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APPENDIX A Drinking Water Contaminant Candidates for Development of Base' ins Data on Formation of DNA AdJucts This appendix presents data on 16 compounds found in drinking water- 13 are contaminants recently reviewed by the NRC (1986) for EPA that are known to be teratogenic, carcinogenic, mutagenic, or genetically toxic in laboratory animals. Of these, five acrylamide, benzotaipyrene (BaP), chromium, dibromochloropropane (DBCP), and ethylene dibromide (EDB) have definitely been shown to form DNA adducts. Trichlorfon probably forms DNA adducts. On the basis of current evidence, diallate, sulfallate, the two chioropropanes, and chloropropene can be considered possible in- ducers of DNA adducts. Evidence on the five remaining compounds arsenic, nitrofen, penta- chlorophenol, and the ethylhexyl phthalates - is insufficient to permit clas- sifying them as inducers of DNA adducts. They are included because they have been shown to be mutagens or carcinogens or because they produce genetic damage of some kind. They might form DNA adducts that have not yet been detected. CONTAMINANTS THAT DEFINITELY FORM DNA ADDUCTS Acrylamide H O 1 ~ CH2 = C-C-NH2 Acrylamide is a monomer of polyacrylamide. It is highly reactive and 61

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62 DRINKING WATER AND HEALTH reacts spontaneously with hydroxyl-, amino-, and sulfhydryl-containing com- pounds. With a solubility in water of 219 g/100 ml, acrylamide polymers are used to improve oil recovery, increase dry strength of paper products, dissipate fog, and stabilize soil. Acrylamides are also used in grouting op- erations, clarification of potable water, and treatment of municipal and in- dustrial effluents. Acrylamide is biodegradable. It is degraded to carbon dioxide in 4-12 days in water and is completely degraded in 6 days in soil. Up to 60% is degraded to carbon dioxide (NRC, 19861. Occurrence No estimate of occurrence in drinking water has been cal- culated. Tissue Distribution Acrylamide is rapidly metabolized in the body, 24 hours after oral administration of acrylamide no trace of the parent compound was found in any tissues. Metabolites of acrylamide accumulate in eryth- rocytes. The half-life of the metabolites in erythrocytes is 10.5 days, and in other tissues 8 days (as measured by the decrease in radioactivity using ~4C- labelled acrylamide) (Miller et al., 1982~. Formation of DNA Adducts Solomon et al. (1985) studied the in vitro reaction of acrylamide with 2'-deoxynucleosides and calf thymus DNA. Acrylamide reacted most strongly at the N6 position of 2'-deoxyadenosine and, to a lesser extent, at the N3 position of 2'-deoxycytidine, although adduct formation of other 2'-deoxynucleosides was recorded as well. With calf thymus DNA, acrylamide reacted strongest at the N1 position of 2- deoxyadenosine. The authors point out that adducts formed were only present in small quantities, even after the long reaction time (10 or 40 days), so the results cannot be readily translated to human exposure to acrylamide. How- ever, the possibility of predicting in viva alkylation with direct-acting al- kylating agents on the basis of in vitro adduct formation has been suggested. Mutagenicity Mutagenicity studies with acrylamide in the Salmonellal microsome assay were negative. Acrylamide is clastogenic in L5178Y mouse lymphoma cells (Moore et al., l987~. It is known to induce dominant lethal mutations in male rodents, and induced translocations in postmeiotic germ cells of mice in a recent study (Shelby et al., 19871. Carcinogenicity A number of reports have shown acrylamide to be car- cinogenic in laboratory animals, although no data have shown that for hu- mans. Male and female Fischer 344-rats have developed tumors after a 2- year exposure to acrylamide in drinking water. Male rats exposed to acry- lamide at 0.5 mg/kg of body weight each day for 2 years developed scrotal mesotheliomas. At 2.0 mg/kg per day, benign thyroid tumors, malignant

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Appendix A 63 thyroid tumors, glial tumors in the CNS, adenomas of the clitoral gland, squamous cell papillomas in the mouth, benign and malignant mammary tumors, and malignant uterine tumors were observed in rats. On the basis of a multistage model, and assuming the consumption of 1 liter of water per day containing acrylamide at 1 ,u~g/liter, the human lifetime carcinogenic risk is estimated at 3.~-~.2 x 10-6 and the upper 95% confidence estimate of lifetime cancer risk is 0.75-1.4 x 10-5 (NRC, 19861. Other Health Effects Acrylamide has been reported to cause neuropathy in humans that leads to progressive symmetric distal sensory abnormalities and motor weakness. Also stated to occur were slurred speech; unsteady gait; memory loss; irrational behavior; visual, tactile, and auditory hallucinations; skin sensitization; cold blue hands; muscle weakness; paresthesia; and numb- ness of hands or feet. Neuropathy has been reported in animals (cats, rats, mice, guinea pigs, rabbits, and monkeys) that were given acrylamide (NRC, 19861. Summary Acrylamide can produce peripheral neuropathy in animals and humans. It is a known carcinogen in animals. BenzoLalpyrene (BaP) &5x: BaP is a ubiquitous polycyclic aromatic hydrocarbon associated with com- bustion. It was first isolated from coal tar. Occurrence BaP concentrations of 3 ng/liter in tap water were reported in a study of European water distribution systems. Concentrations of less than 1 ng/liter were found in a study of six U.S. drinking water systems (NRC, 1982~. Tissue Distribution BaP has been found in the liver, lungs, colon, kid- neys, muscle, brain, and forestomach of mice. It tends to localize in fatty tissues. Formation of DNA Adducts Cytochrome P-450 enzymes and epoxide hydrolases metabolize BaP to the two diastercoisomers responsible for DNA

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64 DRINKING WATER AND HEATH adduct formation. The two diastercoisomers are (+~-7b,8a-dihydroxy-9a,10a- epoxy-7,8,9,10-tetrahydrobenzoLa~pyrene (BPDE I) and ~-)-7b,Sa-dihy- droxy-9b, lOb-epoxy-7,8,9, 10-tetrahydrobenzoLa~pyrene (BPDE II). These two compounds bind mainly to 2-amino groups of guanine residues, but also to the N7 position (NRC, 1982; Sontag, 19811. BaP also forms N6-adenine adducts (Jeffrey et al., 1979), which appear to be important in ras oncogene activation. In rats, an increase in intravenous administration of BaP from 1 ,u~mol to 10 Amos increased adduct concentration in rat lung approximately fivefold and in rat liver about threefold. The pattern of metabolism of BaP was similar in human, monkey, dog, hamster, and rat, but adduct concentration varied widely. The concentration was 30 times higher in human bladder than in rat bladder. In the trachea and bronchi, the incidence of adduct formation differed by a factor of 10 between human and rat. Mutagenicity BaP is a positive mutagen in the Salmonellalmicrosome test (McCann et al., 19751. Carcinogenicity Carcinogenic effects were observed in mice after the administration of 40-45 ppm BaP orally for 110 days (Rigdon and Neal, 1966, 19691. Rats and hamsters have also shown sensitivity to the induction of benign and malignant skin tumors by BaP (NRC, 19771. It is suspected that a possible consequence of long-term exposure to BaP is an increased incidence of bronchial carcinoma. Other Health Effects Repeated oral BaP administration in mice resulted in hypoplastic anemia. Its acute toxicity is low. Summary BaP is mutagenic and carcinogenic in animals and a suspected human carcinogen. Chromium Cr Chromium is usually found as either hexavalent chromium, Cr(VI), or tri- valent chromium, Cr(III). Cr(III) is an essential micronutrient that is low in the typical American diet. It is toxic at high doses. Relatively large quantities of chromium have been found in wastewater from the plating and finishing industries. Cr(VI) is much more toxic than Cr(III). Occurrence A study of more than 1,500 surface waters in the United

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Appendix A 65 States showed a maximal chromium content of 0.11 mg/liter and a mean of 0.01 mg/liter (NRC, 19801. Tissue Distribution In humans, chromium occurs at the highest concen- tration in the lungs. That suggests that the primary human exposure is through air, and not through food or water. Cr(III) is inhibited by membrane barriers; Cr(VI) is absorbed and then reduced to Cr(III) (NRC, 19771. Chromium concentrations of 1-5 ~g/ml of plasma and less than 1 ng/ml of urine have been reported (NRC, 1980~. Formation of DNA Adducts Cr(III) binds to free nucleotides and to nu- cleic acids at nucleophilic sites (such as the unesterified oxygen of phosphate groups and the nitrogen and oxygen atoms of nitrogen bases). Binding to DNA involves regions with high concentrations of guanine and cytosine and produces DNA-DNA cross-links that, if not repaired, lead to extensive DNA fragmentation. Cr(VI) causes breakage of polynucleotide chains that is in- ferred by changes in physicochemical properties of DNA (Merian et al. 1985). Mutagenicity Chromium decreases the fidelity of DNA synthesis and induces gene mutations, chromosomal aberrations, sister-chromatic ex- changes, and malignant transformation in mammalian cells (Merian et al., 1985). Carcinogenicity Cr(VI) has been shown to cause dermal ulcerations and respiratory cancer. Cr(VI) is considered carcinogenic; the carcinogenicity of Cr(III) has not been conclusively established (NRC, 1986). Other Health Effects In humans, allergic contact dermatitis may result from exposure to either Cr(VI) or Cr(IIl). Workers in chromate plants have reported respiratory injury, most commmonly manifested as ulceration and perforation of the nasal septum (U.S. EPA, 1984). Summary Both Cr(VI) and Cr(III) have exhibited a potential for genetic toxicity. However, the potential of Cr(III) for genetic toxicity is much less than that of Cr(VI), due to the inability of Cr(III) to cross cellular membranes. DibromochIoropropane (DBCP) H H H H-C-C-C-H 1 Br Br C1 DBCP is a short-chain aliphatic halogenated hydrocarbon that is used as a soil fumigant and nematocide.

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66 DRINKING WATER AND HEATH Occurrence No data on DBCP concentrations in drinking water were found. Tissue Distribution After exposure, DBCP is found mainly in the kidneys and testes. Formation of DNA Abducts DBCP induces sister-chromatic exchanges and chromosomal aberrations. It also causes unscheduled DNA synthesis and thus can be considered an adduct-forming agent, but the mechanism is un- known. Radiolabeling data indicate that DBCP, or a metabolite, binds to DNA (Kato et al., 1980~. Mutagenicity DBCP is an indirect mutagen in bacteria, in that it requires metabolic activation to induce mutagenic effects. In Drosophila melano- gaster, DBCP caused the loss of X and Y chromosomes and induced increases in heritable translocations. DBCP induced sister-chromatic exchanges and chromosomal aberrations in Chinese hamster ovary cells. In humans, it caused an increase in the number of sperm containing two Y chromosomes, sug- gesting irreversible genetic change. DBCP induced unscheduled DNA syn- thesis (DNA repair) in premeiotic germ cells in prepubertal mice (NRC, 19861. Dominant lethal mutations were induced in male rats, but not in male mice, in a study by Teramoto et al. (19801. Sasaki et al. (1986) showed that DBCP is mutagenic for somatic cells of mice in viva. Carcinogenicity DBCP induced a high incidence of squamous cell car- cinoma of the forestomach and toxic nephropathy in male and female rats and mice and a high incidence of mammary adenocarcinoma in female rats. An upper 95% confidence estimate of lifetime risk for human males drinking 1 liter of water per day containing DBCP at 1 ,ug/liter is 9.9 x 10-6 (NRC, 1986~. Other Health Effects Human exposure to DBCP has been shown to result in azoospermia or severe oligospermia. Reduction in sperm production is accompanied by increases in serum concentrations of follicle-stimulating hormone and luteinizing hormone and by reduction in or absence of sper- matogenic cells in seminiferous tubules. The reduction in spermatogenesis might also involve disturbances in genetic material in the sperm, such as the increased frequency of Y-chromosome nondisjunction found in 18 DBCP- exposed workers by Kapp et al. (19791. Male rats given DBCP at 120 mg/kg of body weight showed marked cytoplasmic vacuolization of the proximal renal tubular epithelium in the outer medulla and hepatic centrilobular necrosis. DBCP at 40 mg/kg produced only mild hepatocellular swelling in the periportal region of the liver lobules.

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Appendix A 67 The testes and epididymides of the rats revealed relatively minor cellular injury 24 hours after the two highest doses (80 and 120 mg/kg) (NRC, 19861. Summary DBCP produces functional disturbances of the liver and kid- neys and is carcinogenic in several organ systems in rats and mice. It is mutagenic in rats, and has adverse effects on human male fertility. Ethylene Dibromide (EDB) H H 1 1 H-C-C-H -1 Br Br EDB has been used as an antiknock constituent in gasoline containing tetraethyl lead, as a fumigant-insecticide, as a nematocide, and as a solvent for resins, gums, and waxes. Occurrence No data on EDB concentrations in Finking water were found. Tissue Distribution After intraperitoneal injection in rats and mice, EDB was concentrated in the liver, kidneys, and small intestine. Formation of DNA Adducts EDB has been shown to bind to DNA in vivo and in vitro. The major adduct formed has been identified as S-~2-(N7- guanyl~ethyl~glutathione (Inskeep et al., 1986~. Mutagenicity EDB is mutagenic at high doses in fungal and bacterial systems. In Drosophila melanogaster, gaseous EDB at a concentration as low as 2.3 ppm x hour (0.2 ppm for 11 hours) produced sex-linked lethal mutations (Kale and Baum, 19791. Carcinogenicity EDB produces squamous cell carcinoma and adenocar- cinoma of the forestomach, liver cancer, and hemangiosarcoma in rats and nasal cavity carcinoma, alveolar carcinoma, bronchiolar carcinoma, heman- giosarcoma, fibrosarcoma, malignant mammary neoplasm, and skin papil- loma in mice (NRC, 1986~. Other Health Elects Humans exposed to EDB have an acute dermal reaction that consists of painful local inflammation, swelling, and blistering. Systemic exposure causes vomiting, diarrhea, and abdominal pain, and in some cases delayed Jung damage, depression of the central nervous system,

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68 DRINKING WATER AND H"LTH metabolic acidosis, hepatic damage, acute renal failure, and death (NRC, 19&6). Studies in animals have shown acute lethality of EDB in several species. An intraperitoneal dose of 188 mg/kg of body weight in mice produced significant increases in liver and kidney weights and resulted in necrosis in those organs (NRC, 1986~. Summary EDB is mutagenic, carcinogenic, and toxic in the reproductive system of laboratory animals. It appears to be a direct-acting mutagen in some bacteria and to bind to DNA. A CONTAMINANT THAT PROBABLY FORMS DNA ADDUCTS TrichIorfon O H 11 1 CH3-O-P-C-CC13 O On CH3 Trichlorfon has been used as a chemotherapeutic agent for schistosomiasis and as an insecticide. Occurrence No data on trichlorfon concentrations in drinking water were found. Tissue Distribution In experiments with l4CH3-labelled trichlorfon, the compound or its metabolites were found in liver, lung, kidney, heart, spleen, and blood. It is also suggested that trichlorfon or a neurologically active metabolite can enter the central nervous system (NRC, 19861. Formation of DNA Adducts Trichlorfon can apparently react directly with DNA in vitro, albeit weakly (NRC, 1986). Mutagenicity Results of mutagenesis tests and tests for cytogenetic dam- age in cultured mammalian cells were positive for trichlorfon. Chromatid aberrations, such as sister-chromatic exchanges, have been reported in factory workers exposed to trichlorfon. The genetic risk to the offspring of patients treated with a therapeutic 15-mg/kg dose was estimated to be of the same

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Appendix A 69 order of magnitude as the risk associated with 100 mrads of gamma radiation (NRC, 1986~. Carcinogenicity Carcinogenicity studies have produced equivocal re- sults. Mammary tumors of three types were seen in laboratory animals (NRC, 19861. Other Health Effects Trichlorfon inhibits serum and red blood cell cho- linesterases in humans. Humans ingesting high doses developed neurologic dysfunction that appeared to be organophosphorus neuropathy. Decreases in sperm counts and sperm motility have also been noted. Short-lived chro- mosomal breaks and exchanges and an increase in stable chromosomal al- terations were found in some people exposed to trichlorfon. It has also been reported to affect sperm structure (NRC, 19861. Studies on trichlorfon exposure in animals indicated effects on cholines- terase inhibition similar to those found in humans (NRC, 1986~. Summary The human genetic toxicity risk associated with trichlorfon exposure is not clear. Studies show it has carcinogenic, teratogenic, and reproductive effects in humans or animals. The suggested no-adverse-re- sponse level (SNARL) calculated by the NRC Safe Drinking Water Com mittee is 88 ~g/liter for a 70-kg human (NRC, 19861. I CONTAMINANTS THAT POSSIBLY FORM DNA ADDUCTS DialIate CH3 CH3-CH ~O CH3-CH' 1 CH3 C1 C1 N-C-S-CH2-C = CH Diallate is an herbicide used in the control of wild oats and weeds in fields of sugar beets, flax, barley, corn, and various other crops. Occurrence Estimated exposure to diallate for workers during application is approximately 0.5 ~g/kg of body weight by inhalation and 980 ~g/kg by dermal deposition (NRC, 19861. No data on occurrence in drinking water were found.

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70 DRINKING WATER AND H"LTH Tissue Distribution No data are available. Formation of DNA Adducts Evidence of DNA-adJuct formation by dial- late is inconclusive. Diallate causes base-pair mutations and thus might form DNA adducts. Mutagenicity Base-pair mutations were produced in Salmonella typhi- murium at doses as low as 1 template. Mutagenic activity depended on metabolic activation by hepatic microsomes (NRC, 19861. Carcinogenicity Diallate produced systemic reticulum cell sarcomas in male mice and hepatomas in both sexes of mice (NRC, 19861. Other Health Effects In cats, rats, and mice, diallate produced central nervous system excitement that rapidly progressed to clonic convulsions. It produced delayed peripheral neuropathy in hens (NRC, 1986~. Summary Diallate is mutagenic, carcinogenic, and produces neurotoxic effects. More complete carcinogenicity data is necessary for estimating risk. SulfalIate c2 Hs C2Hs: S Cl , N-C-S-CH2C= CH2 Sulfallate is a carbamate herbicide used for the control of grasses and weeds in fruit and vegetable crops. It is soluble in water up to 100 ppm at 25C. Occurrence No data on the concentration of sulfallate in drinking water were found. Tissue Distribution No data are available. Formation of DNA Adducts Evidence of DNA-adduct formation by sul- fallate is inconclusive. Mutagenicity Sulfallate produces base-pair substitutions in Salmonella typhimurium at doses as low as 10 ,ug/plate in the presence of metabolic activation enzymes (NRC, 19861.

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Appendix A 71 Carcinogenicity Mammary adenocarcinomas in female rats and.stomach neoplasms in male rats were observed after the administration of sulfallate; the effect appeared to be dose-dependent. Alveolar and bronchiolar carci- nomas and adenomas, with mammary adenocarcinomas, were observed in mice. On the basis of these studies, and assuming consumption of 1 liter of water per day containing sulfallate at 1 ,ug/liter, the lifetime cancer risk estimated for humans is 1.0 x 10-6, and the upper 95~o confidence estimate of lifetime cancer risk is 1.6 x 10-6 (NRC, 19861. Other Health Effects Rats fed sulfallate at 250 ppm for 6 months de- veloped eye irntation, tubular nephropathy, and hyperkeratosis of the fore- stomach (NRC, 19861. Summary Sulfallate appears to be more carcinogenic than diallate, in- asmuch as it produces a broad range of tumors at multiple sites in several organs, whereas diallate produces a limited variety of tumors at a single site (NRC, 1986~. ChIoropropanes and ChIoropropenes 1,2-Dichloropropane (1,2-DCP) H H 1 1 CH3-C-C-H 1 1 Cl C1 1,2,3-Trichloropropane (1,2,3-TCP) H H H 1 1 1 H-C-C-C-H 1 1 1 Cl Cl Cl cis- and trans-1,3-Dichloropropene (1,3-DCP) H H' ~H CH2 Cl CH2 Cl ~H E z ..

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72 DRINKING WATER AND HEALTH Occurrence These compounds are generally found in mixtures used as soil fumigants and fungicides, but they have also been used as commercial solvents, drycleaning agents, and in the production of plastics. No data were found on concentrations of 1,3-pop, 1,2,3-TCP, and 1,2- DCP in drinking water. . . . Tissue Distribution Target organs appeared to be the liver, kidneys, and adrenals in all animals studied (NRC, 19861. Formation of DNA Adducts Evidence of DNA-adduct formation is in- conclusive. Mutagenicity 1,2-pop had equivocal results when tested for mutage- nicity in the Ames Salmonella test, but was shown to induce sister-chromatic exchanges at 1 mg/ml and chromosomal aberrations at a similar concentration in cultured lymphocytes. 1,3-pop (with 1% epichlorhydrin added as a sta- bilizer) produced sex-linked mutations in Drosophila. The observed muta- genicity of commercial 1,3-pop in the Ames test was attributed to the presence of oxygenated and chlorinated degradation products. 1,2,3-TCP proved to be a mutagen in the Ames test at 0.1 ~mol/plate, but only in the presence of S9 microsomal extract (NRC, 19861. Carcinogenicity Laboratory animals developed multiple hepatomas after exposure to 1,2-pop. Exposure to 1,3-pop, given as Telone II (which also contains 1% epichlorohydrin, 2.5% 1,2-pop, and 1.5~% trichloropropene), resulted in tumors of the forestomach and liver nodules in male Fischer-344/ N rats and tumors of the urinary bladder, forestomach, and lung in female B6C3F1 mice. 1,3-pop was shown to be carcinogenic in Swiss mice, but there was insufficient data for a complete assessment. Assuming daily con- sumption of 1 liter of water containing Telone II at 1 1lg/liter, the estimated human lifetime cancer risk is 0.5 x 10-6, and the upper 95% confidence estimate of lifetime cancer risk is 1. 1 x 10-6. Although no information on carcinogenic studies of 1 ,2,3-TCP was found, it must be considered a possible carcinogen because of its structural similarity to other compounds displaying carcinogenicity (NRC, 19861. Other Health Effects Chloropropanes and chloropropenes cause contact dermatitis, headaches, vertigo, tearing, irritation of mucous membranes, and when ingested, liver damage in humans. The oral LDso is 860 mg/kg of body weight in mice and 2,200 mg/kg in rats (NRC, 19861. Summary Most of the studies reported have focused on the toxicity of these compounds in mixtures. 1,2-pop causes injury in the liver, kidneys, and adrenals, and 1,2,3-TCP has the same target organ toxicity. No other

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Appendix A 73 information was found on 1,2,3-TCP, but it is considered carcinogenic be- cause of its structural similarities to the other compounds. 1 ,3-pop (as Telone II) is carcinogenic in rats and mice (NRC, 1986~. Di(2-ethylhexyI) Phthalate (DEHP) and Mono(2-ethy~hexyI) Phthalate (MEHP) COOCH2 CH(C2 Hi; )(CH2 )3 CH3 r~< COOCH2 CH(C2 H5 )(CH2 )3 CH3 COOCH2 CH(C2Hs)(CH2)3CH3 [1~COOH Occurrence DEHP is used as a plasticizer in plastic products. Polyvinyl chloride pipes can contain up to 30% DEHP. Its concentration in water has been found to range from 5 to 130 ng/liter. DEHP is found in animal products; the highest concentrations have been detected in cheese and milk (35 and 31.4 mg/kg of fat, respectively) (NRC, 19861. DEHP is easily hydrolyzed in both the environment and the body to MEHP and 2-ethylhexanol. Plasma concentrations of MEHP are always higher than those of DEHP (NRC, 19861. Tissue Distribution DEHP is found primarily in liver and adipose tissue. Formation of DNA Adducts No evidence of DNA adduct-formation was found. Mutagenicity In the Ames Salmonella test, DEHP and MEHP were not mutagenic. However, DEHP induced sister-chromatic exchanges in Chinese hamster ovary cells after 24-hour exposures and at 1.0-100 mg/ml was positive in the Syrian hamster embryo cell transformation assay (NRC, 19861. Generally, DEHP and MEHP are considered nonmutagenic. Carcinogenicity In light of the observed nonmutagenicity of DEHP, it has been suggested that promotional activity of DEHP might be the mech- anism of action whereby carcinogenicity is induced. DEHP-induced S-phase response in mouse hepatocytes to a greater degree than in rat hepatocytes. That suggests that increased cell turnover can account for the carcinogenic activity of DEHP. Assuming daily consumption of 1 liter of water containing the compound at a concentration of 1 mg/liter, the estimated human lifetime cancer risk is 1.2 x 10-7 (NRC, 19861.

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74 DRINKING WATER AND H"LTH Other Health Elects One study determined that dialysis patients were receiving about 150 mg DEHP per week via leaching from plastics used in their treatment. After 1 month, no structural liver changes were observed; after 1 year, peroxisomes were increased in number. No other data on the effects of DEHP in humans were found. DEHP in the diet of rats at 6,000 and 12,000 ppm and of mice at 3,000 and 6,000 ppm was observed to yield hepatocellular tumors (NRC, 19861. In male rats, DEHP caused gonadal toxicity that led to reproductive, developmental, and fertility effects (NRC, 1986~. Summary DEHP is known to alter liver function; other areas of concern for possible toxic effects are reproductive and fertility effects, developmental effects, and cancer. CONTAMINANTS ON WHICH THERE IS NO EVIDENCE OF DNA-ADDUCT FORMATION Arsenic As Three major sources of arsenic are the smelting of metals, the burning of coal, and arsenic pesticides (for cotton dusting or wood preservation). It is also found in some pigments. Arsenic travels long distances in the atmosphere and precipitates in water. Another source of arsenic in drinking water is its leaching from rocks (Sontag, 19811. Occurrence Arsenic concentrations in drinking water can vary from less than 1 ppb to over 600 ppb, depending on the water source. Only 0.4% of samples taken from U.S. public drinking water supplies in a 1970 survey exceeded a total arsenic concentration of 0.01 mg/liter; however, mineral waters can contain 50 times as much arsenic as normal drinking water, and hot springs 300 times as much (NRC, 1977, 1980~. The U.S. Environmental Protection Agency drinking water standard is 50 ppb. Tissue Distribution Arsenic occurs mainly in the liver, kidneys, spleen, intestinal wall, and lungs (NRC, 1977~. Formation of DNA Adducts No evidence of DNA-adduct formation has been found. However, arsenic is cocarcinogenic and interferes with DNA repair mechanisms (NRC, 19771.

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Appendix A 75 Mutagenicity Trivalent arsenic causes aneuploidy. Sister-chromatid ex- changes and chromosomal aberrations are noted in cells affected by or ex- posed to arsenic compounds. Carcinogenicity Keratosis, skin cancer, and lung cancer have been ob- served in persons exposed to arsenic (NRC, 1977~. Other Health Elects Arsenic primarily affects tissues of the alimentary tract, kidneys, liver, lungs, and epidermis. Its damaging effect on capillaries results in hemorrhage into the gastrointestinal tract, sloughing of mucosal epithelium, renal tubular degeneration, hepatic fatty changes, and necrosis (Merian et al., 1985~. Summary Arsenic is neurotoxic in humans and animals. Environmental exposure to arsenic in drinking water has been linked in epidemiological studies to an increased incidence of several diseases and cancers (NRC, 1983). Nitrofen ,Cl Cl jo NO2 Nitrofen is a contact herbicide used on a variety of food crops to control animal grasses and weeds before and after crops begin to grow. It is activated by sunlight and kills weeds by inhibiting photosynthesis. Occurrence No data were found on nitrofen concentrations in drinking water. Tissue Distribution Nitrofen concentrates in fatty tissue, and occurs in smaller amounts in other tissues (Hurt et al., 19831. Formation of DNA AdJucts No data are available. Mutagenicity No data are available Carcinogenicity In rats fed nitrofen, metastatic and invasive ductal car- cinoma of the pancreas developed. In mice, an increased incidence of he- patocellular carcinomas was observed. On the basis of the no-observed-effect- leve} (NOEL), and assuming a daily consumption of 1 liter of water containing

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76 DRINKING WATER AND HEALTH nitrofen at 1 mg/liter, the estimated human lifetime cancer risk and upper 95% confidence estimate of lifetime cancer risk were 4.4 x 10-5 and 5.6 x 10-5, respectively (NRC, 19863. Other Health Effects A dose-related increase in the weight of the liver, testes, and kidneys was noted in rats fed nitrofen as part of their diet. Elevated liver weights as well as induction of cytochrome P-450 activity levels have been consistent, early signs of low-dose exposure in rodents. Nitrofen pro- duced soft-tissue abnormalities in fetuses of rats, mice, and hamsters (NRC, 19861. Summary Nitrofen is teratogenic and carcinogenic in laboratory animals. Pentachlorophenol Cl Cl Cl^OH Cl Cl Pentachlorophenol and its salts have been widely used as pesticides. Com- mercialpentachlorophenol is composed of 88.4% pentachlorophenol, 4.4% tetrachlorophenol, less than 0.1% trichlorophenol, and 6.2% higher chlori- nated phenoxyphenols (NRC, 19861. Occurrence Pentachlorophenol has been measured in effluent streams at 0.1-10 ~g/liter, in river water at 12.3 ~g/liter, in surface ponds and drainage water at 1-800 ~g/liter, in municipal drinking water at 99 parts per trillion, and in wells at 24 ppm. It has been detected in a variety of wildlife and in fish at 0.35-26 mg/kg of body weight. There has been widespread human exposure to this compound. Pentachlorophenol has been detected in seminal fluid (50-70 mg/kg) of exposed men, in urine (6.3 mg/liter), and in adipose tissue. The plasma of dialysis patients has been shown to contain penta- chlorophenol at 15.7-15.8 ~g/liter, compared with 15.0 1lg/liter in controls (NRC, 19863.

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Appendix A 77 Tissue Distribution The liver, kidneys, brain, spleen, and fat are major depositories in humans (NRC, 1986~. Formation of DNA Abducts No evidence of DNA-adduct formation has been found. Mutagenicity In the mouse spot test, weak mutagenic activity was ob- served. Pentachlorophenol was mutagenic in yeast assay, and chromosomal abnormalities were observed in Vicia faba seedlings, but no increases in chromosomal aberrations were observed in workers with increased concen- trations of pentachlorophenol in serum and urine (NRC, 19861. Carcinogenicity Carcinogenicity studies have not provided a basis for complete evaluation. Other Health Effects Acute exposure of laboratory animals to pentachlo- ropheno} results in vomiting, hyperpyrexia, and increases in blood pressure, respiration rate, and heart rate. Chronic studies have shown alterations in liver structure at all doses when rats ingested 20-500 ppm of pentachloro- phenol over an 8-month penod. Immunotoxicity and neurotoxicity were ob- served in laboratory animals given pentachlorophenol, and developmental effects occurred in the litters of female rats and hamsters dosed during ges- tation (NRC, 1986~. Summary The metabolism of pentachlorophenol is generally similar among mammalian species. However, inadequate characterization of the pentach- lorophenol used in studies has led to uncertainty as to whether observed effects were due to pentachlorophenol or to contaminants. Pentachlorophenol can be absorbed through the skin, by inhalation, and by ingestion. In animals, it has resulted in fetotoxicity and damage to the liver, kidney, and central nervous system; hematologic and immune systems have been affected. In humans, it is neurotoxic. It affects the immune system, liver, and kidneys, and produces hematologic disorders. Some studies have reported production of aplastic anemia and malignancy. REFERENCES Hurt, S. S., J. M. Smith, and A. W. Hayes. 1983. Nitrofen: A review and perspective. Toxicology 29:1-37. Inskeep, P. B., N. Koga, J. L. Cmarik, and F. P. Guengerich. 1986. Covalent binding of 1,2-dihaloalkanes to DNA and stability of the major DNA adduct S-[2-(N7 guanyl)ethyl]glutathione. Cancer Res. 46:2839-2844. Jeffrey, A. M., K. Grzeskowiak, I. B. Weinstein, K. Nakanishi, P. Roller, and R. G. Harvey.

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78 DRINKING WATER AND HEALTH 1979. Benzo(a)pyrene-7,8-dihydrodiol 9,10-oxide adenosine and deoxyadenosine adducts: Structure and stereochemistry. Science 206:1309-1311. Kale, P. G., and J. W. Baum. 1979. Sensitivity of Drosophila melanogaster to low concen- trations of gaseous mutagens. II. Chronic exposures. Mutat. Res. 68:59-68. Kapp, R. W., D. J. Picciano, and C. B. Jacobsen. 1979. Y-Chromosomal nondisjunction in dibromochloropropane-exposed workmen. Mutat. Res. 64:47-51. Kato, Y., K. Sato, O. Matano, and S. Goto. 1980. Alkylation of cellular macromolecules by reactive metabolic intermediate of DBCP. Nippon Noyaku Gakkaishi (J. Pest. Sci.) 5:45- 53. McCann, J., E. Choi, E. Yamasaki, and B. N. Ames. 1975. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. USA 72:5135-5139. Merian, E., R. W. Fret, W. Hardi, and C. Schlatter, eds. 1985. Carcinogenic and Mutagenic Metal Compounds. Current Topics in Environmental and Toxicological Chemistry, Vol. 8. New York: Gordon and Breach. Miller, M. J., D. E. Carter, and I. G. Sipes. 1982. Pharmacokinetics of acrylamide in Fisher- 344 rats. Toxicol. Appl. Pharmacol. 63:36-44. Moore, M. M., A. Amtower, C. Doerr, K. H. Brock, and K. L. Dearf~eld. 1987. Mutagenicity and clastogenicity of acrylamide in L5178Y mouse lymphoma cells. Environ. Mutagen. 9:261-267. NRC (National Research Council). 1977. Drinking Water and Health, Vol. 1. Washington, D.C.: National Academy of Sciences. 939 pp. NRC (National Research Council). 1980. Drinking Water and Health, Vol. 3. Washington, D.C.: National Academy Press. 415 pp. NRC (National Research Council). 1982. Drinking Water and Health, Vol. 4. Washington, D.C.: National Academy Press. 299 pp. NRC (National Research Council). 1983. Drinking Water and Health, Vol. 5. Washington, D.C.: National Academy Press. 157 pp. NRC (National Research Council). 1986. Drinking Water and Health, Vol. 6. Washington, D.C.: National Academy Press. 457 pp. Rigdon, R. H., and J. Neal. 1966. Gastric carcinomas and pulmonary adenomas in mice fed benzo(a)pyrene. Tex. Rep. Biol. Med. 24:195-207. Rigdon, R. H., and J. Neal. 1969. Relationship of leukemia to lung and stomach tumors in mice fed benzo(a)pyrene. Proc. Soc. Exp. Bio. Med. 130:146-148. Sasaki, Y. F., H. Imanishi, M. Watanabe, A. Sekiguchi, M. Moriya, Y. Shirasu, and K. Tutikawa. 1986. Mutagenicity of 1,2-dibromo-3-chloropropane (DBCP) in the mouse spot test. Mutat. Res. 174:145-147. Shelby, M. D., K. T. Cain, C. V. Cornett, and W. M. Generoso. 1987. Acrylamide: Induction of heritable translocation in male mice. Environ. Mutag. 9:363-368. Shubik, P., G. Pietra, and G. Della Portal 1960. Studies of skin carcinogenesis in the Syrian golden hamster. Cancer Res. 20:100-105. Solomon, J. J., J. Fedyk, F. Mukai, and A. Segal. 1985. Direct alkylation of 2'-deoxynu- cleosides and DNA following in vitro reaction with acrylamide. Cancer Res. 45:3465-3470. Sontag, J. M., ed. 1981. Carcinogens in Industry and the Environment. Pollution Engineering and Technology, Vol. 16. New York: Marcel Dekker. 761 pp. Teramoto, S., R. Saito, H. Aoyama, and Y. Shirasu. 1980. Dominant lethal mutation induced in male rats by 1,2-dibromo-3-chloropropane (DBCP). Mutat. Res. 77:71-78. U.S. EPA (Environmental Protection Agency). 1984. Health Assessment Document for Chro- mium. Final Report. EPA-600/8-83-014F. NTIS PB85-115905. Research Triangle Park, N.C.: U.S. Environmental Protection Agency.