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9 Toxicity of Selected Contaminants The 14 compounds reviewed in this chapter were evaluated at the request of the EPA to assist the agency in regulating contaminants in drinking water. In selecting compounds for review, the committee was guided both by EPA's regulatory agenda and by concerns about important current toxicological issues within the research community. The 14 substances selected were, in order of discussion, acrylamide, aldicarb, diallate, sul- fallate, dibromochloropropane, 1,2-dichloropropane, 1,2,3-trichloropro- pane, 1,3-dichloropropene, di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, ethylene dibromide, nitrofen, pentachlorophenol, and trichlor- fon. Ten of the 14 contaminants are reviewed by a Safe Drinking Water Committee for the first time. The other four compounds, which were discussed in previous volumes of Drinking Water and Health, are reeval- uated in this volume. Whenever possible, the committee evaluated pub- lished, peer-reviewed literature pertaining to the compounds under study. For trichlorfon and di(2-ethylhexyl) phthalate, however, it examined re- views prepared by the World Health Organization, followed up by tele- phone calls to the investigators or knowledgeable sponsors. For acrylamide, aldicarb, and nitrofen, important new information was made available to the committee by researchers with projects under way. The committee conducted its own peer review of the unpublished studies and in some cases subjected the data to independent review. At the first stage of evaluation, an intensive literature review was con- ducted for each substance. In addition, data summaries were obtained from several offices of EPA, including the Office of Drinking Water and the Office of Pesticides. These summaries were used as an initial indication 294

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Toxicity of Selected Contaminants 295 of the range of available toxicological data. In some cases, foreign lit- erature was translated and evaluated. Much of the data are the results of 2-year chronic feeding studies in rodents, reflecting past interests in car- cinogenesis testing. However, the committee carefully examined toxico- logical data on other effects, such as teratogenesis, mutagenesis, reproductive effects, and metabolism. In addition, it reviewed the relatively sparse data on current production, manufacture, environmental distribution, and en- vironmental monitoring. The committee recognized that ingestion may not be the sole route of exposure to contaminants in drinking water. Cooking, showers, bathing, swimming, and other activities could theoretically provide important toxic contributions; however, given the absence of data on these noningestion routes, the committee declined to develop specific estimates of exposure for them. In addition, drinking water is not the only means of exposure to many of the compounds evaluated here. All sources of exposure must be considered by regulators in setting acceptable levels of exposure to contaminants in water, regardless of the biological end point under con- sideration. To allow for exposures through other routes, the committee generally assumed that drinking water provided 20% of the total exposure to a given compound. Following its review of the toxicology data, the committee classified compounds according to whether they were or were not known (or sus- pected3 carcinogens. For carcinogens, the risk to humans was expressed as the probability that persons weighing 70 kg would develop cancer some time in their lives as a consequence of ingesting 1 liter of water containing 1 fig of the substance daily over a lifetime of 70 years. Although risks to the 10-kg child were not calculated, the disproportionately high intake of drinking water by children as compared with that of adults would place them at greater risk. The committee then examined models for extrapolating from the high doses used in animal studies to the lower doses common in the environment of humans, and concurred with many experts who believe that several risk quantification techniques should be utilized to produce an estimated range of risks rather than a single number. The selection of models for low-dose extrapolations mus; be somewhat arbitrary except for the mul- tistage model, which is the only one with firm biological criteria at this time. Nonetheless, the committee recognizes that risk quantification re- mains an essential tool for rationalizing regulatory actions. The computation of risk depends on several factors, ranging from the selection of a mathematical model for low-dose extrapolation to the as- sumptions made within the model to fit a specific computer program. Because of the uncertainties involved in determining the true shapes of the dose-response curves used for extrapolation and because recent re-

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296 DRINKING WATER AND H"LTH search indicates several stages in cancer induction, the committee decided that in general the multistage model is the most useful. It appears to have more of a biological basis than most other models and in most cases is more conservative, giving higher estimates of risk at low doses than most other models. The model incorporates the reasonable assumption of back- ground additivity and is thus linear at low doses. Within the multistage model, one can compute the dose associated with a given level of risk by using either a restricted model or a generalized model. In the restricted model, the number of possible stages in the multistage process is limited to the number of doses at which the exper- iment was conducted minus 1. The generalized model places no such limit on the possible number of stages; rather, it permits computation of the best fit to the data without this constraint. A more detailed discussion of the committee's reasoning in selecting the generalized multistage model and its overall framework for risk assessment appears in Chapter 8. Although, as stated in Chapter 8, the committee believes that an un- derstanding of pharmacokinetic principles is useful to the extrapolation of response at high doses to estimate response at low doses, the relative paucity of pharmacokinetic data is apparent in the risk assessments made in this chapter. Adequate data of this type were not available for any of the compounds studied. The committee recommends a review of the needs and potential gains possible through the use of pharmacokinetic data and, where appropriate, stimulation of the acquisition of such data for com- pounds under consideration for future risk assessments. For agents not identified as known or suspected carcinogens and for which there were adequate toxicity data from prolonged ingestion studies in humans or animals, the committee calculated an acceptable daily intake (ADI), using methods developed in earlier volumes of this series and estimating dose-response relationships when data were sufficient. This conventional approach was taken by default in the absence of suitable low-dose extrapolation models and because a "safe level" has not been demonstrated for these noncarcinogenic effects. For carcinogens that pro- duced other toxic effects at low levels, the committee also estimated the minimum exposure levels at which such effects might be expected to occur. The ADI is derived by estimating the no-observed-effect level (NOEL) for any given compound and then dividing it by an uncertainty or safety factor. Aware of the pitfalls encountered in estimating NOELs, the committee carefully weighed the evidence supporting this level in any given study. Also sensitive to possible misinterpretations concerning the use of "safety" factors, the committee recognized that these factors prop- erly indicate levels of confidence in the underlying studies. For some compounds, the data base was adequate to permit an estimate of the magnitude of inter- or intraspecies variability and suggest a safety factor

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Toxicity of Selected Contaminants 297 based on that estimation. Where such an estimation was not possible, the committee used safety factors provided in previous guidelines: 10 when satisfactory data from chronic epidemiological or clinical studies were used; 100 for well-conducted long-term animal studies; and 1,000 for short-term studies or studies with some potential inadequacies. The poly- morphism of human drug metabolism indicates that the range of intra- human variability may be as high as 100-fold, implying that the uncertainty factor of 10 may not be adequately conservative. Furthermore, when extrapolating risk to the general population from epidemiological data, lack of quantitative exposure data may necessitate a further uncertainty factor. ACRYLAM I DE 2-Propenamide CAS No. 79-06-1 RTECS No. AS3325000 H O 1 11 CH2 = CCNH2 Acrylamide, the neurotoxic monomer of a commercially important poly- mer, polyacrylamide, is a highly reactive agent that spontaneously reacts with hydroxyl-, amino-, and sulfhydryl-containing compounds (Hashi- moto and Aldridge, 1970). It has a molecular weight of 71.08, a melting point of 84.5C, and a vapor pressure of 0.007 mm mercury at 20C. Its solubility in water is 215 g/100 ml at 30C. Total U.S. production of acrylamide in 1978 was 34,000 metric tons (MacWilliams, 1978~. Acrylamide polymers are used as additives to enhance oil recovery, in- crease dry strength in paper products, dissipate fog, and stabilize soil. They are also used in grouting operations, clarification of potable water, and treatment of municipal and industrial effluents. The biodegradation and environmental fate of acrylamide have been examined in both water and soil. Cherry et al. (1956) found that acrylamide degraded in filtered river water in 10 to 12 days. However, Croll et al. (1974) found more rapid degradation in river water of approximately 4 days. When acrylamide was added to soil (Lance et al., 1979), complete degradation occurred in approximately 6 days; a maximum of 60% of the acrylamide was degraded to carbon dioxide. Acrylamide should not sig- nificantly accumulate in the environment because of its high water solu- bility (Dow Chemical USA, 19841.

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298 DRINKING WATER AND HEALTH METABOLISM Following administration, acrylamide is rapidly distributed to all tissues, metabolized, and excreted (Edwards, 1975; Miller et al., 19821. After a single dose of ~4C-labeled 2,3-acrylamide, Miller et al. (1982) found equivalent concentrations of acrylamide in all tissues except in erythro- cytes, where acrylamide appears to accumulate (Pastoor and Richardson, 19811. Nervous system tissues accumulated less than 1% of the dose of acrylamide. The tissue content of radiolabeled acrylamide decayed in biexponential fashion (half-life of approximately 8 days), except in eryth- rocytes, where shortly after dosing a plateau was reached with a half-life of approximately 10.5 days (Pastoor and Richardson, 19811. The major route of biotransformation of acrylamide is conjugation with the tripeptide glutathione (Miller et al., 1982; Pastoor et al., 1980~; it is eventually excreted in the urine as N-acetyl-S-~3-amino-3-oxypropyl~cysteine. This route appears to be detoxifying since depletion of the nonprotein sulfhydryl content increases the neurotoxic potency of acrylamide. In addition to conjugation with glutathione, acrylamide appears to un- dergo partial microsomal-mediated metabolism. HEALTH ASPECTS Observations in Humans Although most human exposures to acrylamide result from dermal ab- sorption or ingestion of dust, one report documented exposure and toxicity resulting from drinking water contaminated with acrylamide. Igisu et al. (1975) described a Japanese family of five who ingested well water con- taminated with acrylamide from a nearby grouting operation. The con- centration of acrylamide in drinking water was found to be approximately 400 mg/liter. The children, who consumed acrylamide-free water while at school, developed mild gait disorders and sleep disorders. The parents, who consumed the ac~lamide-contaminated water exclusively, developed slurred speech, unsteady gait, memory loss, irrational behavior, and vi- sual, tactile, and auditory hallucinations. In other studies in humans, all the investigators (Auld and Bedwell, 1967; Davenport et al., 1976; Fullerton, 1969; Garland and Patterson, 1967) described neuropathy with a consistent set of symptoms. The first clinical manifestation of acrylamide neuropathy in humans is slowly pro- gressing symmetric distal sensory abnormalities and motor weakness. Sub- jects commonly reported skin sensitization (contact dermatitis); cold, blue hands; unsteadiness; muscle weakness; paresthesia; and numbness of the

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Toxicity of Selected Contaminants 299 hands or feet. Tendon reflexes disappear and vibrational sense is lost, but heat, pressure, and other objective sensory modalities remain intact. Re- covery from mild forms of acrylamide neuropathy is usually complete, occurring within a few months. Patients with severe neuropathy may never completely recover, but may experience residual ataxia, distal weakness, and sensory loss. Observations in Other Species Acute Effects The oral LD50 for acrylamide is 150 to 180 mg/kg body weight (bw) in rats, guinea pigs, and rabbits and 100 mg/kg bw in cats and monkeys (McCollister et al., 19641. Symptoms of intoxication in cats after high doses of acrylamide include behavioral disturbances, clonic seizures, severe ataxia, tremors, and death due to respiratory failure (Kuperman, 19581. Similiar responses are reported for rats, guinea pigs, rabbits (McCollister et al., 1964), and chickens (Edwards, 1975~. Miller et al. (1983) demonstrated inhibition of retrograde axonal transport in peripheral nerves within 24 hours after intraperitoneal administration of acrylamide to rats at 40 mg/kg. Increased numbers of dopamine receptors have been reported in the corpus striatum of rats following oral treatment with a 25-mg/kg bw dose of acrylamide (Agrawal et al., 19811. Subacute and Chronic Elects Subacute and chronic exposures to acrylamide have been demonstrated to produce symptoms of peripheral neuropathy in cats, rats, mice, guinea pigs, rabbits, and monkeys (McCollister et al., 19641. As with humans, intoxicated animals develop limb incoordination, which progresses to ataxia and weakness. This is most obvious in the hind limbs. Additional symptoms in acrylamide- intoxicated animals include weight loss, enlarged and distended bladders, and testicular atrophy. The enlarged bladders were attributed to "nervous retention"; however, the animals did continue to pass urine. The duration of exposure to acrylamide required to produce neuropathy appears to be a direct function of the magnitude of the acrylamide dose. Kuperman (1958) demonstrated that cats treated with acrylamide (1 to 50 mg/kg/day) developed clinical signs of acrylamide intoxication after re- ceiving an average total dose of approximately 102 mg/kg by a variety of routes, including intravenous and intraperitoneal administration, indepen- dent of whether the dose was administered over 2 days or 4 months. These data indicate that acrylamide is a cumulative neurotoxicant. Fullerton and Barnes (1966) demonstrated that degeneration of the distal processes of large-diameter peripheral nerves was associated with acrylamide-induced neuropathy in rats. Exposure to acrylamide in the diet at daily doses of approximately 15 to 18 mg/kg bw for 10 weeks resulted

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300 DRINKING WATER AND HEALTH in severe axon loss and proliferation of Schwann's cells in distal peripheral nerves. Pathology was most evident in the longest fiber tracts containing large-diameter axons. Electron microscopic studies of acrylamide-treated rats conducted by Prineas (1969) revealed dramatic increases in the number of axoplasmic neurofilaments and organelles. Occasional axons demon- strated invaginations of finger-like Schwann's cell processes that may act to remove damaged or degenerating axonal constituents. The dose of acrylamide required to produce neuropathy following chronic exposure has been investigated in several species. Structural or functional necrologic deficits have been noted after daily oral administration of acrylamide to rats (1 mg/kg bw for 93 days) (Burek et al., 1980), cats (0.7 mg/kg bw for 240 days) (McCollister et al., 1964), and monkeys (1 mg/kg bw for 18 months) (Schaumburg et al., 19821. Mutagenicity Acrylamide has been reported to be nonmutagenic in Salmonella typhimurium strains TA1535, TA1537, TA98, and TA100 at doses of 0.001 to 3 mg/plate with and without metabolic activation (Bull et al., 19841. Lack of acrylamide-induced genotoxicity was confirmed in the hepatocyte primary culture DNA repair test (Miller et al., 19841. Carcinogenicity Bull et al. ~ 1984) investigated the carcinogenic effects of acrylamide by administering it to female Sencar mice six times over 2 weeks at oral and intraperitoneal doses of 12.5, 25, and 50 mg/kg. The shaved back of each animal was subsequently treated with 1 1lg of 12-O- tetradecanoyl-phorbol-13-acetate (TPA) three times a week for 20 weeks, and the animals were sacrificed after 52 weeks. Acrylamide was found to produce dose-dependent increases in incidence of squamous cell car- cinoma. In addition, it produced dose-dependent decreases in the time to tumor appearances. No tumors were seen in animals not treated with TPA. In a separate experiment, Bull et al. (1984) found that oral or intraperi- toneal administration of acrylamide to A/J mice at doses of 6.25, 12.5, and 25 mg/kg three times a week for 8 weeks resulted in dose-dependent increases in the incidence of lung adenomas when measured 4 months after the last dose of acrylamide was given. K. A. Johnson et al. (1984) reported that male and female Fischer 344 rats developed tumors following a 2-year exposure to acrylamide in drink- ing water. Male rats exposed to ac~lamide at 0.5 mg/kg bw a day for 2 years developed scrotal mesotheliomas. At 2.0 mg/kg/day, benign thyroid tumors were also observed in male rats, whereas females demonstrated benign and malignant thyroid tumors, glial tumors within the central ner- vous system, adenomas of the clitoral gland, squamous cell papillomas in the mouth, benign and malignant mammary tumors, and malignant uterine tumors.

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Toxicity of Selected Contaminants 30 ~ TABLE 9-1 Tumor Incidence in Rats Fed Acrylamide-Contaminated Drinking Watera Animal Tumor Dose Sex Site (mglkg/day) Tumor Rates 3/60 0/60 7/60 1 1/60 10/60 Fischer 344 rat Male Scrotum O 0.01 0.1 0.5 2.0 aBased on data from K. A. Johnson et al., 1984. Carcinogenic Risk Estimate In the drinking water study recently com- pleted by K. A. Johnson et al. (1984), there was an increased incidence of scrotal mesothelioma in male Fischer 344 rats. In the study by Bull et al. (1984), there was an increase in lung tumors. The tumor incidences from the K. A. Johnson et al. (1984) study and the Bull et al. (1984) study are summarized in Table 9-1 and Table 9-2, respectively. Using these data, the committee estimated the lifetime risk and upper 95% confidence estimate of lifetime risk in humans after a daily con- sumption of 1 liter of water containing acrylamide at a concentration of 1 ,ug/liter. The conversion of animal to human doses is based on body surface area, assuming the following weights: humans, 70 kg; rats, 400 g; and mice, 33 g. The conversion formula is: animal consumption = human consumption times (human weight/animal weight)i'3. The risk estimates calculated with the generalized multistage model are shown in Table 9-3, and those based on the Weibull model are shown in Table 9-4. It is useful to compare the results obtained from the generalized multistage model with those of the Weibull model, which appeared to fit the data better. (See the discussion of risk-assessment models presented in Chapter 8.) TABLE 9-2 Tumor Incidence in Mice Given Acrylamide Intraperitoneallya Animal Tumor Site Dose (mg/kg/day) Tumor Rates Males 2/16 8/16 6/16 10/17 14/15 Females 1/15 6/17 9/17 1 1/14 14/15 A/J mouse Lung o 3 10 30 aBased on data from Bull et al., 1984.

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302 DRINKING WATER AND HEALTH TABLE 9-3 Carcinogenic Risk Estimates for Acrylamide from the Generalized Multistage Modela Upper 95% Confidence Estimated Human Estimate of Lifetime Animal Sex Lifetime Riskb Cancer Riskb Fischer 344 rats Male 6.6 x 10-6 1.2 x 10-5 A/J moused Male 3.8 x 10-6 7.5 x 10-6 A/J moused Female 8.2 x 10-6 1.4 x 10-s aFrom GLOBAL83, a software program developed in 1983 by R. B. Howe and K. S. Crump; modified for microcomputer compilation in 1985 by M. S. Cohn, U.S. Consumer Product Safety Commission, Washington, D.C. bAssuming daily consumption of 1 liter of water containing the compound in a concentration of 1 ~g/liter. CBased on data from K. A. Johnson et al., 1984. Based on data from Bull et al., 1984. In previous volumes of Drinking Water and Health, the risk estimates for male and female rats and mice were averaged to yield one composite number. If the data for the generalized multistage model in Table 9-3 are averaged, the estimated human lifetime risk is 1.2 x 10-s; the upper 95% confidence estimate of lifetime cancer risk is 2.1 x 1o-s . Developmental Effects Treatment of rats with acrylamide at 200 or 400 ppm daily (20 to 40 mg/kg bw) during gestation has been shown to produce no gross or histologic evidence of teratogenicity (Edwards, 1976~. CONCLUSIONS AND RECOMMENDATIONS Acrylamide is a highly reactive molecule that produces peripheral neuropathy in animals and humans following repeated exposure. The mag- TABLE 9-4 Carcinogenic Risk Estimates for Acrylamide from the Weibull Model Upper 95% Confidence Estimated Human Estimate of Lifetime Animal Sex Lifetime Riska Cancer Riska Fischer 344 ratb Male 1.7 x 10-4 9.7 x 10-4 A/J mouser Male 4.0 x 10-5 1.5 x 10-4 A/J mouser Female 7.4 x 10-5 2.7 x 10-4 aAssuming daily consumption of 1 liter of water containing the compound in a concentration of 1 ~g/liter. bBased on data from K. A. Johnson et al., 1984. CBased on data from Bull et al., 1984.

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Toxicity of Selected Contaminants 303 nitude of the dose of acrylamide required to produce neuropathy is in- versely related to the duration of exposure. Thus, no-observed-effect levels determined from laboratory studies of relatively short duration (less than 2 years) may be of little value in determining human risk following lifetime exposure. For this reason and because acrylamide is a cumulative toxicant, no further risk assessment was attempted for neurotoxicity. Recent data demonstrate that acrylamide is carcinogenic in laboratory animals. The estimated lifetime risk and the upper 95% confidence esti- mate of lifetime risk of cancer in humans presented above are based on both the multistage and Weibull low-dose extrapolation models. CARBAMATE PESTICIDES (ALDICARB, DIALLATE, AND SULFALLATE) ALDICARB 2-MethyI-2-(methy~thio~propanal ~~(methylamino~carbonyI]oxime CAS No. 6-06-3 RTECS No. UE2275000 CH2 0 CH3SCCH = NOCNHCH3 CH2 Since aldicarb was reviewed in Volumes 1 and 5 of Drinking Water and Health (NRC, 1977, pp. 635-643; 1983, pp. 10-12), the following section is primarily an examination of data not considered by the previous committees. HEALTH ASPECTS Observations in Humans The committee subjected to peer review a project report (Cope and Romine, 1973) on acute oral exposure of 12 healthy male volunteers (four males per group). This report indicated that aldicarb doses of 0.025 ma/ kg bw produced approximately 50% inhibition of blood cholinesterase, as measured by a radiometric technique. Cholinesterases are a family of enzymes responsible for hydrolyzing esters of choline such as acelylcho- line or butyrylcholine. At the highest dose, 0.1 mg/kg bw, approximately 70% inhibition of blood cholinesterase occurred attended by signs and

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304 DRINKING WATER AND HEALTH symptoms of hypercholinergic action. The signs and symptoms of poi- soning were for the most part gone within 4 hours after dosing, and the blood cholinesterase level was normal after 6 hours. Observations in Other Species Acute Effects Cambon et al. (1979) gave corn oil solutions of aldicarb to pregnant female Sprague-Dawley rats by gastric intubation (eight rats per group fasted 24 hours). The doses were 0.1, 0.01, and 0.001 mg/kg bw. The effect of this treatment on fetuses was discussed in Volume 5 of Drinking Water and Health (NRC, 1983, pp. 10-12), but the significant inhibition of maternal erythrocyte and liver plasma cholinesterase in dams given 0.1 and 0.01 mg/kg bw was not noted. Subacute Elects Aldicarb sulfoxide is a more effective esterase in- hibitor in vitro than the parent compound, whereas aldicarb sulfone is a poor esterase inhibitor. DePass et al. (1982) gave a 1:1 mixture of aldicarb sulfoxide/aldicarb sulfone to Wistar strain rats (10 rats of each sex per dose level range) in their drinking water for 29 days. The authors reported depressed body weight and food consumption 7 days into the exposure period in a group given 19.2-ppm concentrations of the mixture.These parameters remained depressed throughout the study in males (statistically analyzed on days 14, 21, and 29) but returned to normal in females. However, erythrocyte and plasma cholinesterase activity remained de- pressed after 8, 15, and 29 days in both males and females exposed to 19.2 ppm. Statistically significant reduction of plasma cholinesterase was seen in males exposed to 4.8 ppm for 8 days but not on later assay dates; erythrocyte cholinesterase was not depressed in this exposure group until day 29. Other exposure levels, where effects were not seen, were 1.2, 0.3, and 0.075 ppm. These data are difficult to interpret in that a mixture of aldicarb metabolites was used, and individual analyses of the two metabolites were not described. Chemical analysis revealed concentrations of the compound at only 80% of nominal values. Weil and Carpenter (1968) fed Harlan-Wistar rats (15 animals of each sex per group) aldicarb sulfoxide in the diet in concentrations that were believed to provide daily doses of 1.0, 0.5, 0.25, and 0.125 mg/kg bw. It does not appear that true doses were established. Five rats of each sex were sacrificed after 3 months for assay of plasma, erythrocyte, and brain cholinesterase using a titrimetric method. The surviving animals were killed after 6 months on the diet, and the same measurements were taken (except that a colorimetric assay was used). It was found that plasma and erythrocyte cholinesterases were generally more sensitive than brain cho- linesterases to aldicarb sulfoxide inhibition. The effect at the lowest dose

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428 DRINKING WATER AND HEALTH NTP (National Toxicology Program). 1982c. Carcinogenesis Bioassay of Di(2-ethyl- hexyl)adipate (CAS No. 103-23-1) in F344 Rats and B6C3F~ Mice (Feed Study). NTP Technical Report Series No. 212. NIH Publication No. 81-1768. U.S. Department of Health and Human Services, Washington, D.C. [131 pp.] NTP (National Toxicology Program). 1983a. Carcinogenicity Bioassay of 1,2-Dichloro- propane (Propylene Dichloride) (CAS No. 78-87-5) in F344/N Rats and B6C3F~ Mice (Gavage Studies). NTP Technical Report Series No. 263. NIH Publication No. 84-2519 (preliminary). U.S. Department of Health and Human Services, Washington, D.C. 180 PP NTP (National Toxicology Program). 1983b. Carcinogenesis Bioassay of Di(2-ethyl- hexyl)phthalate (CAS No. 117-81-7) in F344 Rats and B6C3F~ Mice (Feed Study). NTP Technical Report Series No. 217. NIH Publication No. 82-1773. U.S. Department of Health and Human Services, Washington, D.C. [141 pp.] NTP (National Toxicology Program). 1984a. Report of the NTP Ad Hoc Panel on Chemical Carcinogenesis Testing and Evaluation, Board of Scientific Counselors, National Tox- icology Program. U.S. Department of Health and Human Services, Washington, D.C. 280 pp. NTP (National Toxicology Program). 1984b. Review of Current DHHS, DOE, and EPA Research Related to Toxicology. NTP Publication No. 84-024. U.S. Department of Health and Human Services, Washington, D.C. 387 pp. NTP (National Toxicology Program). 1985a. Toxicology and Carcinogenesis Studies of Telone IN (Technical-Grade 1,3-Dichloropropene [CAS No. 542-75-6] Containing 1.0% Epichlorohydrin as a Stabilizer) in F344/N Rats and B6C3F~ Mice (Gavage Studies). NTP Technical Report Series No. 269. NIH Publication No. 85-2525. U.S. Department of Health and Human Services, Washington, D.C. 159 pp. NTP (National Toxicology Program). 1985b. Toxicology Research and Testing Program. Management Status Report. Produced from NTP Chemtrack System. Research Triangle Park, N.C. O'Hara, G. P., P. K. Chan, J. C. Harris, S. S. Burke, J. M. Smith, and A. W. Hayes. 1983. The effect of nitrofen [4-(2,4-dichlorophenoxy)nitrobenzene] on the reproductive performance of male rats. Toxicology 28:323-333. Ohta, T., N. Nakamura, M. Moriya, Y. Shirasu, and T. Kada. 1984. The SOS-function- inducing activity of chemical mutagens in Escherichia coli. Mutat. Res. 131:101-109. Oishi, S. 1984a. Effects of di-2-ethylhexyl phthalate on lipid composition of serum and testis in rats. Toxicol. Lett. 23:67-72. Oishi, S. 1984b. Testicular atrophy of rats induced by di-2-ethylhexyl phthalate: Effects of vitamin A and zinc concentrations in the testis, liver and serum. Toxicol. Lett. 20:75- 78. Oishi, S., and K. Hiraga. 1980a. Testicular atrophy induced by phthalic acid esters: Effect on testosterone and zinc concentrations. Toxicol. Appl. Pharmacol. 53:35-41. Oishi, S., and K. Hiraga. 1980b. Testicular atrophy induced by phthalic acid monoesters: Effects of zinc and testosterone concentrations. Toxicology 15:197-202. Oishi, S., and K. Hiraga. 1982. Distribution and elimination of di-2-ethylhexyl phthalate (DEHP) and mono-2-ethylhexyl phthalate (MEHP) after a single oral administration of DEHP in rats. Arch. Toxicol. 51: 149- 155. Oishi, S., and K. Hiraga. 1983. Testicular atrophy induced by di-2-ethylhexyl phthalate: Effect of zinc supplement. Toxicol. Appl. Pharmacol. 70:43-48. Olajos, E. J., I. Rosenblum, F. Coulston, and N. Strominger. 1979. The dose-response relationship of trichlorfon neurotoxicity in hens. Ecotoxicol. Environ. Safety 3:245-255.

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