory protein expression. Biol Reprod 63(4):1024-33.
Weinhold B (2001). Last call for Lindane. Environ Health Perspect 109(6):A254.
Wendel K, Rompalo A (2002). Scabies and pediculosis pubis: an update of treatment regimens and general review. Clin Infect Dis 35(Suppl 2):S146-51.
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The PHG of 1.2 ppb for inorganic mercury was published by OEHHA in December 1999. Mercury is an element and a component of many items (e.g., thermometers and other monitoring equipment; dental amalgams, batteries, switches). It was reported as found in 150/11,736 drinking water analyses in the DHS survey results for 1984-2001. Various effects have been reported in humans and animals following exposure to mercury-containing compounds. The predominant effect for inorganic mercury compounds is toxicity to the kidney. Chronic toxicity data was found inadequate in the 1999 PHG review and a six-month oral toxicity study was used to calculate the PHG. Based on the kidney toxicity reported, a No-Observable-Adverse-Effect-Level of 0.23 mg/kg-day was used to derive the PHG. The U.S. EPA MCL of 2 ppb (effective 6/24/77) is still in effect, and is consistent with the U.S. EPA RfD developed in 1995; the California MCL is 2 ppb, also established in 1977. Fifty-seven exceedances of the MCL were noted in the DHS overview of monitoring results for 1984-2000. It should be noted that the MCL and PHG focus on inorganic mercury, rather than on the more toxic organic form, methylmercury, since the inorganic form predominates in drinking water.
Pertinent findings since PHG development
Several potentially relevant new studies were identified. The key articles include several toxicological reviews on mercury published in 2002 regarding exposure to mercury from fish; several epidemiological studies regarding possible neurotoxic, cardiac or other effects associated with exposure to mercury from amalgam, dietary, or household sources; and studies on the potential neurotoxicity of mercury in mice following in utero exposure and exposure through breast feeding. However, these reports may not affect the PHG level since several of these studies refer mainly to methylmercury, and where inorganic mercury is involved, the doses are greater than the one used in the PHG calculation.
Afonne OJ, Orisakwe OE, Obi E, Dioka CE, Ndubuka GI (2002). Nephrotoxic actions of low-dose mercury in mice: protection by zinc. Arch Environ Health 57(2):98-102.
Ahlqwist M, Bengtsson C, Lapidus L, Gergdahl IA, Schutz A (1999). Serum mercury concentration in relation to survival, symptoms, and diseases: results from the prospective population study of women in Gothenburg, Sweden. Acta Odontol Scand 57(3):168-74.
Kazantzis G (2002). Mercury exposure and early effects: an overview. Med Lav 93(3):139-47.
Langworth S, Bjorkman L, Elinder CG, Jarup L, Savlin P (2002). Multidisciplinary examination of patients with illness attributed to dental fillings. J Oral Rehabil 29(8):705-13.
Lee YW, Ha MS, Kim YK (2001). Role of reactive oxygen species and glutathione in inorganic mercury-induced injury in human glioma cells. Neurochem Res 26(11):1187-93.
Murata K, Budtz-Jorgensen E, Grandjean P (2002). Benchmark dose calculations for methylmercury-associated delays on evoked potential latencies in two cohorts of children. Risk Anal 22(3):465-74.
Navas-Acien A, Pollan M, Gustavsson P, Plato N (2002). Occupation, exposure to chemicals and risk of gliomas and meningiomas in Sweden. Am J Ind Med 42(3):214-27.
Ochi T (2002). Methylmercury, but not inorganic mercury, causes abnormality of centrosome integrity (multiple foci of gamma-tubulin), multipolar spindles and multinucleated cells without microtubule disruption in cultured Chinese hamster V79 cells. Toxicology 175(1-3):111-21.
Sakamoto M, Kakita A, Wakabayashi K, Takahashi H, Nakano A, Akagi H (2002). Evaluation of changes in methylmercury accumulation in the developing rat brain and its effects: a study with consecutive and moderate dose exposure throughout gestation and lactation periods. Brain Res 949(1-2):51-9.
Torres AD, Rai AN, Hardiek ML (2000). Mercury intoxication and arterial hypertension: report of two patients and review of the literature. Pediatrics 105(3):E34.
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The PHG of 30 ppb for methoxychlor was published by OEHHA in December 1999. Methoxychlor is an organochlorine pesticide similar in insecticidal action to DDT. Due to concern over its toxicity, methoxychlor registration was suspended in California in 1995. Methoxychlor has a variety of effects, some associated with its mild estrogenic activity. It has not been found to be carcinogenic. The PHG is based on a LOAEL of five mg/kg-day associated with effects on the female reproductive system. The U.S. EPA’s MCL for methoxychlor is 40 ppb. The California MCL is also 40 ppb, established in September 1994. Methoxychlor was not detected in the public drinking water supply analyses reported by DHS from 1984-01.
Pertinent findings since PHG development
Many additional studies relating to the effects of methoxychlor have been published since the development of the PHG. These data, including new information on the endocrine disruption potential of methoxychlor, could possibly lead to a revision of the PHG value. The Integrated Risk Assessment Section of OEHHA reviewed the risks of methoxychlor for the Development of Health Criteria for School Site Risk Assessment Pursuant to Health and Safety Code Section 901g): Proposed RfDs for School Site Risk Assessment Draft Report and derived a child-based risk value on the basis of new information which differs from the equivalent risk-based estimate in the PHG document. Since the pesticidal uses of methoxychlor have been banned, there would be a diminishing concern over human exposure, although some residues are expected to persist.
Alworth LC, Howdeshell KL, Ruhlen RL, Day JK, Lubahn DB, Huang TH, Besch-Williford CL, vom Saal FS (2002). Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: effects of low versus high doses. Toxicol Appl Pharmacol 183(1):10-22.
Amstislavksy SY, Kizilova EA, Eroschenko VP (2003). Preimplantation mouse embryo development as a target of the pesticide methoxychlor. Reprod Toxicol 17(1):79-86.
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Borgeest C, Symonds D, Mayer LP, Hoyer PB, Flaws JA (2002). Methoxychlor may cause ovarian follicular atresia and proliferation of the ovarian epithelium in the mouse. Toxicol Sci 68(2):473-8.
Folmar LC, Hemmer MJ, Denslow ND, Kroll K, Chen J, Cheek A, Richman H, Meredith H, Grau EG (2002). A comparison of the estrogenic potencies of estradiol, ethynylestradiol, diethylstilbestrol, nonylphenol and methoxychlor in vivo and in vitro. Aquat Toxicol 60(1-2):101-10.
Hu Y, Kupfer D (2002). Enantioselective metabolism of the endocrine disruptor pesticide methoxychlor by human cytochromes p450 (p450s): major differences in selective enantiomer formation by various p450 isoforms. Drug Metab Dispos 30(12):1329-36.
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N-nitrosodimethylamine (NDMA) is a nitrosamine formed in many industrial and natural processes. It occurs in various foods and alcoholic beverages, is created from nitrates and nitrites in the human gut, and is also detected in cigarette smoke. The nitrosamines are considered as classic carcinogens, and a large amount of basic research on cancer mechanisms has been carried out on them (IARC, 1978; Preussmann and Stewart, 1984; Archer et al., 1994, ATSDR, 1989; NTP, 2000; IRIS, 2004). Formation of DNA and RNA adducts of NDMA has been correlated with incidence of tumors (Belinsky et al., 1989; Chhabra et al., 1995; Souliotis et al., 1995, 2002; Anderson et al., 1996). Because of similarities among animals and humans in its metabolism to reactive intermediates (Herron and Shank, 1980; Yoo et al., 1991; Yamazaki et al., 1992), NDMA is considered to be a probable human carcinogen (IRIS, 2004).
NDMA has become more important in California because of its increasing detection in drinking water. It has been associated with the chloramine drinking water disinfection process, and may be formed from the nitrogen species added for chloramination (CDHS, 2003, 2004). Because of concern over the exposures and the carcinogenic properties of NDMA, California DHS requested that OEHHA develop a PHG for NDMA, to support the development of a California MCL. There is no federal Maximum Contaminant Level (MCL) for NDMA, but there is a California Action Level for NDMA of 0.01 g/L. NDMA is listed as a chemical known to the State of California to cause cancer under Proposition 65 (OEHHA, 2004).
Significant increases in tumors have been observed in numerous species of animals administered NDMA by oral, inhalation, and other routes of exposure. Evidence that specifically links exposure to NDMA to increased incidence of cancer in humans is generally lacking, but the available studies are suggestive (Delzell et al., 1981; Sorahan et al., 1989; Gonzalez et al., 1994; Mirvish, 1995; Pobel et al., 1995; Rogers et al., 1995; De Stefani et al., 1996; Knekt et al., 1999; Straif et al., 2000). Studies on other nitrosamines support the presumption of potential human carcinogenicity of NDMA (Bartsch and Montesano, 1984). The dose-response relationship derived by Peto and associates from the occurrence of liver tumors in female rats appears to be an appropriate study for cancer risk assessment (Peto et al., 1991a,b).
Given the low volatility and skin permeability of NDMA, neither inhalation nor dermal exposure routes are expected to contribute significant amounts of exposure relative to the oral route. However, NDMA contributions from food sources are probably a relevant fraction of total exposure.
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The PHG of 50 ppb for oxamyl was published by OEHHA in December 1997. Oxamyl is a carbamate insecticide/acaracide and nematicide, and a growth plant regulator. The chief effect of oxamyl in animals is cholinesterase inhibition. The PHG is based on a NOAEL of 2.5 mg/kg-day where the critical effect is decreased body weight gain in rats. The PHG is different than the U.S. EPA’s MCL of 200 ppb developed in 1991 because it is based on a different study and uses different assumptions. The California MCL is also 200 ppb, established in September 1994. No detections of oxamyl were reported in the recent surveys of public drinking water supplies (1984-01) reported by DHS.
Pertinent findings since PHG development
Very few new studies relating to the effects of oxamyl have been found since the publication of the PHG. Although the information presented by the new studies doesn’t appear likely to lead to a revision of the PHG value, the document deserves revision because it does not meet our current PHG document standards.
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The PHG of 0.4 ppb for pentachlorophenol was published by OEHHA in December 1997. Pentachlorophenol is a wood-preserving insecticide and disinfectant. Generally considered a very toxic substance, current pentachlorophenol uses are confined to specific outdoor applications such as utility poles. Pentachlorophenol has various noncarcinogenic effects and is considered to be a probable human carcinogen. The PHG is based a human equivalent slope factor of 8.11x10-2 (mg/kg-day)-1 calculated based on tumors in a chronic mouse study. The PHG is different than the U.S. EPA’s MCL of 1 ppb developed in 1991 because it is based on a different subset of information from the same mouse study and uses different assumptions. The California MCL is also 1 ppb, established in September 1994. Pentachlorophenol was detected once in 6,350 measurements of public drinking water supplies in analyses reported by the DHS for the period of 1984-01.
Pertinent findings since PHG development
A large number of new studies relating to the toxic effects of pentachlorophenol were found. These studies cover a wide range of effects, and might lead to a revision of the PHG value. Revision of this PHG document should be made a high priority, because pentachlorophenol is an important environmental pollutant and there is a significant amount of new data available.
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The PHG of 0.1 ppb for thallium was published by OEHHA in 1999. Thallium is a bluish-white metal that is found in trace amounts in the earth’s crust. Thallium has been obtained as a by-product from smelting other metals, but has not been produced in the U.S. since 1984. Currently, all the thallium is obtained from imports and from thallium reserves. Thallium is used mostly in manufacturing electronic devices, switches, and closures, primarily for the semiconductor industry. It also has limited use in the manufacture of special glass and for certain medical procedures. At one time, thallium sulfate was used in medicine as a depilatory agent. Thallium and various thallium compounds were also once used as pesticides, but their use was banned in the U.S. in 1972. Thallium enters the environment primarily from coal-burning and smelting, in which it is a trace contaminant of the raw materials.
Exposure to high levels of thallium can result in harmful effects on the nervous system (numbness in fingers/toes). Studies in people who ingested large amounts of thallium over a short time have reported vomiting, diarrhea, temporary hair loss, and effects on the nervous system, lungs, heart, liver, and kidneys. It has caused death. Studies in rats exposed to high levels of thallium showed adverse reproductive and developmental effects. Animal data suggest that the male reproductive system may be susceptible to damage by low levels of thallium. Thallium has not been classified by any authoritative body as to its human carcinogenicity. No studies are available in people or animals on the carcinogenic effects of breathing, ingesting, or touching thallium. The PHG is based on a noncancer endpoint, alopecia (hair loss) derived from a subchronic gavage study in rats. The U.S. EPA and California MCLs for thallium in drinking water are 2 ppb, which is constrained by the detection limit of 1 ppb. DHS reported 118 detections of thallium in 9689 analyses of drinking water from 1984-2001, and 47 MCL exceedances from 1984-2000. DHS also reports that a method development study is underway, and any considerations about decreasing the California MCL toward the PHG value are being deferred until this is completed (DHS, 2003).
Pertinent findings since PHG development
Little is known about the precise mechanism by which thallium causes neurological manifestations in humans (e.g. ataxia, paralysis). A recent subchronic study in rats (Galvan-Arzate et al., 2000), in which significant changes in lipid peroxidation were noted in both the corpus striatum and cerebellum, suggests an active role of free radicals and oxidative events in the regional susceptibility of the brain to this metal. Male rats exhibited a dose-dependent increase in serum levels of aspartate aminotransferase, alanine transferase, and creatinine, hepatocyte necrosis and vacuolation in the liver and pathological changes in the renal tubules after i.p injection of thallium (Leung and Ooi, 2000). Though published prior to the development of the PHG, a developmental study of the toxicity of thallium in prenatal and postnatal rats on vasomotor activity (Rossi et al., 1988) which was not included in the original PHG should be included because the route of exposure is via drinking water and this endpoint (the developing rat’s vascular autonomic nervous system) may be the most sensitive indicator of developmental toxicity of thallium by the oral route in animals. The study may provide new information about the teratogenic/developmental effects of thallium. Also, the male reproductive system has been shown to be a susceptible target site to the toxic effects of thallium (Formigli et al., 1986).
Several mechanistic studies may provide further perspective on thallium actions and effect. Studies exploring the mechanism of thallium-induced nephrotoxicity found no relation between toxicity in this target organ and riboflavin and/or GSH concentration (Appenroth and Winnefeld, 1999a,b), but may reveal a connection with effects on potassium transport (Zierold, 2000; Appenroth et al., 2001).
Overall, the priority should be relatively high because this chemical has historically been detected in California drinking water at levels well above the current PHG, and the current MCL is 20 times the PHG.
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The PHG of 0.8 ppb for trichloroethylene (TCE) was published by OEHHA in February 1999. TCE is primarily used as an industrial solvent for the vapor degreasing and cold cleaning of fabricated metal parts. It is also used in textile cleaning and solvent extraction processes. The current PHG is based on hepatocellular carcinomas and adenocarcinomas observed in two chronic bioassays on mice, in both sexes, by inhalation and oral routes of exposure. It is classified by IARC as a 2A carcinogen, indicating that it is a probable human carcinogen. The U.S. EPA MCL for TCE of 5 ppb was established in 1987 and the California MCL of 5 ppb was established in 1989. DHS reports that between 1984 and 2001, trichloroethylene has been detected 859 times out of 15,447 water samples taken. Between 1984 and 2000, the MCL for TCE was exceeded 332 times; between 1994 and mid-2002, it was exceeded 259 times. TCE has the most frequently exceeded California MCL for an organic chemical.
Pertinent findings since PHG development
A large number of new animal and epidemiology studies were identified, as well as nearly two dozen reviews of the carcinogenicity and toxicity of TCE. The animal and epidemiological studies include new data on the carcinogenicity, ototoxicity, neurotoxicity, reproductive and developmental toxicity, immunotoxicity, nephrotoxicity, and other toxicological effects associated with TCE exposure. The reviews analyze the toxicological and epidemiological data, and discuss methodologies associated with classification of TCE as a carcinogen. One paper sharply questions IARC’s dismissal of cancer data as irrelevant, citing that the carcinogenic mechanism is purportedly an animal-specific mechanism and not transferable to humans (Huff, 2002). The author contends that TCE data was “down-graded” or “under-graded.” These new studies and analyses may have an effect on the methodology used and the value derived in the TCE document dated February 1999. The U.S. EPA has updated its TCE health risk assessment (U.S. EPA, 2001) since the PHG was published and has also upgraded its toxicity guidance for effects on pregnant women and other potentially sensitive populations. Given that TCE is the most frequently exceeded organic MCL in the State, and that there are significant new data, the OEHHA re-review of this compound should be a high priority.
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Bloemen LJ, Monster AC, Kezic S, Commandeur JN, Veulemans H, Vermeulen NP, Wilmer JW (2001). Study on the cytochrome P-450- and glutathione-dependent biotransformation of trichloroethylene in humans. Int Arch Occup Environ Health 74(2):102-8.
Boice JD Jr, Marano DE, Fryzek JP, Sadler CJ, McLaughlin JK (1999). Mortality among aircraft manufacturing workers. Occup Environ Med 56(9):581-97.
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Bull RJ (2000). Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate. Environ Health Perspect 108 Suppl 2:241-59.
Bull RJ, Orner GA, Cheng RS, Stillwell L, Stauber AJ, Sasser LB, Lingohr MK, Thrall BD (2002). Contribution of dichloroacetate and trichloroacetate to liver tumor induction in mice by trichloroethylene. Toxicol Appl Pharmacol 182(1):55-65.
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Chen SJ, Wang JL, Chen JH, Huang RN (2002). Possible involvement of glutathione and p53 in trichloroethylene- and perchloroethylene-induced lipid peroxidation and apoptosis in human lung cancer cells. Free Radic Biol Med 33(4):464-72.
Cummings BS, Lash LH (2000). Metabolism and toxicity of trichloroethylene and S-(1,2-dichlorovinyl)-L-cysteine in freshly isolated human proximal tubular cells. Toxicol Sci 53(2):458-66.
DHS (2004). Status of MCL reviews in response to PHGs; March 2004 update. Accessed 3/30/2004 at: www.dhs.ca.gov/ps/ddwem/chemicals/
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Fisher JW, Channel SR, Eggers JS, Johnson PD, MacMahon KL, Goodyear CD, Sudberry GL, Warren DA, Latendresse JR, Graeter LJ (2001). Trichloroethylene, trichloroacetic acid, and dichloroacetic acid: do they affect fetal rat heart development? Int J Toxicol 20(5):257-67.
Forkert PG, Lash LH, Nadeau V, Tardif R, Simmonds A (2002). Metabolism and toxicity of trichloroethylene in epididymis and testis. Toxicol Appl Pharmacol 182(3):244-54.
Gilbert KM, Griffin JM, Pumford NR (1999). Trichloroethylene activates CD4+ T cells: potential role in an autoimmune response. Drug Metab Rev 31(4):901-16.
Giver CR, Wong R, Moore DH 2nd, Pallavicini MG (2001). Dermal benzene and trichloroethylene induce aneuploidy in immature hematopoietic subpopulations in vivo. Environ Mol Mutagen 37(3):185-94.
Goon AT, Lee LT, Tay YK, Yosipovitch G, Ng SK, Giam YC (2001). A case of trichloroethylene hypersensitivity syndrome. Arch Dermatol 137(3):274-6.
Green LC, Lash TL (1999). Re: "Renal cell cancer correlated with occupational exposure to trichloroethylene." J Cancer Res Clin Oncol 125(7):430-2.
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Guehl D, Bezard E, Dovero S, Boraud T, Bioulac B, Gross C (1999). Trichloroethylene and Parkinsonism: a human and experimental observation. Eur J Neurol 6(5):609-11.
Hansen J, Raaschou-Nielsen O, Christensen JM, Johansen I, McLaughlin JK, Lipworth L, Blot WJ, Olsen JH (2001). Cancer incidence among Danish workers exposed to trichloroethylene. J Occup Environ Med 43(2):133-9.
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Huff J (2002). IARC monographs, industry influence, and upgrading, downgrading, and under-grading chemicals: a personal point of view. International Agency for Research on Cancer. Int J Occup Environ Health 8(3):249-70.
Kaneko T, Saegusa M, Tasaka K, Sato A (2000). Immunotoxicity of trichloroethylene: a study with MRL-lpr/lpr mice. J Appl Toxicol 20(6):471-5.
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Kumar P, Prasad AK, Maji BK, Mani U, Dutta KK (2001). Hepatoxic alterations induced by inhalation of trichlorethylene (TCE) in rats. Biomed Environ Sci 14(4):325-32.
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Lash LH, Parker JC, Scott CS (2000). Modes of action of trichloroethylene for kidney tumorigenesis. Environ Health Perspect 108 Suppl 2:225-40.
Lash LH, Qian W, Putt DA, Hueni SE, Elfarra AA, Krause RJ, Parker JC (2001). Renal and hepatic toxicity of trichloroethylene and its glutathione-derived metabolites in rats and mice: sex-, species-, and tissue-dependent differences. J Pharmacol Exp Ther 297(1):155-64.
Lee LJ, Chan CC, Chung CW, Ma YC, Wang GS, Wang JD (2002). Health risk assessment on residents exposed to chlorinated hydrocarbons contaminated in groundwater of a hazardous waste site. J Toxicol Environ Health A 65(3-4):219-35.
Lehmann I, Thoelke A, Rehwagen M, Rolle-Kampczyk U, Schlink U, Schulz R, Borte M, Diez U, Herbarth O (2002). The influence of maternal exposure to volatile organic compounds on the cytokine secretion profile of neonatal T cells. Environ Toxicol 17(3):203-10.
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Morgan JW, Cassady RE (2002). Community cancer assessment in response to long-time exposure to perchlorate and trichloroethylene in drinking water. J Occup Environ Med 44(7):616-21.
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Plewka A, Zielinska-Psuja B, Kowalowka-Zawieja J, Nowaczyk-Dura G, Plewka D, Wiaderkiewicz A, Kaminski M, Orlowski J (2002). Influence of acetaminophen and trichloroethylene on liver cytochrome P450-dependent monooxygenase system. Acta Biochim Pol 47(4):1129-36.
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