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.

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.

Material safety data sheets. Caveat emptor.

Numerous hazardous chemicals are present in workplaces and the environment. Physicians are likely to be increasingly challenged with the evaluation of individuals exposed to these chemicals. Recent legislation mandates the creation of material safety data sheets that describe the composition and toxicity of hazardous compounds. This legislation has also greatly increased the availability of material safety data sheets to workers and physicians. While these can be of great assistance in the evaluation of exposed individuals, they often contain deficiencies that preclude the prudent physician from relying exclusively on them. A few typical material safety data sheets are reviewed to illustrate what one can expect to find.

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.

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.

Use of longitudinal analysis of peripheral blood counts to validate historical reconstructions of benzene exposure.

We studied over 17,000 peripheral blood counts, accumulated during hematologic surveillance from 1940 through 1975, from a cohort of 459 benzene-exposed workers. Linear regressions demonstrated significant decreases in white and red cell counts, as well as hemoglobin, for workers exposed during the 1940s, without persistent trends over the ensuing 25 years. Strongly positive correlations were observed between these blood count fluctuations and fluctuations in retrospective estimates of benzene exposures for these workers in the earlier period of surveillance (mean estimated exposure 1940 to 1948, 75 ppm), but not for later years, (mean estimated exposure 1948 to 1975, 15 to 20 ppm). These data suggest substantial limitations of hematologic examination of populations to detect abnormalities in populations currently exposed to benzene. The analysis also demonstrates a novel approach to the biological validation of exposure estimates based upon limited industrial hygiene and historical record data. The application of biologic monitoring data may be useful for assisting decisions in reconstruction of a previous exposure.

The use of portable peak flowmeters in the surveillance of occupational asthma.

The purpose of this study was to identify the strengths and limitations of using portable peak flowmeters to document suspected cases of occupational asthma that were reported to a statewide surveillance project. The New Jersey Department of Health conducts surveillance for occupational asthma as part of the federally sponsored Sentinel Event Notification System for Occupational Risks (SENSOR). Between May 1988 and January 1990, 70 cases were reported voluntarily by physicians. Subjects who were still employed in suspected work sites were requested to test themselves for at least 15 days, using portable peak flowmeters to generate serial measurements of their peak expiratory flow rate (PEFR). For each of the 14 subjects who were successfully tested, the PEFR data provided valuable information about their asthma-work association. However, a large number of subjects whose cases were reported (56) either could not be tested or were not successfully tested. The proportion of subjects completing the test would probably improve if it were conducted when their conditions were first diagnosed. Accordingly, the collection of serial peak flow measurements to document occupational asthma would best be initiated by the treating physician when the patient first sought care, rather than waiting until after the case was reported to the state health department.

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.

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.

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.

Respiratory abnormalities among photographic developers: a report of three cases.

Photographic developing processes employ hazardous chemical substances, many with known adverse effects on the respiratory system. Three cases documenting respiratory symptoms and suggesting small airway abnormalities among photographic developers are reported. Work-related factors which might contribute to these findings, as well as public health implications, are discussed.

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.

Acute occupational respiratory diseases in hospital discharge data.

We investigated the feasibility of using hospital discharge diagnoses of ICD codes 506, 507, and 508, respiratory diseases from external sources, to identify occupational sentinel health events [SHE(O)]. Two hundred sixty-nine records were reviewed and 66 (25%) were incidents where the work-relatedness of the respiratory diseases was documented in the medical records. Twenty-six percent of the 269 records contained no exposure information. Sixty-four of the 66 occupational cases were from ICD codes 506.0-506.9, with the largest number classified as ICD codes 506.0 (bronchitis and pneumonitis due to fumes and vapors) and 506.3 (other acute and subacute respiratory conditions due to fumes and vapors). We conclude that surveillance of ICD codes in the 506 series, where 39% of the cases were secondary to occupational exposures, is a valuable component of a surveillance system for preventable occupational lung disease.

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.

Limitations of hospital discharge diagnoses for surveillance of extrinsic allergic alveolitis.

Hospital discharge diagnoses were used to identify all inpatient cases of extrinsic allergic alveolitis (EAA) from 1979 to 1982 in New Jersey. Of 170 reported cases, the hospital records of 48 were available for review. Based on published criteria for the diagnosis of EAA, only three cases (6%) could be classified as probable EAA, while 10 (21%) were possible cases, and 34 (73%) were not EAA. Limitations were apparent in the accuracy of discharge coding and also in the accuracy of the physician's diagnosis. These findings should promote caution among investigators using unvalidated reports based on ICD-9 hospital coding of EAA. Implications for reporting of other occupational lung diseases are discussed.