Evaluation of adverse human lung function effects in controlled ozone exposure studies

The US EPA is evaluating controlled human ozone exposure studies to determine the adequacy of the current ozone National Ambient Air Quality Standard of 75 ppb. These studies have shown that ozone exposures of 80 ppb and greater are associated with lung function decrements. Here, we critically review studies with exposures below 80 ppb to determine the lowest ozone concentration at which decrements are causally associated with ozone exposure and could be considered adverse using the Adverse Effects/Causation Framework. Regarding causation, the framework includes consideration of whether exposure‐related effects are primary or secondary, statistically significant, isolated or independent, or due to study limitations. Regarding adversity, the framework indicates one should consider whether effects are adaptive, compensatory, precursors to an apical effect, severe, transient and/or reversible. We found that, at exposures below 72 ppb ozone, lung function effects are primary effects, but are isolated, independent and not statistically different compared to effects observed during filtered air exposure, indicating a lack of causation. Up to 72 ppb, lung function effects may be precursors to an apical effect, but are not likely adverse because they are transient, reversible, of low severity, do not interfere with normal activity and do not result in permanent respiratory injury or progressive respiratory dysfunction. Overall, these studies do not demonstrate a causal association between ozone concentrations in the range of the current National Ambient Air Quality Standard and adverse effects on lung function. Copyright © 2013 John Wiley & Sons, Ltd.     

Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo

Human response to isoproterenol induced cardiac injury was evaluated by gene and protein pathway changes in human heart slices, and compared to rat heart slices and rat heart in vivo. Isoproterenol (10 and 100 μM) altered human and rat heart slice markers of oxidative stress (ATP and GSH) at 24 h. In this in vivo rat study (0.5 mg/kg), serum troponin concentrations increased with lesion severity, minimal to mild necrosis at 24 and 48 h. In the rat and the human heart, isoproterenol altered pathways for apoptosis/necrosis, stress/energy, inflammation, and remodeling/fibrosis. The rat and human heart slices were in an apoptotic phase, while the in vivo rat heart exhibited necrosis histologically and further progression of tissue remodeling. In human heart slices genes for several heat shock 70 kD members were altered, indicative of stress to mitigate apoptosis. The stress response included alterations in energy utilization, fatty acid processing, and the up-regulation of inducible nitric oxide synthase, a marker of increased oxidative stress in both species. Inflammation markers linked with remodeling included IL-1α, Il-1β, IL-6 and TNFα in both species. Tissue remodeling changes in both species included increases in the TIMP proteins, inhibitors of matrix degradation, the gene/protein of IL-4 linked with cardiac fibrosis, and the gene Ccl7 a chemokine that induces collagen synthesis, and Reg3b a growth factor for cardiac repair. This study demonstrates that the initial human heart slice response to isoproterenol cardiac injury results in apoptosis, stress/energy status, inflammation and tissue remodeling at concentrations similar to that in rat heart slices.