methylene chloride

JOURNAL OF APPLIED TOXICOLOGY, VOL. 15(4), 329-335 (1995)

Toxicology Update

Note: The Toxicology Update represents a brief review of an often extensive literature base. Only some of the directly related references may be included.

METHYLENE CHLORIDE

Synonyms: Dichloromei hane, methane dichloride, DCM, metlhylene dichloride, methylene bichloride, NCI-C50102. CAS no.: 75-09-2. Boiling range: 40°C (at 760 mmHg). Color: colorless. Conversion factor: 1 ppm = 3.53 mg m-3 DOT designation: Poiscln B; label: St. Andrews Cross. Flammable limits: Autoignition, 1033°F; flash point, none: flammable vapor-air mixture at 100°C; LEL, 14%; UEL, 22%. Henry's law constant: 2.03 X atm m3 mol-' @ 20°C. Melting point: -95.1"C. Molecular formula: CH2C12. Molecular weight: 84.94. Odor: Threshold, 25-150 ppm; charac- teristic, sweetish, not uinpleasant. Solubility: water, 20000 mg 1-l at 20"C, &, = 1.30; miscible with a wide variety of organic solvents, & = 8.80 g m1-l. Specific gravity: 1.33 (water = 1). Vapor density: 2.93 (air = 1). Vapor pressure: 349 and 500 mmHg @ 20 and 30°C. Viscosity: 0.449 cst @ 2!O°C. (References: 1-3).

Composition

Methylene chloride or dichloromethane (DCM) is produced by two major processes in the USA: methane chlorination and chlorination of methyl chloride.4 Dichloromethane occurs in ambient air, drinking water, surface water and commercially bottled artesian water.' Ambient sources of methylene chloride include paint strippers, adhesives and glues, paint thinners, glass frosting and artificial snow, water repellants, wood stain and varnishes, spray paint, cleaning fluids and degrea- sers, aerosol spray p.aint for auto- mobiles, automobile spray primers and products sold as DCM.'j

Dichloromethane forrns an explosive mixture in the presence of liquid oxygen. Heated DCM emits the highly poisonous gas phosgene.'

Uses

Dichloromethane is used as a blowing agent for foams, as a solvent in paint removers, as propellants, degreaser and as processing solvents in the manufac- ture of steroids, vitamins and tablets coatings, a solvent for cellulose esters, fats, oils, resins and rubber and as a solvent and flammability depressant in aerosol products such as coatings, hair sprays, room deodorants, herbicides and insecticides. 15.7

Acute toxicity

In general, DCM has a low order of toxicity and human findings confirm the animal studies. There are sporadic individual case reports associating a variety of symptoms, including neuro- logical symptom^.^,^

Available evidence indicates that most of the pathology from DCM exposure is related to carbon monoxide (C0)-induced hypoxia, a metabolite of DCM. Mechanistically, the CO reduces the available oxyhemoglobin in the blood and shifts the oxyhemoglobin desaturation curve.'" These effects sum- mate to provide less oxygen to the tissues. The extent of the tissue hypoxia determines the extent of the organ damage.

Ingestion. In a suicide attempt, a 38- year-old male ingested 1-2 pints of a paint stripper containing predominantly DCM, some methanol, paraffin wax and detergents (Nitromors Paint Remover, percentage composition not provided). The patient was unconscious and unre- sponsive to painful stimuli and sustained extensive gastrointestinal damage with ulceration of the duodenal jejunal junc- tion, which developed into diverticula at 6 months." In experimental animals, there is some evidence of biochemical changes in rat livers following oral administration. The microsomal cytochrome P-450 content in rats was reduced 18 h after being dosed with 1 g kg-' DCM.I2 Increased triglyceride content, reduced triglyceride secretion and reduced tubulin protein content were reported for mice given 2.7 g kg-' DCM.I3

The L D ~ ~ and LC'" values for various species are presented in Table 1.

Inhalation. Short-term exposure to DCM has been associated with skin and eye irritation, drowsiness, digestive system irritation, respiratory tract irritation and numbness.l.14 Excessive exposure symptoms may include dizziness, nausea, sense of fullness in the head, sense of heat, stupor, dullness, lethargy, and drunkenness. Exposure to very high concentrations may lead to rapid unconsciousness and death.7

A number of case reports indicate multisystem disorders associated with inhalation overexposures. A 19-year- old male who used DCM to remove tiles in a poorly ventilated room exhibited elevated liver enzymes, poorly localized abdominal pain and acute tubular necrosis of the kidneys. Histological studies demonstrated anoxia damage to the liver plasma membranes and mitochondria.I5 A 25-year-old account- ant developed swollen, stiff joints and a profuse pink rash following a 4-h exposure to DCM.16

Accidental death resulted from acute exposure to DCM during paint strip- ping.I7 The exposure concentration was not reported but tissue analysis revealed the presence of DCM in the liver (14.4 mg 100 g-' tissue), blood (510 mg I-') and brain (24.8 mg 100 g-' tissue). In another report, two workers died following exposure to DCM in an enclosed space. The cause of death was stated to be solvent- induced narcosis.ls

In a case report, an individual developed non-cardiogenic pulmonary edema and subsequently hyper-reactive airways following acute exposure to a paint remover that contained DCM (> 80% by weight). The cough and chest discomfort became worse over a 24 h period and subsided by 48 h but cough, wheeze and breathlessness con- tinued over the next year. However, there was a possibility of conversion of DCM to phosgene because the patient also used an electric hot-air gun in the paint-removing operation. l9

Controlled human exposure studies revealed disturbances of psychomotor performance at 800 ppm DCM. There was depression of the flicker fusion threshold and vigilance performance down to 300ppm and a performance decrement in the combined tracking-monitoring task at 200 ppm.20

In several animal species, slight nar-

CCC 0260-437X/95/04032947 0 1995 by John Wiley & Sons, Ltd.

Received 9 September 1994 Accepted (revised) 5 January 1995

330 S. DHILLON AND R. VON BURG

Table 1. The LDS0 and LCs0 values for dichloromethane

Route of adminis- Species tration Type Test concentration

Rat Oral LD,, 1600 rng kg-’ Mouse Oral LD,, 1987 mg kg-’ Mouse lntraperitoneal LD,, 1500 mg kg-’ Rat Inhalation Lc50

2000000 rng rn-3 15 min-’ Mouse Inhalation LC,, 56176 mg m-3 8 h-’ Guinea pig In ha lati on LC,, 40252 mg 6 h-’

From Refs 1 and 65.

cosis occurred following exposure to 6000 ppm for 2.5 hI3 while deep narcosis occurred in rats at levels of 16000-18000 ppm for 6 h.21 Fatty infiltration of the liver was reported following inhalation of 5200 pprn for 6 h in rats.22

Skin contact. Dichloromethane may cause skin irritation and the effect may be accentuated if the chemical is confined to the skin by shoes or tight clothing.’ Skin exposure can contribute to systemic toxicity.

Eye contact. Dichloromethane irri- tates the eyes. When the compound was instilled into the conjunctiva sac of rabbits, inflammation of the cojunctiva and eyelids, keratitis and iritis and increased corneal thickness and intraoc- ular tension were observed.”

Chronic toxicity

Ingestion. Prolonged ingestion of DCM may cause liver damage in experimental animals. Fatty infiltration was reported in Fischer 344 rats following ingestion of water containing 125 or 250 mg kg-’ DCM day-’ for 78 or 104 weeks, respectively. All liver effects consisted of histological alterations of liver cells, such as those seen in aging animals. The fatty changes reported were re~ersible.’~ In another study, male and female B6C3F1 mice exposed to 0,60,125,185, or 250 mg kg-’ day-’ of DCM in their drinking water for 2 years exhibited liver effects only at the highest dose.25

Inhalation. Chronic inhalation of DCM may produce a variety of CNS effects, including headaches, dizziness, nausea, memory loss, paresthesia, tingling in hands and feet and loss of consciousness. Cherry et al, found significant changes in a subjective assessment of sleepiness, physical tiredness and mental tiredness among morning shift workers exposed to 28-173 ppm DCM. Furthermore, the magnitude of

the response was associated significantly with blood COHb levels.2h

Chronic CO intoxication and increased levels of carboxyhemoglobin were implicated in a case report of bilateral temporal lobe degeneration following a 3-year exposure to DCM levels of 300-1000 ppm. This patient complained of loss of recent memory, exhibited difficulty with speech and had an unsteady gait.’,’’ Dichloromethane was also implicated in the production of ‘organic brain damage’ with daily exposure in seven out of eight workers. Typical symptoms included dizziness, loss of consciousness, memory loss, depression and personality change.” Welch2’ attributed the etiology of slow onset of neurobehavioral changes to exposure to DCM and other solvent mixtures and suggests that neurotoxicity symptoms can develop at DCM levels as low as 1G70 ppm. This report documents 100 workers who complained of headache, dizziness, nausea, memory loss, paresthesia in the hands and feet (subjective) and loss of consciousness. These effects occurred during painting, cleaning and spraying operations. The DCM levels were estimated to be in the range of 100 ppm because such levels, or greater, were measured during similar operations. The duration of exposure was 6 months to 2 years2’

In addition to CNS effects, chronic inhalation of DCM may also cause liver toxicity. Continuous inhalation exposure to DCM (100 ppm) for 10 weeks resulted in elevated liver fat, decreased hepatocyte glycogen and cen- trilobular fatty infiltration in ICR mice.I3 In another study, exposure to DCM (low dose, 1000 ppm; high dose 4000 pprn), was associated with the increased incidence of hemosiderosis, cytomegaly and cytoplasmic vacuoliz- ation .30

Prolonged exposure to DCM caused kidney effects in experimental animals but epidemiological studies failed to show an association between exposure and adverse kidney effects.’

Skin contact. Prolonged skin contact may cause dermatitis. For other effects refer to Skin contact: acute toxicity.

Sensitization. Memon and Davidson16 report on a patient who developed swollen, stiff joints and a profuse pink body rash within 72 h of a 3 4 h exposure to a DCM-containing paint stripper. Welchz9 reported on a stencil maker who developed contact dermatitis secondary to DCM exposure. This patient subsequently developed memory loss and a renal failure that was diagnosed as a result of amyloidosis.

Target organ effects

Animal and some human studies indicate that the primary target organs for toxicity to DCM are the liver and CNS. In addition to these effects, exposure to vapors may cause irritation of the skin and eyes.

There is little available literature on the acute hepatotoxocity of DCM in humans. However, a laboratory tech- nician developed acute hepatitis following a spill of 2-4 quarts of DCM onto the floor, hands, legs and feet. The actual spill was cleaned up within 5-10 min but clothing was not changed. The duration of exposure was estimated to be 4 h. The patient was admitted to hospital the following day and subsequently recovered.” Other long-term studies involving occupational exposures also suggest that DCM may cause hepatitis and altered triglyceride levels, although quantitative data are lacking.’

An association between cardiovascular disease (CVD) and DCM has also been proposed owing to the metabolic production of C0.32 However, the caus- ality of DCM to CVD remains unclear.

Absorption-metabolism-excretion

Dichloromethane is rapidly absorbed from the lungs and from the gastrointestinal tract. Dermal absorption may also occur.’ The quantity of DCM absorbed is dependent on body weight and fat content of the body. The risk of accumulation of DCM in adipose tissue is expected to be greater for obese per- s o n ~ . ~ ~

Stewart and D ~ d d ~ ~ estimated the rate of dermal absorption of DCM in humans by measuring alveolar air in four subjects who immersed their thumbs in liquid DCM for 30 min. Peak levels of DCM in the alveolar air (3.1 ppm) occurred within 30 min and relative to other chlorinated hydro- carbons was absorbed 3-5 times more rapidly than carbon tetrachloride, perchloroethylene, trichloroethylene and trichloroethane.

In viuo studies on the metabolism of

TOXICOLOGY UPDATE 33 1

DCM confirm the exktence of two metabolic pathways for the chemical: an oxidative (Mixed Function Oxidase) pathway mediated by the P-450 system that yields CO and CO,; and a gluta- thione-dependent (GST) pathway that only yields COz. The MFO pathway saturates at air concentrations of ca. 500 ppm but the GST pathway shows no indication of saturation at inhaled concentrations of up to 10000 pprn. Clinical evidence suggesfs that the peak COHb levels of l>l6% are not attained until several hours after the onset of exposure.35 but COHb levels of 26, 40 and 50% have been r e p ~ r t e d . ~ ~ , ~ ~ in vitro studies also demonstrated

two metabolic pathways. An oxidative pathway mediated by the P-450 system yields CO, and a second pathway mediated by a GST reaction yields formaldehyde and formic acid, which are further metabolized to C02. ' A high correlation has been found between the incidence of cancer in rodent species and DCM and/or reactive metabolites produced by the GST pathway. More- over, this pathway has been found to be more active in the mouse than in the rat. Additional work with hamster and human tissue indicates that the GST pathway is significantly less active in these species than in either rats or mice.

Elimination is primarily via expired air from the lungs as the unchanged parent compound or as CO or C02 . In rats, a single oral dose, or 1 or 50 mg kg-' [I4C]DCM, was eliminated in expired air as unchanged DCM (12.3 or 72%, respectively) within 48 h. For corresponding duration <and dose, fecal (< 1%) and urinary (5%, 2% of the administered dose, respectively) elimin- ations were

Genotoxicity

There is clear evidence of mutagenicity of DCM in bacteria. However, results were equivocal in tesits with yeast, drosophila and mammalian cell cultures and mainly negative with mammalian cells in vivo. Based on the insensitivity of in vivo unscheduled ]DNA synthesis and DNA binding studies, the Environ- mental Protection Agency (EPA) con- cluded that DCM may be a weak mutagen in mammalian s y ~ t e m s . ~ ' , ~ ~

Immunotoxicity

No information was found in the available literature on the immunotoxicity of DCM.

Neurotoxicity

Chronic exposure to DCM primarily produces neurotoxic effects such as depression, change of personality, irri-

tability, insomnia and disturbances of v i~ ion , '~ .~ ' as well as liver damage. Neurotoxicity was the most prominent symptom reported in over 100 cases involving occupational exposure to DCM.z9 Complaints included headaches, dizziness, nausea, memory loss, paresthesia, tingling in the hands and feet and loss of consciousness. One individual suffered anxiety symptoms for 1 month after an acute neurotoxic episode from DCM exposure. Dichloro- methane was present at levels of up to 100 ppm and the duration of exposure was from 6 months to 2 years. However, the author noted that workers in this study were exposed concomitantly to other unspecified solvents. Mental confusion, amnesia, slowness of mental reaction and insomnia were reported in an individual exposed to DCM for 10 years42 and a chemist developed toxic encephalosis after a chronic (5-year) exposure to DCM (5660 ppm) by inhalation and skin contact.43 In other case reports, it was estimated that a 60-year- old male patient who was routinely exposed to DCM levels of 500-1000 pprn for 3 years complained of memory loss and difficulty with word enunciation' while Tariots described the neuropsychiatric course of a 52-year- old male strip tank operator with a 4- year duration of exposure. The pre- senting symptoms were intermittent headaches, blurred vision, short-term memory deficits, auditory hallucination, violent behavior to hospital staff and delusions. Seven days later local and generalized seizures manifested which was confirmed by EEG in the right hemisphere.

In human volunteers, eye/hand coordination was adversely affected at exposure levels of 20G300 pprn for 3-4 h. Exposure to levels in excess of 300 ppm for up to 4 h altered some behavioral modalities in visual and auditory functions. There was a decrease in the critical flicker fusion frequency (CFF) and a decrease in auditory vigilance. At 800 ppm there was a decrement in psychomotor tasks, such as reaction time and digit symbol substi- tution t e ~ t i n g . ~ ~ . ~ ~

No deleterious effects on health or performance were detected in healthy humans when adults of both sexes were exposed to levels of DCM up to 250 ppm for 2, 3 or 7.5 h day-', 5 days per week for 2 weeks.45 Factory workers exposed to levels of DCM in the range 400-1000ppm for 7.7 years showed weakness in cerebral function, weakness in perception, weakness in the ability to concentrate and abnormal E E G s . ~ ~

Cherry et al. were unable to demon- strate any exposure-related subjective symptoms, neurobehavioral effects, motor nerve conduction velocity changes, electrocardiographic changes

or other clinical effects in workers that were exposed to 75-100 ppm of DCM. In the authors opinion, this was the no observable adverse effect level (NOAEL).47 In a subsequent study these same investigators evaluated the subjective symptoms of sleepiness and physical/mental tiredness in 56 workers exposed to 28-173 ppm DCM in an atmosphere that also contained methanol. Only the morning shift showed a significant statistical change in the parameters tested and the changes were correlated to the CO levels in the blood.26

In animal studies, high levels of exposure are necessary to induce signs of DCM toxicity. During the inhalation of 500 ppm for 4 days, rats demonstrated increased preening activity: 500 ppm, 7 h day-', 5 days a week for 6 months decreased spontaneous motor activity in male rats, 500 pprn for 24 h had no effect on the sleeping EEG but levels of 100&3000 ppm for 2.5-6 h produced a reduction in rapid eye move- ment (REM) during sleep. Slight narcosis was observed in several animal species at levels of 40004000 ppm for the same time periods (Table 2). Learn- ing ability was impaired in mice 1-4 days after a single exposure to 168 mg I-' DCM.48 Gerbils exposed to 210 ppm continuously for 3 months demonstrated a significant decrease in the DNA content of the hippocampal area of the brain, indicating cell loss and suggesting a hypothesis for changes that might account for the memory deficit observed with DCM exposure^.^^^^^

The mechanism of action of DCM on the nervous sytem can be attributed to its lipophilic properties. Lipophilic substances can enter the brain more easily than ionic compounds and in the process depress nerve cell membrane function.51 Dichloromethane was shown to adversely affect nerve conduction velocityS2 and reduce the peak inward current in voltage-clamped giant squid ax on^.^^ Furthermore, the nervous system depends upon adequate mitochon- drial respiration. Substances such as hydrogen sulfide, cyanide and formate interfere with the mitochondria1 respiratory chain at the cytochrome a/a3 level.51 As a result, DCM may inflict three insults to produce CNS depression: a direct inhibitory action on the nerve membrane that reduces nerve activity; a reduced oxygen-carry- ing capacity of hemoglobin by forming carboxyhemoglobin (COHb); and production of formate as a metabolic intermediate that inhibits mitochondria1 respiration and exacerbates the COHb hypoxia by inflicting a tissue hypoxia that can potentially produce nerve cell damage and loss.

332 S. DHILLON AND R. VON BURG

Table 2. Toxic effects of dichloromethane

Concentration (PPmf Duration Effects

300-800 Acute

1000-3000 2800 4000

5000 5000

5000-9000

6000

10 000 14500 15 000-20 000

24 h 14h 2.5 h 6 h 30 min day-’ 7 days

8 h

2 h 2.5 h 4 h 2 h 2 h 10-20 min

2 5 3 5 min

100 Acute Upper respiratory tract irritation 200-300 4 h Interference with eye/hand coordination > 500 Acute Headache, impaired concentration and

coordination, loss of balance, nausea, flushing, slurred speech, confusion, cardiac pain, respiratory distress- carboxyhemoglobin content 15% Impaired visual, auditory and psychomotor functions Reduced REM sleep in rats Reduced REM sleep to total sleep in rats Light narcosis in dogs Light narcosis in rabbits Reduced running activity in rats Initial increase in physical activity followed by a decrease in food and water intake and lethargy in mice. Also signs of liver degeneration in mice Long sleeping phase and no desynchronization period in rats Slight narcosis in dogs Slight narcosis in guinea pigs Slight narcosis in rabbits and cats Narcosis in mice Death in mice Loss of pupillary and corneal reflexes in dogs Complete muscle relaxation followed by a fall in blood pressure and rapid narcosis in dogs

Modified from Refs 1 and 67.

Reproductive toxicity

Four workers with chronic exposure to DCM who provided semen samples were reported to have semen counts in the infertile range, abnormal sperm motility and morphology and bilateral testicular atrophy. Another four workers declined to participate in the semen sampling but also reported the symptoms of dizziness, memory loss, depression and personality changes. Subsequent measurements of the workplace found an average of 69 ppm DCM with a range of 3.3-154.4 pprn.**

Dichloromethane did not adversely affect reproduction in rats exposed to 0, 100, 500 or 1500 ppm via inhalation for two generation^.'^ Mice exposed to 1250ppm DCM from day 6 through day 15 of gestation for 7 h per day produced fetuses with a significant increase in mean body weight.” Both mice and rats showed an increase in the absolute weight of the liver and delayed ossification of the sternebrae. The National Toxicology Program (NTP)30 reported that a 2-year exposure to high concentrations of DCM (4000 ppm) produced an increased incidence of testicular atrophy in male mice

and an increased incidence of ovarian atrophy in female mice (2000 ppm).

Carcinogenicity

Dichloromethane is considered an animal carcinogen and has been categor- ized as a probable human carcinogen by the EPA (group B2). A study by the NTP reported a statistically significant increase in the incidence of liver cancer in mice exposed to 2000 or 4000 ppm for 102 week^.^" A statistically significant increased incidence of lung adenomas and carcinomas in mice of both sexes was also observed in both treatment groups. Although not statistically significant, mammary adenomas and fib- roadenomas were increased in male and femaie rats, as were mononuclear cell leukemias in female rats. Based on the sufficient evidence of carcinogenicity in animals and inadequate evidence in humans, the International Agency for Research on Cancer (IARC) categor- izes DCM as an agent possibly carcinogenic to humans, i.e. Group 2B carcinogen.56 According to the NTP there is sufficient evidence for the carcinogenicity of DCM in experimental animals.30

The Occupational Safety and Health Administration (OSHA) has not listed DCM as a carcinogen. The American Conference of Governmental Industrial Hygienists (ACGIH)” considers DCM as a suspected human carcinogen and the National Institute for Occupational Safety and Health (NIOSH) rec- ommends that DCM be regulated as an occupational carcinogen. For findings of human cohort studies refer to Epidemi-

Burek et al. exposed rats and ham- sters to 0, 500, 1500 or 3500 ppm DCM vapor for 2 years. A statistically significant increase in salivary gland sarcomas was reported in male rats in the 3500 ppm group. In a follow-up study, male and female rats exposed to 0, 50, 200 or 500 ppm DCM did not develop salivary tumors but did have mammary tumors at the 500 ppm

In a 2-year study by the National Coffee Association, F344 rats received 0, 5, 50, 125 or 250 mgkgg’ DCM daily in the drinking water. Female rats showed an increased incidence of neoplastic nodules or hepatocelluar carcinomas, which was significant when compared to matched controls, but not historical controls. Male mice had an elevated, although not significant, incidence of combined neoplastic nodules and hepatocellular c a r ~ i n o r n a s . ~ ~ . ~ ~

ology.

Epidemiology

Epidemiological data by the Eastman Kodak Company do not show an association between the types of cancers seen in laboratory animals and h u ~ n a n s . ~ ~ * ~ Two cohort studies examined the mortality incidence in workers occu- pationally exposed to DCM. The first study evaluated the deaths of 344 male workers exposed to TWA concentrations of 30-125 ppm for up to 30 years. No excess cancer mortality was found in comparison to the unexposed population.60

The second study evaluated male workers exposed to an average of 26 ppm DCM for 22 years.59 Compari- son to the general population revealed no statistically significant excesses in cancer, although an increased incidence of pancreatic cancer deaths (8 vs 3.1 expected) was reported.

These studies have been used to argue that the cancer potency factor derived from animals may overestimate risks to humans. However, analysis of these studies by the EPA states that while the epidemiological studies do not show increases in cancer, they lack the power of resolution to detect the number of cancers that might be pre- dicted using the animal-based p~tency .~’ Furthermore, these studies offer some evidence of pancreatic car-

TOXICOLOGY UPDATE 333

Table 3. Ecotoxicity values for different species

Species TY Pe lest concentration

Lepomis macrochirus Lc50 230 mg I-' 24 h-l Daphnia magna Lc50 224000 pg I-' 48 h-' Mysid shrimp LC50 256000 pg I-' 96 h-' Pimephales promelas Ra finesque Lc50 193 mg I-' 96 h-' (fathead minnow) Poecilla reticulata (guppy) Lc50 294 ppm 14 day-'

(Ref. 64)

Table 4. Environmental Proteetion Agency health advisory levels

Health advisory Value (mg I- ')

1 day (child) 13.3 10 day (child) 1.5 Long term NA" DWELb (adult) 1.75

a NA: not available.

From Ref. 1. DWEL: drinking water exposure limit.

cinogenesis (a site not observed in experimental animals) resulting from exposure to DCM vapors.

Based on rat bioassay studies,30.58-61,62 Bogen et al.63 have calculated 94 alternative human cancer potency values. These values range from 3.6 x to 1.4 X lo-' (mg kg-' day-')-' or a ,380-fold range.

Environmental fate Approximately 85% of all DCM produced in the USA is released into the environment primarily in industrialized areas, with the majority probably released to the air.'

In the atmosphere, DCM readily disperses and is tranported some dis- tance from its source. Degradation of DCM by hydroxyl radicals, photolysis and intermedia transfer via rainout pre- vent its accumulation in the atmosphere. Based on reaction rate studies summar- ized by the EPA, the lifetime of DCM in the troposphere ranges from a minimum of a few months to a maximum of 1.4 years under typical US conditions.@

Dichloromethane is soluble in water, which makes its leaching from soil and transport in ground water important. The rate of volatilization from surface water is strongly affected by wind and mixing conditions. Soil adsorption and abiotic transformation processes in aquatic systems are not considered major factors. Biodegraldation may be an important fate process under both aerobic and anaerobic conditions.' Hydrolysis is not an important degradation process under normal environmental conditions. The minimum reported half-life for hydrolysis is ca. 18 months.65

Environmental toxicity

Environmental toxicity values for DCM in a variety of different species are presented in Table 3.

Low-level exposure of the general population would be expected from ambient DCM emissions from paint removal, aerosol use, metal degreasing, photo processing, electronics, pharma-

ceuticals, food processing and miscel- laneous uses. A potential exposure is also possible through a wide variety of consumer products containing DCM. Exposures are highest in occupational settings and releases from hazardous waste sites.

Regulatory status

The EPA has estimated that over one million workers are currently exposed to DCM. The National Occupational Hazard Survey, conducted by NIOSH from 1972 to 1974, estimated that 2.5 million workers were potentially exposed to DCM vapors.%

Dichloromethane is considered a probable human carcinogen based on its carcinogenic nature in animals. It is classified as B2 under the EPA weight- of-evidence scheme. The oral potency slope of 7.5 x (mg kg-' day-')-' was based on two studies in which exposures to B6C3F1 mice resulted in hepatocellular carcinomas or adenomas.29-30 The inhalation potency slope of 1.4 X lo-* mg kg-' day-')-' is based on a study by the NTP in which exposures in female B6C3F1 mice produced combined carcinomas and adenomas of the lung or liver.30 This potency estimate was calculated by the EPA Carcinogenic Assessment Group, by fitting the liver and lung tumor data from female B6C3F1 mice in the NTP inhalation study with the linearized multistage The unit risk estimate for inhalation exposures is 4.1 x lop6 ( ~ m - ~ ) - ' . The EPA intends to lower this unit risk estimate to 4.7 x lo-' (p m-3)-1 on the basis of pharmacokinetic data.38,39

The exposure levels corresponding to excess lifetime cancer risks of

are 200,20 and 2 pg m-3 (0.057, 0.0057, and 0.00057 ppm), respectively, according to the revised unit risk. The EPA risk estimate is based on the linearized multistage model. The risk estimate made with this model should be regarded as conservative, representing a plausible upper limit for the risk. The true risk is not likely to

and

be higher than the estimate, but it may be lower.'

The oral reference dose for DCM is 0.06 mg kg-' day-' based on a study by the National Coffee As~oc ia t ion .~~ In this study, 85 rats were exposed to 5, 50, 125 or 250 mg kg-' day-' for 24 months. Histological changes in the liver at 50 mg kg-' day-' and no effects at 5 mg kg day-' established a NOAEL. An uncertainty factor of 100 was used to account for both intra- and interspecies variability. No reference dose for inhalation exposures has been established.

The EPA health advisory levels are presented in Table 4. The EPA Office of Drinking Water has promulgated monitoring regulations for 51 unregu- lated volatile organic compounds (VOCs), including DCM (40 CFR 141.40 (07/08/87)). The reportable quantity (RQ) of DCM set by the EPA Office of Emergency and Remedial Response (OERR) is 1000 lb, required for notification under the Comprehen- sive Environmental Response, Com- pensation, and Liability Act of 1980 (CERCLA) (40 CFR 302.4 (04/04/85)).

When DCM as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product becomes a waste, it must be managed according to Federal and/or State Hazardous Waste Regulations (40 CFR 261.33 (7/ 1/88)). When DCM is a spent solvent, it is classified as a hazardous waste from a non-specific source (F002) and must be managed according to State and/or Federal Hazardous Waste Regu- lations (40 CFR 261.31 (7/1/88).

The insecticide DCM is exempt from the requirement of a tolerance for residues when used as a fumigant after harvest for several grains and citrus fruits (40 CFR 180.1010 (7/1/88)). Dichloromethane is also exempt from the requirement of a tolerance when used as a solvent or co-solvent in accordance with good agricultural prac- tice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only (40 CFR 180.1001 (d) (7/1/88)).

Dichloromethane has been listed as

334 S . DHILLON AND R. VON BURG

Table 5. Worker exposure limit values

ACGIH: T L V m A STEL Ceiling

OSHA: PEL Ceiling IDLH

NIOSH: REL

MSHA:

50 ppm (174 mg m-3) NA” NA

500 ppm 1000 pprn 5000 ppm

Lowest feasible limit NA

a NA: not available. From Refs 1 and 3.

a carcinogen under the Safe Drinking Water and Toxic Enforcement Act o f 1986 (Proposition 65), California Health and Safety Code section 25249.5 et seq. Proposition 65 requires a warning to be given if an individual i s exposed to D C M causing a significant risk of cancer, which is typically greater than lop5 risk from exposure. A non-significant dose for DCM has been established at 50 pg dayp1 for a 70 kg adult under Proposition 65 (22 California Code of Regulations section 12711 (a)(2) (1991)).

Occupational exposure values are presented in Table 5.

S. Dhillon and R. Von Burg? ICF Kaiser Engineers Inc., 1800 Harrison St., Oakland, CA 94612, USA

t Author to whom correspondence should be addressed.

References 1.

2.

3.

4.

5.

6.

Agency for Toxic Substances and Disease Registry (ATSDR), Toxico- logical Profile for Methylene Chloride. Prepared by Life Systems, Inc. under contract no. 68-02-4228. US Public Health Service. Atlanta, GA (1987). Merck, The Merck Index, 70th Edn ed. by M. Windholtz, S. Budavari, R. Blumetti and E. Otterbein. Merck Rahway, NJ (1983). National Institute for Occupational Safety and Health (NIOSH), Pocket Guide to Chemical Hazards, NIOSH Pub. No. 90-117. Cincinnati, OH (1990). Occupational Safety and Health Administration (OSHA), Occupational exposure to methylene chloride. Fed. Reg. 51, 42257 (1986). National Toxicology Program (NTP), Fifth Annual Report on Carcinogens (89-239). US Department of Health and Human Services, Public Health Service (1989). Consumer Product Safety Com-

mission (CPSC) Labeling of certain household products containing methylene chloride; statement of interpretation and enforcement pol- icy. Fed. Reg. 52(7), 34698 (1987).

7. G. E. Clayton and F. E. Clayton, (eds), Patty’s Industrial Hygiene and Toxicology. 3rd revised Edn, Vol. 28. Wiley, New York (1981).

8. P. Tariot, Delirium resulting from methylene chloride exposure: case report. J. CIin. Psychiatry44.340-342 (1983).

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