There is considerable evidence that inhaled toxicants such as cigarette smoke can cause irreversible changes to the genetic material (DNA mutations) as well as produce putatively reversible changes in gene expression and to the epigenetic landscape (changes in the DNA methylation and chromatin modification state). The diseases that are believed to involve genomic and epigenetic perturbations include Lung Cancer, Chronic Obstructive Pulmonary Disease (COPD), and Cardiovascular Disease (CVD), all of which are strongly linked epidemiologically to cigarette smoking.In the frame of a systems biology-based risk assessment approach for environmental toxicants including tobacco products, we are building a series of computable biological models and tools specific to non-diseased pulmonary and cardiovascular cells and tissues which capture the molecular events that can be activated following exposure to environmental toxicants. Here we report the construction and evaluation of a mechanistic network model focused on DNA damage response and the four main cellular fates induced by stress: autophagy, apoptosis, necroptosis, and senescence. The network model consist of cause-and-effect relationships, typically activation or inhibition, between molecular entities and activities (such as the activation of a particular kinase or an increased protein abundance) described using the Biological Expression Language (BEL), which allows for the semantic representation of life science relationships in a computable format. Additionally, the establishment of a mouse model which could reproduce the main changes seen in humans (e.g., inflammation and emphysema) is needed for the study of the pathogenesis of lung diseases. We present the use of C57BL/6 mouse as a model to investigate cigarette smoke-induced emphysema and show a variety of endpoints ranging from transcriptomics, indicating the molecular changes of the lungs, to pulmonary function and histopathological evaluations. Finally, we review state-of-the-art genomics such as high-throughput sequencing and genome-wide chromatin assays, rapidly evolving techniques which have allowed epigenetic changes to be characterized at the genome level. These techniques have the potential to significantly improve our understanding of the specific mechanisms by which exposure to environmental chemicals causes diseases. Such mechanistic knowledge provides a variety of opportunities for enhanced product safety assessment and the discovery of novel therapeutic interventions.