Click for next page ( 58


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 57
Dichioromethane Hector D. Garcia, Ph.D. NASA-Johnson Space Center Toxicology Group Habitability anc!Environmental Factors Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Dichioromethane (DCM) is a nonflammable, clear, colorless, volatile, dense liquid with a mild, sweet, pleasant odor (see Table 2-1) (ATSDR 1998~. OCCURRENCE AND USE DCM is widely used as an industrial solvent and a paint stripper, and it is used in the manufacture of photographic film and in some aerosol prod- ucts, including spray paints and other household products. DCM is not used in spacecraft, but it out-gases from nonmetallic materials in spacecraft and can be produced during thermodegradation of chlorine-containing materials, such as polyvinyl chloride plastics. DCM has been detected in the space shuttle atmosphere in 28 of 33 missions from STS-26 to STS-55 at levels of 0.1-1 mg/m3 (James et al. 1994~. DCM vapors would be expected to condense along with water vapors and form "humidity condensate" in spacecraft air-cooling systems. Drinking water on the International Space Station (ISS) is generated from humidity condensate, recycled hygiene water, and urine and is supplemented by water from the shuttle or the 57

OCR for page 57
58 Spacecraft Water Exposure Guidelines TABLE 2-1 Physical and Chemical Properties of DCM Formula CH2C12 Chemical name Dichloromethane Synonyms Methylene chloride, methylene C dichloride H C H Cl CAS registry no. 75-09-02 Molecular weight 84.9 Boiling point 40C Melting point -95.1 C Liquid density 1.3182 g/mL at 25C Vapor pressure 349 tort at 20C; 500 tort at 30C Solubility 1 mL dissolves in 50 mL of water (2.0% w/v; approx- imately 20 g/L at 20C; 16.7 gAL at 25C) Taste and odor 9. 1 ppm in water; 160-620 ppm vapor in air (most threshold people can detect its odor at >300 ppm vapor in air) Miscible with alcohol, ether, acetone, chloroform, and carbon tetrachloride. Russian Progress spacecraft. Because the air-to-water partition coefficient for DCM is approximately 6 at 37C (Gargas et al. 1989), most DCM in spacecraft will be present as vapor in the atmosphere, but it is expected that traces of DCM might be found in the ISS drinking water under normal conditions. PHARMACOKINETICS AND METABOLISM Limited data are available on the uptake, metabolism, and elimination of DCM ingested through drinking water by humans or animals. The de- scription below presents data mostly for DCM administered to rodents by gavage in water or corn oil.

OCR for page 57
Dich1/toromethane 59 Absorption No quantitative studies were found describing the absorption of in- gested DCM in humans, although several case reports of individuals who attempted suicide by consuming DCM provide evidence (in the form of profound CNS depression) that ingested DCM is absorbed in humans. In mice exposed to DCM at 50 mg per kilogram (kg) by gavage in water, DCM was rapidly absorbed from both the upper and lower portions ofthe gut, with 75/O ofthe dose absorbed within 10 minute (min) and about 98/O of the dose absorbed within 20 min (Angelo et al. 1986a). Distribution No studies were found that described the tissue distribution of ingested DCM in humans. In mice and rats, whole-body autoradiograms were prepared 1 hour (h) after oral gavage with ~4C-labeled DCM in corn oil at 100 mg/kg and 50 mg/kg, respectively. The tissues highlighted by their ~4C content were the liver, blood, lungs, heart, spleen, bone marrow, salivary glands, and pan- creas in mice; and the liver, blood, lungs, kidneys, spleen, brain, salivary glands, intestine, and stomach in rats (Yesair et al. 1977~. The liver ap- peared to be the major site of metabolism. The autoradiograms also indi- cated that absorption from the digestive tract is relatively rapid. In rats given doses of radioactive DCM at 50-1,000 mg/kg for 14 4, the label was rapidly cleared from all tissues during the 240 min after each exposure, suggesting that DMC and/or its metabolites do not accumulate in any tis- sues (Angelo et al. 1986a,b). Excretion No studies were found that described the excretion of DCM or its me- tabolites in humans. In mice exposed to DCM at 50 mg/kg by gavage in water, DCM was rapidly eliminated from all tissues examined (Angelo et al. 1986a). DCM elimination was mainly in expired air; 53-61% was ex- creted as unchanged DCM; S-23% was excreted as carbon dioxide (CON; and 0.5-12% was excreted es carbon monoxide (CO). Within4 h of dosing, the DCM concentrations in the blood and most ofthe tissues were below the

OCR for page 57
60 Spacecraft Water Exposure Guidelines limit of detection (<0.05 micrograms begs of DCM per gram of tissue) (Angelo et al. 1986a). In rats given oral doses of radiolabeled DCM at 1 mg/kg or 50 mg/kg in water, expired air accounted for 78-90/O of the ex- creted dose in the 48 h following administration (McKenna and Zempel 1981). Radiolabel in the urine accounted for 2-5% of the dose, and 1% or less ofthe dose was found in the feces (McKenna and Zempel 1981~. Metabolism At low doses, DCM is almost completely (more than 98/O) metabolized to CO and CO2 in all species studied (rats, mice, hamsters, and humans) (Kirschman et al. 1986~. Saturable kinetics are seen between 10 mg/kg/d and 50 mg/kg/d administered orally in both rats and mice. Greater fractions of DCM are expired unmetabolized at or above 50 mg/kg/d (Kirschman et al.1986~. Kirschman et al. (1986) found that metabolism is dose-dependent in mice. They showed a significant change in the proportion of adminis- tered DCM that is expired unchanged at doses above 1 mg/kg/d, as shown in Table 2-2 (Yesair et al. 1977; Kirschman et al. 1986~. The discontinuity in the proportion of DCM expired unchanged with increasing dose suggests the involvement of a saturable metabolic mecha- nism or mechanisms and indicates that doses at or above 50 mg/kg/d may be inappropriate for use in the safety assessment of exposure levels appre- ciably below those (Kirschman et al. 1986~. DCM is metabolized in mammals by two pathways (Gargas et al.1986~. A portion of ingested DCM is oxidized to CO by cytochrome P-450-de- pendent mixed-function oxidase enzymes. In humans, a smaller fraction is conjugated by glutathione-S-transferase (GST) to S-chioromethy! gluta- thione and subsequently to formaldehyde and to CO2 (Hallier et al. 1994~. The S-chIoromethyl glutathione conjugate is extremely unstable and short- lived, but if alkylation can occur before the conjugate breaks down, it could lead to mutagenesis (Green 1991~. Production of formaldehyde is also believed to be involved in the lung and liver carcinogenicity of DCM seen in mice (Casanova et al. 1996, 1997~. The GST pathway is several times more active in mice than in rats or in humans (Green 1991). The distribution of theta glutathione-S-transferase (GSTT1-1), the major enzyme involved in the metabolism of DCM, differs markedly between species (Green 1991). In mice, very high concentrations of mRNA for GSTT1-1 enzyme were found in the centrilobular region and in nuclei in liver parenchyma. In rat end human liver, GSTT1-1 was not localized in specific regions ofthe liver

OCR for page 57
Dich1/toromethane TABLE 2-2 Excretion of DCM Equivalentsa 61 Recovery (HO of Dose) Total Dose Expired Air Excretion (mg/kg) CH2C12 CO2 CO Urine Feces (HO of Dose) 0.1 1.7 34.6 34.1 10.4 ND 80.8 1.0 1.9 37.7 21.2 5.0 1.3 67.1 50 36.4 26.2 20.2 2.5 ND 85.3 100 40.5 10.7 3.6 1.4 0.3 56.5 500 55.2 10.5 6.8 1.7 0.05 74.2 aWithin 24 h of administration of an oral dose of ~4C-labeled DCM at 0.1-500 mg in water to B6C3F~ mice. Abbreviations: ND, not detected. Source: Data from Kirschman et al. 1986. Or in nuclei. Similar species differences were seen in the lung. These dif- ferences in the localization and level of activity of GSTT1-1 correlate with the species differences in the carcinogenicity of DCM. In humans, glutathione-S-transferase theta-1 (GST-T1) is polymorphic; about three- quarters of the population possesses this enzyme activity, and one-quarter lacks it (Nelson et al. 1995~. If GST-mediated conjugation is required for carcinogenesis by DCM, then individuals with no measurable glutathione conjugation activity would be expected to have little risk of developing cancer from exposure to DCM (Clewell 1995~. Significant ethnic differ- ences in the prevalence of the homozygous deleted genotype of GST-T1 have been reported, with null genotypes seen in the circulating red blood cells of 64% of Chinese, 60% of Koreans, 22% of African-Americans, 20% of Caucasian-Americans, 10% of Mexican-Americans (Nelson et al. 1995), and 38/0 of Europeans (Premble et al. 1994~. TOXICITY SUMMARY There are no reports of effects on the central nervous system (CNS) resulting from exposure to DCM in drinking water. High concentrations of inhaled DCM vapor or ingestion of large amounts of DCM as paint stripper have pronounced CNS effects that are reversible upon cessation of expo- sure. In rodents, hepatotoxicity, rather than CNS depression, is the main

OCR for page 57
62 Spacecraft Water Exposure Guidelines effect of intermediate and long-term exposure to moderate doses of DCM in drinking water. At higher doses in drinking water, mild kidney and hematologic changes have been reported. Inhaled DCM has been shown to be a carcinogen in mice and rats at high doses. Acute Toxicity (<1 d) Lethality Two human fatalities have been attributed to ingestion of DCM. A woman ingested about 300 milliliters (mL) of Nitromors paint remover, which contains DCM as its main ingredient. Other ingredients include methanol, cellulose acetate, triethanolamine, paraffin wax, and detergent. Her death, which occurred about 25 days (~) after ingestion, was attributed to the corrosive effects ofthe solvent on the intestinal tract rather than to the metabolic consequences of carboxyhemogIobinemia, which peaked at 12.1% 36 h after ingestion (Hughes and Tracey 1993~. A 49-y-old man successfully committed suicide by ingesting 300 mL of DCM (Chang et al. 1999~. His death occurred 9 ~ after ingestion, probably due to pulmonary edema complicated by anuria. His COHb levels were 35/O at ~ h post- ingestion, 18% at 28 h post-ingestion, 14% at 34 h post-ingestion, 11% at 73 h and 97 h post-ingestion, and 9/O at 120 h post-ingestion. An early report described the case of a man who survived ingesting "between one and two pints" of Nitromors (Roberts and Marshall 1976~. CarboxyhemogIobin levels were not measured in that case. Five additional cases have been reported in which patients ingested between 25 mL and 350 mL of DCM and survived after intensive symptomatic and supportive medi- cal treatment (Chang et al.1999~. General signs and symptoms of ingestion of large quantities of DCM in these cases included CNS depression, tachyp- nea, blistering and ulceration of the GI tract, hemogIobinuria, metabolic acidosis, and gastrointestinal hemorrhage. Hepatic and renal failures were reported in two of six cases. None of these patients developed significant cardiac arrhythmia. Inhalation of paint stripper vapors containing 80/O DCM and 20% methanol was reported to produce delayed and prolonged elevation of carboxyhemogIobin levels in four volunteers (Stewart and Hake 1976~. Levels of carboxyhemogIobin peaked about 4 h after a 3-h exposure; val- ues were measured at 6-9%. Stewart and Hale also reported a case of one 66-y-oldmanwho developed symptoms of cardiac infarction 1 h after using

OCR for page 57
Dich1/toromethane 63 a paint stripper for 3 h in his basement. Two weeks after recovery, he re- turned to stripping the furniture and was again hospitalized with myocardial infarction. He survived, but 6 months (mo) later, he returned to stripping the furniture, collapsed, and died. Stewart and Hake (1976) showed that simultaneous exposure to methanol extends the biologic half-life of carboxyhemogiobin derived from DCM (Stewart and Hake 1976~. In rats exposed by gavage in water, the LD50 (dose lethal to 50/O of subjects) of DCM was reported to be 2,100 mg/kg (Kimura et al.1971), and the LDg5 for rats exposed by gavage in oil was reported to be 4,382 mg/kg (Ugazio et al. 1973~. CNS Toxicity DCM vapor inhaled at 1,000 parts per million (ppm) for 1 h produced light-headedness in two of three volunteers and altered visual evoked re- sponses in all three subjects, but no subjective symptoms or objective signs were observed in eight subjects during a 1-h exposure to DCM vapor at 515 ppm (Stewart et al. 1972~. Winneke (1974) reported that a 4-h inhalation exposure to DCM at 300 ppm produced subtle but statistically significant CNS effects in human volunteers (including decreased critical flicker frequency and a decrease in auditory vigilance). Reitz et al. (1997) used Winneke's data in aphysiolog- ically based pharmacokinetic (PBPK) model to calculate a brain tissue concentration of DCM at 3.95 mg per liter (L). They extrapolated the inha- lation parameters to an exposure to drinking water containing 562 mg of DCM per liter, assuming a 70-kg person consuming 2.0 L/~. The U.S. Agency for Toxic Substances and Disease Registry (ATSDR) (1998) used these data to calculate a minimal risk level (MRL) of 0.5 mg/kg/d after applying an uncertainty factor of 30 (10 for the use of a minimal LOAEL tiowest-observed-adverse-effect level] and 3 for human variability) to the LOAEL of 16 mg/kg/d calculated by Reitz et al. (1997~. Nephrotoxicity Initial hemogIobinuria and progressive renal failure were seen in a woman who ingested a fatal quantity (300 mL) of paint remover predomi- nantly comprising DCM; acute tubular necrosis was observed postmortem (Hughes and Tracey 1993~. HemogIobinuria was also reported in the case

OCR for page 57
64 Spacecraft Water Exposure Guidelines of a man who survived ingestion of a similar quantity (1-2 pints) of the same paint remover (Roberts and Marshall 1976~. Cardiac and Hematologic Effects Because DCM metabolizes to CO, increased levels of carboxy- hemogiobin (COHb) are observed in exposed humans and animals. Never- theless, DCM ingestion is not associated with significant cardiac toxicity. Tachycardia (120 beats per minute) and marked hemolysis were observed in a woman who ingested a fatal quantity (300 mL) of paint remover (Hughes and Tracey 1993~. Intravascular hemolysis was also reported in the case of a man who survived ingestion of a comparable quantity (1-2 pints) of the same paint remover (Roberts and Marshall 1976~. No signifi- cant cardiac arrhythmia was found in medical case reports for eight individ- uals admitted to hospitals after ingesting DCM, despite high carb- oxyhemogiobin levels (measured at up to 35/O in some cases) that remained elevated for several days (Roberts and Marshall 1976; Hughes and Tracey 1993; Chang et al. 1999~. It should be noted, however, that in many of those cases, blood oxygen levels were monitored during treatments that often included assisted ventilation with 100% oxygen during portions ofthe hospital stays. The oxygen treatment was required because of dyspnea and, in some cases, pulmonary edema. Although three of the eight exposed individuals died, the deaths were not attributed to the CO produced by metabolism from DCM, but rather to the corrosive effects of DCM on the GI tract. NASA previously set exposure limits for inhaled CO based on a maxi- mum blood COHb concentration of 3/O (NRC 1994~. They reported that 3% COHb would be achieved by a person inhaling CO at 20 ppm for 24 h. Assuming an average minute-volume of 20 L/min over a 24 h period, that would mean 20 L/min x 60 min/h x 24 hid x 20/1,000,000 x 1 mole (mol)/22.4 L = 0.026 mol/d. Assuming, as a worst-case scenario, that 100% of the administered DCM were converted to CO, the concentration of DCM in drinking water needed to achieve a blood COHb concentration of 3/O for 1 d would be 0.026 mol/d x (84.9 g/mo! 2.8 L) = 0.78 g/L = 780 mg/L.

OCR for page 57
Dich1/toromethane 65 Thus, concentrations of DCM in drinking water at 780 mg/L would not be expected to produce clinically significant COHb concentrations. Short Term Toxicity (2-10 d) No reports were found of short-term (2-10 d) human or animal expo- sures to DCM. Hepatotoxicity Subchronic Toxicity (11-100 d) In preparation for a 2-y drinking water study (see Serota et al. l 986a,b), Kirschman et al. (1986) conducted a 90-d study in B6C3F, mice and F-344 rats ingesting water containing nominal levels of DCM at 0,0.15,0.45, and 1.5%. The intakes for these three nominal levels over the duration of the study, calculated based on analysis of DCM concentration and liquid con- sumption, were 166, 420, and 1,200 mg/kg/d for male rats and 209, 607, and 1,469 mg/kg/d for female rats. For mice, the corresponding values were 226, 587, and 1,911 mg/kg/d for males and 231, 586, and 2,030 mg/kg/d for females. For both rats and mice, the liver was the only target organ noted (Kirschman et al. l 986~. At a 30-d interim necropsy, no com- pound-related effects were found. At the terminal 3-mo necropsy, however, histopathology was found in the liver, including hepatocyte vacuolization, central lobular fatty change, necrosis with fatty change, and pigment depo- sition. The lowest effect levels were 587 mg/kg/d in mice and 166 mg/kg/d in rats (the lowest tested dose) (Kirschman et al. 1986~. Chronic Toxicity (>101 d) Hepatotoxicity The liver has been shown to be the primary toxicity target of DCM after long-term ingestion. Serota et al. (1986a,b) conducted 2-y drinking water carcinogenicity and toxicity studies in rats and mice administered DCM at target levels of 0, 0, 5, 50, 125, and 250 mg/kg/d in rats and 0, 0, 60, 125, 185, and 250 mg/kg/d in mice. These studies identified the liver as the only

OCR for page 57
66 Spacecraft Water Exposure Guidelines organ showing DCM toxicity, but there were considerable differences in sensitivity between rats and mice (Serota et al.1986a,b). Doses of 50,125, or 250 mg/kg/d produced both fatty changes and foci or areas of cellular alteration in the livers of both genders of rats. There was a NOAEL (no- observed-adverse-effect level) of 6 mg/kg/d (actual dose) in both male and female rats. In a parallel study in mice, treatment-related toxic changes were noted in both male and female livers only at the highest dose, with a NOAEL of 185 mg/kg/d in both genders of mice (Serota et al. 1986b). Decreased Water Consumption and Decreased Weight Gain In the 2-y study of Serota et al. (1986a), rats of both genders receiving DCM at target dose rates of 125 mg/kg/d or 250 mg/kg/d (actual rates: 131 mg/kg/d and 249 mg/kg/~), but not those receiving target dose rates of 5 mg/kg/d or 50 mg/kg/d (actual rates: 6 mg/kg/d and 55 mg/kg/~), had lower body weights and body-weight gains than controls and lower levels of food and water consumption. The authors considered these effects to be interre- lated and attributed to DCM treatment. In a parallel study in mice, no treat- ment-related effects on body weight or water consumption were observed during the study up to the highest dose, 250 mg/kg/d (Serota et al.1986b). Carcinogenicity Cancer in Animals Oral DCM ingestion. An elevated incidence of liver tumors were seen in female, but not male F-344 rats receiving DCM at up to 250 mg/kg/d in drinking water for 2 y, but this incidence was within the historical control range (Serota et al. 1986a). Male rats exhibited a lower incidence of both neoplastic nodules and hepatocellular carcinomas than seen in control groups (Serota et al. 1986a). Similarly exposed B6C3F~ mice showed no increase in the incidence of liver tumors (Serota et al.1986b). Female mice receiving DCM by gavage in olive oil at 500 mg/kg/d for 64 wk showed a slight, but not statistically significant increase in the incidence of mammary tumors (Maltoni et al. 1988~. Inhalation of DCM vapors. Inhalation exposure of B6C3F~ mice (50 mice per gender per dose) to DCM at 2,000 ppm and 4,000 ppm for 6 in/d,

OCR for page 57
Dich1/toromethane 67 5 d/wk for 2 y significantly increased the incidences of lung and liver tu- mors in both male and female mice compared with controls (NIP 1986~. F-344 rats exposed under the same conditions showed increased incidences of mammary gland tumors in female and, to a lesser extent, male rats (NIP 1986~. No increases in tumor incidence were seen in Sprague-Dawley rats or Syrian golden hamsters exposed by inhalation to DCM at 0, 50, 1,500, or 3,500 ppm for 6 in/d, 5 d/wk for 2 y, but a statistically significant dose- related increase in the number of mammary tumors per tumor-bearing fe- male rat was observed (Burek et al. 1984~. Cancer In Humans Oral ingestion of DCM. No reports of carcinogenic effects in humans after oral exposure to DCM were found. However, several studies exam- ined the potential for carcinogenic effects from inhalation of DCM vapors during occupational exposures. Inhalation of DCM vapors. Epidemiology studies have been per- formed using large cohorts of workers occupationally exposed to DCM in the photographic film base manufacturing industry and in triacetate fiber production. The available data from human epidemiological studies to date provide contradictory evidence concerning DCM's association with cancer of several organs; however, the studies are of limited power, or of only moderate latency since first exposure, or in some instances involve low and possibly ineffective doses. These studies have provided suggestive, but not persuasive evidence of an association between occupational exposure to DCM and increased cancer risk in humans. The studies are summarized below. FriedIander et al. (1978) conducted a proportionate mortality study and a retrospective mortality study of workers exposedto DCM at a Kodak film manufacturing facility in New York. No statistically significant differences between the two were observed. Hearne et al. (1987, 1990) updated FriedIander et al.'s cohort study and also reported no statistically significant findings for any cause of death. Hearne et al. conducted a second study with a different cohort of 1,311 workers at the same Kodak facility and followed them through 1990. The mean career individual exposure was approximately 40 ppm for 17 y, and the average interval between first expo- sure and end of follow-up was about 32 y. Total mortality for this cohort

OCR for page 57
Dich1/toromethane TABLE 2-5 Drinking Water Standards for DCM Set by Other Organizations 77 Organization Standard Amount 1-hHA Concentration (2 L/d x 70 kg) 10 mg/L for children 2 mg/L for children 2 mg/L O mg/L EpAa EpAa EpAa EpAa EPA ATSDR 10-dHA MCLG (final, 1998) RfD (oral, 1998) 0-14 d MRL ATSDR 15-364 d MRL ATSDR 365 d MRL 0.057 mg/kg/d 0 mg/kg/d 0.06 mg/kg/d 0.5 mg/kg/d Nsb 0.2 mg/kg/d 2 mg/L 17.5 mg/L Nsb 7 mg/L aSet by EPA's Office of Drinking Water. bATSDR did not derive an oral MRL for exposures of 15-364 d because of an inadequate database. Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry; DWEL, drinking water equivalent level; EPA, U.S. Environmental Protection Agency; HA, health advisory; MCLG, maximum contaminant level goal; MRL, minimal risk level; NS, not set; RfD, reference dose. (1997) used Winneke's data in a PBPK model to calculate a brain tissue concentration of 3.95 mg/L and extrapolated the inhalation parameters to an exposure to drinking water containing DCM at 562 mg/L, assuming a 70-kg person consuming 2.0 LO Reitz et al.'s calculated LOAEL of 16 mg/kg/d was used to calculate an AC assuming consumption of 2.8 L of water per day by a 70-kg person and using an uncertainty factor of 10 to estimate the NOAEL from the LOAEL. Because DCM does not accumu- late in the body, this AC would apply for all exposure durations. AC = 16 mg/kg/d x 70 kg 2.8L 10; AC = 40 mg/L. Hepatotoxicity The evidence and logic used to determine the ACs for hepatotoxicity for each exposure duration are documented below.

OCR for page 57
78 Spacecraft Water Exposure Guidelines ACs for hepatotoxicity for 1-d and 10-d exposures are based on Kirschman et al. 's ~ 1986) negative histopathology results at the interim 30-d necropsy of rats and mice given DCM in drinking water for 90 ~ at concen- trations of 0,0.15,0.45, and 1.5%. The calculated doses for rats were 166, 420, and 1,200 mg/kg/~ (males) and 209,607, and 1,469 mg/kg/~ (females); end the calculated doses formice were 226,587, and 1,911 mg/kg/d (males) and 231, 586, and 2,030 mg/kg/d (females). ACs were determined using the NOAEL of 2,030 mg/kg/d in mice necropsied 30 ~ postexposure. A factor of 10 was used for interspecies extrapolation because, although hu- mans appear to metabolize DCM at a much slower rate than do mice or rats, it is not known if the observed hepatotoxicity is due to metabolites or to the parent compound. If an appreciable fraction ofthe observed hepatotoxicity is due to the parent compound, the available data do not permit comparison of interspecies differences in susceptibility. Thus, the default factor of 10 was used. 1 -d and 10-d acceptable doses = 2,030 mg/kg/d x 70 kg 10 = 14,200 mug/. Astronauts consume an average of 2.8 L of drinking water per day, so the 1-d and 10-d AC in drinking water was calculated to be 14,200 mg/d 2.8 L/~= 5,000 mg/L. The 100-d AC for hepatotoxicity is based on Kirschman et al.'s (1986) 90-d LOAEL of 166 mg/kg/d reported for rats. A factor of 10 was applied for extrapolation from a LOAEL to a NOAEL, and a second factor of 10 was applied for extrapolation from rats to humans. Thus, the acceptable dose would be 166 mg/kg/d x 70 kg 10 10 = 116 my/. Astronauts consume an average of 2.8 L of drinking water per day, so the 100-d AC in drinking water was calculated to be 116 mg/d 2.8 L/d = 42 mg/L. An AC in drinking water for 1,000 ~ was calculated using Serota et al. 's (1986a) NOAEL of 6 mg/kg/d for hepatotoxicity reported for rats consum- ing DCM in drinking water, and an interspecies factor of 10 was applied. The calculation assumed consumption of 2.8 L/d for a 70-kg person.

OCR for page 57
Dich1/toromethane 79 1,000-d AC = 6 mg/kg/d x 70 kg 10 2.8 L/d; 1,000-d AC = 15 mg/L. Taste Aversion and Reduced Water Consumption Using Serota et al.'s (1986a) rat NOAEL of 55 mg/kg/d for reduced water consumption and reduced weight gain in rats treated with DCM in drinking water, the concentration of DCM that did not reduce water con- sumption in rats can be estimated. Assuming an average rat weight of 200 g and average consumption of 20 mL/d. the 55 ma/lea/d would be achieved at a DCM concentration of , ~ ~ 55 mg/kg/d x 0.20 kg 0.02L = 550 mg/L. An AC for humans was calculated by applying an interspecies factor of 10. 1-1,000-d AC = 550 mg/L 10 = 55 mg/L. Carcinogenicity Using the lung cancer incidence data from the NTP's 2-y bioassay of DCM in mice and rats as input for a PBPK model, Clewell (2000) calcu- lated the DCM concentrations in drinking water that would yield a cancer risk of 1 in 10,000 in astronauts who consumed 2.8 L/d. The model pro- duced the following results. 1000-d AC = 275 mg/L; 100-d AC = 1,650 mg/L; 10-d AC = 13,000 mg/L; and 1 -d AC = greater than the solubility of DCM in water (22 g/L). Spaceflight Effects Spaceflight causes a shift of body fluids to the chest with a subsequent reduction in blood volume over the course of several days. The reduced blood volume is believed to contribute to orthostatic intolerance on return to 1-g. DCM at high concentrations in drinking water has been reported to

OCR for page 57
80 v o . - Al o v Al Cot Cat o of o o -i O V ~ ~ V9c= ~s set o sat ~ 'all En ~ C) C) ~ ~ o o I~ o o o o o o o o o o o o o o to to to to m O O O m O O ,34 ~ 0 ~ O Z o 0 3 ,,, - v 6 v oo ~ oo ~ ~ ~ - ^ Ct ~ Ct ~ _1 ~ _1 . ~ ~ =^ ~ ~ 0 0 ti E 0 {o ,;~ ;^ ~ ;^ ~ 0 E ~ ~ 0 11 ~ 11 ~ 11 ~ 11 ~ 11 ~ ~ ~ ~ ~ ,c ~ ~ 0 ~ 0 ~ ~ ~ ~ ~ = = ~ . c~ c.~ ~ 43 0 5 ~ E E ~ e S Y ~ ~0 o o =' ~o F~ ~o O O~ 5 EO 0 >0 v ct - 0 0 F~ .~ ~0< cd ~ ~ ~ 6^ O ^ ~ ~ ~ O ~20 ~ 5^ :~ ~ ~ E 5 O D C) rO S~ Ct

OCR for page 57
Dich1/toromethane TABLE 2-7 Comparison of Daily DCM Exposure at the SWEGs and SMACs 81 Exposure SWEGs SMACs Duration mg/L mg/d Effect 1 h mg/m3 mg/d Effect 350 3,850 CNS depression 24 h 40 112 Taste aversion, 120 1,320 CNS depression (1 d) CNS depression 7d 50 550 CNS depression 10 d 40 112 Taste aversion, CNS depression 30d 20 220 Hepatotoxicity 100 d 40 112 Hepatoxicity, Taste aversion, CNS depression 180 d 10 110 Hepatotoxicity 1,000 d 15 42 Hepatotoxicity, CNS depression cause a reduction in water consumption, which might exacerbate the normal reduction in blood volume and the resulting orthostatic intolerance. Comparison of SWEGs to Inhalation Limits (SMACs) for DCM The amount of DCM to which an individual would be exposed through drinking water at the SWEG values is compared in Table 2-7 (above) with the exposures that would result from inhalation at the recommended space- craft maximum allowable concentrations (SMACs) for DCM vapors. The SWEG values assume consumption of 2.8 L of water per day and 100% absorption. The daily amounts that would be absorbed during inhalation of air containing the SMACs for DCM vapors assume inhalation of 20 m3/d and retention of 55/O (NRC 1996~. The daily amounts absorbed (edge) are comparable for the two routes of exposure, except for exposure durations less than 10 d. Because taste aversion is independent of duration, the ACs will not increase as the expo- sure duration is reduced from 10 ~ to 1 d.

OCR for page 57
82 C) o AN A O o .; ~ C=) 5 V2 g O O o V] o .~ V X V: ~ so o .- ~ -m == -~ ~ ~ o {I,, ~ o ~ Ct , . ~ .= .O C) a, o o En ~ a, 50 a, a, C) a, V: o o ~ To ~ ED v: no .g 0 o ~ a, o ~ . - Ct ~ at at ~ At, cd a, En ~ V: o ~ .~ ~ ~ c~) C) C) 50 ~ ~ ~ ~ ~ C ~ ~ ~ Ct Ct a, a, N~ N .- <5~ At = OO ~ 0~ - -- O ~ O ~ ~ ~ ~ Z ~ ~ At, ~ O ~ ~ V: ~ ~ ~ ~ ~ V: V V: Z Z Ct a, a, O Ct a, a, Ct ~ Ct a, ~ a, ~ Cd 00 Cd 00 O ~ O At At V: Ct V: Ct rip ~ O ~ ~ ~ ~ O ~ ~ ~ ,2j ~ V: Al ,~j V: V: En Z V: me . ~ a, C) a, a, a, Ct a, o o o . ~ ;^ o Ct a, V: . ~ 50 - ~ a., ~ ~ ~ o v: ~ Ad .m ~ a, ~ ~ 5-1 v: c) En ~ o ~= A` lo So a, ~ ~ to ~ ~^ v: o ~ = I

OCR for page 57
Dich1/toromethane Comparison of SWEGs to Standards Set by Other Organizations 83 The daily amounts ingested using the acceptable concentrations recom- mended above and assuming consumption of 2.8 L of water per day and 100% absorption are compared in Table 2-8 (above) with the drinking water standards set by other organizations. RECOMMENDATIONS FOR FUTURE RESEARCH Research is necessary to establish at what concentration of DCM dr~nk- ing water becomes unpalatable to adult humans. REFERENCES Allen, J., A. Kligerman, J. Campbell, B. Westbrook-Collins, G. Erexson, F. Karl, and E. Zeiger. l 990. Cytogenetic analysis of mice exposed to dichloromethane. Environ. Mol. Mutagen. 15 :221 -228. Andrae, U., and R. Wolff. 1983. Dichloromethane is not genotoxic in isolated rat hepatocytes. Arch. Toxicol. 52:287-290. Angelo, M.J., A.B. Pritchard, D.R. Hawkins, A.R. Walter, and A. Roberts.1986a. The pharmacokinetics of dichloromethane. I. Disposition in B6C3F~ mice following intravenous and oral administration. Food Chem. Toxicol. 24(9):965-974. Angelo, M.J., A.B. Pritchard, D.R. Hawkins, et al. 1986b. The pharmacokinetics of dichloromethane. II. Disposition in Fischer 344 rats following intravenous and oral administration. Food Chem. Toxicol. 24:975-980. ATSDR.1998. Toxicological Profile for Methylene Chloride (Update) (DRAFT). Agency for Toxic Substances and Disease Registry. Public Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia. Burek, J.D., K.D. Nitschke, T.J. Bell, D.L. Wackerle, R.C. Childs, J.E. Beyer, D.A. Dittenber, L.W. Rampy, and M.J. McKenna.1984. Methylene chloride: A two year inhalation toxicity and oncogenicity study in rats and hamsters. Fundam. Appl. Toxicol. 4:30-47. Casanova, M., D.A. Bell, and H.A. Heck. 1997. Dichloromethane metabolism to formaldehyde and reaction of formaldehyde with nucleic acids in hepatocytes of rodents and humans with and without glutathione S-transferase T1 and M1 genes. Fundam. Appl. Toxicol. 37: 168-180. Casanova, M., R.B. Conolly, andH.A. Heck.1996. DNA-protein crosslinks (DPX) and cell proliferation in B6C3F~ mice but not Syrian Golden Hamsters exposed to dichloromethane: Pharmacokinetics and risk assessment with DPX as do- simeter. Fundam. Appl. Toxicol. 31:103-116.

OCR for page 57
84 Spacecraft Water Exposure Guidelines Chang, Y.L., C.C. Yang, J.F. Deng, J. Ger, W.J. Tsai, M.L. Wu, H.C. Liaw, and S.J. Liaw. l 999. Diverse manifestations of oral methylene chloride poisoning: Report of 6 cases. Journal of Toxicology. Clin. Toxicol. 37~4~:497. Clewell, H. 2000. Determination of acceptable drinking water concentrations for short-term exposures. Report prepared by K.S. Crump Group, ICE Consulting, Inc., for Wyle Laboratories, Houston, TX. Clewell, H.J.1995. Incorporating biological information in quantitative risk assess- ment: An example with methylene chloride. Toxicology 103:83-94. Friedlander, B.R., F.T. Hearne, and S. Hall 1978. Epidemiologic investigation of employees chronically exposed to methylene chloride mortality analysis. J. Occup. Med 20:657-666. Gargas, M.L., R.J. Burgess, D.E. Voisard, G.H. Cason, and M.E. Anderson.1989. Partition coefficients of low-molecular weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Pharmacol. 98:87-99. Gargas, M.L., H.J. Clewell, and M.E. Anderson. 1986. Metabolism of inhaled dihalomethanes in vivo: Differentiation of kinetic constants for two independ- ent pathways. Toxicol. Appl. Pharmacol. 82:211-223. Gibbs, G.W. 1992. The mortality of workers employed at a cellulose acetate and triacetate fibers plant in Cumberland, Maryland; a 1970 cohort followed 1970-1989. Safety Health Environmental International Consultants, Winter- burn, Alberta, Canada. Hoechst Celanese. Gibbs, G.W., J. Amsel, and K. Soden 1996. A cohort mortality study of cellulose triacetate fiber workers exposed to methylene chloride. J. Occup. Environ. Med. 38:693-697. Gocke, E., M.-T. King, K. Eckhardt, and D. Wild.1981. Mutagenicity of cosmetic ingredients licensed by European Communities. Mutat. Res. 90:91 - 109. Graves, R.J., C. Coutts, and T. Green. 1985. Methylene chloride-induced DNA damage: An interspecies comparison. Carcinogenesis 16: 1919- 1926. Green, T.1991. Species differences in carcinogenicity: The role of metabolism and pharmacokinetics in risk assessment. Ann. Ist. Super. Sanita. 27:595-600. Green, T. 1997. Methylene chloride induced mouse liver and lung tumours: An overview ofthe role of mechanistic studies in human safety assessment. Hum. Exp. Toxicol. 16:3-13. Hallier, E., K.R. Schroder, K. Asmuth, A. Dommermuth, B. Aust, and H.W. Goergens. 1994. Metabolism of dichloromethane (methylene chloride) to formaldehyde in human erythrocytes: Influence of polymorphism of gluta- thione transferase theta (GST Tl-l). Arch. Toxicol. 68:423-427. Hearne, F.T., F. Grose, J.W. Pifer, B.R. Friedlander, andR.L. Raleigh.1987. Meth- ylene chloride mortality study: Dose-response characterization and animal model comparison. J. Occup. Med. 29:217-228. Hearne, F.T., J.W. Pifer, and F. Grose.1990. Absence of adverse mortality effects in workers exposed to methylene chloride: An update. J. Occup. Med. 32:234-240. Heineman, E.F., P. Cocco, M.R. Gomez, M. Dosemeci, P.A. Stewart, R.B. Hayes, S.H. Zahm, T.L. Thomas, and A. Blair 1994. Occupational exposure to chlori-

OCR for page 57
Dich1/toromethane 85 nated aliphatic hydrocarbons and risk of astrocytic brain cancer. Am. J. Ind. Med. 26~2~:155-169. Hughes, N.J., and J.A. Tracey. 1993. A case of methylene chloride (Nitromors) poisoning, effects oncarboxyhaemoglobinlevels. Hum. Exp. Toxicol.12:159- 160. IARC (International Agency for Research on Cancer). l 999. IARC monographs on the evaluation of carcinogenic risks to humans. Lyon, France: IARC. James, J.T., T.L. Limero, H.J. Leano, J.F. BoydandP.A. Covington.1994. Volatile organic contaminants found in the habitable environment ofthe Space Shuttle: STS-26 to STS-55. Aviation Space and Environ. Med. 65:851 -857. Jongen, W.M.F., P.H.M. Lohman, M.J. Kottenhagen, et al. 1981. Mutagenicity testing of dichloromethane in short-term mammalian test systems. Mutat. Res. 81 :203-213. Kimura, E.T., D.M. Ebert, and P.W. Dodge. 1971. Acute toxicity and limits of solvent residue for sixteen organic solvents. Toxicol. Appl. Pharmacol. 19:699-704. Kirschman, J.C., N.M. Brown, R.H. Coots, and K. Morgareidge. 1986. Review of investigations of dichloromethane metabolism and subchronic oral toxicity as the basis for the design of chronic oral studies in rats and mice. Food Chem. Toxicol. 24~9~:943-949. Lanes, S.F., A. Cohen, K.J. Rothman, N.A. Dreyer, and K.J. Soden. 1990. Mortal- ity of cellulose fiber production workers. Scand. J. Work Environ. Health 16:247-251. Lanes, S.F., K.J. Rothman, N.A. Dreyer, and K.J. Soden. 1993. Mortality update of cellulose fiber production workers. Scand. J. Work, Environ. Health 19:426-428. Maltoni, C., G. Cotti, and G. Perino.1988. Carcinogenicity bioassays on methylene chloride administered by ingestioin to Sprague-Dawley rats and Swiss mice and by inhalation to Sprague-Dawley rats. Ann. NY Acad. Sci. 534:352-366. McKenna, M.J., and J.A. Zempel 1981. The dose-dependent metabolism of 14C methylene chloride following oral administration to rat. Food Cosmet. Toxicol. 19:73-78. Nelson, H.H., J.K. Weincke, D.C. Christiani, T.-J. Cheng, Z.-F. Zuo, B.S. Schwartz, B.-K. Lee, M.R. Spitz, M. Wang, X.P. Xu, and K.T. Kelsey. 1995. Ethnic differences in the prevalence of the homozygous deleted genotype of glutathione S-transferase theta. Carcinogenesis 16~5~:1243-1245. NRC (National Research Council). 1994. Pp. 61-90 in Spacecraft Maximum A1- lowable Concentrations for Selected Airborne Contaminants, Vol.1. Washing- ton, DC: National Academy Press. NRC (National Academy Press). 1996. Pp. 277-305 in Spacecraft Maximum A1- lowable Concentrations for Selected Airborne Contaminants, Vol.2. Washing- ton, DC: National Academy Press. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NTP (National Toxicology Program).1986. National Toxicology Program technical

OCR for page 57
86 Spacecraft Water Exposure Guidelines report on the toxicology and carcinogenesis studies of dichloromethane in F344/N rats and B6C3F~ mice. NTP TR 306 Final Report. National Toxicol- ogy Program, U.S. Department of Health and Human Services, Washington, DC. OSHA.1997. Occupational Exposure to Methylene Chloride, Final Rule. Fed. Reg. 62(7):1494-1619. Ott, M.G., L.K. Skory, B.B. Holder, M.J. Bronson, and P.R. Williams. 1983a. Health evaluation of employees occupationally exposedto methylene chloride: Clinical laboratory evaluation. Scand. J. Work Environ. Health 9(Suppl 1~: 17-25. Ott, M.G., L.K. Skory, B.B. Holder, M.J. Bronson, and P.R. Williams. 1983b. Health evaluation of employees occupationally exposedto methylene chloride: Mortality. Scand. J. Work Environ. Health 9(Suppl 1~:8-16. Ott, M.G., L.K. Skory, B.B. Holder, M.J. Bronson, and P.R. Williams. 1983c. Health evaluation of employees occupationally exposed to methylene chloride. Twenty-four hour electrocardiographic monitoring. Scand. J. Work Environ. Health 9(Suppl 1~:26-30. Ott, M.G., L.K. Skory, B.B. Holder, M.J. Bronson, and P.R. Williams. 1983d. Health evaluation of employees occupationally exposed to methylene chloride. Metabolism data and oxygen half saturation pressure. Scand. J. Work Environ. Health 9(Suppl 1~:31-38. Peroco, P., and G. Prodi. 1981. DNA damage by haloalkanes in human lympho- cytes cultured in vitro. Cancer Lett. 13:213-218. Premble, S., K.R. Schroeder, S.R. Spencer, D.J. Meyer, E. Hallier, H.M. Bolt, B. Ketterer, and J.B. Taylor. 1994. Human glutathione S-transferase theta (GSST1~: cDNA cloning and the characterizatioin of a genetic polymorphism. Biochem. J. 300:271-276. Raje, R., M. Basso, T. Tolen, et al. 1988. Evaluation of in vivo mutagenicity of low-dose methylene chloride in mice. J. Am. Coll. Toxicol. 7:699-703. Reitz, R.H., S.M. Hays, and M.L. Gargas.1997. Addressing priority data needs for methylene chloride with physiologically based pharmacokinetic modeling. Prepared for the Agency for Toxic Substances and Disease RecistrY on behalf of the Halogenated Solvents Industry Alliance. ~ , Roberts, C.J., and F.P. Marshall. 1976. Recovery after lethal quantity of paint remover. Br. Med. J. (January):20-21. Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M. Brown, R.H. Coots, and K. Morgareidge. 1986a. A two-year drinking water study of dichloro- methane in rodents. I. Rats. Food Chem. Toxicol. 24~9~:951-958. Serota, D.G., A.K. Thakur, B.M. Ulland, J.C. Kirschman, N.M. Brown, R.H. Coots, and K. Morgareidge. 1986b. A two-year drinking water study of dichloro- methane in rodents. II. Mice. Food Chem. Toxicol. 24~9~:959-963. Sheldon, T., C.R. Richardson, and B.M. Elliott. 1987. Inactivity of methylene chloride in the mouse bone marrow micronucleus assay. Mutagenesis 2:57-59. Stewart, R.D., T.N. Fischer, M.J. Hosko, J.E. Peterson, E.D. Baretta, and H.C.

OCR for page 57
Dich1/toromethane 87 Dodd. 1972. Experimental human exposures to methylene chloride. Arch. Environ. Health 25~5~:342-348. Stewart, R.D., and C.L. Hake.1976. Paint remover hazard. JAMA 235~4~:398-401. Thilagar, A.K., A.M. Back, P.E. Kirby, etal.1984a. Evaluation ofdichloromethane in short term in vitro genetic toxicity assays. Environ. Mutagen. 6:418-419. Thilagar, A.K., P.V. Kumaroo, J.J. Clark, et al. 1984b. Induction of chromosome damage by dichloromethane in cultured human peripheral lymphocytes, CHO cells and mouse lymphoma L5178Y cells. Environ. Mutagen. 6:422. Tomenson, J.A., S.M. Bonner, C.G. Heijne, D.G. Farrar, and T.F. Cummings.1997. Mortality of workers exposed to methylene chloride employed at a plant pro- ducing cellulose triacetate film base. Occup. Environ. Med. 54:470-476. Tomenson, J.A., S.M. Bonner, C.G. Heijne, and D.G. Ferrar. 1996. Mortality of workers employed at a plans producing cellulose triacetate filmbase. Toxicolo- gist 30:481. Trueman, R.W., and J. Ashby.1987. Lack of UDS activity in the livers of mice and rats exposed to dichloromethane. Environ. Mol. Mutagen. 10: 198-195. Ugazio, G., E. Burdino, O. Danni, and P.A. Milillo. 1973. Hepatotoxicity and lethality of halogenoalkanes. Biochem. Soc. Trans. 1 :968-972. Wiger, R.1991. Effects on reproduction of dichloromethane (methylene chloride). KemI Report; 10/91, 11-27, Nordic Chemicals Control Group. Winneke, G.1974. Behavioral effects of methylene chloride and carbon monoxide as assessed by sensory and psychomotor performance.Pp. 130-144 in Behav- ioral Toxicology. C. Xinitaras, B.L. Johnson, and I. deGroot, eds. Washington, DC: U.S. Government Printing Office. Yesair, D.W., D. Jaques, P. Schepis, and R.H. Liss.1977. Dose related pharmaco- kinetics of (14C) methylene chloride in mice. Fed. Proc. Fed. Am. Soc. Exp. Biol. 36:988 (abstr. 3836~.