REFORMULATED GASOLINE: A SOURCE OF ILLNESS? Peter M. Joseph, Ph.D. Professor of Radiologic Physics in Radiology Hospital of the University of Pennsylvania Philadelphia, PA, 19104 April 15, 1996 I believe there is a new illness in our region which is affecting thousands of people and is largely unknown and unrecognized by most patients and physicians.1 It is due to a sensitivity reaction to a chemical used in the new "reformulated" gasoline (RFG) whose sole purpose is, ironically, to improve our health. The chemical is methyl tertiary butyl ether (MTBE). The symptoms can be roughly categorized as respiratory, neurological, or allergic. The respiratory symptoms include inflammation of any of the mucous membranes in the upper respiratory track (URT), including sinusitis, rhinitis, pharyngitis, or bronchitis. These symptoms are almost indistinguishable from those of common viral URT infections. However there is rarely any fever, and any discharge can be categorized as more typical of allergic reactions than of infection. More important, the time course is very different from URT infections, since the symptoms continue for an indefinite period of time, usually many weeks or months, but are often modulated by subtle changes in the weather conditions (see below). Patients report a feeling of severe malaise, described as "I just feel terrible". Antihistamines are usually not helpful, certainly not as much as they are in conventional seasonal allergies. The neurological symptoms include headache, nausea, insomnia, and sometimes visual disturbances. One symptom I have found most troubling is a sense of lightheadedness, similar to ethanol intoxication. Some patients complain of lethargy. These can be modulated by weather conditions or be constant for many weeks. The allergic symptoms commonly are skin rash or tearing in the eyes. These are exacerbated by exposure to gasoline fumes or byproducts, such as by riding in cars in heavy traffic. Some people, including myself, experience a hot flushed feeling in the skin of the head and neck. Very few people get all of these symptoms, more commonly only a few are seen. It is relatively common for one person to have either the respiratory or neurological symptoms, but not both. Some of these symptoms would normally be attributable to more conventional causes, such as emotional stress or viral infections. To make it clear why I am convinced that they are caused by the gasoline additive MTBE, I must describe some history. When MTBE was added to gasoline in Fairbanks, Alaska, in the winter of 1992, many people (estimated to be 10% of the population) complained of the above symptoms. The symptoms were associated with gasoline fumes and/or exhaust in that they got worse when people drove in traffic and better in their homes out of town. The CDC did a thorough investigation, including measuring blood levels of MTBE and its metabolite TBA.2 The governor of Alaska demanded that MTBE be removed and the symptoms complaints promptly subsided. The same scenario was repeated at the same time in Missoula, Montana with the same result, except that the CDC was not involved. Since then, spontaneous citizen protest groups have arisen in New Jersey, Connecticut, Colorado, and Wisconsin. In New Jersey, the citizens' group "Oxybusters" has collected about 13,000 petition signatures against MTBE. In January, 1995, ABC Television ran a 15 minute documentary explaining the history of this problem. MTBE has been used as a gasoline additive since approximately 1979. However, it was used solely to increase the octane of some brands of premium gasoline and the total amount used was at least an order of magnitude less than today. In our region, we were required to have 15% MTBE in all gasoline starting in the winter of 92-93, and again each winter since then. We are currently (since March 1) required to have 11% MTBE as part of the national RFG program. My own history started also in the winter of 92-93. At that time my symptoms were mainly neurological, including intractable insomnia. I had several extensive diagnostic workups, and was diagnosed with multiple environmental allergies, including dust mites. After cleaning up my home environment, I noticed some improvement in the early spring. (Note that pollen allergies get worse in spring!) I did suffer pollen allergy symptoms throughout most of 1993, and started on immunotherapy shots in September of 1993. I did not notice any severe problems in November 1993 when MTBE was again reintroduced. I did contract pneumonia in mid December which was treated with antibiotics. However, even after the pneumonia cleared I continued to feel sick, with the symptoms of malaise and lightheaded described above. I found that a light box designed to treat winter depression was not effective. Around the end of January 1994, I noticed that many colleagues were not feeling well. Through casual conversation I found two men and two women who also had the lightheaded feeling. One woman also had a continuous headache for which her doctor's prescription of analgesics were not helpful. The symptoms of the three men not only varied from day to day, but almost always in synchrony! This certainly suggests some sort of environmental cause. We all got better on sunny days and worse on cloudy days. For example, Sunday February 20 started out as a bright, cold, winter day. I felt fine that morning and went walking in my suburban neighborhood. By afternoon, the skies clouded over, and by evening I felt very sick (malaise, nauseous) and slept poorly. The next day I discovered that the other two men had identical experiences. By comparison, March 10 (when oxygenated gasoline was no longer required) was also a cloudy day and we all felt fine. All symptoms of all five people disappeared by the middle of march, and we all remained well throughout the spring, summer, and fall of 1994. However, in November 1994 when MTBE was again put into gasoline, four of us again developed the same symptoms as before. I found that an air filtering machine which could absorb organic compounds including formaldehyde was very helpful in controlling my symptoms. This story was described in the February 19 issue of the Philadelphia Inquirer. During the winter of 1994-95 my own symptoms in the URT became worse, with definite pain in the chest, cough, and several difficult URT infections. These symptoms, together with the malaise and lightheadedness described above, are always much worse on cloudy days when there is no rain or wind. Cloudy days with rain or wind are noticeably better, but not as good as sunny days. During March almost every evening, when the sun went down, I would feel ill . In January and February of 1995 I made several public appearances on radio and television asking for people with similar problems to contact me. I have spoken to over 100 people who believe their symptoms may be caused by MTBE. In some cases, the people had pre- existing medical conditions which could also explain their symptoms. However, in most cases it is my judgement that MTBE is the most likely cause. A few of those people have written letters giving their detailed history and in most cases it is very hard to find any other plausible explanation other than MTBE. In some cases, the symptoms recurred in synchrony with our regional MTBE usage, and in other cases the symptoms completely resolved when the people (temporarily) travelled to another geographic region which did not have the high levels of MTBE. Personally, I am completely convinced that MTBE is capable of causing the illnesses reported. We should ask how this situation could come about, and whether the government had not tested MTBE before requiring us to use it. The Environmental Protection Agency (EPA) is the primary advocate of the use of so-called "oxygenate" chemicals in gasoline, the goal being to reduce carbon monoxide emissions by more complete oxidation (so-called "cleaner burning"). The EPA imposed MTBE on Denver starting in the winter of 1988, and claims that no significant complaints were received. However, I personally know of several individuals in that area who were affected and who say that the EPA dismissed their complaints as being groundless. I have copies of written complaints by 65 people in Colorado Springs from the winter of 1992. There have been several toxicologic studies of MTBE in rats and mice which indicated no permanent damage. However, there are short term neurological effects such as would be expected from any ether. There have been a few short term acute exposure studies with human volunteers; these were all done with healthy young adults. The CDC did another driver survey study in Stamford Connecticut in March 1993 and found people reporting the same symptoms as in Fairbanks, Alaska3. They concluded that "Persons with high blood concentrations of MTBE reported a high prevalence of one or more of the key symptoms ... that had been previously associated with MTBE exposure in Fairbanks, Alaska. This association appears to be specific to these symptoms." A study of New Jersey garage workers in 1993 compared northern and southern workers who had high and low MTBE exposure, respectively and claimed to find no difference. However, their group of northern workers who pump gasoline more than 5 hours per day did show a statistically significant increase in MTBE symptoms. Some people interpret that study as negative because in a specially selected subgroup of only 11 individuals no increase in MTBE-type symptoms was found. That obviously does not rule out a possible sensitive subgroup on the order of a few percent. Meanwhile, since 1993, many more automobile and gasoline workers in New Jersey have concluded that MTBE in gasoline is ruining their health. I have spoken to several of them. I am convinced that the EPA has not properly understood the nature of this problem. When MTBE is dispersed in the atmosphere, it can be converted by atmospheric chemistry into tertiary butyl formate (TBF), which is an ester of formic acid. This conversion is mainly dependent on humidity for a source of hydroxyl radicals. Subsequent degradation of TBF into other compounds, including formaldehyde, is strongly dependent on sunlight. Thus one expects environmental TBF levels to increase on cloudy, humid, days, and to decrease on dry sunny days. So far, the EPA has totally ignored any biological or clinical effects from the TBF produced from MTBE, and there is virtually no information on it in the toxicologic literature. However, it is expected to be similar to other formates, such as formic acid (FA). FA is known to be extremely irritating to the mucous membranes of the respiratory system. It is also toxic to the nervous system and is the major toxin active in methanol poisoning. FA will accumulate in monkeys and humans but not in lower animals 4. This might explain why experiments with rodents did not show any problems. It is not known how the metabolism of TBF compares with FA. The only information on TBF itself I could locate is this description of the acute effects, taken from the manufacturers "MSDS" (material safety data sheet): ACUTE EFFECTS HARMFUL IF SWALLOWED, INHALED, OR ABSORBED THROUGH THE SKIN MATERIAL IS EXTREMELY DESTRUCTIVE TO TISSUE OF THE MUCOUS MEMBRANES AND UPPER RESPIRATORY TRACT, EYES, AND SKIN. INHALATION MAY BE FATAL AS A RESULT OF SPASM, INFLAMMATION AND EDEMA OF THE LARYNX AND BRONCHI, CHEMICAL PNEUMONITIS AND PULMONARY EDEMA. SYMPTOMS OF EXPOSURE MAY INCLUDE BURNING SENSATION, COUGHING, WHEEZING, LARYNGITIS, SHORTNESS OF BREATH, HEADACHE, NAUSEA AND VOMITING. TO THE BEST OF OUR KNOWLEDGE, THE CHEMICAL, PHYSICAL, AND TOXICOLOGICAL PROPERTIES HAVE NOT BEEN THOROUGHLY INVESTIGATED. In addition to the cloudy day effect, many individuals report that their symptoms get worse at night. This might be due to an alternate chemical pathway for conversion of MTBE into TBF which uses nitrate radicals, rather than hydroxyl radicals, and is expected to function only at night.5 However, since TBF is the most obvious reaction product from the incomplete oxidation of MTBE, I consider it at least as likely that TBF is being produced by incomplete combustion of MTBE in the engines of cars. This would provide another direct source of TBF independent of atmospheric chemistry, and without photolysis from sunlight it would be expected to increase at night. This effect would be maximal during the winter when the evening commuters rush hour occurs in darkness. All experimental studies of automobile exhaust that I have seen ignore the production of TBF; it is lumped in with all other volatile organic compounds. Furthermore, one would expect production of TBF to be maximal during periods of acceleration when the car's air/fuel system tends to burn a mixture which has excessive fuel, thus greatly enhancing production of TBF and other products of partial oxidation. It is known that the main metabolic products of MTBE are formaldehyde (F) and tertiary butyl alcohol (TBA). F is known to be both toxic and a potent sensitizer. TBA is not as well known, but there is a report of allergy6 which suggests that it also can sensitize. Many Philadelphians would agree with the statement that the 1995 flu season was one of the worst they can remember. This impression has been publicly documented for New York City by the New York Times7 on January 17, which said "The flu and cold season has singled out New York with particular fury this year. While much of the country has remained unusually healthy this winter, many New Yorkers have coughed, sneezed and wheezed their way into the new year", and on February 2, "upstate New York, (was) not as badly hit by the flu epidemic"8. One would normally attribute this to increased virulence of the virus causing the infections. However, the unusually severe symptoms were seen in a only few east coast cities, and not in upstate New York or Boston, for example. These other areas have not been exposed to MTBE in gasoline for nearly as long (three winters) as we have. I propose that the true explanation lies in the irritative effects of TBF on the respiratory mucous membranes which, coupled with induced sensitization in some manner not fully understood, weakened our normal ability to resist the influenza virus. The New York Times did not run any articles commenting on the severity of the 1996 flu season, except that it arrived unusually early9. However, I do know of several individuals in Philadelphia who suffered with extremely resistant respiratory infections that required many weeks of antibiotic therapy before resolution. It seems clear that only a small minority of people are continually affected by these new pollutants; I estimate the fraction to be a few percent. We are clearly dealing with a question of a subpopulation which is or has become sensitive to one or more of these chemicals. Since many more people are reporting these symptoms now than in the previous two years, we can conclude that more people are becoming sensitized through chronic exposure. There is no doubt in my mind that thousands of people are suffering from this without any suspicion of the true cause. There is now preliminary evidence that some component of MTBE induced pollution is inducing cardiac arrhythmias in some susceptible people. These people report that their heart sometimes skip beats, and the problem disappears when they travel to areas not requiring oxygenated gasoline. One person reported that his heart immediately stabilized when he flew in an airplane. He has since moved from New York City because he could not tolerate the medical problems he was having that he attributed to the MTBE- related air quality. The observation that this problem gets worse at night suggests that TBF may be a factor. Obviously, further research on this problem is needed. The intensity of symptoms decreased for myself and many others in early April 1995. The reason for this is not clear. It is probably due to the reduced emission of TBF from cars which are not being driven while very cold as in the winter. However, I and others I know with this sensitivity still often feel worse on most dark, cloudy days. Furthermore, in the fall and winter both I and many others I know again experienced increasing difficulties, although generally not quite as bad as the winter of 1995. This relative improvement is probably due to the fact that Philadelphia was required to use only 11% MTBE in 1995-96, rather than the 15% of the previous winters. A similar reduction in intensity of symptoms was not reported by individuals in Fairfield County, Connecticut, where the gas was again required to contain 15% MTBE. The general worsening of symptoms in winter may be due to the shortening of daylight hours, thus exposing us to more TBF. The question of what the practicing physician can do is difficult. Since the very existence of the disease is controversial, there are no established treatment guidelines. Anti histamines are usually not helpful, with the possible exception of the skin rashes. This is not surprising since sensitivity to small molecules is sometimes not mediated by the IgE allergic responses that lead to excessive histamine release. I speculate that sensitivity to poison ivy may be a more chemically accurate analogy. However, in this case the agent is being inhaled rather than applied to the skin. Current medical opinion is divided on the nature of the neurological or immunological reactions in this type of sensitivity reaction. Some people go on to develop major respiratory problems similar to, or possibly including, asthma, which require inhaled steroids for management. It is a strong probability that the increase in asthma rates in cities in recent years is partly attributable to the increased usage of MTBE in gasoline over this period of time. MTBE was first approved for use in gasoline in 1979. The Philadelphia Inquirer10 said that asthma deaths in Philadelphia have tripled since 1981. Recent statistics from the Philadelphia Department of Health showed an increase of 52% in office visits for asthma from 1993 to 1995, exactly the period when MTBE and RFG have been required. No one has offered any other plausible explanation for this explosive growth in asthma other than TBF. On September 5, 1995 the New York Times ran a front page article11 describing rising asthma rates in the Bronx; the death rate of 11.0/100,000 is 26 times the national average in 1988! I have spoken to several school nurses (two in Delaware County, two in Chester County, and one in Nutley New Jersey) who were (independently) unanimous in their observation that they have seen a huge increase in childhood asthma over roughly the last two or three years. Some writers have suggested that the increase in childhood asthma is limited to the minority populations in the inner cities. My information does not support that idea. One man who coaches athletics in a very wealthy "Main Line" suburb of Philadelphia says he has seen a huge increase in asthma in children over "the last three or four years". Further evidence that usage of MTBE in gasoline exacerbates asthma comes from Dr. Kevin Fennelly of the National Jewish Center for Immunology and Respiratory Medicine in Denver. Dr. Fennelly observed that some of his asthma patients got worse when MTBE was mandated in their gasoline. Denver was given oxygenated gasoline in 1988, four years earlier than most other cities. He applied to the EPA for funding to study this problem but the money was never given. Obviously, an epidemiologic study of this problem is imperative. Unfortunately, I have not succeeded in inducing any of the state health departments to take the slightest interest in this problem. As I indicated, the Colorado Department of Health has been especially zealous in its promotion of oxygenated gasoline and ignored many complaints from the citizens of that state. One nurse said she has seen a huge, almost an order of magnitude, increase in the number of children diagnosed with attention deficit disorder (ADD). Since many of the neurological symptoms experienced by myself and other adults are very similar (lighheadedness, difficulty in concentrating, etc.), it is not unreasonable to attribute this diagnosed condition in children to some component of MTBE-induced air pollution. Certainly MTBE should have a high index of suspicion for automobile or gasoline workers with these symptoms. People whose homes have attached garages may get sick from the fumes from their cars kept there. Because of the widespread protest against MTBE, the EPA and the White House Office of Science and Technology Policy contracted a detailed review of published research by the Health Effects Institute (HEI) of Cambridge, MA. I have prepared a detailed critique of the report produced by that group which is available on request from me. In general, they ignored the evidence that I sent them and misinterpreted the evidence in the public literature. This misinterpretation was due to a series of false assumptions they made about the nature of the problem, for example, that all symptoms are due to MTBE rather than to TBF. A list of their fallacious assumptions is enclosed. Nevertheless, the report offers these summary conclusions: "They [the studies] do provide an imperative for further research...Also to be considered is that MTBE exacerbates the effects of other health factors. Individuals with preexisting respiratory health conditions or allergies and older people are among the groups who may be more sensitive...these studies provide an indication that some individuals exposed to emissions from automotive gasoline containing MTBE may experience acute symptoms such as headache or eye and nose irritation." What is amazing is that in view of these facts, the HEI committee nevertheless concludes that [front page] "the potential health risks of oxygenates are not sufficient to warrant an immediate reduction in oxygenate use". Unless there is some overwhelming advantage to public health from the use of oxygenates, it is difficult to see how this conclusion can be derived from all of the preceding data and uncertainties. In my opinion, this is really a problem of public health policy rather than clinical medicine. However, because of the confusing and controversial nature of the problem, more clinical input is essential. I encourage any physicians who are interested to contact me for more detailed information. I also encourage anyone interested to contact me to take part in the political movement whose purpose is to ban or reduce the level of this noxious chemical in our environment. I can be reached at the Hospital of the University of Pennsylvania, telephone number 215-662-6679. email: joseph@rad.upenn.edu REFERENCES 1. P.M.Joseph, "Letter: Atmospheric Byproducts of MTBE as a Source of Community-wide Illness," Arch. Env. Health 50, 395-396 (1995). 2. R.L.Moolenaar, B.J.Hefflin, D.L.Ashley, J.P.Middaugh, and R.A.Etzel, "Methy tertiary butyl ether in human blood after exposure to oxygenated fuel in Fairbanks, Alaska," Arch. Env. Health 49, 402-408 (1994). 3. M.C.White, C.A.Johnson, D.L.Ashley, T.M.Buchta, and D.J.Pelletier, "Exposure to Methyl Tertiary-Butyl Ether from Oxygenated Gasoline in Stamford, Connecticut," Arch. Env. Health 50, 183-189 (1995). 4. T.R.Tephly, "The toxicity of methanol," Life Sci. 48, 1031-1041 (1991). 5. S.Langer, and E.Ljungstroem, "Reaction of the nitrate radical with some potential automotive fuel additives. A kinetic and mechanistic study," J. Phys. Chem. 98, 5906-5912 (1994). 6. E.K.EdwardsJr, and E.K.Edwards, "Allergic reactions to tertiary butyl alcohol in a sunscreen," Cutis. 29, 476-478 (1982). 7. E.Rosenthal, "Flu casts fevered misery across New York region," (New York Times, New York, 1995), pp. 1-2. 8. E.B.Fein, "With blood shortage near crisis, hospitals prepare to delay operations," (New York Times, New York, 1995), pp. 3-3. 9. P.Belluck, "Sneezing Season is Early and Hospitals Reflect It," (New York Times Dec. 6, New York, 1995), pp. 1-5. 10. S.Fitzgerald, "Asthma's grip baffles the experts," (Phila. Inq. June 11, Philadelphia, 1995), pp. 1-18. 11. A.Nossiter, "Asthma Common and on Rise In the Crowded South Bronx," (New York Times September 5, New York, 1995), pp. 1-2. FALLACIES OF EXISTING INTERPRETATIONS OF DATA 1. Only MTBE is causing problems, not TBF or TBA; i.e. symptoms should correlate with blood [MTBE]. 2. No TBF is created in automobile exhaust. 3. Ambient TBF levels are too small to create problems. 4. People with MCS are most likely to suffer; or, all chemical sensitization is psychological. 5. Irritation symptoms are a "short term" effect. 6. TBF is no more irritating than ethyl formate. 7. Asthma increase is limited to minority people in cities. 8. Asthma increase is due to sub-micron particles. 9. Respiratory infections are not affected by TBF. 10. Cloudy days and sunshine are irrelevant.