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There is growing epidemiological evidence for statistical associations between increases in air pollution, especially particulate matter, and increases in cardiovascular morbidity and mortality. Laboratory studies have shown that transition metals contribute strongly to the effects of high lung doses of model particles on changes in the electrocardiograms of animals. The present study evaluated the effects of short-term inhalation exposure to respirable particles of specific oxide and sulfate forms of transition metals on heart rate and the electrocardiogram of old dogs having preexisting cardiac abnormalities. Conscious beagle dogs were exposed by oral inhalation for 3 h on each of 3 successive days to aerosols of manganese, nickel, vanadium, iron, and copper oxides, and nickel and vanadium sulfates as single compounds at concentrations of 0.05 mg/m 3 . Electrocardiograms were recorded and evaluated for exposure-related changes in heart rate, heart rate variability, and abnormalities of waveforms. Although the electrocardiograms of this population of dogs having potential age and cardiovascular susceptibility factors reflected their underlying clinical abnormalities, no significant effect of exposure to the transition metal aerosols was observed. [ABSTRACT FROM AUTHOR]

Carbon tetrachloride is hepatotoxic in rats, mice, and hamsters. However, rats are less sensitive to the hepatotoxic effects of CCl4 than the other two species. The purpose of this study was to compare the uptake, tissue distribution, and elimination of CCl[sub 4] by these three rodent species. Groups of 20 F344/Crl BR rats, B6C3F[sub 1] mice, and Syrian hamsters were exposed by nose-only inhalation for 4 h to 20 ppm [sup 14]C-labeled CCl[sub 4]. The fate of [sup 14]C was followed in tissues, excreta, and exhaled breath for 48 h after the exposure. At the end of the exposure, concentrations of CCl[sub 4] equivalents (CE) in tissue were highest in liver of rats and mice, but highest in fat for rats. The liver received the highest dose of CCl[sub 4] equivalents with the following species ranking: mouse > hamster > rat. Patterns of CE elimination were species and tissue dependent, with the majority of elimination occurring within 48 h after exposure. Rats eliminated less radioactivity associated with metabolism ([sup 14]CO[sub 2], urine and feces) and more radioactivity associated with parent compound (exhaled activity trapped on charcoal) than did mice or hamsters. The results indicate that ranking of species sensitivity to the hepatotoxic effects of inhaled CCl[sub 4] correlates with CE dose to liver and with the ability to metabolize CCl[sub 4]. [ABSTRACT FROM AUTHOR]

No study has comprehensively compared the rate of metabolism of carbon tetrachloride (CCl[sub 4]) across species. Therefore, the in vivo metabolism of CCl[sub 4] was evaluated using groups of male animals (F344 rats, B6C3F[sub 1] mice, and Syrian hamsters) exposed to 40-1800 ppm CCl[sub 4] in a closed, recirculating gas-uptake system. For each species, an optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants K [sub m] (affinity) and V [sub max] (capacity) using a physiologically based pharmacokinetic (PBPK) model. The results show that the mouse has a slightly higher capacity and lower affinity for metabolizing CCl[sub 4] compared to the rat, while the hamster has a higher capacity and lower affinity than either rat or mouse. A comparison of the V [sub max] to K [sub m] ratio, normalized for milligrams of liver protein (L/ h/ mg) across species, indicates that hamsters metabolize more CCl[sub 4] than either rats or mice, and should be more susceptible to CCl[sub 4]-induced hepatotoxicity. These species comparisons were evaluated against toxicokinetic studies conducted in animals exposed by nose-only inhalation to 20 ppm 14C-labeled CCl[sub 4] for 4 h. The toxicokinetic study results are consistent with the in vivo rates of metabolism, with rats eliminating less radioactivity associated with metabolism ( 14CO [sub 2] and urine/ feces) and more radioactivity associated with the parent compound (radioactivity trapped on charcoal) compared to either hamsters or mice. The in vivo metabolic constants determined here, together with in vitro constants determined using rat, mouse, hamster, and human liver microsomes, were used to estimate human in vivo metabolic rates of 1.49 mg/ h/ kg body weight and 0.25 mg/ L for V [sub max] and K [sub m], respectively. Normalizing the rate of metabolism ( V [sub ma] / K [sub m]) by milligrams liver protein, the rate of metabolism of CCl[sub 4] differs across species, with[sup x]hamster > mouse > rat > human. [ABSTRACT FROM AUTHOR]

Beryllium/copper (BeCu) alloys are commonly used in the electronics, automotive, consumer, defense, and aerospace industries. Some individuals exposed occupationally to BeCu alloys have developed chronic beryllium disease. However, little is known of the toxicity and fate of BeCu alloys in the respiratory tract. To begin to address this question, we investigated the pulmonary toxicity and clearance of BeCu alloy (2% Be; 98% Cu) in mice. Groups of 40 female C3H/HeJ mice were administered 12.5, 25, and 100 µg BeCu alloy or 2 and 8 µg Be metal by intratracheal instillation. Mice were sacrificed at 1h and 1, 7, 14, and 28 days postinstillation. Left lungs were evaluated for histopathological change. Right lungs were analyzed for Be and Cu content. Twentyfive percent of the high-dose BeCu mice and 7.5% of the mid-dose BeCu mice died within 24h of dosing. Acute pulmonary lesions included acute alveolitis and interstitial inflammation. Type II epithelial cell hyperplasia and centriacinar fibrosis were present by 7 days after dosing. Lesions persisted through 28 days after instillation. No lesions attributable to alloy exposure were present in liver or kidney. Be metal instillation caused no deaths and minimal pulmonary changes over the time studied, indicating that the pulmonary lesions were due to Cu rather than Be. Cu cleared the lung with a half-time of 0.5-2 days. Be cleared with a half-time of several weeks or longer. Results of this study suggest that exposure to BeCu alloy is more acutely toxic to lung than Be metal. The results of tissue analyses also indicate that, while the Cu component of the alloy clears the lung rapidly, Be is retained and may accumulate upon repeated exposure. [ABSTRACT FROM AUTHOR]