Sleep interruption associated with house staff work schedules alters circadian gene expression.

BACKGROUND: Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor ß (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers. METHODS: Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least seven days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing seven days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses. RESULTS: The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p <0.0001). CONCLUSION: Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies.

A controlled trial of acute effects of human exposure to traffic particles on pulmonary oxidative stress and heart rate variability.

BACKGROUND: For many individuals, daily commuting activities on roadways account for a substantial proportion of total exposure, as well as peak-level exposures, to traffic-related air pollutants (TRAPS) including ultrafine particles, but the health impacts of these exposures are not well-understood. We sought to determine if exposure to TRAPs particles during commuting causes acute oxidative stress in the respiratory tract or changes in heart rate variability (HRV), a measure of autonomic activity. METHODS: We conducted a randomized, cross-over trial in which twenty-one young adults took two 1.5-hr rides in a passenger vehicle in morning rush-hour traffic. The subjects wore a powered-air-purifying respirator, and were blinded to high-efficiency particulate air (HEPA) filtration during one of the rides. At time points before and after the rides, we measured HRV and markers of oxidative stress in exhaled breath condensate (EBC) including nitrite, the sum of nitrite and nitrate, malondialdehyde, and 8-isoprostane. We used mixed linear models to evaluate the effect of exposure on EBC and HRV outcomes, adjusting for pre-exposure response levels. We used linear models to examine the effects of particle concentrations on EBC outcomes at post-exposure time points. RESULTS: Mean EBC nitrite and the sum of nitrite and nitrate were increased from baseline at immediately post-exposure comparing unfiltered to filtered rides (2.11 µM vs 1.70 µM, p = 0.02 and 19.1 µM vs 10.0 µM, p = 0.02, respectively). Mean EBC malondialdehyde (MDA) concentrations were about 10% greater following the unfiltered vs. filtered exposures, although this result was not statistically significant. We found no significant associations between exposure to traffic particles and HRV outcomes at any of the time points. At immediately post-exposure, an interquartile range increase in particle number concentration was associated with statistically significant increases in nitrite (99.4%, 95% CI 32.1% to 166.7%) and nitrite + nitrate (75.7%, 95% CI 21.5% to 130.0%). CONCLUSIONS: Increases in markers of oxidative stress in EBC may represent early biological responses to widespread exposures to TRAPs particles that affect passengers in vehicles on heavily trafficked roadways.

Controlled exposure to diesel exhaust causes increased nitrite in exhaled breath condensate among subjects with asthma.

OBJECTIVE: To determine whether oxidative/nitrosative stress plays a role in the acute effects of diesel exhaust (DE) on subjects with asthma. METHODS: In this crossover study, 16 subjects with mild to moderate asthma were exposed to clean filtered air or diluted DE (300 µg/m as PM2.5) for 1 hour with intermittent exercise. RESULTS: Airway hyperreactivity increased 24 hours after exposure to DE compared with clean filtered air (PC20, 14.9 mg/mL vs 19.7 mg/mL; P = 0.012). Nitrite in exhaled breath condensate was elevated immediately after diesel exposure (P = 0.052) and remained elevated 4 and 24 hours after exposure. CONCLUSIONS: After exposure to DE, subjects with asthma demonstrated increased airway hyperreactivity and obstruction. Increased nitrite in exhaled breath condensate, in the absence of increased exhaled nitric oxide, suggests a noninflammatory oxidative stress mechanism by which DE affects the lung.

Unique features of obstructive sleep apnea in World Trade Center responders with aerodigestive disorders.

OBJECTIVES: To compare obstructive sleep apnea (OSA) in World Trade Center (WTC) responders with aerodigestive disorders and snoring with non-WTC habitual snorers, and to distinguish features of OSA in a subset of responders with worsening of snoring after 9/11 from responders with previous habitual snoring. METHODS: Cross-sectional comparative study of 50 WTC Medical Monitoring and Treatment Program responders with aerodigestive disorders and snoring and 50 nonresponders with snoring. Responders with worsening of snoring after 9/11 were compared with previous habitual snorers. RESULTS: : While there was a strong correlation between body mass index (BMI), weight, and Apnea + Hypopnea Index (r = 0.36, P = 0.001; r = 0.29, P = 0.044) in the nonresponders, no correlation between either BMI or weight and Apnea + Hypopnea Index was found in the responders. Responders with worsening of snoring after 9/11 had a significantly lower BMI than previous habitual snorers. CONCLUSION: Mechanisms other than obesity are important in the pathogenesis of OSA in WTC responders with aerodigestive disorders.

Sickness response symptoms among healthy volunteers after controlled exposures to diesel exhaust and psychological stress.

BACKGROUND: Interactions between acute exposures to environmental chemical contaminants and psychological stress may be important in situations where they are likely to co-occur, ranging in intensity from daily urban living to participation in war. Modification of symptomatic responses by stress may play a role in medically unexplained symptoms attributed to low-level chemical exposures. OBJECTIVES: We hypothesized that the combination of exposure to diesel exhaust (DE) and acute psychological stress would cause sickness responses in healthy volunteers. Moreover, these responses would be greater in individuals with self-reported prior chemical odor intolerance. METHODS: One hundred adult subjects underwent 1-hr exposures to diluted DE and clean air control. Half of the subjects performed a public-speaking stressor task during the exposures. Subjects completed questionnaires to determine their Chemical Odor Intolerance Index score. Plasma cortisol, end-tidal carbon dioxide, and the severity of 35 symptoms were measured at time points before and after the exposures. RESULTS: Subjects exposed to DE demonstrated small but statistically significant increases in severity for several symptom categories, including sickness response and upper respiratory, central nervous system, and total symptoms. The psychological stressor did not increase symptom severity independently or via interaction with DE. Subjects with prior self-reported chemical intolerance had more severe sickness response symptoms from DE. CONCLUSIONS: These results suggest that exposure to DE can cause acute sickness response symptoms and that these symptoms are also associated with increased levels of self-reported chemical intolerance. The results did not confirm our hypothesis that an acute stressor would increase sickness response symptom severity during the exposure.

Quantification of 1-aminopyrene in human urine after a controlled exposure to diesel exhaust.

Diesel exhaust (DE) is a significant source of air pollution that has been linked to respiratory and cardiovascular morbidity and mortality. Many components in DE, such as polycyclic aromatic hydrocarbons, are present in the environment from other sources. 1-Nitropyrene appears to be a more specific marker of DE exposure. 1-Nitropyrene is partially metabolized to 1-aminopyrene and excreted in urine. We developed a practical, sensitive method for measuring 1-aminopyrene in human urine using a HPLC-fluorescence technique. We measured 1-aminopyrene concentrations in spot urine samples collected prior to and during 24 h following the start of 1 h controlled exposures to DE (target concentration 300 microg m(-3) as PM(10)) and clean air control. Time-weighted-average concentrations of urinary 1-aminopyrene were significantly greater following the DE exposure compared to the control (median 138.7 ng g(-1) creatinine vs. 21.7 ng g(-1) creatinine, p < 0.0001). Comparing DE to control exposures, we observed significant increases in 1-aminopyrine concentration from pre-exposure to either first post-exposure void or peak spot urine concentration following exposure (p = 0.027 and p = 0.0026, respectively). Large inter-individual variability, in both the concentration of urinary 1-aminopyrene and the time course of appearance in the urine following the standardized exposure to DE, suggests the need to explore subject variables that may affect conversion of inhaled 1-nitropyrene to urinary excretion of 1-aminopyrene.

Sensory and cognitive effects of acute exposure to hydrogen sulfide.

BACKGROUND: Some epidemiologic studies have reported compromised cognitive and sensory performance among individuals exposed to low concentrations of hydrogen sulfide (H2S). OBJECTIVES: We hypothesized a dose-response increase in symptom severity and reduction in sensory and cognitive performance in response to controlled H2S exposures. METHODS: In separate exposure sessions administered in random order over three consecutive weeks, 74 healthy subjects [35 females, 39 males; mean age (+/- SD) = 24.7 +/- 4.2; mean years of education = 16.5 +/- 2.4], were exposed to 0.05, 0.5, and 5 ppm H2S. During each exposure session, subjects completed ratings and tests before H2S exposure (baseline) and during the final hour of the 2-hr exposure period. RESULTS: Dose-response reduction in air quality and increases in ratings of odor intensity, irritation, and unpleasantness were observed. Total symptom severity was not significantly elevated across any exposure condition, but anxiety symptoms were significantly greater in the 5-ppm than in the 0.05-ppm condition. No dose-response effect was observed for sensory or cognitive measures. Verbal learning was compromised during each exposure condition. CONCLUSIONS: Although some symptoms increased with exposure, the magnitude of these changes was relatively minor. Increased anxiety was significantly related to ratings of irritation due to odor. Whether the effect on verbal learning represents a threshold effect of H2S or an effect due to fatigue across exposure requires further investigation. These acute effects in a healthy sample cannot be directly generalized to communities where individuals have other health conditions and concomitant exposures.

Negative affect and chemical intolerance as risk factors for building-related symptoms: a controlled exposure study.

OBJECTIVE: To assess whether differences in negative affect (NA) and chemical intolerance (CI) affect responses to chemical mixtures and stress in a controlled experimental model. METHODS: Participants were 130 nonsmoking, healthy women, recruited from a university community. Participants completed the Positive and Negative Affect Scale and the Chemical Odor Intolerance Index. In separate sessions 1 week apart, they were exposed to volatile organic compounds (VOCs), VOCs with ozone (VOCs+O3), and ambient or filtered air with a 1-minute spike of VOCs (masked clean air). During each session, half of the participants performed a videotaped speech stressor and half performed simple arithmetic. Before, during, and after each session, salivary cortisol samples were collected, and subjects completed neurobehavioral tests and used a ratio scale to rate physical, cognitive, and anxiety symptoms. RESULTS: Relative to low NA or low CI, neither the high NA nor the high CI groups reported significantly more symptoms in response to any exposure condition. High NA subjects reported more anxiety symptoms in response to the speech stressor but did not have higher cortisol than low NA subjects. High NA subjects, however, were more distressed by the experimental conditions than were low NA subjects. Low NA subjects reported more severe anxiety in the VOCs+O3 with psychological stress condition. CONCLUSIONS: Subjects high in NA were more anxious after a stressor but were not more physically symptomatic in response to increasing chemical exposures. A disposition toward high or low CI did not result in a differential symptomatic response to controlled chemical exposures.

Health effects of a mixture of indoor air volatile organics, their ozone oxidation products, and stress.

In our present study we tested the health effects among women of controlled exposures to volatile organic compounds (VOCs), with and without ozone (O3), and psychological stress. Each subject was exposed to the following three conditions at 1-week intervals (within-subject factor): VOCs (26 mg/m3), VOCs + O3 (26 mg/m3 + 40 ppb), and ambient air with a 1-min spike of VOCs (2.5 mg/m3). As a between-subjects factor, half the subjects were randomly assigned to perform a stressor. Subjects were 130 healthy women (mean age, 27.2 years; mean education, 15.2 years). Health effects measured before, during, and after each 140-min exposure included symptoms, neurobehavioral performance, salivary cortisol, and lung function. Mixing VOCs with O3 was shown to produce irritating compounds including aldehydes, hydrogen peroxide, organic acids, secondary organic aerosols, and ultrafine particles (particulate matter with aerodynamic diameter < 0.1 microm). Exposure to VOCs with and without O3 did not result in significant subjective or objective health effects. Psychological stress significantly increased salivary cortisol and symptoms of anxiety regardless of exposure condition. Neither lung function nor neurobehavioral performance was compromised by exposure to VOCs or VOCs + O3. Although numerous epidemiologic studies suggest that symptoms are significantly increased among workers in buildings with poor ventilation and mixtures of VOCs, our acute exposure study was not consistent with these epidemiologic findings. Stress appears to be a more significant factor than chemical exposures in affecting some of the health end points measured in our present study.

Nasal effects of a mixture of volatile organic compounds and their ozone oxidation products.

OBJECTIVE: Our objective was to determine if low levels of a mixture of volatile organic compounds (VOCs) and their ozone (O3) oxidation products, similar to what might be found in "sick buildings," cause nasal irritation and inflammation under controlled exposure conditions. METHODS: Healthy, nonsmoking women (n=130) completed 2-hour controlled exposures to VOCs, VOCs and O3, and a masked air "MA" control in random order at least 1 week apart. VOCs and O3 concentrations were approximately 25 mg/m and approximately 40 ppb, respectively. Nasal symptoms were rated before, during, and after exposure. Nasal lavage fluid was analyzed for polymorphonuclear cells, total protein, interleukin-6, and interleukin-8. RESULTS: We found no significant differences in symptoms or markers of nasal inflammation between exposure conditions. CONCLUSIONS: Results suggest that VOCs and their oxidation products may not cause acute nasal effects at low concentrations.

Responses to controlled diesel vapor exposure among chemically sensitive Gulf War veterans.

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 CO(2) 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.

Cognitive effects of chronic exposure to lead and solvents.

BACKGROUND: Occupational exposure to lead and solvents has declined steadily over the past 20 years, however, construction workers continue to be exposed to these neurotoxicants. The purpose of this study was to investigate the cognitive effects of chronic occupational exposure to lead and solvents. METHOD: Based on K-XRF of tibial bone lead and occupational history of solvent exposure, subjects were classified into four exposure groups: lead (N = 40), solvent (N = 39), lead/solvent (N = 45), and control (N = 33). All subjects completed tests to assess concentration, motor skills, memory, and mood. RESULTS: Relative to controls, the lead, solvent, and lead/solvent groups performed significantly more poorly on a test of verbal memory, while the lead and lead/solvent groups were slower than the solvent and control groups on a task of processing speed. Bone lead was a significant predictor of information processing speed and latency of response while solvent exposure was a significant predictor of verbal learning and memory. CONCLUSIONS: Bone lead was associated with slower speed of processing while exposure to lead and/or solvents reduced efficiency of verbal learning.

Anxiety sensitivity and depression in multiple chemical sensitivities and asthma.

Patients with sensitivities to multiple chemicals report symptoms of cognitive dysfunction, respiratory distress, and mood disturbance. Lifetime and current psychiatric disorders, personality traits associated with symptom reporting, and tests of cognitive function were compared between 30 subjects with Multiple Chemical Sensitivities (MCS), 19 asthmatics, and 31 healthy controls. Relative to asthmatics and controls, more MCS subjects met criteria for current depression and somatization disorder. MCS subjects and asthmatics scored significantly higher than controls on scales of chemical odor intolerance and anxiety sensitivity, both of which were significant predictors of physical symptoms. Few differences on objective neuropsychological tests were noted. However, MCS subjects with comorbid depression performed significantly worse on a verbal memory test relative to asthmatics but not to controls. Anxiety and depression are significant contributors to the physical and cognitive symptoms of MCS subjects.