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Andrea Baccarelli,^1,2 Antonella Zanobetti,¹ Ida Martinelli,³ Paolo Grillo,² Lifang Hou,⁴ Guido Lanzani,⁵ Pier Mannuccio Mannucci,³ Pier Alberto Bertazzi,² and Joel Schwartz¹

¹Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; ²Department of Environmental and Occupational Health, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation and University of Milan, Milan, Italy; ³A. Bianchi Bonomi Haemophilia and Thrombosis Center, Department of Internal Medicine and Medical Specialties, University of Milan and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy; ⁴Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA; ⁵Air Quality Unit, Regional Environmental Protection Agency ARPA Lombardia, Milan, Italy

Abstract
Background: Mild hyperhomocysteinemia is independently associated with an increased risk of cardiovascular disease. Air pollution exposure induces short-term inflammatory changes that may determine hyperhomocysteinemia, particularly in the presence of a preexisting proinflammatory status such as that found in cigarette smokers.

Objective: We examined the relation of air pollution levels with fasting and postmethionine-load total homocysteine (tHcy) in 1,213 normal subjects from Lombardia, Italy.

Methods: We obtained hourly concentrations of particulate matter < 10 µm in aerodynamic diameter (PM₁₀) and gaseous pollutants (carbon monoxide, nitrogen dioxide, sulfur dioxide, ozone) from 53 monitoring sites covering the study area. We applied generalized additive models to compute standardized regression coefficients controlled for age, sex, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long-term trends.

Results: The estimated difference in tHcy associated with an interquartile increase in average PM₁₀ concentrations in the 24 hr before the study was nonsignificant [0.4% ; 95% confidence interval (CI) , –2.4 to 3.3 for fasting ; and 1.1%, 95% CI, –1.5 to 3.7 for postmethionine-load tHcy]. In smokers, 24-hr PM₁₀ levels were associated with 6.3% (95% CI, 1.3 to 11.6 ; p < 0.05) and 4.9% (95% CI, 0.5 to 9.6 ; p < 0.05) increases in fasting and postmethionine-load tHcy, respectively, but no association was seen in nonsmokers (p-interaction = 0.005 for fasting and 0.039 for postmethionine-load tHcy) . Average 24-hr O₃ concentrations were associated with significant differences in fasting tHcy (6.7% ; 95% CI, 0.9 to 12.8 ; p < 0.05) , but no consistent associations were found when postmethionine-load tHcy and/or 7-day average O₃ concentrations were considered.

Conclusions: Air particles may interact with cigarette smoking and increase plasma homocysteine in healthy subjects.

Key words: air pollution, cardiovascular risk, generalized additive models, homocysteine, particulate matter, smoking. Environ Health Perspect 115:176–181 (2007) . doi:10.1289/ehp.9517 available via http://dx.doi.org/ [Online 13 November 2006]

Address correspondence to A. Baccarelli, Exposure, Epidemiology and Risk Program, Harvard School of Public Health, 401 Park Dr., Landmark Center, Suite 412F West, P.O. Box 15698, Boston, MA 02215 USA. Telephone: (617) 384-8838. Fax: (617) 384-8745. E-mail: abaccare@hsph.harvard.edu

We are indebted to N. Carfagno and A. Cazzullo for support in air-monitoring data handling and selection, and to S. Melly for assistance in geographic map creation.

This work was funded by the Regional Government of Lombardia (Health Directorate Contract 8956/RCC) , Cassa di Risparmio delle Provincie Lombarde Foundation ("Health Effects of Airborne Pollutants" Project) , Italian Ministry for University and Research (University System Internationalization Program, 99C/2005) , and U.S. Environmental Protection Agency Particulate Matter Center grant R827353.

The authors declare they have no competing financial interests.

Received 14 July 2006 ; accepted 13 November 2006.