Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 2 (1996)

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

Methyl ethyl ketone (MEK) is a flammable, colorless liquid with an acetone-like odor (ACGIH, 1991).

MEK is used as a solvent in synthetic resins manufacturing and in the surface-coating industry (ACGIH, 1991). We are not aware of any use of MEK in the spacecraft, but MEK has been found in the cabin atmosphere during several space-shuttle missions, ranging from 0.3 to 69 ppb (Huntoon, 1993). Off-gassing is probably the source of MEK in space shuttles. Based on the off-gassing data in the Spacelab, it was estimated that 3.8 g of MEK will be generated in the space station each

day (J. Perry, Marshall Space Flight Center, personal commun., 1989).

Most disposition studies of MEK were performed on humans, so the following review refers to human results unless specified otherwise. The average pulmonary uptake rate of MEK was 1.05 mg/min in workers exposed to MEK at a concentration of 100 ppm (Perbellini et al., 1984). In resting male volunteers exposed to MEK at 200 ppm for 4 h, the expired MEK concentration was about 53 % of the inhaled MEK all through the exposure (Liira et al., 1988a). It remained unchanged at 53% when the volunteers performed three 10-min, 100-watt-workload exercises during the 4-h MEK exposure beginning at 5, 95, and 225 min (Liira et al., 1988a). At the end of the 4-h MEK exposure at 200 ppm, the venous blood concentration reached 80 µmol/L (5.8 µg/mL) in the resting volunteers, and the venous blood concentration was 80% higher in the volunteers who did the exercises (Liira et al., 1988a). In another study, during a 4-h exposure to MEK at 100 or 200 ppm, the venous blood concentrations of MEK reached about 1.8 or 3.5 µg/mL, respectively, at 4 h (Liira et al., 1988a; Dick et al., 1988). The venous blood concentrations at 4 h were approximately 10-30% higher than those at 2 h (Brown et al., 1987; Liira et al., 1988a; Dick et al., 1988).

In guinea pigs, MEK is reduced to 2-butanol or oxidized to 3-hydroxy-2-butanone and 2,3-butanediol (DiVincenzo et al., 1976). In human volunteers exposed to MEK at 200 ppm, Liira et al. (1988a) discovered 2,3-butanediol in the urine. In contrast, Perbellini et al. (1984) did not find 2-butanol or 2,3-butanediol in the urine of workers exposed to MEK at concentrations equal to or lower than 300 mg/m³ (100 ppm); they found only 3-hydroxy-2-butanone in the urine. Liira et al. (1988a) reported that 3 % of the absorbed MEK was exhaled unchanged and 2%

was excreted as 2,3-butanediol in the urine during the 4 h of exposure and 20 h after exposure. Miyasaka et al. (1982) found that only approximately 0.1% of MEK absorbed during an inhalation exposure was excreted unchanged in the urine after the exposure in humans. These data suggest that most of the absorbed MEK apparently entered into intermediary metabolism (Liira et al., 1988a), so that, had these investigators used radioactively labeled MEK, they would have found that most of the MEK absorbed is eliminated from the body as CO₂. Using a physiologically based pharmacokinetic model, Liira et al. (1990a) estimated that MEK metabolism would be saturated at an airborne MEK concentration of 100 ppm at rest or 50 ppm during exercise. The saturable metabolism of MEK explains why the MEK concentrations in blood tend to vary nonlinearly with exposure concentrations above 100 ppm: the peak MEK concentrations in blood during a 4-h exposure of resting human volunteers at 25, 200, or 400 ppm were 0.3 µg/mL, 7.5 µg/mL, or 23.0 µg/mL, respectively (Liira et al., 1990a).

In humans exposed to MEK at a concentration of 200 ppm, MEK was cleared from the blood in two exponential phases (Liira et al., 1988a). The initial phase had a 30-min half-life and the second phase had an 81-min half-life. One and a half hours after a 4-h MEK exposure at 200 ppm, the venous blood concentration of MEK dropped from 3.5 µg/mL to 1.0 µg/mL, and it decreased to below detectable concentrations 20 h after exposure in 22 volunteers (Dick et al., 1988). In guinea pigs given MEK intraperitoneally at 450 mg/kg (a much higher dose than the estimated dose of 28 mg/kg used in the inhalation study by Liira et al. (1988a)), MEK was cleared from the blood monoexponentially with a much longer half-life of 270 min (DiVincenzo et al., 1976).

The major acute toxicity of MEK is mucosal irritation. Nelson et al. (1943) exposed 10 human subjects for 3-5 min to MEK or to 1 of 15

other organic solvents and told them to rank the effects on the eye, nose, and throat as either no irritation, slightly irritating, or very irritating. They were not told of the exposure concentrations. Unfortunately, Nelson et al. did not report whether they analytically determined the exposure concentrations, and it appears that the exposures were done using nominal concentrations. In the study, MEK at a concentration of 100 ppm resulted in slight nose and throat irritation. Mild eye irritation was reported by some subjects at 200 ppm. Most, if not all of the subjects, rejected the vapor at 300 ppm. In a mouse model of sensory irritation, a 5-min exposure to MEK at 10,745 ppm reduced the respiratory rate by 50% (De Ceaurriz et al., 1981).

In subchronic exposures, MEK is known to cause death, hepatic effects, and central nervous system (CNS) impairment.

Although methyl n-butyl ketone is neurotoxic, MEK has been found not to cause peripheral neuropathy in rats. A continuous exposure of rats to MEK at 1125 ppm, 24 h/d. for up to 55 d in one study (Saida et al., 1976) or a repetitive exposure to MEK at 700 ppm, 8 h/d, 5 d/w, for 16 w in another (Duckett et al., 1979) failed to cause any peripheral neuropathy. An exposure of five rats to MEK at 10,000 ppm in the first few days and 6000 ppm thereafter for 8 h/d, 7 d/w, for 7 w resulted in no neurological signs (Altenkirch et al., 1978). During the MEK exposure, all the rats were excited in the initial several minutes, but they became somnolent within 5-10 min (Altenkirch et al., 1978). In the seventh week, all the rats died of severe bronchopneumonia as determined by gross pathological and histological examinations (Altenkirch et al., 1978). Electron microscopic examination revealed no alterations of the sciatic, tibial, peroneal, and sural nerves (Altenkirch et al., 1978).

As mentioned earlier, all five rats died after an exposure to MEK for 8 h/d, 7 d/w, for 7 w (Altenkirch et al., 1978). The exposure concentrations were 10,000 ppm in the first several days and' 6000 ppm for the balance of the 7 w. The 100% mortality was again obtained when the experiment was repeated (Altenkirch et al., 1978). The mortality at 6000-ppm MEK seen in that study was probably of little significance at lower exposure concentrations, because a 90-d study showed that exposures of rats to MEK at 1250, 2500, or 5000 ppm, 6 h/d, 5 d/w, for 13 w failed to cause any increase in mortality compared with the control group (Cavender et al., 1983).

A 90-d exposure to MEK at 5000 ppm, 6 h/d, 5 d/w did not change the morphology of any tissues, but it increased the liver weight and the liver-to-body-weight ratio (Cavender et al., 1983). A similar exposure at 2500 ppm increased the liver weight in the female rats but not in the male rats, and it had no effect on the liver-to-body-weight ratio (Cavender et al., 1983). It can be concluded that a subchronic MEK exposure could have a mild effect on the liver. In the same study, MEK at 5000 ppm decreased the SGPT slightly, and it increased the serum potassium, glucose, and alkaline phosphatase levels in the females. A similar exposure to MEK at 1250 ppm failed to elicit any toxic effects (Cavender et al., 1983).

Like most organic solvents, MEK might also impair the CNS at relatively high concentrations (Patty et al., 1935; Altenkirch et al., 1978). In an exposure of rats to MEK at 6000 ppm, 8 h/d, 7 d/w for 7 w, it was discovered that the rats developed transient excitation in the first few minutes of exposure followed by somnolence (Altenkirch et al., 1978). After the somnolence set in, the rats were still arousable. An

exposure of guinea pigs to MEK at 10,000 ppm for 13.5 h resulted in incoordination in 90 min and narcosis in about 250 min (Patty et al., 1935).

No carcinogenicity bioassay of inhaled MEK was found in the literature (EPA, 1990). A study with only 10 C3H/He mice per group showed that a cutaneous application, twice a week for 1 y, of 50 mL of a solution containing 25% MEK resulted in no skin tumors, whereas a skin tumor was found in 1 of 10 mice after a similar application of 29% MEK (Horton, 1965). The animal data to assess the carcinogenicity of MEK are inadequate..

Likewise, there are insufficient epidemiological data to determine MEK's carcinogenicity, if any, in humans. Generally, uncertainties on the exposure history of the study populations make it difficult to interpret the epidemiological data reported in the literature.

In a retrospective cohort mortality study of 14,067 aircraft manufacturing workers who have spent, on the average, 15.8 y in the facility, there was no significant excess of mortality from cancer of various organs (Garabrandt et al., 1988). These workers were exposed to various substances on their jobs, including aluminum alloy dusts, welding fumes, methylene chloride, trichloroethylene, MEK, lubricating oils and greases, and metal cutting fluids (Garabrandt et al., 1988). Forty-seven percent of their jobs had a potential for MEK exposure (Garabrandt et al., 1988). In another retrospective cohort mortality study, the standardized mortality ratio (SMR) for all cancers was much lower than unity in 1008 male oil-refinery workers, and the SMR for prostate cancer was 1.82, which was not statistically significant (Wen et al., 1985). These workers have been working in a lubricating-dewaxing process with exposures to various solvents, primarily MEK and toluene, at concentrations below OSHA's standards (Wen et al., 1985).

In an historical prospective study of 446 men who had worked in two MEK dewaxing plants, where they had been followed for 13.9 y on the average, there was a statistically significant excess of deaths from buccal cavity and pharynx cancers and fewer deaths from lung cancer

(Alderson and Rattan, 1980). The investigators concluded that ''there is no clear evidence of a cancer hazard in these workers.'' Finally, childhood leukemia might be related to parents' occupational exposure to MEK. A case-control study of children less than 10 y old showed a statistically significant increase of leukemogenic risk in children whose fathers had been occupationally exposed, after the children's birth, to MEK, chlorinated solvents, spray paint, dyes, pigments, and cutting oil (Lowengart et al., 1987). Because of exposure to a wide mixture of chemicals, these epidemiology studies failed to demonstrate carcinogenicity specifically associated with MEK in humans.

MEK was not mutagenic for several strains of Salmonella typhimurium (Douglas et al., 1980; Florin et al., 1980), but it induced aneuploidy in Saccharomyces cerevisiae strain M (Zimmermann et al., 1985). MEK was not found to be genotoxic in the mouse lymphoma assay, unscheduled DNA synthesis assay, and micronucleus assay (O'Donoghue et al., 1988).

MEK exposure at a concentration of 3000 ppm for 7 h/d on gestation days 6-15 was not teratogenic in rats (Deacon et al., 1981). However, a similar MEK exposure was mildly teratogenic in mice because a concentration-related trend of increases in misaligned sternebrae was found, but no increase in any single malformation was seen at exposure concentrations up to 3000 ppm (Schwetz et al., 1991). MEK exposure at 3000 ppm for 7 h/d on gestation days 6-15 is slightly toxic to the fetus by delaying ossification in the rat and reducing fetal weight in the mouse (Deacon et al., 1981; Schwetz et al., 1991). It also decreased the body-weight gain and increased the water consumption in the pregnant rats (Deacon et al., 1981), and it increased the maternal liver-to-body-weight ratio in the mouse (Schwetz et al., 1991). It can be concluded that MEK has only very slight developmental toxicity.

Ethanol has been found to affect MEK metabolism. In humans, ingestion of ethanol at 0.8 g/kg just before a 4-h exposure to MEK at 200 ppm resulted in increased blood concentrations of MEK and 2-butanol and decreased blood concentrations of 2,3-butanediol (Liira et al., 1990b).

Although MEK is not neurotoxic, it potentiates the neurotoxicity of n-hexane. A weekly exposure of rats to n-hexane at 10,000 ppm, 8 h/d, 7 d/w led to slight weakness and severe paresis in some of the rats in the eighth week (Altenkirch et al., 1978). A similar exposure to a mixture of 1000-ppm MEK with 9000-ppm n-hexane hastened the neurotoxicity development by the third week and caused a higher percent of the rats to be inflicted with slight weakness and severe paresis (Altenkirch et al., 1978). Exposure to the MEK and n-hexane mixture also caused hypersalivation not produced by an exposure to n-hexane alone (Altenkirch et al., 1978).

An explanation for the potentiation is that co-exposure to MEK and n-hexane reduced the clearance of methyl n-butyl ketone, n-hexane's neurotoxic metabolite, in rats (Shibata et al., 1990a), although MEK also inhibited the oxidation of n-hexane to 2,5-hexanedione, another neurotoxic metabolite (Shibata et al., 1990b). These findings were made by the same investigators by exposing rats for 8 h to n-hexane at a concentration of 2000 ppm plus MEK at concentrations of 0, 200, 630, or 2000 ppm (Shibata et al, 1990a,b). Because MEK reduced the clearance of methyl n-butyl ketone, it is reasonable that an exposure of rats to 1125-ppm MEK and 225-ppm methyl n-butyl ketone, 24 h/d for 35 or 55 d resulted in more severe nerve injuries than an exposure to methyl n-butyl ketone alone at 225 ppm (Saida et al., 1976).

In addition to affecting n-hexane's metabolism, MEK also has an influence on xylene's metabolism. Exposure of male volunteers to MEK at 200 ppm and m-xylene at 100 ppm for 4 h resulted in higher xylene concentrations in the blood than an exposure to m-xylene alone at 100 ppm, because MEK inhibited m-xylene metabolism (Liira et al., 1988b). However, m-xylene did not change the blood concentration of MEK and the urinary excretion of 2,3-butanediol, an MEK metabolite (Liira et al., 1988b).

In conclusion, the interaction findings indicate that NASA needs to be aware of the possibility that ethanol ingestion might potentiate MEK's toxicity and MEK inhalation could potentiate the toxicity of n-hexane, methyl n-butyl ketone, and m-xylene during combined exposure. Due to the large number of possible combinations of these chemicals, MEK's SMACs are not set based on the interaction information.

To set MEK's SMACs, the maximum acceptable concentrations (ACs) for the various exposure durations, according to the different toxic end points, are compared. The noncarcinogenic end points produced by MEK include mucosal irritation (Nelson et al., 1943), hepatomegaly (Cavender et al., 1983), and CNS impairment (Altenkirch et al., 1978). The NRC's Committee on Toxicology advised that MEK's SMACs need not be set using hepatomegaly as an end point because of doubtful clinical significance of a mild increase in liver weight absent any histological hepatic damages. Accordingly, ACs are derived for only mucosal irritation and CNS impairment.

A 3-5 min exposure at 100-ppm MEK produced slight nose and throat irritation, but not eye irritation, in 10 human subjects (Nelson et

al., 1943). There are no data on MEK's irritancy at 1 h. The best time-response data on mucosal irritants are those gathered by Weber-Tschopp et al. (1977) with acrolein. They showed that the nose irritation at 0.3-ppm acrolein increased from no irritation in the first few minutes to mild irritation at 40 min, and the degree of throat irritation went from no irritation in the first few minutes to very mild irritation at 40 min. The severity of nasal and throat irritation did not change from 40 to 60 min of the 1-h exposure (Weber-Tschopp et al., 1977). Assuming that MEK's irritancy develops with time like that of acrolein, the nose and throat irritation produced by 100-ppm MEK at 1 h probably would be only mild-to-moderate.

There are no time-response data on MEK's mucosal irritation. However, if the exposure to MEK at 100 ppm were prolonged to more than 1 h, the degree of nose and throat irritation would most likely remain mild-to-moderate because mucosal irritation, being a surface response, is not expected to increase with time after the first hour. This is supported by the time-response data of two other irritants, acrolein and formaldehyde. The mucosal irritancy of acrolein did not increase from 40 to 60 min into a 1-h exposure (Weber-Tschopp et al., 1977), and the mucosal irritancy in volunteers exposed to formaldehyde at 3 ppm was mild-to-moderate at 1 or 3 h (Sauder et al., 1986; Green et al., 1987).

The 1-h and 24-h ACs based on mucosal irritation should be lower than 100 ppm, because NASA should not subject the crew to more than mild mucosal irritation in a 1-h or 24-h contingency. MEK's irritancy appears to have quite a steep concentration-response curve. Although all the subjects found a 3-5 min exposure to MEK at 300 ppm not tolerable, only slight nose and throat irritation was felt at 100 ppm (Weber-Tschopp et al., 1977). Therefore, a factor of 3 applied to the mildly to moderately irritating concentration of 100 ppm should yield a nonirritating concentration of 33 ppm. Since some degree of nose and throat irritation is acceptable in a 1-h or 24-h contingency, the 1-h and 24-h ACs should be set slightly higher than the nonirritating concentration of 33 ppm, so the 100-ppm concentration is divided by an extrapolation factor of 2 instead of 3.

For the 7-d, 30-d, and 180-d ACs, it is important that mucosal irritation be prevented completely, so an extrapolation factor of 3 is used to derive a nonirritating concentration from a mildly to moderately irritating concentration. To compensate for the relatively small number of subjects used in getting the mildly to moderately irritating concentration, a safety factor is also used.

Dick et al. (1984, 1988) showed that a 4-h exposure of 137 human volunteers to MEK at a concentration of 200 ppm had no effects on the choice reaction time, visual vigilance, auditory tone tracking, auditory discrimination, memory scanning, and postural sway test. Thus, the NOAEL for CNS impairment is 200 ppm for a 4-h MEK exposure.

Classical pharmacokinetics analysis is used instead of the conservative Haber's rule to derive ACs for MEK on the basis of CNS impairment. A pharmacokinetic technique is used to predict an MEK concentration in blood during an inhalation exposure of humans to MEK. By assuming that MEK's CNS effect is dependent on its concentration in the blood, the pharmacokinetic technique can predict an acceptable exposure concentration based on the prevention of CNS impairment. The assumption is probably valid for two reasons. First, only 2% of the absorbed MEK is excreted in the urine as 2,3-butanediol in human subjects within a day of an MEK exposure (Liira et al., 1988a). This suggests that only a very small fraction of absorbed MEK is converted into organic metabolites in the body, with the majority going into intermediary metabolism (Liira et al., 1988a). Second, even when MEK is converted into organic metabolites, such as 3-hydroxy-2-butanone and 2,3-butanediol, they are more polar than MEK and should be eliminated much faster than MEK. From the data of Liira et al. (1988a) on the rate of urinary excretion of 2,3-butanediol in human subjects after an

MEK exposure, it can be estimated that the elimination half-life of 2,3-butanediol is about 1 h, which is less than MEK's elimination half-life of 81 min determined in that study. Therefore, the organic metabolites are not expected to contribute much to the CNS effect of MEK.

According to classical pharmacokinetics, during a continuous exposure in which the subject is exposed to the same dose throughout, the blood concentration would reach 87.5 % or 99% of the final steady-state value at 3 or 7 elimination half-lives, respectively, past the start of the exposure (Gibaldi and Perrier et al., 1975). It follows that the blood concentration, expressed in percent of the final steady-state value that is reached at a given time, expressed in number of elimination half-lives, after the start of a continuous exposure, can be calculated with the following formula:

where t = n x elimination half-life.

Although the absorption rate might not stay constant in an inhalation exposure (in fact as the body gradually absorbs a vapor, the absorption rate should decrease with time of exposure), to simplify the analysis and to err slightly on the conservative side, the absorption rate is assumed to be constant throughout a continuous inhalation exposure. With MEK, for instance, the expired MEK concentration was about 53% of the inhaled MEK concentration all through a 4-h exposure of human subjects at 200 ppm, indicating that the MEK absorption rate remained constant through at least 4 h of an inhalation exposure. It is, therefore, safe to assume that the blood concentration of the vapor will be no higher than the concentration predicted by the formula above.

According to the formula, when an individual inhales a constant concentration of a vapor for time t equaled to 3 times the chemical's elimination half-life, the blood concentration will be 87.5%, or about 90%, of the steady-state concentration. The half-life of the elimination phase of MEK is 81 min in humans (Liira et al., 1988a). In other words, the blood concentration at 3 x 81 min, or 4 h, into an MEK inhalation exposure is about 90% of the steady-state concentration. It can be calculated with the formula that the MEK concentrations in blood achieved in a 4-h inhalation exposure should be 37% higher than those in a 2-h exposure. Because measurements done in 70 male and female human

subjects exposed to MEK at 100 or 200 ppm showed that the 4-h blood concentration was, on the average, 35% higher than that at 2 h, the formula predicts the blood concentration quite well (Brown et al., 1987).

As predicted by the formula, the blood concentration will reach 99% of the steady-state concentration if the inhalation exposure is extended to time t equaled to 7 elimination half-lives. That means at 7 x 81 min, or 9.5 h, into an inhalation exposure to a fixed airborne MEK concentration, the MEK concentration in blood would practically reach steady state. If MEK's CNS effect is proportional to its blood concentration, as assumed above, an airborne MEK concentration acceptable for 9.5 h should also be acceptable for up to 180 d.

Dick et al. (1984, 1988) showed that a 4-h exposure to MEK at 200 ppm does not cause CNS impairment. Since the elimination half-life of MEK is 81 min, 4 h is 3 elimination half-lives. As shown previously, at 3 elimination half-lives into an inhalation exposure, the blood concentration should be about 90% of the final steady-state concentration. So the data of Dick et al. can be interpreted to mean that a blood MEK concentration of 90% the steady-state blood concentration produced by a long-term continuous exposure to MEK at 200 ppm does not cause CNS impairment. Therefore, the steady-state blood concentration of MEK produced by a long-term continuous exposure to MEK at 180 ppm, which is equal to 90% of 200 ppm, should also be devoid of CNS effects. Because it only takes an MEK exposure of 9.5 h for the blood concentration to reach steady state, the ACs based on CNS impairment for 24 h, 7 d, 30 d, and 180 d are all estimated to be 180 ppm.

The 1-h AC can be derived as follows: The pharmacokinetic formula shows that, during an inhalation exposure to MEK, the MEK concentration in blood reached in 1 h should be 40% of that reached in 4 h. So a 1-h exposure to twice the 4-h no-observed-adverse-effect level (NOAEL) of 200 ppm should also yield an MEK blood concentration that would not impair the CNS. Therefore, 400 ppm, which is twice the 4-h NOAEL, is selected as the 1-h AC on the basis of CNS impairment.

The various ACs are given in Table 9-4. Comparison of the ACs for

mucosal irritation and CNS impairment shows that the 1-h, 24-h, 7-d, 30-d, and 180-d SMACs are set at 50, 50, 10, 10, and 10 ppm, respectively. Because neither irritation nor CNS impairment is expected to be affected by microgravity-induced physiological changes, no microgravity adjustments are needed for the SMACs.

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