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EFFECTS OF INHALATION OF METALLIC CONSTITUENTS OF PARTICULATE MATTER AIR POLLUTION ON CARDIOPULMONARY AND THERMOREGULATORY PARAMETERS IN HEALTH AND COMPROMISED RATS
Citation:
Watkinson, W P., J. P. Nolan, U P. Kodavanti, M. Schladweiler, P A. Evansky, E. R. Lappi, D L. Costa, M. J. Campen, AND L. B. Wichers. EFFECTS OF INHALATION OF METALLIC CONSTITUENTS OF PARTICULATE MATTER AIR POLLUTION ON CARDIOPULMONARY AND THERMOREGULATORY PARAMETERS IN HEALTH AND COMPROMISED RATS. Presented at 34th World Congress of the International Union of Physiological Sciences, Christchurch, New Zealand, Aug 26-31,2001.
Description:
EFFECTS OF INHALATION OF METALLIC CONSTITUENTS OF PARTICULATE MATTER AIR POLLUTION ON CARDIOPULMONARY AND THERMOREGULATORY PARAMETERS IN HEALTHY AND COMPROMISED RATS. Watkinson, WP, Campen, MJ, Wichers, LB, Nolan, JP, Kodavanti, UP, Schladweiler, MCJ, Evansky, PA, Lappi, ER, and Costa, DL. National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC USA and School of Public Health and Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC USA.
Epidemiological studies have reported a robust relationship between exposure to elevated levels of ambient particulate matter (PM) and increased cardiovascular-related morbidity and mortality. It has been proposed that these adverse effects may be mediated via the soluble transition metallic constituents of PM, specifically Fe, V, and Ni. It is also known that rodents respond to exposure to toxic xenobiotic agents by initiating significant acute and subacute decreases in important indices of cardiac and thermoregulatory function, along with similar decreases in related parameters (e.g., metabolic rate, cardiac output, respiratory rate). These responses appear remarkably consistent and may predispose treated animals to adverse arrhythmic events and lethalities. These effects, termed the hypothermic response, have been observed in a number of studies in our laboratory using a variety of agents (anesthetics, pesticides, ozone, particulate matter, metals, others) and routes of exposure (intravenous, intraperitoneal, intratrachael instillation, inhaled). Given that rodents are used in the vast majority of animal studies examining PM toxicity, reconciliation of the results of such studies vis a vis the hypothermic response can be particularly challenging. Thus, we have examined the impact of inhaled metal sulfate constituents (Ni, V, Fe) of PM on cardiopulmonary and thermoregulatory toxicological indices in healthy and compromised rats (Sprague-Dawley, male, 60?70d). Subsets of animals were implanted with radiotelemetry transmitters capable of monitoring electrocardiogram (ECG), heart rate (HR), and core body temperature (Tco). The concentrations of metals used were chosen to cumulatively match the metal content of instilled PM (residual oil fly ash) used in previous studies. In the first study, rats (n=48) were preexposed to either filtered air or O3 (0.5ppm?6h/d?1d) to produce acute pulmonary inflammation. At 18h postexposure to air or O3, animals were further exposed (6h/d?4d) to sulfates of nickel (Ni; 0.46 mg/m3)+vanadium (V; 0.46 mg/m3)+iron (Fe; 0.21 mg/m3), with or without concurrent exposure to O3 (0.5ppm?6h/d?4d). Preexposure to O3 produced decreases in HR and Tco of 50?75 bpm and 1.0?1.5 C, respectively. Subsequent exposure to Ni+V+Fe induced similar deficits in these parameters that persisted throughout the 4d exposure period. In rats concurrently exposed to Ni+V+Fe and O3, these decreases were potentiated by 50 bpm and 1.0 C on the first day and gradually subsided over the exposure period. The greatest effects were seen following concurrent exposure to Ni+V+Fe and O3 without O3 preexposure. In the second study, there was no preexposure to O3 and rats (n=48) were exposed to only Ni+V, with and without concurrent exposure to O3. In this study, there was a clear potentiation of effects with concurrent O3 exposure. In the third study, rats (n=48) were equally divided into two groups, injected with either monocrotaline (MCT; 60 mg/kg, ip) or saline, and allowed 14d for the development of pulmonary hypertension. Rats were exposed (6h/d?4d) to a range of metal concentrations (0.3?2.3 mg Ni2+/m3, 0.3?1.2 mg V2+/m3, 0.4?0.8 mg Fe3+/m3) that caused dose-related decreases in HR (up to 150 bpm) and Tco (up to 3.2 C), and increases in lethality rates (up to 25%). Responses were similar in magnitude and time course to those of the instillation studies: V induced an immediate response, Ni was associated with a delayed response, and combination exposures produced additive effects. There were significant increases in blood hematocrit, platelets, and fibrinogen, with marked pulmonary vascular leakage and inflammation. These studies demonstrate substantial cardiopulmonary toxicity in rats after inhalation exposure to PM-associated metals and also show the time-dependent modulatory potential that varying combinations of inhaled pollutants may have on resultant adverse effects. (Abstract does not represent USEPA policy.)