Traffic-related air pollution, chronic stress, and changes in exhaled nitric oxide and lung function among a panel of children with asthma living in an underresourced community.

We examined associations between short-term exposure to traffic-related air pollutants (TRAP) and airway inflammation and lung function in children with asthma, and whether these associations are modified by chronic psychological stress. Residents of underresourced port-adjacent communities in New Jersey were concerned about the cumulative impacts of exposure to TRAP, particularly diesel-engine truck emissions, and stress on exacerbation of asthma among children. Children with asthma aged 9-14 (n = 35) were recruited from non-smoking households. We measured each participant's (1) continuous personal exposure to black carbon (BC, a surrogate of TRAP) at 1-min intervals, (2) 24-h integrated personal exposure to nitrogen dioxide (NO2), (3) daily fractional exhaled nitric oxide (FeNO), and (4) lung function for up to 30 consecutive days. Personal BC was recorded by micro-aethalometers. We measured daily FeNO using the NIOX MINO, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) using Easy One Frontline spirometers. Chronic stress was measured with the UCLA Life Stress Interview for Children. The association was examined using linear mixed-effect models. In the fully adjusted model, an interquartile range (IQR) increase in BC at lag 0-6 h before the FeNO measurement was associated with 8 % (95 % CI: 3 % - 12 %) increase in FeNO, whereas an IQR increase in BC at lag 7-12 h and lag 0-24 h were associated with 6 % (95 % CI: 2 % - 11 %) and 7 % (2 % - 12 %) FeNO increases, respectively. There were no significant lung function changes per IQR increase in BC. No interactions were observed between chronic stress and BC on FeNO. Chronic stress was negatively associated with individual average FeNO levels. Our findings suggest that higher levels of BC exposure within the prior 24 h increased airway inflammation levels in children with asthma, with the strongest effect observed within the first 6 h.

Exposure to traffic-related air pollution and changes in exhaled nitric oxide and DNA methylation in arginase and nitric oxide synthase in children with asthma.

BACKGROUND: Traffic-related air pollution (TRAP) has been associated with increased risk of airway inflammation in children with asthma. While epigenetic changes could potentially modulate TRAP-induced inflammatory responses, few studies have assessed the temporal pattern of exposure to TRAP, epigenetic changes and inflammation in children with asthma. Our goal was to test the time-lag patterns of personal exposure to TRAP, airway inflammation (measured as fractional exhaled nitric oxide, FeNO), and DNA methylation in the promoter regions of genes involved in nitric oxide synthesis among children with asthma. METHODS: We measured personal exposure to black carbon (BC) and FeNO for up to 30 days in a panel of children with asthma. We collected 90 buccal cell samples for DNA methylation analysis from 18 children (5 per child). Methylation in promoter regions of nitric oxide synthase (NOS1, NOS2A, NOS3) and arginase (ARG1, ARG2) was assessed by bisulfite pyrosequencing. Linear-mixed effect models were used to test the associations of BC at different lag periods, percent DNA methylation at each site and FeNO level. RESULTS: Exposure to BC was positively associated with FeNO, and negatively associated with DNA methylation in NOS3. We found strongest association between FeNO and BC at lag 0-6 h while strongest associations between methylation at positions 1 and 2 in NOS3 and BC were at lag 13-24 h and lag 0-24 h, respectively. The strengths of associations were attenuated at longer lag periods. No significant associations between exposure to TRAP and methylation levels in other NOS and ARG isoforms were observed. CONCLUSIONS: Exposure to TRAP was associated with higher levels of FeNO and lower levels of DNA methylation in the promoter regions of the NOS3 gene, indicating that DNA methylation of the NOS3 gene could be an important epigenetic mechanism in physiological responses to TRAP in children with asthma.

Controlled exposures to volatile organic compounds in sensitive groups.

Sensitivities to chemicals are characterized by symptoms in multiple organ systems in response to low-level chemical exposures. This paper reviews studies of controlled exposures to odorants and to mixtures of volatile organic compounds. Sensitive subgroups include subjects who met Cullen's 1987 criteria for multiple chemical sensitivity (MCS), Gulf War veterans with chronic fatigue syndrome and chemical sensitivity (CFS/CS), and subjects with specific self-reported sensitivities to methyl terbutyl ether (MTBE) in gasoline (MTBE-sensitive). All studies include comparison of age- and sex-matched healthy controls. Studies of olfaction did not support unusual sensitivity, defined as lower odor thresholds, among MCS subjects; however, a dose-response pattern of symptoms was observed in response to suprathreshold concentrations of phenyl ethyl alcohol. In blinded, controlled exposures to clean air, gasoline, gasoline/11% MTBE, and gasoline/15% MTBE, a threshold effect was observed with MTBE-sensitive subjects reporting significantly increased symptoms to gasoline/15% MTBE exposure. Autonomic arousal (heart and respiration rate; end-tidal CO2) in response to odor of chemical mixtures may mediate symptoms for subjects with generalized chemical sensitivities, but not for those whose sensitivities are confined to specific chemicals. For example, Gulf War veterans with CFS/CS experienced reduced end-tidal CO2 when exposed to diesel fumes, while exposure to MTBE did not produce any psychophysiologic changes in MTBE-sensitive subjects. Controlled olfactory and exposure studies reveal that significant responses can be observed in chemically sensitive subjects even when de-adaptation has not occurred. However, these studies suggest that symptoms are not necessarily accompanied by changes in physiologic arousal. Subject characteristics play a critical role in outcomes.

Health effects of asbestos and nonasbestos fibers.

Exposures to asbestos and synthetic fibers remain areas of great concern in the field of occupational lung disease. Despite extensive study, the health effects associated with fibers remains an area of substantial controversy. In particular, effects of fibers at relatively low doses, particularly for mesothelioma, remain a matter of evolving opinion, especially when integrated with the divergence of opinion on relative pathogenicity of different fiber types. Mechanistic studies continue to provide a window into pathogenesis and some hope for understanding dose-response relationships at the lower levels seen in contemporary Western workplaces and the general environment. Changes in clinical assessment based on use of new chest imaging techniques beyond the traditional plain film are also an area of evolution and begin to challenge B-reading as the definitive tool for noninvasive assessment of disease. Public health concerns have to a great extent been transported to the developing world where there is a strong trend toward increased use of asbestos, although it has been virtually eliminated from commerce in most developed countries. For nonasbestos fibers, the major unsettled issues are their relative potencies as carcinogens for the human lung and mesothelium and the need to sort out the relation between physical and chemical properties of these fibers and their pathogenicity. The recent discovery of "flock worker's lung" due to synthetic fibers once again alerts us to emerging diseases associated with new technologies.

A 37-year-old mechanic with multiple chemical sensitivities.

A 37-year-old heating, ventilation, and air-conditioning mechanic developed respiratory, musculoskeletal, and central nervous system symptoms associated with a variety of odorous environmental chemicals. Organic disease was not evident, but the patient was distressed by these symptoms and was at risk for becoming disabled by them. His symptoms fit broadly into the condition recognized as multiple chemical sensitivity. Multiple chemical sensitivity is a diagnostic term for a group of symptoms without demonstrated organic basis. The symptoms are characteristic of dysfunction in multiple organ systems, they increase and decrease according to exposure to low levels of chemical agents in the patient's environment, and they sometimes occur after a distinct environmental change or insult such as an industrial accident or remodeling. Although traditional medical organizations have not agreed on a definition for this syndrome, it is being increasingly recognized and makes up an increasing percentage of the caseload at occupational and environmental medicine clinics. Although there is often dispute about whether the symptoms have a functional or organic basis, an informed approach to evaluation, diagnosis, and management and a careful assessment of impairment, disability, and work relatedness are necessary. Careful exclusion of organic causes is critical, and this should be followed by a judicious approach to coping with symptoms.

Prevalence of chronic fatigue and chemical sensitivities in Gulf Registry Veterans.

More than 68000 of the 700000 veterans of the Gulf War have become members of the Veteran Affairs' Gulf War Registry. In 1995, we undertook a questionnaire study of the symptoms and medical histories reported by a randomly selected subsample of 1935 of these veterans to characterize their complaints. All results reported were based on questionnaire responses without face-to-face evaluation or physical examinations. Inasmuch as initial registry symptoms overlapped those of Chronic Fatigue Syndrome and Multiple Chemical Sensitivities, we also included standard questions for these syndromes in the questionnaire. A total of 1161 (60%) individuals responded, and there were no major demographic biases; therefore, 15.7% of registry veterans qualified for Chronic Fatigue Syndrome in accordance with the 1994 Centers for Disease Control definition. In addition, 13.1% qualified for multiple chemical sensitivities in accordance with a widely used definition, and 3.3% of the respondents had both conditions. There were no effects of gender, race, branch, duty status (active or reserve), or rank, although Multiple Chemical Sensitivities was somewhat more prevalent in women and African Americans. The data gleaned in this study suggested that the unexplained symptom syndromes of Chronic Fatigue and Multiple Chemical Sensitivities may characterize an appreciable portion of the complaints of those who volunteered for the Veterans Affairs' Gulf War Registry, and further investigation is warranted.

Gulf War illnesses: causation and treatment.

Soldiers returning from the Gulf War in 1991 described a range of symptoms, including some consistent with the chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity. Well-defined adverse health events attributable to service in the Gulf occurred. However, controlled epidemiological studies in Gulf War veterans and controls describe significant excesses of symptoms that were not clearly associated with pathologic disease. At least 12% of veterans currently receive some form of disability from the Department of Veterans Affairs. A number of reports outline theories proposed to explain the excess, but few are scientifically supported. Management guidelines for this spectrum of disorders resembles that of many of "emerging overlap syndromes," including multiple chemical sensitivity, chronic fatigue syndrome, and fibromyalgia. They include the establishment of a trusting doctor-patient relationship, negotiations around a common ground of scientific and etiologic beliefs, non-labeling of the disorder, and work toward recovery in the absence of clear etiologic answers.

A controlled comparison of multiple chemical sensitivities and chronic fatigue syndrome.

The present study had two objectives: 1) to determine the characteristics that differentiated subjects with multiple chemical sensitivities (MCS), chemical sensitivities (CS), and chronic fatigue syndrome (CFS); and 2) to evaluate the psychiatric and neuropsychological complaints of these groups relative to normal controls. A cross-sectional comparison was made of the following groups matched for age, sex, and education: 1) patients whose sensitivities to multiple low level chemical exposures began with a defined exposure (MCS; N = 23); 2) patients with sensitivities to multiple chemicals without a clear date of onset (CS; N = 13); 3) patients meeting CDC criteria for Chronic Fatigue Syndrome (CFS; N = 18); and 4) normal controls (N = 18). Subjects with sensitivities to chemicals (MCS and CS) reported significantly more lifestyle changes due to chemical sensitivities and significantly more chemical substances that made them ill compared with chronic fatigue and normal controls. MCS, CS, and CFS patients had significantly higher rates of current psychiatric disorders than normal controls and reported significantly more physical symptoms with no medical explanation. Seventy-four percent of MCS and 61% of CFS did not qualify for any current Axis I psychiatric diagnosis. Chemically sensitive subjects without a defined date of onset (CS) had the highest rate of Axis I psychiatric disorders (69%). On the MMPI-2, 44% of MCS, 42% of CS, 53% of CFS, and none of the controls achieved clinically significant elevations on scales associated with somatoform disorders. With the exception of one complex test of visual memory, no significant differences were noted among the groups on tests of neuropsychological function. Standardized measures of psychiatric and neuropsychological function did not differentiate subjects with sensitivities to chemicals from those with chronic fatigue. Subjects with sensitivities to chemicals and no clear date of onset had the highest rate of psychiatric morbidity. Standardized neuropsychological tests did not substantiate the cognitive impairment reported symptomatically. Cognitive deficits may become apparent under controlled exposure conditions.

Measuring chemical sensitivity prevalence: a questionnaire for population studies.

Because no information exists on the prevalence of chemical sensitivity syndromes such as multiple chemical sensitivities, a questionnaire for use in population studies was developed and tested to assess the presence or absence of chemical sensitivity. Seven hundred five individuals attending clinics answered a questionnaire asking whether each of 122 common substances caused symptoms. Results showed that patients with multiple chemical sensitivities and asthma had average total scores that were significantly different from each other and from those of each of the other diagnostic categories. Higher total scores were also reported by female patients. The instrument described here may facilitate meaningful prevalence studies of multiple chemical sensitivities. It will also allow study of chemically induced symptoms in other conditions such as asthma.

Asthma experience in an occupational and environmental medicine clinic. Low-dose reactive airways dysfunction syndrome.

The etiology of adult-onset asthma is incompletely understood. High-intensity exposure to irritants is one accepted risk factor and such cases are termed Reactive Airways Dysfunction Syndrome. The contribution to asthma of less intense and less acute exposure to irritants remains to be clarified. We report on 10 cases of nonsensitization adult-onset asthma in settings of exposure to noticeable but distinctly "tolerable" levels of inhalation irritants. This series of 10 cases represent 31% of verified asthma cases seen in our environmental and occupational medicine referral clinic over a 5-year period. We believe further exploration of this phenomenon of low dose Reactive Airways Dysfunction Syndrome is warranted.

Multiple chemical sensitivity syndrome: a clinical perspective. I. Case definition, theories of pathogenesis, and research needs.

Multiple chemical sensitivity syndrome (MCS) does not appear to fit established principles of toxicology. Yet social, political, and economic forces are demanding that MCS be defined medically, even though to date scientific studies have not identified pathogenic mechanisms for the condition or any objective diagnostic criteria. Consequently, a working definition of MCS can rely only on an individual's subjective symptoms of distress and attribution to environmental exposures rather than currently measurable objective evidence of disease. Nevertheless, patients labeled with MCS are clearly distressed and many are functionally disabled. In this review, four theories of causation are explored: (1) MCS is a purely biologic/physical or psychophysiologic reaction to low-level chemical exposures. (2) MCS symptoms may be elicited by low-level environmental chemical exposures, but the sensitivity is initiated by psychologic stress. (3) MCS is a misdiagnosis and chemical exposure is not the cause. The symptoms may be due to misdiagnosed physical or psychologic illness. (4) MCS is an illness belief system manifest by culturally shaped illness behavior. Areas for further research regarding the etiologies of MCS are suggested. Recognizing that the cause of the syndrome may be multifactorial, strategies are proposed for clinical evaluation and management in Part II of this manuscript using a biopsychosocial model of illness.

Multiple chemical sensitivity syndrome: a clinical perspective. II. Evaluation, diagnostic testing, treatment, and social considerations.

Multiple chemical sensitivity syndrome (MCS) does not appear to fit established principles of toxicology. Social, political, and economic forces are demanding that MCS be defined medically, even though scientific studies have failed as yet to identify pathogenic mechanisms for the condition or any objective diagnostic criteria. Consequently, a working definition of MCS can only rely on a person's subjective symptoms of distress and attribution to environmental exposures rather than currently measurable objective evidence of disease. Nevertheless, patients labeled with MCS are clearly distressed and many are functionally disabled. Without reconciling the different theories of etiology of MCS discussed in Part I of this report, and recognizing that the cause of the syndrome may be multifactorial, strategies are proposed for clinical evaluation and management of patients with MCS using a biopsychosocial model of illness. The social implications of this illness are also discussed.

Hematologic effects of benzene. Job-specific trends during the first year of employment among a cohort of benzene-exposed rubber workers.

Hematologic surveillance data from 1940 to 1975 were analyzed for a benzene-exposed cohort of 459 rubber workers. The present analyses are restricted to 161 workers with "preemployment" counts done before exposure and rely on their subsequent counts from the first 12 months of employment. While blood cell counts declined approximately 1000 cells/mm3 over the first 4 months of exposure. Using repeated-measures analysis of variance, workers exposed above the median benzene exposure at the plant had significantly lower average white and red blood cell counts at each month during the first year of work when compared with workers exposed below the median. These decreased counts suggest that clinically detectable bone marrow depression accompanied the onset of work in this plant during the 1940s and support exposure assessments that favor higher benzene levels in the 1940s when compared with subsequent decades. The general utility of repeated-measures analytic techniques for medical surveillance data is also demonstrated by this analysis.

Sentinel pathophysiologic conditions: an adjunct to teaching occupational and environmental disease recognition and history taking.

Primary care physicians have an increasingly important role in identifying occupational and environmental (O/E) disease. However, the basic skills in O/E history taking, diagnosis, and management have not been adequately incorporated into traditional American medical education or practice. Reasons for these educational barriers are discussed. A new approach to O/E history taking, based on a modified list of occupational sentinel health events, is described. This list will give medical students and residents a practical, directed approach to recognizing O/E conditions and evaluating exposures in formulating a differential diagnosis. Through improved detection and assessment on the part of primary care physicians, appropriate referrals to occupational health specialists can be made for further investigation and public health surveillance.