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Psychosomatic Medicine 66:588-598 (2004)
© 2004 American Psychosomatic Society

ORIGINAL ARTICLES

Responses to Controlled Diesel Vapor Exposure Among Chemically Sensitive Gulf War Veterans

Nancy Fiedler, PhD, Nicholas Giardino, PhD, Benjamin Natelson, MD, John E. Ottenweller, PhD, Clifford Weisel, PhD, Paul Lioy, PhD, Paul Lehrer, PhD, Pamela Ohman-Strickland, PhD, Kathie Kelly-McNeil, BA and Howard Kipen, MD, MPH

From the Department of Environmental and Community Medicine of UMDNJ-RWJ Medical School (N.F., C.W., P. Lioy., K.K.-M., H.K.) Piscataway, NJ; Department of Psychology (N.G.), University of Cincinnati, Cincinnati, OH; Biometrics Division (P.O.-S.), UMDNJ-School of Public Health, Piscataway, NJ; Department of Neurosciences (B.N., J.E.O.), UMDNJ-New Jersey Medical School, East Orange, NJ; and Department of Psychiatry (P.Lehrer), UMDNJ-RWJ Medical School, Piscataway, NJ.

Address correspondence and reprint requests to Nancy Fiedler, PhD, UMDNJ-RWJ Medical School, 170 Frelinghuysen Road, Room 210, Piscataway, NJ 08854. E-mail: nfiedler{at}eohsi.rutgers.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
OBJECTIVE: A significant proportion of Gulf War veterans (GWVs) report chemical sensitivity, fatigue, and unexplained symptoms resulting in ongoing disability. GWVs frequently recall an association between diesel and petrochemical fume exposure and symptoms during service. The purpose of the present study among GWVs was to evaluate the immediate health effects of acute exposure to chemicals (diesel vapors with acetaldehyde) with and without stress.

METHODS: In a single, controlled exposure to 5 parts per million (ppm) diesel vapors, symptoms, odor ratings, neurobehavioral performance, and psychophysiologic responses of 12 ill GWVs (GWV-I) were compared with 19 age- and gender-matched healthy GWVs (GWV-H).

RESULTS: Relative to baseline and to GWV-H, GWV-I reported significantly increased symptoms such as disorientation and dizziness and displayed significantly reduced end-tidal CO2 just after the onset of exposure. As exposure increased over time, GWV-I relative to GWV-H reported significantly increased symptoms of respiratory discomfort and general malaise. GWV-I were also physiologically hyporeactive in response to behavioral tasks administered during but not before exposure.

CONCLUSIONS: Current symptoms among GWV-I may be exacerbated by ongoing environmental chemical exposures reminiscent of the Gulf War. Both psychologic and physiologic mechanisms contribute to current symptomatic responses of GWV-I.

Key Words: GWVs, • chemical sensitivity, • psychophysiology, • diesel vapors, • hyperventilation.

Abbreviations: CDC = Centers for Disease Control;; CEF = Controlled Environment Facility;; CII = Chemical Odor Intolerance Index;; DIS = Diagnostic Interview Schedule;; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised;; ETCO2 = end-tidal CO2;; ECG = electrocardiogram;; FFT = Fast Fourier Transformation;; GWV = Gulf War veterans;; GWV-H = Gulf War veterans-healthy;; GWV-I = Gulf War veterans-ill;; HEI = Health Effects Institute;; HEPA = high efficiency particulate air;; HF = high frequency;; MANOVA = multivariate analysis of variance;; POET = pulse oximeter end-tidal;; POL = Performance On-Line;; rMSSD = square root of the mean of squared successive differences;; VOC = volatile organic compounds.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Veterans returning from the Gulf War reported medically unexplained symptoms, some of which they attributed to wartime chemical exposures such as pesticides, nerve agents, diesel fuels, and chemical odors (1–3). A significant proportion of U.S. and U.K. war veterans report greater sensitivity to chemicals than nondeployed (4) and Bosnia veterans of the same era (5). Notwithstanding Haley et al. (6), most medical evaluations have not found significant organic pathology to account for the current illness of veterans (7,8). Because the role of chemical exposure in the illness of Gulf War veterans (GWVs) remains controversial (2,3,12–15), the stress of war is implicated as an alternative or additional factor contributing to their unexplained symptoms (9–11).

Regardless of the etiology, it is not clear why veterans’ illness became chronic. A conditioning paradigm would suggest that the combination of chemical odors and war stress set up conditioned physiologic responses and that these responses continue to be reinforced by similar exposures in civilian life. In support of this, Van den Bergh et al. (16) tested a conditioning model of chemical sensitivity by presenting chemical odors with or without nasal exposure to high concentrations of CO2 as the unconditioned stimulus. In healthy subjects, they found increased somatic symptoms and altered respiratory rate on subsequent presentation of the conditioned odor. Neurally mediated sensitization is an alternative mechanism proposed to account for chemical intolerance and has been demonstrated among animals repeatedly exposed to chemicals (19–21). Either of these mechanisms would support a model of Gulf War illness in which ongoing low level chemical exposures both during and after the war contribute to the chronic, unexplained symptoms of GWVs (5,22). Therefore, the present study assesses whether ill GWVs (GWV-I) will experience an exacerbation of their illness in response to a chemical exposure reminiscent of the war (diesel vapors) and in combination with psychologic stress.

Despite the widespread use of diesel fuel in military and civilian applications, no studies have evaluated acute human responses to diesel vapors. In contrast, diesel exhaust has been extensively investigated (10,23–27), including controlled exposure studies of respiratory outcomes (25,28,29) and one neurobehavioral study of workers (30). While diesel vapors and exhaust are both complex mixtures of hydrocarbons, exhaust has more irritants (eg, acetaldehyde). Eighty percent of all GWVs and 90% of veterans from the Department of Veteran Affairs (VA) Health Registry reported exposure to diesel, kerosene, and/or other petrochemical fumes (31). Furthermore, Reid et al. (5) found that vehicle exhaust or fumes was the chemical exposure that U.K. Gulf veterans associated most frequently with symptoms, while a significant proportion of highly symptomatic U.S veterans also reported being exposed to and becoming ill from diesel exhaust during their service in the Gulf War (14). Odors from petrochemicals such as diesel and other gasoline products are also frequently cited by individuals with chemical sensitivities to cause exacerbation of symptoms, although this has not been experimentally validated (32).

In a controlled exposure to five parts per million (ppm) diesel vapors with acetaldehyde and psychologic stress, the present study assessed subjective and objective responses among GWVs using the following measures: symptoms and odor ratings, physiologic indicators of the stress response, and neurobehavioral performance as an objective indicator of function. The following hypotheses were tested: Hypothesis 1: At the onset of chemical exposure and relative to baseline before exposure, GWV-I are expected to report significantly increased symptoms and ratings of odor intensity, unpleasantness, and irritation relative to healthy GWV (GWV-H). Hypothesis 2: Relative to baseline symptoms before chemical exposure and symptoms after the onset of exposure, the addition of psychological stress is expected to significantly increase symptoms for GWV-I compared with GWV-H. Hypothesis 3: After controlling for baseline performance, GWV-I will exhibit significantly poorer performance than GWV-H on a neurobehavioral test of vigilance administered during exposure. Hypothesis 4: After controlling for baseline psychophysiologic status, GWV-I will show significantly increased autonomic arousal relative to GWV-H as indicated by increased heart rate, blood pressure, and respiration rate, and decreased end-tidal CO2 following the initial onset of chemical exposure.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Subjects
A follow-up screening questionnaire to assess current health status was sent to 145 veterans. They were originally recruited from the VA Persian Gulf Registry and had previously been research subjects for a study at the VA in East Orange, NJ (33). Veterans received a complete physical and psychiatric examination during the original evaluation and were categorized as healthy controls or met criteria for a fatiguing illness and/or chemical sensitivity (33,34). To study Gulf War illness in subjects without confounding due to other diseases or injuries, veterans with the following medical conditions were excluded from participation: neurologic disease or brain injury; stroke or cardiovascular disease; serious pulmonary disease including asthma; liver, or kidney disease; serious gastrointestinal disorders; major psychiatric conditions including psychoses, bipolar disorder, alcohol or drug abuse, eating disorders; pregnancy; and lactation. Of the 96 veterans (96 of 145; 66%) who returned the questionnaire, 30 were unwilling to participate in the proposed study due to work commitments or lack of interest. Two veterans declined participation and expressed concerns about the proposed chemical exposure. Twenty-eight were excluded for new onset of medical or psychiatric conditions that might explain their illness. One ill veteran no longer met criteria for fatigue. Thirty-five veterans were invited to participate.

Twenty GWV-H and 15 GWV-I, who met criteria for chronic fatigue syndrome (34) and self-reported chemical sensitivity participated in the exposure study. Chemical sensitivity was indicated by sensitivity to ≥ 5 of 8 chemicals (eg, perfume, household cleaners, newsprint) and ≥ 1 lifestyle change due to chemical sensitivities (35). Of the 35 subjects, three GWV-I and one GWV-H were excluded because of health complications detected at the time of study (eg, high blood pressure; lack of sleep). Thus, 19 GWV-H and 12 GWV-I completed the full protocol. Subjects were paid $125 for participation and $75 if they did not complete the entire protocol. The protocol was approved by the Institutional Review Board of Robert Wood Johnson Medical School and the VA of East Orange, N.J.

Measures
Symptom, Environmental, and Odor Questionnaires
Each symptom was rated on a ratio scale from 0 (barely detectable/ no sensation) to 100 (strongest imaginable) (36). Symptoms were chosen based on the literature documenting the irritative and respiratory health effects of diesel exhaust, (29) the cognitive and somatic effects of volatile organic mixtures such as those produced from the evaporation of diesel fuel (37,38), anxiety symptoms associated with the odor of exposure, and general somatic symptoms not associated with volatile organic mixtures (Table 1) (39). Environmental qualities were rated on a 5-point scale (38). Subjects rated odor intensity and irritation from 0 to 100 using the same scale as that for symptoms while odor pleasantness was rated from 1 (very pleasant) to 9 (very unpleasant).


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  		TABLE 1. Symptom Subscales and Environmental Questionnaire
 
Psychological Questionnaires
Subjects completed the neuroticism subscale of the Neuroticism, Extroversion, Openness Personality Inventory (40) to assess negative affect, the Multidimensional Fatigue Inventory (41) to assess general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity, and the Chemical Odor Intolerance Index (CII) (42) to assess illness associated with odors of perfume, pesticide, paint, car exhaust, and new carpet, all common substances reported to provoke illness exacerbation among patients with multiple chemical sensitivity (32).

Neurobehavioral Task
Performance On-Line (POL) (40) is a divided attention, computerized, driving simulation test that is sensitive to the acute effects of low-dose ethanol (40). The subject was instructed to respond simultaneously to a central task when a "safe" traffic condition exists (ie, left lane, white head lights, right lane, red tail lights) and a peripheral task when a critical stimulus appears (octagon shape representing a stop sign). After practice, 10 trials of 45 displays were presented at the most complex level. A composite performance score incorporated speed and accuracy of all responses (41).

"Vanilla" Baseline Task
To maintain subjects’ alertness during periods of relaxation, a computerized color detection task in which the subject counts color changes of the stimulus, was administered (42).

Stroop Color-Word Test
This demanding task was presented in its computerized version (43,44) for 10 minutes during exposure to assess the combined effects of psychologic stress and chemical exposure.

Physiologic Measures
Previous studies of GWV-I exposed to psychologic stress, (45) and normal subjects exposed to chemical odors (16,46) have suggested that cardiovascular and respiratory responses may be altered in response to challenges with chemicals and/or stress. Therefore, the following physiologic measures were assessed continuously.

Cardiovascular
The electrocardiogram (ECG) signal was collected using disposable electrodes and sampled at 996 Hz through the Flexcomp Biomonitoring system 1.51B (Thought Technology Limited, Montreal, Quebec, Canada). Continuous blood pressure was measured by the vascular unloading technique (47) using a Finapres unit (Ohmeda, Louisville, CO). The finger cuff sensor was placed on the subject’s nondominant middle finger and the hand elevated to approximately the level of the heart. An analog output of the blood pressure waveform was sampled online at 31 Hz through the Flexcomp unit.

Data Reduction: Physiologic Variables
Heart Rate Variability
R-R intervals computed to the nearest millisecond from the ECG were furthered processed using MXEDIT, a PC-based program that allows editing of data for faulty R-wave detection and calculation of band variance (48). Records were rejected for further processing if more than 10% of the data points required editing or if the usable record length was less than 2 minutes. Heart rate variability measures were calculated using the standard Fast Fourier Transformation (FFT) method (49). High frequency (HF) heart rate variability was measured between 0.15 and 0.40 Hz, and low frequency heart rate variability was measured between 0.05 and 0.15 Hz. The natural logarithm of the resulting band variances was then calculated.

Respiratory
Respiration rate was measured by a respiration belt fastened around the abdomen. Voltage output from the belt was amplified through the Flexcomp system and recorded online at 31 Hz. End-tidal CO2 (ETCO2) was collected through a 1/16 inch disposable cannula inserted approximately 1/4 inch into the subject’s nostril and connected to a Criticare Systems Pulse Oximeter End Tidal (POET) II (Waukesha, WI) CO2 monitor. Analog output of the CO2 waveform was sampled online at 31 Hz through the Flexcomp system. Stability of respiratory activity was computed by taking the square root of the mean of squared successive differences (rMSSD) in respiratory intervals. This calculation has been shown to be a sensitive discriminator of subjects with anxiety and hyperventilation disorders (50).

Controlled Environment Facility (CEF)
The CEF is a 7.3' high by 9'x13.5' stainless steel chamber in which conditions of temperature and humidity are controlled. Low concentrations of chemical compounds are maintained in the chamber by constant injections into the filtered (high efficiency particulate air and carbon trap scrubber) air supply, which flows through the chamber without recirculation. A two-way mirror allows direct observation of the subject at all times. The CEF contains chairs, a stainless steel table, computer monitor and keyboard, and a private lavatory.

The exposure concentration of 5 ppm diesel vapor was based on an estimate of typical exposure concentrations found in garages where diesel and other fuels are used. Peak exposures to diesel fuels and exhaust are encountered during refueling of vehicles. The breathing zone hydrocarbon (C3-C11) air concentration during refueling at service stations has been reported to range from 4.5 ppm to 21 ppm (51). The air concentrations during the refueling of jet planes was 5.5 ppm for the refueling technician and 3 ppm in the general vicinity for JP-5 and JP-8 (52). The experimental exposure concentration of 5 ppm is less than 50% of the threshold limit value (53). Acetaldehyde (54) is a pulmonary irritant found in diesel exhaust. It was added at a concentration of 0.5 ppm to more closely approximate the environmental conditions encountered by soldiers (55).

The exposure was produced by heating a mixture of diesel fuel and acetaldehyde and transferring the headspace gases through heated lines (to prevent condensation) to the mixing plenum of the CEF. A total hydrocarbon concentration of 5.0 ppm and an acetaldehyde concentration of 0.5 ppm was maintained throughout each 50-minute exposure period. The hydrocarbon concentration was continuously monitored using a Teledyne total hydrocarbon monitor (model 402R). Two integrated air samples were collected continuously during the CEF exposure. To examine the profile of the peaks from the evaporated diesel fuel, a Tenax-filled absorbent trap was analyzed by thermal desorption coupled to a gas chromatograph/mass spectrometer. The second integrated air sample was a C-18 coated DNPH Sep-Pak that was analyzed to determine the level of acetaldehyde by high pressure liquid chromatography-ultraviolet spectroscopy.

Ramp up and the clean out of the mixture from the CEF was ≤ 5 minutes and 7 minutes, respectively. The test gas concentration, and the temperature (±11°F), relative humidity (±2%) and air flow (0.1" of water negative pressure) in the CEF were monitored and controlled by a computerized system. The CEF has redundant backups, and a trained environmental specialist was in attendance at all times.

Procedure
Subjects signed informed consent and completed medical and psychological questionnaires, examinations, ECG, and spirometry. The Diagnostic Interview Schedule (DIS) for the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R) (56) was administered to assess current and lifetime psychiatric diagnoses. Subjects were then taken to the CEF where they practiced POL and were given an orientation to the questionnaires and physiologic procedures. Subjects were given lunch followed by a 30-minute break. To assess epinephrine, norepinephrine, cortisol, adrenocorticotropic hormone, prolactin, and growth hormone, each subject had an indwelling catheter placed in the antecubital vein by a trained nurse. Results of these measures and the DIS psychiatric interview will be reported separately.

Subjects were escorted to the CEF where they were seated in a comfortable chair and physiologic sensors were attached (Figure 1). Physiologic measures were monitored continuously throughout clean air baseline and diesel exposure. Baseline measures before diesel exposure were collected while the subject sat quietly with circulating room air after which the exposure was administered for 50 minutes. Twenty-five minutes after the onset of exposure, subjects performed the psychological stressor (ie, Stroop task). Subjects completed the symptom and environmental questionnaires, POL, and odor ratings during clean air baseline, the diesel exposure period, and following exposure and removal from the CEF.



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  		Fig. 1. Time line.

 
Statistical Analyses
Symptoms, Environmental Questionnaire, Odor Ratings, and POL Change Score Computation
Clean air baseline symptom and environmental quality ratings at minute 10 were subtracted from the same measures collected at minutes 45 and 75, and then 30 and 60 minutes postexposure. Clean air baseline odor ratings at minute 35 were subtracted from each subsequent set of odor ratings assessed during exposure. Clean air baseline POL score was subtracted from POL administered during and 30 minutes postexposure. Symptoms, environmental quality, and odor ratings (baseline 2) at minute 45, just after the onset of exposure, controlled for the initial reaction to the odor of exposure and were subtracted from subsequent symptom, environmental, and odor ratings.

Symptom and Odor Rating Analyses
To assess the effects of exposure, change scores for total symptoms and odor ratings were compared between GWV-I and GWV-H using the nonparametric, one-tailed, Wilcoxon Rank Sum test due to lack of homogeneity of variances between groups and nonnormality of score distributions. When total symptom scores were significantly different, subscale scores were then analyzed and the Bonferroni correction was applied to correct for multiple comparisons. Bonferroni corrections were also applied for the multiple comparisons of odor intensity, irritation, and pleasantness ratings. In an exploratory analysis, rank regression and Spearman correlation coefficients were used to determine the importance of any of the following variables as predictors of total symptom change scores at time points where significant differences were observed between groups: age, gender, years of education, neuroticism, physical fatigue, and chemical odor intolerance. A backwards stepwise procedure was used to select the significant predictors for the regression model.

Environmental Quality Analyses
A two-sided Wilcoxon Rank Sum test was used to test change scores between GWV-I and GWV-H for ratings of environmental qualities since both high and low scores could signify an adverse effect on ratings of environmental quality.

Neurobehavioral Analyses
For POL, one-way analyses of variance with group as the between-subjects factor was used to compare change scores. If composite scores were significantly different, then component scores from POL were compared between groups in the same manner.

Physiologic Variables
Physiologic variables were averaged for 5-minute epochs at rest and recovery and for 10-minute epochs during completion of the POL and Stroop. Mean differences during the first clean air baseline rest period between GWV-I and GWV-H were examined using a multivariate analysis of variance (MANOVA) followed by univariate analyses for each variable. To determine the efficacy of the performance and stressor tasks in altering physiological activity, a one-way repeated-measures analysis of variance was computed on each physiologic dependent variable. When violations of the sphericity assumption occurred, statistical significance was determined using degrees of freedom corrected by the Huynh-Feldt method (57). To examine differences in physiological reactivity and recovery between GWV-I and GWV-H during the experimental protocol, a repeated measures analysis of variance was computed. Group and Group by Task effects were examined. For those dependent variables that produced significant Group by Task effects, change scores were computed for each rest-to-task (POL or Stroop reactivity) and task-to-recovery (POL or Stroop recovery) epoch (Figure 1). In addition, a change score subtracting baseline rest before exposure (minutes 35–40) from reactivity to exposure (minutes 40–45) was compared between GWV-I and GWV-H to examine the effect of chemical exposure (ie, excluding task effects). Between-group differences in these change scores were tested using MANOVA. When age, gender, or baseline measures were found to be significantly correlated with change scores, they were entered as covariates into the MANOVA.

To examine the relative influence of demographic and individual differences on physiological reactivity, regression analyses were computed with neuroticism, physical fatigue, and chemical odor intolerance entered as independent variables for each significant change score dependent variable. When age, gender, or baseline values were found to be significantly correlated with change scores, they were entered first; demographics were entered simultaneously as one block while baseline values were entered as another block into the regression equation.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Pretest and Baseline Characteristics
GWV-I and GWV-H did not differ significantly in age or gender, but GWV-H were significantly more educated than GWV-I. GWV-I scored significantly higher than GWV-H on NEO-neuroticism, Multidimensional Fatigue Inventory-physical fatigue, and CII scale (Table 2). A greater percentage of GWV-I reported becoming ill during service in the Gulf from exposure to smoke from tent heaters and oil wells, pesticides, vehicle exhaust, and anti-nerve gas pills than GWV-H (Table 2). However, the percentage who reported receiving anthrax and other vaccinations was comparable between the groups (not shown). No significant differences were observed for heart rate, systolic, or diastolic blood pressure taken at rest during the physical examination or at baseline before chemical exposure inside the CEF. However, GWV-I had significantly lower end-tidal CO2 relative to GWV-H at baseline before chemical exposure inside the CEF (Table 2). GWV-I did not differ from GWV-H at baseline in respiration rate, or high and low frequency heart rate variability (data not shown). GWV-I reported significantly greater (p = .03) total symptom severity (mean = 3.29; SD = 3.16) than GWV-H (mean = 1.06; SD = 1.04) at baseline (minute 10) before chemical exposure (Figure 2).


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  		TABLE 2. Pretest and Baseline Group Characteristics
 


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  		Fig. 2. Total symptom severity for ill relative to healthy Gulf War veterans.

 
Hypothesis 1: Symptoms, Odor, and Environmental Ratings
The experiment confirmed the hypothesis that total symptom severity difference scores were significantly greater for GWV-I than GWV-H after exposure onset (minute 45) and after the psychologic stressor (Stroop, minute 75). Total symptoms were not significantly different at 30 and 60 minutes postexposure relative to baseline. As hypothesized, GWV-I rated odor as significantly more irritating and unpleasant than did GWV-H at several points after the onset of exposure (minutes 45, 65, 75 for irritation; Figure 3; minutes 50 and 75 for unpleasantness, not shown). However, GWV-I rated odor intensity significantly greater than GWV-H only after the Stroop (minute 75) but not at other time points (not shown). Comparing symptom subscale difference scores revealed that GWV-I difference scores were significantly greater than GWV-H for volatile organic compounds (VOC) cognitive, VOC general, and somatic symptoms at minute 45 and for lower respiratory, and VOC general symptoms at minute 75 (data not shown). Relative to baseline (minute 10), no significant differences between GWV-I and GWV-H were observed for the environmental quality ratings at any subsequent measurement.



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  		Fig. 3. Odor irritation ratings for ill relative to healthy Gulf War veterans.

 
Hypothesis 2: Symptoms and Odor Ratings Following Chemical Exposure With Psychological Stress
The experiment did not confirm the hypothesis that the addition of a psychologic stressor would significantly increase total symptoms beyond those observed with diesel exposure alone. That is, relative to the exposure baseline (minute 45), total symptom severity difference scores and ratings of odor intensity, pleasantness, and irritation were not significantly different between GWV-I and GWV-H after the stressor (minute 75) or at 30 minutes postexposure. GWV-I reported significantly greater reductions in total symptom severity and in subscales of eye irritation, lower respiratory, VOC cognitive, and VOC general symptoms than GWV-H at 60 minutes postexposure.

Hypothesis 3: Chemical Exposure and Neurobehavioral Performance
After controlling for baseline performance, analyses of variance comparing POL composite scores between GWV-I and GWV-H did not support the hypothesis that exposure significantly impairs the performance of GWV-I. No significant differences were observed at minute 50 or 30 minutes postexposure [baseline mean: GWV-I = 56.97 (SD = 14.88), GWV-H = 67.62 (SD = 18.32); minute 50 mean: GWV-I = 64.48 (SD = 13.49), GWV-H = 69.50 (SD = 19.32); 30 minutes postexposure mean: GWV-I = 64.26 (SD = 19.27), GWV-H = 69.05 (SD = 17.99)].

Hypothesis 4: Chemical Exposure and Psychophysiologic Responses
The hypothesis that autonomic arousal would be significantly increased for GWV-I relative to GWV-H in response to diesel exposure was confirmed (Figure 4). After the onset of exposure (minutes 40–45), GWV-I exhibited significantly greater changes from baseline than GWV-H, showing increased systolic blood pressure, lower end-tidal CO2, and greater respiratory variability. No other significant differences were observed.



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  		Fig. 4. Systolic blood pressure, end-tidal CO2, and respiratory variability in response to psychological tasks and diesel exposure.

 
To examine reactivity and recovery in response to exposure and to behavioral tasks, multivariate analyses were performed for each dependent measure where a significant task by group effect was observed. These MANOVAs were conducted for the following difference scores: baseline rest (minutes 35–40) - exposure reactivity (minutes 40–45); task - rest (task reactivity); recovery - task (task recovery). Baseline end-tidal CO2 was positively correlated with end-tidal CO2 change at the onset of exposure and negatively correlated with recovery to rest period change scores. Baseline respiration rate was negatively correlated with heart rate variability measures. Therefore, for these measures, baseline values were entered as covariates in the MANOVAs. No other significant correlations were observed for age or gender.

No significant changes were observed for task reactivity to baseline POL before exposure. However, for POL during diesel exposure, GWV-I exhibited a significantly smaller increase in systolic blood pressure (Figure 4) and greater decrease in low frequency heart rate variability (not shown) with no other significant psychophysiologic differences. Change scores reflecting task reactivity to the Stroop (minutes 65–75) revealed that GWV-I showed a significant increase in high frequency heart rate variability while GWV-H exhibited a decrease. No other significant task reactivity differences were observed.

Task Recovery
Change scores reflecting task recovery for baseline POL before exposure revealed significantly smaller increases in high and low frequency heart rate variability relative to controls with no other physiologic differences observed (not shown). Likewise, task recovery for the POL during diesel exposure found that GWV-I also had a significantly smaller increase in high frequency heart rate variability relative to GWV-H with no other significant physiologic differences observed. Recovery following the Stroop revealed that GWV-I subjects had a significantly smaller decrease in systolic (Figure 4) and diastolic blood pressure than GWV-H with no other significant differences observed. Thus, GWV-I displayed lower physiologic reactivity in response to and recovery from psychologic tasks.

Regression Analyses
Results of the backwards stepwise procedure to predict total symptom differences found that only the individual difference characteristic of chemical odor intolerance was a significant predictor at both minutes 45 and 75. Backwards stepwise regression analyses also revealed that neuroticism was significantly associated with smaller changes in systolic blood pressure in response to the POL task (B = –0.53; t = –2.46; p < .05) during diesel exposure. Higher CII was associated with changes in systolic blood pressure (B = 0.45; t = 2.23; p < .05) during the onset of diesel exposure and during recovery from the Stroop. CII was also associated with smaller increases in low frequency heart rate variability (B = –0.56; t = 2.11; p < .05) following the baseline POL task and with larger decreases in low frequency heart rate variability for the POL performed during diesel exposure (B = –0.59; t = 2.33; p < .05). Finally, CII (B = –0.55; t = –2.10; p < .05) and neuroticism were each significantly associated with changes in end-tidal CO2 in response to the onset of diesel exposure.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
GWV-I demonstrated significantly reduced end-tidal CO2, increased systolic blood pressure, and increased respiratory variability in response to the odor of diesel vapors. Concurrently, GWV-I reported significantly increased severity of symptoms such as difficulty concentrating, disorientation, dizziness, and headache, all consistent with reduced end-tidal CO2 and hyperventilation. Chemical odor intolerance was the most significant predictor of the reduced end-tidal CO2 and of increased symptom severity shortly after the onset of diesel exposure. Despite reports of poor concentration among GWV-I, neurobehavioral performance was not compromised relative to GWV-H. From the differences in neurobehavioral performance observed in this study, hundreds of subjects would be needed to detect a performance decrement at this exposure concentration. Overall, the data suggest that the chronic symptoms of GWVs may be maintained and exacerbated, in part, by a hyperventilation response to recurrent, ambient exposures of chemical agents commonly encountered in civilian life, such as diesel vapors.

Although symptoms of difficulty concentrating, disorientation, dizziness, and headache are consistent with reduced end-tidal CO2, hyperventilation may not fully account for these or other symptoms reported just after exposure onset (drowsy, general somatic). Hyperventilation of the magnitude experienced by most subjects (ETCO2 < 38 mm Hg) does not always produce symptoms (58). However, the ETCO2 of several GWV-I subjects (N = 4; ETCO2 ≤ 35) approached a value that may be associated with symptoms particularly for those sensitive to hypocapnic symptoms (59). Reduced end-tidal CO2 did not persist and probably does not explain symptoms with onset later during exposure. Instead, the symptoms that increased significantly with exposure duration such as cough and wheeze suggest a lower respiratory response and may reflect an increasing response to irritants.

GWV-I also reported increased fatigue with prolonged exposure, a finding consistent with the physiologic hyporeactivity observed in response to the behavioral tasks administered during diesel exposure and to similar tasks administered in a previous study with GWV-I (45). It is noteworthy that GWV-I reactivity to the POL under clean air conditions was similar to that of GWV-H. Thus, it appears that the addition of chemical exposure diminished cardiovascular reactivity among GWV-I. Similar findings are observed in other patient groups (eg, anxiety disorder, chronic fatigue syndrome) (45,60–64) who also do not show a typical pattern of healthy physiologic response to acute stress (eg, decreased heart rate variability). Hyporeactivity to mental stressors may result from lack of task involvement. However, since no differences in POL task performance were observed between GWV-I and GWV-H, lack of task involvement is an unlikely explanation. These findings support patient anecdotal reports, suggesting that symptoms and physiologic responses are exacerbated by chemical exposures (32).

The hyperventilation response observed in the present study is highly consistent with other studies of patients with multiple chemical sensitivities or idiopathic environmental intolerance. In previous studies, patients with idiopathic environmental intolerance were significantly more likely than controls to hyperventilate in response to CO2 challenge (65) or lactate infusion (66). However, this is the first time such a response has been documented with environmentally relevant concentrations of chemicals rather than the established panicogenic stimulus of high-level CO2. Additionally, several investigators have suggested that some of the symptoms reported by subjects with chemical intolerance may be a function of a conditioned physiologic response (16,67–71) such as hyperventilation. It is unlikely that the initial response to this level of chemical exposure was due to a direct toxic effect, particularly since the response occurred within the first 5 minutes after the onset of exposure. Rather, it is more likely that GWV-I were exhibiting a conditioned response to the odor of diesel fumes as demonstrated by Ley (72) and by Van den bergh et al. (16) Moreover, relative to GWV-H, GWV-I rated the odor of exposure as significantly more unpleasant and irritating within the first 5 to 10 minutes after exposure onset. The association of diesel odors with the Gulf War may have contributed to a hypervigilance to physical sensations, thereby exacerbating symptoms and physiological responses during exposure.

Several caveats should be taken into account in the interpretation of the present results. Because of time and travel constraints, veterans were given a single exposure and were informed that they would be exposed to diesel vapors with acetaldehyde. There was no control condition other than baseline before exposure. Therefore, findings from the present study cannot unambiguously be attributed to diesel vapors as opposed to the stress of anticipating an exposure and the unpleasantness of the odor. While the psychological stressor did not increase symptoms beyond those observed with diesel exposure, the order of stressor administration was not counterbalanced with exposure, and the stressor was never administered during a no-exposure condition. Therefore, the effect of psychological stress could not be fully examined in the present single-exposure design. The sample selected for this study consisted of veterans who were ill and yet willing to travel to New Jersey and undergo a chemical exposure protocol. A few GWV-I (N = 2) refused to participate because of the chemical exposure. However, it seems likely that this selection bias would have compromised rather than enhanced the ability to find significant effects of exposure.

The present study suggests that the odors associated with deployment could elicit conditioned physiologic responses and symptoms, particularly among veterans who report chemical sensitivity. Several investigators have documented a higher prevalence of chemical sensitivity and fatiguing illness among ill relative to healthy veterans (4,14,73–75). The prevalence of chemical sensitivity among veterans also appears to be greater than that cited for community samples (74,76–79). Whether these conditioned responses are occurring among veterans affected by chemical sensitivity in the "real world" remains to be established. However, it appears that GWV-I have a relatively specific symptomatic response to low exposure concentrations of diesel vapors, not experienced by healthy veterans, not entirely accounted for by hyperventilation, and potentially associated with the unpleasant and irritating odor of the exposure. These results suggest a model for ongoing Gulf War illness in which veterans are anxious about chemical exposures due to previous illness episodes associated with Gulf War exposures. Functioning in this heightened, chronic anxiety state may contribute to more general somatic symptoms such as fatigue and also may increase veterans’ likelihood of panic symptoms such as hyperventilation when acute chemical exposures are encountered. If they are unable to escape the chemical exposure, then increased monitoring of other body systems could enhance symptom perception and reporting. If the present results are validated, then a psychological deconditioning treatment may reduce some of the disability associated with current chemical exposures.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
This research was supported in part by the National Institute of Environmental Health Sciences Center Grant #P30 ES05022 and the Department of Veterans Affairs, East Orange, NJ.

Received for publication May 9, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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