Controlled Human Exposure to Methyl Tertiary Butyl Ether in Gasoline: Symptoms, Psychophysiologic and Neurobehavioral Responses of Self-Reported Sensitive Persons

Abstract

The 1990 Clean Air Act mandated oxygenation of gasoline in regions where carbon monoxide standards were not met. To achieve this standard, methyl tertiary butyl ether (MTBE) was increased to 15% by volume during winter months in many locations. Subsequent to the increase of MTBE in gasoline, commuters reported increases in symptoms such as headache, nausea, and eye, nose, and throat irritation. The present study compared 12 individuals selected based on selfreport of symptoms (self-reported sensitives; SRSs) associated with MTBE to 19 controls without self-reported sensitivities. In a double-blind, repeated measures, controlled exposure, subjects were exposed for 15 min to dean air, gasoline, gasoline with 11% MTBE, and gasoline with 15% MTBE. Symptoms, odor ratings, neurobehavioral performance on a task of driving simulation, and psychophysiologic responses (heart and respiration rate, end-tidal CO2, finger pulse volume, electromyograph, finger temperature) were measured before, during, and immediately after exposure. Relative to controls, SRSs reported significantly more total symptoms when exposed to gasoline with 15% MTBE than when exposed to gasoline with 11% MTBE or to dean air.However, these differences in symptoms were not accompanied by significant differences in neurobehavioral performance or psychophysiologic responses. No Using a double-blind cross-over design, Prah et al. (8) exposed healthy subjects to 1.4 ppm MTBE versus clean air for 1 hr.Cain et al. (9) exposed healthy subjects for 1 hr to each of three conditions: 1.7 ppm MTBE, 7.1 ppm mixture of 17 volatile organic compounds, and clean air. Neither study found an increase in symptoms, a reduction in neurobehavioral performance, or changes on measures of eye irritation (tear film breakup). The number of polymorphonuclear neutrophil leukocytes in nasal lavage fluid samples was increased only 18-24 hr after exposure to volatile organic compounds (9). In these studies, blood levels of MTBE were higher than the upper quartile levels assessed in the cross-sectional studies of workers. More recently, Nihlen et al. (7) exposed 10 healthy males to 5, 25, and 50 ppm MTBE and found that subjects reported significantly higher ratings of solvent smell with higher exposure to MTBE. Ratings of odor declined over time, suggesting habituation to the odor. No increase in symptoms or changes in objective measures of eye irritation was observed (e.g., tear film breakup time, redness). Nasal airway resistance increased significantly after exposure, but the effect was not correlated with exposure. Thus, in healthy subjects, MTBE exposures under controlled conditions did not replicate the symptoms reported either anecdotally or in cross-sectional community studies. These controlled exposures to MTBE, however, were not those of typical exposures such as refueling or driving, where MTBE is encountered only as an additive to gasoline. Moreover, controlled exposure studies to date have not included self-reported sensitive individuals.As is observed with other noxio...

Multiple chemical sensitivities: A systematic review of provocation studies

“…20 Studies were categorized by the quality of blinding used: double-or single-blind studies that also included an odorous masking agent to prevent identification of the stimuli (Table I), [21][22][23][24][25][26] double-blind studies without masking (Table II), 11,12,[15][16][17][18][19][27][28][29][30][31][32] single-blind studies without masking (Table III), 13,14,[33][34][35][36][37][38][39][40][41][42][43][44] and open-label studies or studies with unclear blinding (see Table E1 in the Online Repository at www.jacionline.org). 10,[45][46][47] Studies using olfactory masking agents or nose clips Three studies testing 70 chemically sensitive participants incorporated blinding and an olfactory mask and failed to show any significant effects on subjects with MCS after provocation with chemicals.…”

“…9 Duplicate publications were included as one study. [10][11][12][13][14] However, assessment of certain duplicate publications was not always clear-cut. For example, we have included 3 articles by as separate studies, given that they appeared to report slightly different results.…”

“…29 One other study reported greater methyl terbutyl ether (MTBE) symptoms after 15% MTBE/gasoline provocations versus 11% MTBE/gasoline provocations. 11 However, the forced-choice stages of this trial failed to demonstrate that chemically sensitive individuals were better at differentiating between gasoline-only/gasoline-MTBE exposures with or without olfactory masking. 11 Fourteen studies incorporated single-blind methodology without olfactory masking agents (Table III).…”

“…11 However, the forced-choice stages of this trial failed to demonstrate that chemically sensitive individuals were better at differentiating between gasoline-only/gasoline-MTBE exposures with or without olfactory masking. 11 Fourteen studies incorporated single-blind methodology without olfactory masking agents (Table III). Five of these studies used forced-choice methods of discrimination, and all of these studies failed to demonstrate that chemically sensitive participants were better at detecting odors than healthy control subjects, whereas 1 of the forcedchoice studies showed that participants with MCS were more likely to report negative responses to phenyl ethyl alcohol, usually described as a pleasant odor and commonly found in perfume.…”

Is multiple chemical sensitivity a learned response? A critical evaluation of provocation studies

“…This was a factor in studies which compared highly noxious chemicals such as gasoline as the active agent and clear air as the control [3]. They concluded that where investigators had used chemicals at or below odour thresholds, most of these failed to demonstrate that people with MCS were better at detecting the active agent compared with healthy participants.…”