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DIR Papers of the Month

By Eddy Ball
September 2006

Occupational Exposures Linked to Adult-Onset Asthma and Chronic Respiratory Problems

In an NIEHS-funded study published in the American Journal of Epidemiology in June, researchers evaluated the role of specific occupational exposures in asthma, chronic bronchitis and respiratory symptoms in the Singapore Chinese Health Study. Study results added to a growing body of evidence for a role of cleaning agents in asthma and made a significant contribution to the body of data on occupational exposure in a large general population in Asia.

The study investigated respiratory outcomes in a follow-up examination of a population-based cohort of adults aged 45-74 years at enrollment in 1993-1998. Information on occupations and occupational exposures was collected at enrollment for 52,325 subjects for whom respiratory outcomes were obtained via follow-up interviews between 1999 and 2004.

Investigators found significant associations between exposures to dusts from cotton, wood, metal, minerals, and/or asbestos and non-chronic cough and/or phlegm, chronic bronchitis and adult-onset asthma. Participants with occupational exposure to smoke showed increased odds of non-chronic cough or phlegm. Vapor exposure from chemical solvents, dyes, cooling oils, paints, wood preservatives and/or pesticides was associated with non-chronic cough or phlegm, chronic dry cough and adult-onset asthma. Chemical solvents, cooling oils and pesticides were major contributors to respiratory symptoms.

Study results supported the contribution of occupational exposures to respiratory illness in a population-based cohort in Singapore with a low prevalence of illness caused by allergens. The average age of the study population (over 62) suggested that occupational exposure can have long-lasting effects on respiratory health. Because of the tropical climate and the high proportion of never smokers in Singapore, the study was able to minimize confounding by exposures to smoking and coal or wood heating fumes.

Citation: LeVan, TD, Koh WP, Lee HP, Koh D, Yu MC, London SJ. 2006. Vapor, dust, and smoke exposure in relation to adult-onset asthma and chronic respiratory symptoms -The Singapore Chinese Health Study. Am J Epidemiol 163(12):1118-1128.

Specific Pesticide Exposures Associated with Wheeze among Workers

Researchers supported by NIEHS and the National Cancer Institute (NCI) have identified specific commonly used herbicides and insecticides associated with wheeze in a large population of workers without prolonged exposure to other farm irritants, such as animals and grains. Published in the June issue of the American Journal of Epidemiology, the study analyzed data from 2,255 Iowa commercial pesticide applicators enrolled between 1993 and 1997 in the Agricultural Health Study (AHS). Study results add to the emerging literature linking organophosphate insecticides and respiratory health and suggest a role for the frequently used compound chlorimuron-ethyl in wheeze in these workers.

Controlling for age, smoking status, asthma and atopy history, and body mass index, the authors examined the relationship between wheeze and 36 individual pesticides used by the participants during the year before enrollment. Eight of 16 herbicides were associated with wheeze in single-agent models; however, the risk was almost exclusively associated with the herbicide chlorimuron-ethyl. Inclusion of chlorimuron-ethyl in models for the other herbicides virtually eliminated the associations.

The odds ratios for four organophosphate insecticides (terbufos, fonofos, chlorpyrifos and phorate) were elevated when these chemicals were modeled individually. Odds ratios remained elevated, though attenuated somewhat, when chlorimuron-ethyl was included. The association for dichlorvos, another organophosphate insecticide, was not attenuated by chlorimuron-ethyl. Dose-response trends were observed for chlorimuron-ethyl, chlorpyrifos and phorate; the strongest association existed among workers applying chlorpyrifos on more than 40 days per year.

NIEHS scientists collaborated with researchers from the University of Iowa and NCI. To the knowledge of the researchers, the participants of the AHS constituted the largest group of commercial pesticide applicators ever studied in this way. The study also provided specific information that could be useful to applicators about individual chemicals.

Citation: Hoppin JA, Umbach DM, London SJ, Lynch CF, Alavanja MC, Sandler DP. 2006. Pesticides associated with wheeze among commercial pesticide applicators in the Agricultural Health Study. Am J Epidemiol 163(12):1129-1137.

Gender Differences in Mouse Airway Responsiveness to Lung Injury

In a study published July 1 in The Journal of Immunology, an NIEHS research team discovered significant gender differences in the airway responsiveness of naïve mice. Male mice showed exaggerated airway inflammatory and functional responses to lipopolysaccharide (LPS) compared with females. The study presented strong evidence that androgens promoted airway inflammation and hyperresponsiveness induced by LPS.

The researchers analyzed male and female mice using invasive and non-invasive measures under five conditions: at baseline, after administration of LPS, following stimulation with a bronchoconstrictive agent, three weeks after gonadectomy and three to four weeks following implantation of androgen (females) or anti-androgen (males) pellets.

Sham-treated mice received placebo pellets or saline aspiration. Researchers carried out experiments on C57BL/6 and BALB/c mice strains to determine any effect strain might have on results.

The study found evidence that androgen in males at physiologic levels or in females receiving exogenous hormone significantly affected airway response as determined by analysis of lung function, assessment of LPS-induced airway inflammation, lung histopathology and immunoblotting. Castrated males, males receiving anti-androgen pellets and intact females were less responsive to lung injury than intact males and androgen-treated females. Ovariectomized females responded to lung injury in ways similar to those shown by sham-operated females. Researchers also demonstrated that the severity of hypothermia in response to LPS was affected by gender. There were no significant differences found attributable to mouse strain.

The NIEHS researchers stated that their data suggest the importance of carefully considering gender in the design of murine studies of the pulmonary effects of LPS. An important contribution of this study is its in-depth investigation of the role of androgens, a factor not addressed in earlier studies. Based on the results of their study, the NIEHS researchers concluded that sex hormones may provide novel targets for therapeutic intervention in inflammatory lung disease.

Citation: Card JW, Carey MA, Bradbury JA, DeGraff LM, Morgan DL, Moorman MP, Flake GP, Zeldin DC. 2006. Gender differences in murine airway responsiveness and lipopolysaccharide-induced inflammation. J Immunol 177(1):621-630.

Irradiation by Ultraviolet A Rays in Sunshine Induces Malignant Transformation in Human Skin Cells

In an effort to determine the effects of UVA on keratinocytes in human skin, a team of NIEHS and National Cancer Institute researchers have demonstrated that chronic exposures in vitro can induce a malignant transformation associated with acquired resistance to apoptosis, or natural cell death. Published in the June 22 issue of Oncogene, the study is the first to provide clear evidence of the capability of UVA, at doses people may be exposed to in the environment, to produce this transformation in a cell line analogous to a potential in vivo target site of UVA carcinogenesis.

In the study, UVA-long-treated human keratinocyte cell line (HaCaT) cells, referred to in the study as ULTH cells, showed increased secretion of tumor related compounds, altered morphology and anchorage-independent growth - characteristic signs of malignancy. The study found evidence of malignant transformation with the production of aggressive squamous cell carcinomas after inoculation of the treated human cells into nude mice, hairless mutants with certain immune system deficiencies. ULTH cells were resistant to apoptosis induced by UVA as well as by UVB and arsenite, two other human skin carcinogens. ULTH cells also became chemo-resistant to three drugs used to treat cancer. Researchers also detected chromosome changes in ULTH cells.

The results of this study provide compelling evidence that UVA alone has the potential to be a human skin carcinogen. Researchers also identified mechanisms that may contribute to and reverse this malignant transformation by UVA. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help to identify biomarkers for UVA-induced skin malignancies. Further studies may provide insights for the development of chemo preventive strategies.

Citation: He Y-Y, Pi J, Huang J-L, Diwan BA, Waalkes MP, Chignell CF. 2006. Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance. Oncogene 25(26): 3680-3688.

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