Thomas J. Keefe

A Multivariate Analysis of Risk Factors for the Air-Trapping Asthmatic Phenotype as Measured by Quantitative CT Analysis

BACKGROUND Patients with severe asthma have increased physiologically measured air trapping; however, a study using CT measures of air trapping has not been performed. This study was designed to address two hypotheses: (1) air trapping measured by multidetector CT (MDCT) quantitative methodology would be a predictor of a more severe asthma phenotype; and (2) historical, clinical, allergic, or inflammatory risk factors could be identified via multivariate analysis. METHODS MDCT scanning of a subset of Severe Asthma Research Program subjects was performed at functional residual capacity. Air trapping was defined as >or= 9.66% of the lung tissue < - 850 Hounsfield units (HU). Subjects classified as having air trapping were then compared to subjects without air trapping on clinical and demographic factors using both univariate and multivariate statistical analyses. RESULTS Subjects with air trapping were significantly more likely to have a history of asthma-related hospitalizations, ICU visits, and/or mechanical ventilation. Duration of asthma (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.08 to 1.87), history of pneumonia (OR, 8.55; 95% CI, 2.07 to 35.26), high levels of airway neutrophils (OR, 8.67; 95% CI, 2.05 to 36.57), airflow obstruction (FEV(1)/FVC) [OR, 1.61; 95% CI, 1.21 to 2.14], and atopy (OR, 11.54; 95% CI, 1.97 to 67.70) were identified as independent risk factors associated with the air-trapping phenotype. CONCLUSIONS Quantitative CT-determined air trapping in asthmatic subjects identifies a group of individuals at high risk for severe disease. Several independent risk factors for the presence of this phenotype were identified: perhaps most interestingly, history of pneumonia, neutrophilic inflammation, and atopy.

RISK FACTORS FOR ADENOCARCINOMA OF THE LUNG

The relation between various risk factors and adenocarcinoma of the lung was evaluated in a case-control study. Subjects were selected from the Colorado Central Cancer Registry from 1979-1982 in the Denver metropolitan area. A total of 102 (50 males and 52 females) adenocarcinoma case interviews and 131 (65 males and 66 females) control interviews were completed. The control group consisted of persons with cancers of the colon and bone marrow. The risk estimates associated with cigarette smoking were significantly elevated among males (odds ratio (OR) = 4.49) and females (OR = 3.95) and were found to increase significantly (p less than 0.01) with increasing levels of cigarette smoking for both males and females. For adenocarcinoma in females, the age- and smoking-adjusted odds ratios at different levels of passive smoke exposure followed an increasing overall trend (p = 0.05). After additional adjustment for potential confounders, prior cigarette use remained the most significant predictor of risk of adenocarcinoma among males and females. Analysis restricted to nonsmoking females revealed a risk of adenocarcinoma of 1.68 (95% confidence interval (Cl) = 0.39-2.97) for passive smoke exposure of four or more hours per day. Neither sex showed significantly elevated risk for occupational exposures, although males bordered on significance (OR = 2.23, 95% Cl = 0.97-5.12). The results suggest the need to develop cell type-specific etiologic hypotheses.

Depression and Pesticide Exposures among Private Pesticide Applicators Enrolled in the Agricultural Health Study

Background We evaluated the relationship between diagnosed depression and pesticide exposure using information from private pesticide applicators enrolled in the Agricultural Health Study between 1993 and 1997 in Iowa and North Carolina. Methods There were 534 cases who self-reported a physician-diagnosed depression and 17,051 controls who reported never having been diagnosed with depression and did not feel depressed more than once a week in the past year. Lifetime pesticide exposure was categorized in three mutually exclusive groups: low (< 226 days, the reference group), intermediate (226–752 days), and high (> 752 days). Two additional measures represented acute high-intensity pesticide exposures: an unusually high pesticide exposure event (HPEE) and physician-diagnosed pesticide poisoning. Logistic regression analyses were performed relating pesticide exposure to depression. Results After adjusting for state, age, education, marital status, doctor visits, alcohol use, smoking, solvent exposure, not currently having crops or animals, and ever working a job off the farm, pesticide poisoning was more strongly associated with depression [odds ratio (OR) = 2.57; 95% confidence interval (CI), 1.74–3.79] than intermediate (OR = 1.07; 95% CI, 0.87–1.31) or high (OR = 1.11; 95% CI, 0.87–1.42) cumulative exposure or an HPEE (OR = 1.65; 95% CI, 1.33–2.05). In analysis of a subgroup without a history of acute poisoning, high cumulative exposure was significantly associated with depression (OR = 1.54; 95% CI, 1.16–2.04). Conclusion These findings suggest that both acute high-intensity and cumulative pesticide exposure may contribute to depression in pesticide applicators. Our study is unique in reporting that depression is also associated with chronic pesticide exposure in the absence of a physician-diagnosed poisoning.

Variability in Biological Exposure Indices Using Physiologically Based Pharmacokinetic Modeling and Monte Carlo Simulation

By using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation, the interindividual variability in the concentrations of chemicals in a workers exhaled breath and urine were estimated and compared with existing biological exposure indices (BEIs). The PBPK model simulated an exposure regimen similar to a typical workday, while exposure concentrations were set to equal the ambient threshold limit values (TLVs) of six industrial solvents (benzene, chloroform, carbon tetrachloride, methylene chloride, methyl chloroform, and trichloroethylene). Based on model predictions incorporating interindividual variability, the percentage of population protected was derived using TLVs as the basis for worker protection. Results showed that current BEIs may not protect the majority or all of the workers in an occupational setting. For instance, current end-expired air indices for benzene and methyl chloroform protect 95% and less than 10% of the worker population, respectively. Urinary metabolite concentrations for benzene, methyl chloroform, and trichloroethylene were also estimated. The current BEI recommendation for phenol metabolite concentration at the end-of-shift sampling interval was estimated to protect 68% of the worker population, while trichloroacetic acid (TCAA) and trichloroethanol (TCOH) concentrations for methyl chloroform exposure were estimated to protect 54% and 97%, respectively. The recommended concentration of TCAA in urine as a determinant of trichloroethylene exposure protects an estimated 84% of the workers. Although many of the existing BEIs considered appear to protect a majority of the worker population, an inconsistent proportion of the population is protected. The information presented in this study may provide a new approach for administrative decisions establishing BEIs and allow uniform application of biological monitoring among different chemicals.

DEPRESSION AND PESTICIDE EXPOSURES IN FEMALE SPOUSES OF LICENSED PESTICIDE APPLICATORS IN THE AGRICULTURAL HEALTH STUDY COHORT

Objective: This nested case–control study evaluated the association between depression and pesticide exposure among women. Methods: The study population included 29,074 female spouses of private pesticide applicators enrolled in the Agricultural Health Study between 1993 and 1997. Cases were women who had physician-diagnosed depression requiring medication. Lifetime pesticide use was categorized as never mixed/applied pesticides, low exposure (up to 225 days), high exposure (>225 days), and a history of diagnosed pesticide poisoning. Results: After adjustment for state, age, race, off-farm work, alcohol, cigarette smoking, physician visits, and solvent exposure, depression was significantly associated with a history of pesticide poisoning (odds ratio [OR] = 3.26; 95% confidence interval [CI] = 1.72–6.19) but not low (OR = 1.09; CI = 0.91–1.31) or high (OR = 1.09; 95% CI = 0.91–1.31) cumulative pesticide exposure. Conclusion: Pesticide poisoning may contribute to risk of depression.

Association of semen quality and occupational factors: comparison of case-control analysis and analysis of continuous variables

OBJECTIVE To compare two statistical approaches, case-control and analysis of continuous parameters of semen, in examining the relationship between occupational exposures and male reproductive function. DESIGN Case-control study. SETTING Males providing semen samples at a university infertility clinic. PATIENT(S) Nonvasectomized males who provided at least one semen sample at an infertility clinic. MAIN OUTCOME MEASURE(S) Standard clinical semen analysis. RESULT(S) Analyses using a dichotomous dependent variable did not uncover significant associations between any occupational factor and infertility case status. However, linear models incorporating continuous variables identified a number of occupational factors that were associated with specific parameters of semen. A reduction in percentage of progressive sperm and an increase in percentage of coiled tail sperm defects in welders, compared with unexposed subjects, were found. Significant dose-response relationships between level of perceived job stress and percentage of progressive sperm, total motile count, morphology, abnormal heads, and coiled tail defects were found. CONCLUSION(S) The findings suggest that subtle changes in semen variables, possibly associated with workplace exposure, may be detected only with parametric analyses of continuous variables of semen.

Evaluation of the Limulus Amebocyte Lysate and Recombinant Factor C Assays for Assessment of Airborne Endotoxin

ABSTRACT As a potent inflammatory agent, endotoxin is a key analyte of interest for studies of lung ailments in domestic environments and occupational settings with organic dust. A relatively unexplored advance in endotoxin exposure assessment is the use of recombinant factor C (rFC) from the Limulus pathway in a fluorometric assay. In this study, we compared airborne endotoxin concentrations in laboratory- and field-collected parallel air samples using the kinetic Limulus amebocyte lysate (LAL) assay and the rFC assay. Air sampling was performed using paired Institute of Occupational Medicine (IOM) samplers, Button samplers, closed-face cassettes, and cyclone samplers. Field sampling was performed in 10 livestock production facilities, including those housing swine, chicken, turkey, dairy cows, cattle, and horses. Laboratory sampling was performed in exposure chambers using resuspended airborne dust collected in five livestock facilities. Paired samples were extracted in pyrogen-free water with 0.05% Tween 20 and analyzed using LAL and rFC assays. In 402 field sample pairs there was excellent agreement between endotoxin concentrations determined by LAL and rFC (r = 0.93; P < 0.0001). In 510 laboratory sample pairs there was also excellent agreement between the two assays (r = 0.86; P < 0.0001). Correlations for subgroups of facility or dust type ranged from 0.65 to 0.96. Mixed-model analysis of variance (ANOVA) for the field studies showed significant interactions of facility-sampler and facility-assay. rFC/LAL ratios of the geometric means were 0.9 to 1.14 for the samplers (not significantly different from 1.0). The data from this study demonstrate that the LAL assay and the rFC assay return similar estimates of exposure in livestock facilities. Both methods provided suitable lower limits of detection such that all but 19 of 1,824 samples were quantifiable.

Agricultural work-related injuries among farmers in Hubei, People's Republic of China.

OBJECTIVES This population-based study evaluated patterns of and risk factors for, agricultural injuries among farmers in the Peoples Republic of China. METHODS A multistage sample of 1500 Chinese farmers was selected from 14 villages. Face-to-face interviews with 1358 farmers were conducted between July 1997 and September 1997 (response rate = 91%). Agricultural work-related injuries that occurred in the previous 24 months and the associated factors were evaluated. RESULTS A total of 33% of the farmers reported at least 1 work-related injury in the 24 months before the survey. Major external causes of the injuries were hand tools (50%), falls (26%), and heavy falling objects (10%). The statistically significant risk factors for injury were low family income, 1 to 6 school years of education, self-reported pesticide exposure, tension in relationships with neighbors, and stress in life. The most notable result was the relation between self-reported pesticide exposure and injury, with farmers with greater pesticide exposure at significantly greater risk for injury. CONCLUSIONS The results of this study indicated that injuries occurring among Chinese farmers may have unique patterns and potential risk factors.

Endotoxin Exposure and Inflammation Markers Among Agricultural Workers in Colorado and Nebraska

The adverse respiratory effects of agricultural dust inhalation are mediated in part by endotoxin, a constituent of gram-negative bacterial cell walls. This study quantified personal work-shift exposures to inhalable dust, endotoxin, and its reactive 3-hydroxy fatty acid (3-OHFA) constituents among workers in grain elevators, cattle feedlots, dairies, and on corn farms. Exposures were compared with post-work-shift nasal lavage fluid inflammation markers and respiratory symptoms. Breathing-zone personal air monitoring was performed over one work shift to quantify inhalable dust (Institute of Medicine samplers), endotoxin (recombinant factor C [rFC] assay), and 3-OHFA (gas chromatography/mass spectrometry). Post-shift nasal lavage fluids were assayed for polymorphonuclear neutrophils (PMN), myeloperoxidase (MPO), interleukin 8 (IL-8), albumin, and eosinophilic cation protein (ECP) concentrations. The geometric mean (GSD) of endotoxin exposure (rFC assay) among the 125 male participants was 888 ± (6.5) EU/m3, and 93% exceeded the proposed exposure limit (50 EU/m3). Mean PMN, MPO, albumin, and ECP levels were two- to threefold higher among workers in the upper quartile of 3‐OHFA exposure compared to the lowest exposure quartile. Even numbered 3-OHFA were most strongly associated with nasal inflammation. Symptom prevalence was not elevated among exposed workers, possibly due to endotoxin tolerance or a healthy worker effect in this population. This is the first study to evaluate the relationship between endotoxins 3-OHFA constituents in agricultural dust and nasal airway inflammation. More research is needed to characterize the extent to which these agents contribute to respiratory disease among agricultural workers.

INFECTIOUS DISEASE MONITORING OF THE ENDANGERED HAWAIIAN MONK SEAL

As part of conservation efforts between 1997 and 2001, more than 25% (332 animals) of the endangered Hawaiian monk seal (Monachus schauinslandi) population was sampled in the northwestern Hawaiian Islands. Serum samples were tested for antibodies to viruses, bacteria, and parasites known to cause morbidity and mortality in other marine mammal species. Antibodies were found to phocine herpesvirus-1 by using an enzyme-linked immunosorbent assay, but seropositive results were not confirmed by virus neutralization test. Antibodies to Leptospira bratislava, L. hardjo, L. icterohaemorrhagiae, and L. pomona were detected in seals from several sites with the microagglutination test. Antibodies to Brucella spp. were detected using 10 conventional serologic tests, but because of inconsistencies in test results and laboratories used, and the lack of validation by culture, the Brucella serology should be interpreted with caution. Antibodies to B. canis were not detected by card test. Chlamydophila abortus antibodies were detected by complement fixation (CF) test, and prevalence increased significantly as a function of age; the low sensitivity and specificity associated with the CF make interpretation of results difficult. Antibodies to Toxoplasma gondii and Dirofilaria immitis were rarely found. There was no serologic evidence of exposure to four morbilliviruses, influenza A virus, canine adenovirus, caliciviruses, or other selected viruses. Continuous surveillance provides a means to detect the introduction or emergence of these or other infectious diseases, but it is dependent on the development or improvement of diagnostic tools. Continued and improved surveillance are both needed as part of future conservation efforts of Hawaiian monk seals.