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Long-Term Goal 3-13: Research Description

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Research Descriptions and Posters

Title: Central role of Life stage on induction/ exacerbation of asthma.

Presenter: Frank Gilliland (University of Southern California, S. California Children's Centre), David Diaz-Sanchez (NHEERL)

Contributors: Robert Devlin, Martha Sue Carraway, Ian Gilmour (NHEERL) Frederica Perrera, (Columbia University) Rob McConnell, Frank Gilliland (Patrick Breysse (Centres)

Science Questions:

The Research:

Since the ORD Asthma Research Strategy was published in 2002, there has been increasing evidence of the role of life stage in determining susceptibility to environmental factors that induce or exacerbate asthma. While much of the past research has focused on young adults, there is a growing realization that the environment may be most pertinent in those people with immature or compromised airways, lungs and immune systems. Thus, both the young and the old may be at increased risk to the development and exacerbation of asthma. Moreover, an important new concept is evolving that in utero and early life exposure to air pollutants may determine development of asthma and other respiratory diseases in later life. ORD research has therefore has centered on identifying:

1) critical windows of exposure that establish formation of asthma

2) key environmental factors that drive life stage susceptibility to asthma

3) key pathways in asthma by which environmental factors differentially affect different life stages

ORD research has coordinated its research on asthma across the intramural, extramural programs and its cooperative agreements based on the categorization of life stages by the EPA Risk Assessment Forum and the Children's Environmental Health Research highlight document:

Pre-natal: Maternal exposure to both the indoor and outdoor environment has been shown to be potentially important for the future development of asthma in the offspring. In particular, in utero exposure to air pollutants and their components increase the risk of asthma. In animal models of mothers exposed to diesel exhaust, pups had increased allergic sensitization and airway hyperreactivity. Epidemiological studies have shown that maternal smoking has both direct effects on the development of early life asthma, as well as increasing asthma susceptibility soon after active smoking begins during adolescence. In addition, prenatal exposures to polyaromatic hydrocarbons (PAHs) increase the risk of precursor symptoms to asthma. By 12 months of age, more cough and wheeze are reported in children exposed to prenatal PAH in concert with ETS postnatally. Of great potential importance is the finding that smoking by a grandmother contributes a 4-fold risk of early childhood asthma. The possibility of transgenerational effects on asthma is enhanced by the finding that inhaled environmental exposures to air pollution can influence methylation of Th2 genes in vivo.

Infant: The first year of life may be critical for asthma development since the potential for environmental exposures is thought to be elevated in crawlers (see poster xx). ORD funded studies have shown that asthma diagnosis before 5 years of age is associated with exposures in the first year of life to combustion products, bioaerosols, herbicides and pesticides.

Toddler 1 to<2 years: Support for early life as a determinant of future asthma is provided by separate studies that show that asthma and wheeze outcomes in children at 24 months of age are associated with elevated Th2 status in children at one year old. In turn, this Th2 status in infants is associated with maternal agricultural work. Preschooler 2 to < 6 years: As children age the environment remains a factor in the prevalence of asthma but also builds a growing role in exacerbation of asthma-related symptoms. At this stage, elevated indoor particulate matter (PM) levels are associated with increased respiratory symptoms. Additionally, mouse allergen exposure and asthma-related outcomes now show a strong and consistent relationship. High exposure to mouse allergens have more asthma-related unscheduled doctor visits, emergency department visits, and hospitalization than unexposed children.

School age 6 to <11 years: The impact of the environment on older asthmatic children can extend beyond purely clinical outcomes. Compared with unexposed children without asthma, children with asthma are at increased risk of respiratory-illness-related school absences when exposed to ETS. This results in an increased social and economic burden. This is especially so for disadvantaged asthmatic children in urban areas, as ORD has shown they are at increased risk for higher residential allergen levels, elevated air-pollution exposure, and higher levels of asthma triggers in the home. In order to better elucidate these triggers, EPA scientists are applying computational methods to analyze, characterize, and quantify combined risk factors that relate to asthma severity in childhood by measuring biomarkers of exposure and effects in clinical samples from 100 children with asthma and 100 without asthma, aged 9 to12 years and integrating results from controlled human and rodent exposures.

Adolescents 11 to 16 years: Physiological and immunologic changes continue through adolescence. Ongoing research suggests that children at this age have reduced defenses to oxidative stress, a critical pathway in the action of many environmental pollutants. This results in increased inflammatory responses to air pollutants. Exposures at this life stage may have life time consequences. We have shown that children who live within 500 meters of a freeway, since age 10 have substantial deficits in lung function by the age of 18 years, compared to children living at least 1500 meters away.

Older Adults: >45 years: While the majority of research on life stage and asthma has been focused on the very young, asthma can develop throughout life. As lung function diminishes with age, the role of the environment may increase. ORD has therefore expanding its life stage research to older adults. We have recently initiated studies to compare respiratory and cardiac responses in young (18-21) vs. older (<45 years) adults with asthma exposed to concentrated air particles in a chamber. Concomitantly, we are following young and old asthmatics in everyday activity and comparing daily fluctuations in pollutant levels (using personal and outside home monitoring) with daily fluctuations in biological effects.

Impact and Outcomes

Key Products:

Gauderman W, et al.,. The effect of residential exposure to traffic on lung development from 10 to 18 years of age. Lancet 2007 Feb 17;369(9561):571-7.

Eggleston PA, et al., Lessons Learned for the Study of Childhood Asthma from the Centers for Children's Environmental Health and Disease Prevention Research. Environ Health Perspect. 2005 Oct;113(10):1430-6.

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