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Toxicology
of Methyl Nitrite and Related Compounds
Peter M. Joseph, Professor Also by Peter M. Joseph: Methyl nitrite (MN) is one of a class of compounds called alkyl nitrites, with the generalized formula R-O-N-O. MN is the simplest and lightest compound in this class. MN is not available commercially, but is used in certain industrial processes. Higher members of the alkyl nitrite family, including butyl and amyl nitrite, are available and have been widely abused for their neurological effects. For this reason, there is considerably more toxicological data on the higher alkyl nitrites than on MN itself. However, the existing data suggest that, if anything, MN is many times more toxic than butyl or amyl nitrite. Some of the acute effects of MN are known from animal experiments as well as from accidental industrial exposure to humans. The lethal concentration of MN by inhalation in a four hour exposure to rats is only 170 ppm.(8) This is 100 times less than the corresponding value for benzene, and 200 times less than the value for MTBE. In other words, by this test MN is 100 times more toxic than benzene. The cause of death is apparently massive pulmonary hemorrhage. The data also indicate that MN is many times more toxic than the drugs of abuse, butyl and amyl nitrite. There have been several reports of accidental exposure of industrial workers to MN, resulting in methemoglobinemia sufficiently serious to require immediate hospitalization. Prominent symptoms include headache and heart palpitations.(9,10) These are both very significant for our purpose, since headache was the most common complaint found by the CDC investigations of health problems from MTBE in both Alaska(11) and Connecticut(12). Furthermore, statistical data from the Philadelphia Department of Health indicate that the number of people treated for cardiac dysrhythmia increased very substantially between 1993 and 1996, the first three years of large scale MTBE usage here.(1) There are much more data on the abused drugs butyl and amyl nitrite. They are known to depress the function of the immune system in both humans and animals.(13) They can also induce respiratory problems such as tracheobronchitis, cough, and dyspnea(14). In some cases, people have developed allergic reactions to amyl nitrite.(15) The possibility of allergy to MN is important because there are reports of people developing true and serious allergic reactions to exhaust from fuel containing MTBE. In general, the toxicity of the alkyl nitrites is sufficiently serious that the U.S. Congress has twice passed laws to make their sale illegal (public laws 100-690: section 2404, and 101-647:section 3202). MN is known to be mutagenic by the Ames test.(16) This implies, with a probability of about 90%, that it is carcinogenic. The whole question of cancer attributable to nitrites has received considerable attention. There is a very plausible biochemical model that suggests that nitrites may be converted into other compounds, called nitrosamides, which are definitely carcinogenic. There are serious proposals that amyl or butyl nitrite may be the cause of Kaposi's sarcoma, and that the induction of this cancer may be related to suppression of immune function in people who abuse the higher nitrites.(13) It has also been proposed that certain brain tumors in children may be due to in utero exposure to nitrosamides stemming from the mother's exposure to nitrites.(17) There are some indications that excessive nitrite (or nitrate) in the food may cause cancer, but most epidemiological studies are inconclusive. Here we want to point out that there are two major differences between MN in the ambient air and nitrites as food additives. First, nitrite in food is invariably inorganic, such as sodium nitrite, which is ionic and water soluble. MN, on the other hand, is fat soluble. Secondly, the mode of entry of MN is via inhalation, rather than oral ingestion. There are many substances that are safe to swallow but are highly toxic when inhaled. Therefore, a failure to demonstrate that inorganic nitrites in food are carcinogenic must not be interpreted to mean that inhaled MN is not carcinogenic. Furthermore, even if inorganic nitrite is eventually shown not to be carcinogenic, the experiments of Tornqvist et al (16) clearly show that the mutagenicity of MN is independent of its conversion to inorganic nitrite, or, as they put it, "the mutagenicity of methyl nitrite is now clear". Environmental Research in Methyl Nitrite Environmental scientists have been concerned about MN for many years. MN will be rapidly photolyzed by sunlight, with a mean lifetime of about 10-15 minutes.(18) The result is the production of NOx, which would then contribute to an increase in ozone. This may be a factor to explain why the use of RFG with MTBE has not produced significant reductions in ozone, according to a recent report by the National Research Council.(19) In 1982, a Swedish group demonstrated that the addition of methanol to diesel fuel produced small amounts of MN in the exhaust, but they saw none when methanol was added to gasoline (20). Other groups claimed to find MN in exhaust from methanol- fueled engines. However, these results were later shown to be incorrect, due to the artifactual production of MN from the reaction of methanol with NO2, the reaction occurring mainly not in the combustion chamber or exhaust pipe, but in the bag that held the exhaust gases for a period of several hours prior to analysis. Current opinion holds that MN is not produced by methanol in gasoline engines. Methyl ethers, as a fuel component, are virtually unique in the likelihood of dissociation into methoxy radicals at relatively low temperatures. This has especially been demonstrated with DME. Methyl nitrite (MN) is formed by the reaction of methoxy radicals with NO. It is quite feasible that MN is formed in automotive engines when methyl tert-butyl ether, MTBE, is present in the fuel. MTBE, which is CH3-O-tC4H9, breaks apart at the C-O bond to form methoxy and tert-butyl radicals. This pathway is quite prevalent because the tert-butyl radical is quite stable. The details of this process are discussed in the 1999 AWMA paper by Dr. Joseph.(1) Substantial amounts of NO can be formed in the cylinder of the engine due to very high ignition temperatures. The result may be the formation of MN inside the cylinder, which will then travel through the exhaust port and be emitted from the engine as exhaust. Alternatively, the combination of NO and methoxy radicals to form MN may occur in the exhaust system rather than in the combustion chamber. The proposed experiments will distinguish between these two possibilities. It should be emphasized that the equipment used in these proposed measurements, as well as the experimental plan, eliminate the possibility of erroneous identification of MN due to the reaction of methanol with NO2 . For More Information, Contact: Peter
M. Joseph, Ph.D. Barry
Grossman Ivo
Granata REFERENCES |