Recent epidemiological studies have shown an association between daily morbidity and mortality and ambient particulate matter (PM) air pollution. It has been proposed that bioavailable metal constituents of PM are responsible for many of the reported adverse health effects. Studies of instilled residual oil fly ash (ROFA) demonstrated immediate and delayed responses, consisting of bradycardia, hypothermia, and arrhythmogenesis in conscious, unrestrained rats. Further investigation of instilled ROFA-associated transition metals showed that vanadium (V) induced the immediate responses, while nickel (Ni) was responsible for the delayed effects. Furthermore, Ni potentiated the immediate effects caused by V when administered concomitantly. The present study examined the responses to these metals in a whole-body inhalation exposure. To ensure valid dosimetric comparisons with instillation studies, 4 target exposure concentrations ranging from 0.3-2.4 mg/m(3) were used to incorporate estimates of total inhalation dose derived using different ventilatory parameters. Rats were implanted with radiotelemetry transmitters to continuously acquire heart rate (HR), core temperature (T(CO)), and electrocardiographic data throughout the exposure. Animals were exposed to aerosolized Ni, V, or Ni + V for 6 h per day x 4 days, after which serum and bronchoalveolar lavage samples were taken. Even at the highest concentration, V failed to induce any significant change in HR or T(CO). Ni caused delayed bradycardia, hypothermia, and arrhythmogenesis at concentrations > 1.2 mg/m(3). When combined, Ni and V produced observable delayed effects at 0.5 mg/m(3) and potentiated responses at 1.3 mg/m(3), greater than were produced by the highest concentration of Ni (2.1 mg/m(3)) alone. These results indicate a possible synergistic relationship between inhaled Ni and V, and provide insight into potential interactions regarding the toxicity of PM-associated metals.

539Over the past decade our laboratory has been investigating the nature and extent of specific extrapulmonary responses observed in rodents following exposure to ambient pollutants and other xenobiotic agents. These responses are characterized by primary decreases in important indices of cardiac and thermoregulatory functions, along with secondary decreases in associated parameters. The summation of these effects, termed the hypothermic response (1), has both physiological and behavioral components, appears to be most pronounced in (and possibly unique to) the rodent, and may significantly impact the interpretation of experimental data and its subsequent extrapolation to the human situation. Typically, healthy adult rats may exhibit decreases in heart rate (HR) of 50-100 beats per minute (bpm) and decreases in core temperature (T co ) of 1.5-2.5°C following routine exposures to moderate levels of ambient pollutants, such as ozone (O 3 ) or particulate matter (PM). In addition, there appear to be similar, albeit related, decreases in other functional parameters, including metabolism, minute ventilation, blood pressure, and cardiac output. Furthermore, it has been demonstrated that the magnitudes of these observed decreases may be significantly modulated by changes in experimental conditions. For example, experimental stresses related to exercise, restraint, and handling, as well as the imposition of changes in ambient temperature (T a ), have all been shown to have profound effects on these responses. Finally, it has been proposed that a moderate hypothermic response may afford protection and improve survivability following toxic exposures, whereas a more severe response may actually potentiate the toxicity. Although the underlying mechanisms of the hypothermic response are still largely unexplored and unknown, preliminary experimental evidence suggests that these effects may be mediated, at least partly, via components of the parasympathetic nervous system. O 3 is a ubiquitous ambient pollutant and a known pulmonary irritant (2). In a series of earlier studies from our laboratory (3-6), we investigated both the pulmonary and systemic consequences of O 3 exposures (0.25-2.0 ppm) in rodents. With respect to nonpulmonary end points, these studies used radiotelemetry procedures to examine HR, T co , and electrocardiographic changes in rats and mice over a variety of experimental conditions. These studies were among the first to report consistent, robust concentration-related decreases in the abovementioned parameters in rodents following exposure to routine experimental levels of O 3 .More recently, the putative toxicity of PM has attracted considerable attention, and numerous epidemiological studies published over the last few years have reported a slight but consistent association between the concentration of ambient PM and the incidence of adverse health effects in man (7-12). Despite limited supporting experimental evidence, there is a growing consensus that higher levels of PM in the air are associated with in...

Particulate matter air pollution has been associated with cardiopulmonary morbidity and mortality in many recent epidemiological studies. Previous toxicological research has demonstrated profound cardiac and thermoregulatory changes in rats following exposure to residual oil fly ash (ROFA), a combustion-derived particulate. The response to ROFA appeared biphasic, consisting of both immediate (0-6 h) and delayed (24-96 h) bradycardia and hypothermia. Other studies have demonstrated that much of the pulmonary toxicity of ROFA was caused by its constitutive transition metals, namely, Fe, Ni, and V. This study examined the contributions of these metals to the observed cardiac and thermoregulatory changes caused by ROFA in conscious, unrestrained rats. Prior to exposure, each animal was surgically implanted with a radiotelemetry device capable of continuously monitoring heart rate, electrocardiographic, and core temperature data. Individual metals were intratracheally instilled in healthy rats (n = 4 per metal species) and in rats with monocrotaline (MCT; 60 mg/kg)-induced pulmonary hypertension (n = 10 per metal species); combinations of metals were instilled in MCT-treated rats only (n = 6 per combination of metal species). Metals were administered in doses equivalent to those found in the highest dose of ROFA used in previous studies, that is, 105 microg Fe(2)(SO(4))(3), 263 microg NiSO(4), and 245 microg VSO(4). Healthy and MCT-treated rats demonstrated similar responses to metals. Fe caused little response, whereas V caused marked bradycardia, arrhythmogenesis, and hypothermia immediately following instillation and lasting approximately 6 h. Ni caused no immediate response, but induced a delayed bradycardia, arrhythmogenesis, and hypothermia that began approximately 24 h after instillation and lasted for several days. When instilled in combination, Ni appeared to exacerbate the immediate effects of V, whereas Fe attenuated them. These data suggest that the biphasic response to instilled ROFA may result from a summation of the temporally different effects of V and Ni.

Striking similarities have been observed in a number of extrapulmonary responses of rodents to seemingly disparate ambient pollutants. These responses are often characterized by primary decreases in important indices of cardiac and thermoregulatory function, along with secondary decreases in associated parameters. For example, when rats are exposed to typical experimental concentrations of ozone (O(3), they demonstrate robust and consistent decreases in heart rate (HR) ranging from 50 to 100 beats per minute, whereas core temperature (T(co) often falls 1.5-2.5 degrees C. Other related indices, such as metabolism, minute ventilation, blood pressure, and cardiac output, appear to exhibit similar deficits. The magnitudes of the observed decreases may be modulated by changes in experimental conditions and appear to vary inversely with both ambient temperature and body mass. More recent studies in which both healthy and compromised rats were exposed to either particulate matter or its specific components yielded similar results. The agents studied included representative examples of ambient, combustion, and natural source particles, along with individual or combined exposures to their primary metallic constituents. In addition to the substantial decreases in HR and T(co), similar to those seen with the O(3)-exposed rats, these animals also displayed numerous adverse changes in electrocardiographic waveforms and cardiac rhythm, frequently resulting in fatal outcomes. Although there is only limited experimental evidence that addresses the underlying mechanisms of these responses, there is some indication that they may be related to stimulation of pulmonary irritant receptors and that they may be at least partially mediated via the parasympathetic nervous system.