DIMETHYL SULFATE: REVIEW OF TOXICITY

ADOLF VYSKOCIL, CLAUDE VIAU

Corresponding author: Adolf Vyskocil, Ph.D.
Département de médecine du travail et d’hygiéne du milieu
Faculté de médecine, Université de Montréal
c. p. 6128, succursale Centre-ville, Montréal (Québec)
H3C 3J7 Canada
Tel.: 514-343-6146
Fax: 514-343-2200
E-mail: Adolf.Vyskocil@Umontreal.ca

CEJOEM 1999, Vol.5. No.1.:72-82

KEY WORDS: Dimethyl sulfate, toxicity, hazard identification

Dimethyl sulfate (DMS) in the environment is a result of combustion processes (World Health Organization, 1985). In the atmosphere, DMS is present in both particles and in the gas phase. Total gas-phase methyl sulfates were found to vary from 34 to 178 nmol/m3 (4.29 to 22.4 ?g/m3) during smog episode in Los Angeles (Eatough et al., 1986). DMS has also been identified in fly ash and airborne particulate matter originating from coal combustion (Tan et al., 1983).

There is a suspicion that the use of methanol as an alternative fuel may lead to the formation of organic sulfates such as DMS. Little is known about the supposed formation of DMS from methanol and, as a first step in hazard identification, the toxicological effects of that compound were reviewed. A summary of this work is presented in this article. More details can be found in our report presented to Health Canada in 1996 (Vyskocil and Viau, 1996).

TOXICOKINETICS

DMS is readily absorbed through mucous membranes, the intestinal tract, and skin (U.S. Environmental Protection Agency, 1985). As DMS has a half-time of 4.5 h in pH 7 buffered aqueous solution, it is assumed that DMS is rapidly metabolized in mammalian tissues (Swann, 1968). Initial hydrolytic products are monomethyl sulfate and methanol; complete conversion to sulfuric acid occurs more slowly (World Health Organization, 1985).

As an alkylating agent, DMS reacts with DNA by an SN2 mechanism and therefore alkylates DNA almost exclusively at nitrogen sites; alkylation at oxygen sites is very infrequent (Hoffmann, 1980). It was found that after i.v. injection into rat the lung and the brain exhibited a much higher degree of nucleic acid alkylation than the liver and kidney (Swann and Magee, 1968). It seems likely that the compound does not equilibrate throughout the body but breaks down in the first organs that it penetrates. It is possible that the hydrolysis of DMS and the subsequent methylation of component molecules of the cells and tissues, including DNA (Lofroth et al., 1995), are responsible for the local effects, systemic toxic effects, and possibly carcinogenicity.

The ultimate metabolites in the human body are sulfate and carbon dioxide, which are excreted by the kidneys and released by the lungs, respectively. However, no urinary metabolites other than low levels of methanol have been reported (Ghiringhelli et al., 1957).

ACUTE TOXICITY

Effects in animals

No study has established a dose-response relationship for acute toxicity to DMS in any animal species. It is difficult to compare the results of different studies as some were designed to observe the effects of a given dose, others report only lethal doses or median lethal concentrations and duration of exposure was not the same for each dose. For details, see a review by WHO (1985).

Rats (strain BD) exposed through oral, subcutaneous and i.v. routes to DMS at the LD50, of 440, 100 and 40 mg/kg, respectively, developed periodically recurring cramps approximatively 30 min after dosing, followed by clinical deterioration, shallow respiration, with death occurring after 10–24 h. Oral dosing caused severe necrosis in the forestomach and stomach (Druckrey et al., 1966). Twice lower oral LD50 (205 mg/kg) was reported by Molodkina et al. (1979).

Bacura et al. (1980) reported that rats (strain not reported) inhaling 45 mg/m3 (LC50) of DMS for 4 hours developed acute respiratory insufficiency accompanied by emphysema, focal atelectasis, hemorrhages in the internal organs and interstitial swelling. Some animals had a nasal discharge. After a latent period of 5–6 h, accumulation of edematous fluid in the air spaces developed progressively over 24–48 h. Molodkina et al. (1979) (seemingly from the same team of scientists) reported LC50 of 45 and 280 mg/m3 (4-h exposure) in Wistar rat and SHK mice.

Ghiringhelli et al. (1957) observed congestion of the kidneys, spleen, liver, and lungs in the mice, guinea pig, and rat (strains not reported) following inhalation of DMS at LC50 of 393 mg/m3 (75 ppm) for 17, 24 and 26 min, respectively. Histological examination showed marked pulmonary emphysema and peribronchitis. In the mouse, there was fatty degeneration with necrotic areas in the liver.

Verschueren et al. (1977) reported LC50 of 167, 335 and 513 mg/m3 after inhalation of DMS for 60 minutes in guinea pigs, rats and mouse, respectively (strains not reproted).

Effects in humans

Several case reports of occupational poisoning were presented in literature. However, exposure doses were not reported. For more details and references, see a review by WHO (1985).

There is usually a latency period of 4 to 12 hours between exposure and onset of symptoms which makes exposure particularly hazardous (World Health Organization, 1985; Ip et al., 1989). Initial discomfort from exposure may be slight but death may result (Anonymous, 1979). DMS causes marked irritation of nasal, pharyngo-laryngeal and ocular mucosa with the following symptoms: lacrimation, conjonctival inflammation, blurred vision, photophobia, palpebral edema, dry cough, whitish sputum, dysphonia, hoarseness. Other signs include nausea, vomiting, dysphagia, headache, dyspnea, chest pain and constriction, bronchial spasm and agitation. These symptoms may persist for up to 2 weeks (Kolesov and Starodubcev, 1988; World Health Organization, 1985; Roux et al., 1977). Acute exposure leads to severe tissue inflammation and necrosis. A major cause of mortality in DMS intoxication is respiratory failure, a consequence of mucosal inflammation and edema of major airways and of noncardiogenic pulmonary edema. Other systemic effects include convulsion, delirium, coma, and renal, hepatic, and cardiac failure.

The danger of DMS is due to the corrosive action of sulfuric acid and to the toxic effect on the nervous system of methanol (Roux et al., 1977). DMS also penetrates the skin (Anonymous, 1979). When liquid DMS contacts the skin, it causes contact dermatitis.

Zhao (1989) observed the eyes of 35 males and 15 females exposed to a mean concentration of 2.89 mg/m3 DMS in a factory and in 40 control workers. Many of the exposed workers had blurred vision, eyepains, lacrimations and photesthesia. The most obvious sign was conjuctival congestion.

Sixty-two cases of accidental acute intoxication from the inhalation of DMS from 1 min to 8 h are reported by Ying et al. (1988). Unfortunately, exposure concentrations were not reported. The authors only estimated that exposure concentration was in excess of 5 mg/m3. Symptoms appeared 20 min to 12 h after exposure; the mean latent period was 3 h. Mucosal irritations in eyes, nose and pharynx, irritative and erosive actions on the respiratory tract (congestion of pharynx, larynx, and uvula, abnormal breath sounds), peribronchitis, leukocytosis following a “mild” intoxication were reported. Following a “moderate” intoxication, they observed in addition necrosis, and desquamation of respiratory mucosa, pneumonia, and ECG demonstrated myocardial damage. A “severe” intoxication caused in addition laryngeal edema, pulmonary edema, toxic shock, toxic encephalopathy and myocardial damage. Within 1–2 h of skin contamination by DMS, a local burn was evident with the appearance of redness, swelling, pain, and bleb formation. In addition, patients experienced nausea, vomiting, dyspnea, headache, and irritability. Follow-up studies for 2–12 years have found only mild to moderate impairment in ventilatory capacity in eight cases, with no abnormal findings in ECG, chest films, and routine blood tests.

Deichmann and Gerade (1969) reported that exposure by inhalation to 508 mg/m3 (97 ppm) for 10 min may be fatal.

SUBCHRONIC AND CHRONIC TOXICITY AND CHRONIC TOXICITY

Effects in animals

In an inhalation study by Schlogel and Bannasch (1972; 1970) groups of Golden hamsters, Wistar rats and NMRI mice were exposed to 0.5 ppm (2.6 mg/m3) DMS for 6 h/d, 2 d/w or to 2 ppm (10.5 mg/m3) for 6 h every 2 weeks for 15 months. Animals were observed for additional 15 months. It was reported that all species treated at 2 ppm had decreased body weights and that rats and mice treated at 2 ppm had increased mortality.

In the study by Druckrey et al. (1970), 27 BD rats were exposed to 3 or 10 ppm (15.7 or 52.4 mg/m3) DMS for 1 h/d, 5 d/w for 130 days and observed up to 643 days. Several early deaths from inflammation of the nasal cavity and pneumonia were reported in the high dose group and some early deaths occurred at the low dose group due to the necrotizing effect of DMS in the nasal passage. However, controls were not used.

In a subchronic study, Molodkina et al. (1986) exposed Wistar rats and guinea pigs to 0.29 and 2.69 mg/m3 DMS for 4 months. Again, the exposure was not described in detail, and neither the number of animals, nor the utilization of a control group were reported. The authors reported functional and morphological changes in the nervous system, lungs, kidney, liver and blood after the exposure to the higher concentration of DMS. These changes were only transitory. A complete recovery except bronchitis was observed after the end of exposure (no information on duration of observation period was provided). Exposure to 0.29 mg/m3 induced only minor changes (increased body weight and decreased level of hippuric acid). No pathomorphologic effects in organs or tissues were observed. Authors suggest that this concentration is not far from NOAEL for chronic exposure. However, due to the lack of many substantial information, we cannot take this study in consideration.

In a study by Molodkina and Obbarius (1981), one group of 10 rats (strain not reported) was exposed to 0.2 mg/m3 DMS for 4 months (no more details on exposure reported). Nine months after the end of exposure rats were killed at the age of 16 months. A second group of 15 rats and a third group of 9 rats were used as controls and were killed at the age of 6 and 16 months, respectively. Three weeks before killing the animals of all groups were immunized to study the immunologic response. This study indicated that inhalation of DMS by rats may accelerate the aging of the immune system, as evidenced by an increase in platelet-forming cells in the spleen, but do not affect the primary immune response.

Effects in humans

Molodkina et al. (1985) reported that the prolonged exposure (duration not reported) of 23 workers to DMS in concentrations exceeding the Maximal Acceptable Concentration of 0.1 mg/m3 (in USSR) induced chronic catarrhal and subatrophic pharyngitis. DMS also affected the immune system as seen by reduced counts of active E rosette-forming cells and increased count of lymphocytes reacting with autoerythrocytes when compared with 19 controls. However, the exposure was not sufficiently described and the workers were also exposed to benzaldehyde and SO3.

TERATOGENICITY

In the study of Druckrey (1970), no malformations were observed in the newborn of rats given a single i.v. dose of 20 mg/kg in the 15th day of gestation.

Molodkina et al. (1986), Sanotsky and Ulvanova (1983) (cited in World Health Organization, 1985) and Fomenko et al. (1984) (cited in World Health Organization, 1985) reported that inhalation of DMS at concentrations of 0.3 or 3.0 mg/m3 for 1.5 months did not have any effects on the germ cells or the spermatogenic epithelium of Wistar rats. In SHK mice and Wistar rats, inhalation of DMS at 0.5–20 mg/m3, throughout pregnancy, was reported to induce pre-implantation losses, and embryotoxic effects including anomalies of the cardiovascular system. However, the higher concentrations of DMS, used in this study, were surely toxic for mothers (see previous section). Embryotoxic effects were found in CBAxC57BC/GI mice but not SHK mice and Wistar rats exposed to 0.29 mg/m3. Reports of Sanotsky et Ulvanova and Fomenko et al. were not available for us and study of Molodkina provided insufficient description of methods and results. So we cannot make an evaluation of the results.

Recently, Alvarez et al. (1997) exposed pregnant rats (strain Crl:CD BR) by nose-only inhalation to 0, 0.5, 3.7 or 7.9 mg/m3 DMS for 6 h/day from Days 7 to 16 of gestation. None of the reproductive patrameters (corpora lutea, implants, resorption, live fetuses, fetal body weight) was altered in any of the groups and no statistically significant fetal effects were detected.

MUTAGENICITY

Genotoxic effects of DMS have been extensively reviewed (International Agency for Research on Cancer, 1987; Anonymous, 1988; World Health Organization, 1985; Freemer et al., 1988). There are hundreds of studies employing DMS. The mutagenicity and carcinogenicity of alkylating chemicals, and especially methylating and ethylating agents, are thought to result partly from the formation and persistence of minor, miscoding DNA adducts such as O6-alkylguanine and O4-alkylthymine (Hoffmann, 1980; Barbin and Bartsch, 1989). The formation of O6-methylguanine following DMS treatment of DNA in vitro represents less than 0.2 % of the total alkylation products (Beranek et al. 1980). Because they produce little alkylation at oxygen sites, the mutagenicity of SN2 reactants like DMS must be explained differently from other alkylating agents. Indirect mutagenesis, in which the occurence of mutation depends upon errors in enzymatic repair processes, is thought to contribute substantially to its genetic activity.

DMS induced both structural and numerical chromosomal aberrations in bone-marrow cells of rats treated in vivo and chromatid breaks in mouse embryos treated transplacentally. It alkylated DNA in rats treated in vivo and in cultured rodent cells. It induced sister chromatid exchanges, unscheduled DNA synthesis and DNA strand breaks in human and rodent cells in vitro, and chromosomal aberrations and mutation in cultured rodent cells. For details, see above cited reviews.

Two studies (Molodkina et al., 1985; Sanotsky and Ulvanova, 1983) reported increased chromosome and chromatid aberrations in lymphocytes of exposed workers. However one study (Sanotsky and Ulvanova, 1983) was not available and in the second (Molodkina et al., 1985) the workers were exposed also to other chemicals. So no definitive conclusion can be made.

CARCINOGENICITY

Animal studies

DMS has been shown to be carcinogenic in rats, mice, or hamsters, by subchronic and chronic inhalation, single and multiple subcutaneous injection. The carcinogenic effect was observed in rats after inhalation, over 15 months, of concentrations down to 3 mg/m3 in the study by Schlogel and Bannasch (1972; 1970), as described above. Similar effects were reported in the study by Druckrey et al. (1970), also described above. Predominantly local tumors at the site of contact such as nasal carcinomas and local sarcomas with occasional metastases were induced after long latency periods, but the significance of the occurence of tumors is unclear because either control data were not reported (Druckrey et al., 1966) or because one study was available only in the abstract form (Schlogel and Bannasch, 1970). However, tumors did not develop in rats that were given repeated i.v. injections (Swann and Magee, 1968; Druckrey et al., 1970). This could be due to its rapid disappearance from the bloodstream and the low level of alkylation of nucleic acids.

There was a limited evidence of transplacental carcinogenicity in rats. Prenatal exposure via maternal i.v. injection appeared to be carcinogenic to the offspring, causing tumors, particularly of the nervous system (Druckrey et al., 1970). However, no controls were reported. Authors report that the fetal nervous system is approximately 50 times more sensitive to carcinogenesis by alkylating agents than tissues of the adult rats.

Human studies

Cases of lung cancer, bronchial carcinoma and choriodal melanoma were reported in men exposed occupationally to DMS (Thiess et al., 1969; Bettendorf, 1977; Albert and Puliafito, 1977; Druckrey et al., 1966). However, exposure concentrations were not given and exposure to other chemicals was possible.

A follow-up study by Ying et al. (1988), described above, did not detect malignant changes in the respiratory system of 62 workers. Authors stated that epidemiologic studies of those exposed to DMS in China have not reported any carcinogenic effect of DMS. However, no more details were given.

ACGIH (1991) cites a report by E. I. du Pont de Nemours & Co. Inc. (1975) from two plants manufacturing and using DMS. Fifty-six workers were exposed to DMS from 1 month to 26 years. Air concentrations determined in each plant showed levels varying from less than 0.2 ppm to much greater than 1 ppm (1.0 to 5.24 mg/m3) with concentrations around 1 ppm or slightly greater. There was no evidence of excess cancer death, indicating DMS to be of low carcinogenic potency for exposed workers at these concentrations.

A similar experience has been found at E.I. du Pont’s three plants manufacturing DMS in a 1972 epidemiologic study covering a period of 15 years (Pell, 1972) (cited by ACGIH, 1991). The data obtained in this investigation showed no excess incidence of total number of deaths or cancers of the respiratory tract among 145 DMS workers. However, no quantitative data on exposure were provided.

CONCLUSIONS AND FUTURE CONSIDERATIONS

DMS is toxic for all cells. It causes severe inflammation of the eye, respiratory epithelium, and skin beginning minutes or hours after exposure. There is little initial discomfort but severe functional disturbances follow. In addition, it is readily absorbed by all routes and produces systemic toxic effects, principally on the nervous system, heart, liver, and kidneys. On the eye, DMS produces toxic effects similar to those of methanol. DMS is highly toxic for man, particularly for the respiratory tract. Relatively short-term exposure (10 min) to 500 mg/m3 may be fatal (Deichmann and Gerade, 1969).

It is important to evaluate the potential public health impact of increased exposures, especially for sensitive populations. It seems that subjects suffering from pulmonary diseases could be more vulnerable to the toxic effect of DMS. However, no report was found studying the effects of DMS in subjects with pulmonary diseases.

In one recent study, none of the reproductive patrameters was altered and no statistically significant fetal effects were detected in the rats exposed up to 7.9 mg/m3 during gestation. No other pertinent information regarding the reproductive effects of DMS were located in the available literature. The teratogenic effects of DMS have not been investigated extensively either. Further research is needed in these areas.

Existing data are insufficient to determine complete dose-response relationships with LOAEL and/or NOAEL for DMS in human or animal studies and to calculate an RfC. Due to the known anatomical differences between the respiratory system of rats and humans, we do not believe the rat to be a suitable model for derivation of human RfC. Humans are more likely to inhale through their mouths than rodents which are obligatory nose breathers. Mouth breathing means bypassing filtration by the nasal passages. If a sufficient cohort of workers occupationally exposed to DMS was identified, it should be studied with a design allowing for the assessment of dose-response relationship. Otherwise, to obtain a better understanding of the toxicity of DMS and to be able to derive an RfC, it should be preferable to perform acute and chronic inhalation studies on primates at several concentrations to determine dose-response relationships. It should be noted that the derivation of RfC will not be pertinent if carcinogenic effects appear at lower concentrations.

Several studies demonstrated association of exposure to DMS with the induction of nasal cavity carcinomas, nervous system, thorax and lung tumors, and local sarcomas in three species (Druckrey et al., 1966; Schlogel and Bannasch, 1970; Druckrey et al., 1970). It should be noted that a concentration of 3 mg/m3 induced respiratory tract tumors in animals (Schlogel and Bannasch, 1970). Tumors of the nervous system and liver developed in the offspring of female rats injected i.v. with DMS (Druckrey et al., 1970). However, a lack of control data and limited details provided in the reports precludes the calculation of a carcinogenic potency factor for DMS. A limited evidence of transplacental carcinogenicity warrants careful investigation.

Several cases of lung cancer, bronchial carcinoma and choriodal melanoma in men exposed occupationally to DMS raise some suspiction as to the possible carcinogenicity of DMS in man (Thiess et al., 1969; Bettendorf, 1977; Albert and Puliafito, 1977; Druckrey et al., 1966) but epidemiologic studies (Thiess et al., 1969; Ying et al., 1988) did not confirm this. Further studies are necessary to make a definitive conclusion. So, in present, the evidence for carcinogenicity in animals is sufficient, but in humans, it is inadequate. Our evaluation agree with those of IARC, EPA and ACGIH. IARC (1987) classified DMS as weight-of-evidence Group 2A (probably carcinogenic in humans). EPA (1988) classified DMS as a probable human carcinogen in the Group B2 and ACGIH (1991) as a suspected human carcinogen in the Group A2.

Little is known about regional DNA adduct dosimetry throughout the respiratory tract or the proliferative cellular responses that facilitate the production of mutations. Studies which will characterize regional dosimetry and the kinetics of DNA damage following exposure to DMS are recommended.

ACKNOWLEDGEMENT

Authors thank Mr. Serge Lamy, Dr. Renaud Vincent, Mr. Daniel Galarneau and Mrs. Grace Wood (Health Canada) for helpful discussions.

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