Review Impact of Environmental Chemicals on Lung Development Mark D. Miller1,2 and Melanie A. Marty1 1Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, California, USA; 2Pediatric Environmental Health Specialty Unit, University of California–San Francisco, San Francisco, California, USA Background d at osurce synthei : Disruption of fundamental biologic processes and associated signaling events may result in clinically significant alterations in lung development. o Bjectivs : We reviewed evidence on the impact of environmental chemicals on lung development and key signaling events in lung morphogenesis, and the relevance of potential outcomes to public health and regulatory science. : We evaluated the peer-reviewed literature on developmental lung biology and toxi- cology, mechanistic studies, and supporting epidemiology. d at : Lung function in infancy predicts pulmonary function throughout life. In utero and early postnatal exposures influence both childhood and adult lung structure and function and may predispose individuals to chronic obstructive lung disease and other disorders. The nutritional and endogenous chemical environment affects development of the lung and can result in altered function in the adult. Studies now suggest that similar adverse impacts may occur in animals and humans after exposure to environmentally relevant doses of certain xenobiotics during critical windows in early life. Potential mechanisms include interference with highly conserved factors in developmental processes such as gene regulation, molecular signaling, and growth factors involved in branching morphogenesis and alveolarization. c onclusi : Assessment of environmental chemical impacts on the lung requires studies that evaluate specific alterations in structure or function—end points not regularly assessed in standard toxicity tests. Identifying effects on important signaling events may inform protocols of develop- mental toxicology studies. Such knowledge may enable policies promoting true primary prevention of lung diseases. Evidence of relevant signaling disruption in the absence of adequate developmental toxicology data should influence the size of the uncertainty factors used in risk assessments. k ey words : cell signaling, children’s environmental health, developmental toxicology, lung devel- opment, lung disease, risk assessment, science policy. Environ Health Perspect 118:1155–1164 (2010). doi:10.1289/ehp.0901856 [Online 5 May 2010] Over the past 20 years, acknowledgment of the unique vulnerabilities of children to the disrup- tion of normal growth and development caused by environmental exposures has grown. The health impacts of many chemicals have been shown to differ based on the developmental window of susceptibility (e.g., periods of rapid cell proliferation or differentiation) when expo- sure occurs. Although the neurologic system has been most widely studied in this regard, there is a growing body of knowledge about the potential impacts of environmental expo- sures on lung growth and function. Respiratory disease has a large public health impact. An estimated 24 million U.S. adults have chronic obstructive pulmonary disease; 23 million have asthma; and chronic lower respiratory diseases rank as the fourth leading cause of death in the United States (Kung et al. 2008; National Heart, Lung, and Blood Institute 2007). In this article, we first present an overview of essential processes in lung development, followed by examples of xenobiotics, including important environmental contaminants, that can disrupt these processes. Epidemiologic confirmation of the impor- tance of the impact of early-life exposures, as originally described by Barker (the Barker hypothesis; Barker and Osmond 1986), has developed into a burgeoning field of study: the fetal origins of adult disease. Barker’s work demonstrating that poorer fetal nutrition and lower birth weight are associated with cardiovascular disease in adults has since been confirmed in multiple longitudinal studies around the world (Barker 2007). This finding was based on the observation that populations living in regions with poor fetal nutrition had higher risk of adult cardiovascular disease. Yet, paradoxically, geographical areas most associated with fetal or neonatal mortality and low birth weight (e.g., from poor nutri- tion) were not those at greatest risk for known postnatal risk factors for cardiovascular disease (e.g., high income, increased fat in diet). The premise for the early origins of adult disease is that during early life, “programming” in response to poor fetal nutrition results in per- manent changes in organ structure, metabo- lism, and function. For example, lower birth weight has been associated with increased likelihood of having adult lipid profiles linked to cardiovascular risk as well as hypertension and impaired glucose regulation (Gluckman et al. 2008; Kajantie et al. 2008). Although Barker’s original ecologic epide- miologic findings also showed a link between low birth weight and adult respiratory health, this was not accorded the same importance because geographic areas that had higher Environmental Health Perspectives • volume 118 | number 8 | August 2010 incidence of low birth weight and neonatal mortality were also regions with more post- natal risk factors (e.g., infection) for adult respiratory diseases. However, more recent studies provide evidence that in utero and early postnatal exposures set the stage for both childhood and later-life deficiencies in lung function that are predisposing factors for chronic obstructive lung disease and other disorders (Bush 2008; Canoy et al. 2007; Shi et al. 2007). For example, Stern et al. (2007) found that maximal expiratory flow at functional residual capacity measured in 123 infants at 2 months of age was associated with lung function measurements, includ- ing forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), forced expiratory flow between 25% and 75% of FVC (FEF25–75), and FEV1, up to 22 years of age (Figure 1). In a longitudinal study of 243 infants, 4-week-olds with flow-limited tidal expansion (inability to increase expira- tory flow with increased effort) were 7 times more likely to be diagnosed with asthma at 2 years of age (Young et al. 1994). These investigators observed a statistically significant increase in wheezing and a trend to reduced FEF25–75 at 11 years of age compared with children who had normal tidal expansion as infants (Turner et al. 2002). Similarly, airway responsiveness to histamine at 1 month of age was associated with abnormal airway function (decreased FEV1 and FVC), lower respira- tory symptoms, and emergence of asthma by 6 years of age in a study of 95 children (Palmer et al. 2001). Several sizable studies from various countries have demonstrated that lung function in both asthmatics and nonasthmatics tracks from early childhood through adolescence and up to midlife, and is set by early-life events (Haland et al. 2006; Morgan et al. 2005; Oswald et al. 1997; Phelan et al. 2002; Stern et al. 2007). These studies support the importance of early-life Address correspondence to M. Miller, Office of Environmental Health Hazard Assessment, 1515 Clay St. 16th Floor, Oakland, CA 94612 USA. Telephone: (510) 622-3159. Fax: (510) 622-3210. E-mail: mmiller@oehha.ca.gov The views expressed by the authors are their own and do not necessarily represent those of the Office of Environmental Health Hazard Assessment, the California Environmental Protection Agency, or the State of California. The authors declare they have no actual or potential competing financial interests. Received 20 December 2009; accepted 5 May 2010. 1155