Chemical-specific respiratory and neuroendocrine effects of hazardous air pollutants
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Methodologically challenging hazardous air pollutants (HAPs) known to cause significant health risks including cancer, airway irritancy, inflammation, or immunotoxicity were prioritized for acute in vivo toxicity assessment to validate in vitro findings. Based on our recent results with ozone, we hypothesized that acute effects of these HAPs will be mediated by the activation of the neuroendocrine system, proportional to their irritancy to the respiratory system. Thus far, 2 of 8 selected chemicals have been tested; acrolein and trichloroethylene (TCE). Twelve week old male and female Wistar-Kyoto rats were exposed nose-only to air or selected chemicals in progressively increasing concentration over first 30 min followed by a 3.5 hour exposure to the highest concentration (acrolein, 0.1, 0.316, 1, 3.16 ppm; TCE, 3.16, 10, 31.6, 100 ppm) while head-out plethysmography measures were continuously performed (n=8/group). Within 1 hour post-exposure, blood samples were collected, nasal airways and pulmonary airways lavaged to collect fluids (NALF and BALF). At the highest concentration over a 30 min period for both chemicals, minute volume and peak inspiratory flow began to decrease (males>females) indicating airway irritancy. Acrolein but not TCE exposure led to significant increases in NALF lactate dehydrogenase activity and cellular inflammation (males ≥ females). Nasal and pulmonary inflammation was associated with marked depletion of circulating lymphocytes, monocytes and neutrophils (each ~50% in case of acrolein) in both sexes (acrolein > TCE) indicating systemic effects, likely mediated by neuroendocrine activation as observed with ozone. Acrolein exposure also led to significant increases in NALF but not BALF TNF- and CXCL1 (males > females). Acrolein increased IL-6 levels in both NALF and BALF (NALF > BALF) in both sexes; effect in NALF was greater in males when compared to females, indicating overall significant impact of acrolein in nasal airways where males are more affected. In summary, we show that two selected HAPs produced toxicity in nasal and respiratory airways that is linked to systemic depletion of white blood cell populations. When completed, this assessment will validate and refine on-going in vitro approaches for toxicity testing. (This abstract does not reflect US EPA policy)