The uptake and elimination of 1,1,1-trichloroethane during and following inhalation exposures in rats

The pharmacokinetics of 1,1,1-trichloroethane (TRI) was studied in male Sprague-Dawley rats in order to characterize and quantify TRI uptake and elimination oby direct measurements of the inhaled and exhaled compound. Fifty or 500 ppm TRI was inhaled for 2 hr through a one-way breathing valve by unanesthetized rats of 325-375 g. Repetitive samples of the separate inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently both during and following TRI inhalation and analyzed for TRI by gas chromatography. Respiratory rates and volumes were continuously monitored during and following exposure and were used in conjunction with the pharmacokinetic data to characterize profiles of uptake and elimination. TRI was very rapidly absorbed from the lung, in that substantial levels were present in arterial blood at the first sampling time (i.e., 2 min). Blood and exhaled breath concentrations of TRI increased rapidly after the initiation of exposure, approaching but not reaching steady state during the 2-hr exposures. The blood and exhaled breath concentrations were directly proportional to the exposure concentration during the exposures. Percentage uptake of TRI decreased 30-35% during the first hour of inhalation, diminishing to approximately 45-50% by the end of the exposure. Total cumulative uptake in the 50 and 500 ppm groups over the 2-hr inhalation exposures was determined to be 6 and 48 mg/kg body wt, respectively. By the end of the exposure period, 2.1 and 20.8 mg, respectively, of inhaled TRI was eliminated from rats inhaling 50 and 500 ppm TRI. A physiological pharmacokinetic model for TRI inhalation was utilized to predict blood and exhaled breath concentrations for comparison with observed experimental values. Overall, values predicted by the physiological pharmacokinetic model for TRI levels in the blood and exhaled breath were in close agreement with measured values both during and following TRI inhalation.     

Increased airway responsiveness of a common fragrance component, 3-carene, after skin sensitisation--a study in isolated guinea pig lungs

Lungs from skin-sensitised and non-sensitised guinea pigs were exposed via the airways to 3-carene (1900 mg/m3) and perfused with buffer containing either autologous plasma or lymphocytes. The experiments were performed in order to investigate the importance of blood components for the increased lung responsiveness seen in skin-sensitised animals. A reduction in lung function was noted in all lungs during 3-carene exposure. There was no difference in the 3-carene response between lungs from skin-sensitised animals versus lungs from non-sensitised animals when the perfusion buffer contained lymphocytes. However, when plasma diluted with buffer was used as perfusion medium, there was a significant enhancement in the response in lungs from sensitised versus lungs from non-sensitised animals. This implies that skin sensitisation increases lung responses to inhaled 3-carene and those components in plasma, and not the lymphocyte fraction, contributes to the observed increased lung responsiveness.     

Uptake and disposition of inhaled methanol vapor in humans.

Methanol is a widely used solvent and a potential fuel for motor vehicles. Human kinetic data of methanol are sparse. As a basis for biological exposure monitoring and risk assessment, we studied the inhalation toxicokinetics of methanol vapor in four female and four male human volunteers during light physical exercise (50 W) in an exposure chamber. The relative uptake of methanol was about 50% (range 47-53%). Methanol in blood increased from a background level of about 20 to 116 and 244 microM after 2 h exposure at 0, 100 ppm (131 mg/m3) and 200 ppm (262 mg/m3), respectively. Saliva showed substantially higher levels than blood immediately after exposure. This difference disappeared in a few minutes; thereafter the concentrations and time courses in blood, urine, and saliva were similar, with half times of 1.4, 1.7, and 1.3 h, respectively. The postexposure decrease of methanol in exhaled air was faster, with a half time of 0.8 h. The methanol concentrations were approximately twice as high in all four types of biological samples at 200 compared to 100 ppm. No increase in urinary formic acid was seen in exposed subjects. Our study indicates non-saturated, dose-proportional kinetics of methanol up to 200 ppm for 2 h. No gender differences were detected. Similar, parallel patterns were seen with regard to the methanol time courses in blood, urine, and saliva, whereas the concentration in exhaled air decreased markedly faster. Thus, apart from blood and urine, saliva also seems suitable for biomonitoring of methanol exposure.     

Chronic maternal methanol inhalation in nonhuman primates (Macaca fascicularis): exposure and toxicokinetics prior to and during pregnancy

Toxicokinetic studies were conducted following daily inhalation exposure to methanol vapor prior to and throughout pregnancy in adult female Macaca fascicularis monkeys. They were part of a larger study to investigate the effects of chronic methanol exposure on maternal reproductive performance and early offspring effects. In a two-cohort study design, 48 females (24/cohort) were assigned to parallel exposure groups at 0 (control), 200, 600, or 1800 ppm methanol vapor for approximately 2.5 h/day, 7 days/week throughout breeding and pregnancy. Blood methanol at 30 min postexposure was monitored biweekly. The time course for the clearance of blood MeOH concentrations following exposure was characterized on four occasions: twice during the prebreeding period and during mid- and late pregnancy. Average blood methanol concentrations at 30 min postexposure were 5, 11, and 35 microg/ml across all four toxicokinetic studies in the 200, 600 and 1800 ppm groups, respectively. Blood concentrations in the 200 ppm group were barely above basal (preexposure) blood methanol concentrations or those observed in the control group (approximately 3 microg/ml). Nonlinear elimination kinetics were observed in most of the 1800 ppm group females. There was a decrease in elimination half-life (7-20%) and an increase in clearance (30%) after 3-months of daily MeOH exposure compared to the initial exposure. There were no statistically significant changes in the first-order blood methanol half-life or clearance during pregnancy, but the mean distribution volume per kilogram body weight decreased by 22% and 17% in the 600 and 1800 ppm groups. Plasma formate levels did not differ between the methanol and control exposure groups. Plasma formate and serum folate concentrations increased slightly over the course of this study in both the exposed and control groups but these increases were not related to methanol exposure.     

Increased airway responsiveness after skin sensitisation to 3-carene, studied in isolated guinea pig lungs

Inhalation of 3-carene has been shown to induce bronchoconstriction in concentrations not far from the threshold limit value. In this study, one group of guinea-pigs were sensitised by dermal exposure to 3-carene according to the modified Cumulative Contact Enhancement Test protocol and another group of animals was used as controls. Lungs from the skin-sensitised and control guinea-pigs were perfused with diluted autologous blood (13 ml blood/87 ml buffer) and exposed to 3-carene at an air concentration of 3000 mg/m(3). In both groups there was a reduction in compliance and conductance but this reduction was significantly (P<0.05) more pronounced (2.5-3 times) in lungs obtained from sensitised animals than from control animals. In a previous study with similar design, but with plain buffer instead of diluted autologous blood as perfusate, we found no statistically significant difference in lung bronchoconstriction. Thus, it is concluded that skin sensitisation can increase lung reactivity to 3-carene and that important mediators of this effect seem to be present in the blood.     

Inhalation pharmacokinetics of technical grade 1,3-dichloropropene in rats

Kinetic data on the uptake of vapors of technical grade 1,3-dichloropropene (DCP) and resultant cis- and trans-DCP blood concentrations were obtained in rats exposed to 30, 90, 300, or 900 ppm DCP for 3 hr. The uptake of DCP did not increase proportionately with increasing exposure concentration due to an exposure level-related decrease in the respiratory ventilatory frequency of rats exposed to greater than or equal to 90 ppm DCP and the saturation of metabolism of DCP by rats exposed to greater than or equal to 300 ppm DCP. Absorption of inhaled DCP occurred primarily in the lower respiratory tract, although a small amount of the chemical was absorbed via the nasal mucosa, a known target tissue of inhaled DCP in rats. Following absorption, both isomers of DCP were, at less than or equal to 300 ppm exposure levels, rapidly eliminated from the bloodstream (3-6 min half-life). In addition, data obtained in rats exposed to 300 ppm DCP revealed that this rapid elimination phase was followed by a slower elimination phase having a 33-43 min half-life. Rats exposed to 900 ppm vapors also eliminated DCP in a biphasic manner; however, in this case the blood half-life of DCP during the initial phase of excretion was 14 to 27 min. Exposure to 90 ppm DCP also produced a significant decrease in renal (31%) and hepatic (41%), but not pulmonary, nonprotein sulfhydryl content. Overall, these data demonstrated that a combination of saturable metabolism and chemically induced changes in respiration control DCP uptake and body burden in rats.     

Sex differences in the toxicokinetics of inhaled solvent vapors in humans 2. 2-propanol

The aim of this study was to evaluate possible sex differences in the inhalation toxicokinetics of 2-propanol vapor. Nine women and eight men were exposed on different occasions for 2 h during light physical exercise (50 W) to 2-propanol (350 mg/m3) and to clean air (control exposure). The level corresponds to the Swedish occupational exposure limit. 2-Propanol and its metabolite acetone were monitored up to 24 h after exposure in exhaled air, blood, saliva, and urine by headspace gas chromatography. Body fat and lean body mass were estimated from sex-specific equations using bioelectrical impedance, body weight, height, and age. Genotypes were determined by PCR-based assays for alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1). The CYP2E1 phenotype was assessed by the 2-h plasma 6-hydroxychlorzoxazone/chlorzoxazone metabolic ratio in vivo. The toxicokinetic profile in blood was analyzed using a one-compartment population model. The following sex differences were significant at the p = 0.05 level (Student's t test). The respiratory uptake was lower and the volume of distribution smaller in females. The women had a slightly shorter half-time of 2-propanol in blood and a higher apparent total clearance when corrected for body composition. However, women reached approximately four times higher 2-propanol levels in exhaled air at 10-min postexposure and onward. Acetone in blood was markedly higher in females than in males in the control experiment and slightly higher following exposure to 2-propanol. A marked sex difference was that of a 10-fold higher in vivo blood:breath ratio in men, suggesting sex differences in the lung metabolism of 2-propanol. The most marked sex difference was that of salivary acetone, for which an approximately 100-fold increase was seen in women, but no increase in men, after exposure to 2-propanol compared to clean air. The toxicokinetic analysis revealed no significant differences in toxicokinetics between subjects of different metabolic genotypes or phenotypes. In conclusion, the study indicates several sex differences in the inhalation toxicokinetics of 2-propanol. Most of these differences are consistent with anatomical differences between women and men. However, body build can not explain the sex differences in 2-propanol levels in expired air and acetone in saliva.     

Blood-bound carbon disulfide: An indicator of carbon disulfide exposure, and its accumulation in repeatedly exposed rats

Carbon disulfide is present in exposed subjects in free and bound or acid-labile forms. Sensitivities of the blood acid-labile CS2 (AL CS2) concentration and the modified iodine-azide test (IAT) were compared as indicators of CS2 exposure. Rats were exposed to 15 (approximately 5 ppm), 30, 60, or 120 mg/m3 of CS2. Exposure to 15 or 30 mg/m3 of CS2 could not be detected by the modified IAT. However, a linear relationship between blood CS2 (free or AL CS2) concentrations and these exposure levels was observed. Free CS2 is eliminated rapidly, while AL CS2 is eliminated very slowly from the exposed subjects. Repetitive daily exposures (8 hr/day) to 120 mg/m3 of CS2 were carried out in rats. Blood AL CS2 concentrations in exposed rats increased with each successive exposure while the free CS2 level remained relatively constant. By the sixth or seventh daily exposure the blood AL CS2 concentration was about 2.5 times that of the first 8-hr exposure and about 3 times the level of free CS2. These results indicated an appreciable accumulation of CS2 in subjects repeatedly exposed to low concentrations of the solvent. Rats were also exposed to CS2 8 hr/day for 5 days. After a 2-day nonexposure period (Days 6 and 7), the animals were reexposed on Day 8. The blood AL CS2 concentration in animals exposed on Day 8 was substantially higher than in those that received a single 8-hr exposure (Day 1), despite the hiatus on Days 6 and 7. These results indicated that blood AL CS2 was not totally eliminated during the 2-day nonexposure period. In in vitro experiments, the binding profile of CS2 to human blood was remarkably similar to that of rats exposed to CS2 by inhalation.     

Placental and lactational transfer of lead in rats: a study on the lactational process and effects on offspring

 The effects of placental and lactational exposure to lead (Pb) were studied in suckling rats after long-term exposure of their dams to Pb in drinking water. Dams were given 12 mM Pb-acetate in the drinking water 8 weeks prior to mating and during gestation. One group of dams was also continuously exposed during lactation until day 15. Neonates from Pb-treated dams were cross-fostered at birth to control dams treated with Na-acetate (12 mM) in the drinking water. In the same way, neonates from dams receiving control water were in the same way cross-fostered to Pb-exposed dams. All animals were killed at day 15 of lactation, when measurements were performed. Continuous Pb exposure during gestation and lactation resulted in milk Pb levels approximately 2.5 times higher than the blood Pb levels. When Pb exposure was terminated at parturition the milk Pb levels were at a level similar to those of blood Pb at day 15 of lactation, and only 10% of the milk levels found after continuous Pb exposure. Exposure to Pb via placenta and milk in offspring from dams exposed continuously resulted in more than 6 times higher blood and brain Pb levels than in offspring exposed only via the placenta. Exposure only via milk in offspring from dams exposed to Pb until parturition resulted in higher blood Pb levels than in offspring exposed to Pb only via the placenta. This indicates that the lactational transfer after current or recent exposure of Pb in dams is considerably higher than placental transfer. Offspring in all the exposed groups had decreased ALAD activity in the blood. An exponential relationship between blood Pb levels and ALAD activity was demonstrated in the offspring. Due to the exponential decrease in ALAD activity at increasing blood Pb levels, ALAD is particularly sensitive in reflecting differences in Pb exposure within the lowest range of blood Pb levels. There was a slight effect on weight gain in the offspring. However, there was no effect on milk quality, as measured by milk lipid, protein and calcium concentrations, nor on milk production assessed by the mammary gland RNA and DNA content. This indicates that the effect on weight gain was a direct effect of Pb in the offspring. Received: 4 January 1995/Accepted: 10 March 1995     

Nasal NPSH depletion and propylene oxide uptake in the upper respiratory tract of the mouse.

Propylene oxide is a nasal toxicant and weak site-of-contact carcinogen in the mouse and rat. To aid in inhalation risk assessment of this vapor and to provide data for comparison to the rat, the current study was aimed at providing quantitative information on upper respiratory tract (URT) dosimetry of this vapor in the mouse. Toward this end, uptake efficiencies of propylene oxide were measured in the surgically isolated URT of the male B6C3F1 mouse under constant velocity inspiratory flow conditions at flow rates of 12 and 50 ml/min and exposure concentrations of 25, 50, 100, 300, or 500 ppm. URT uptake efficiencies were measured continuously during 1 h exposure; mice were terminated immediately after exposure and nasal respiratory and olfactory mucosal nonprotein sulfhydryl (NPSH) levels were determined. Propylene oxide was scrubbed with moderate efficiency in the URT, with uptake efficiencies of < or = 33 and < or = 16% at the low and high inspiratory flow rates, respectively. Uptake efficiencies were slightly (approximately 5%) higher at low (25 or 50 ppm) than high (300 or 500 ppm) exposure concentrations, suggesting that a saturable uptake pathway may exist. Nasal tissue NPSH levels were significantly depleted at exposure concentrations of 300 and 500 ppm but not at concentrations of 100 ppm or lower. Similar levels of NPSH depletion were observed in both nasal respiratory and olfactory mucosa. These data from mouse show some key differences when compared with those reported for the rat.     

Gastrointestinal uptake and fate of cadmium in rainbow trout acclimated to sublethal dietary cadmium

Adult rainbow trout were pre-exposed to a sublethal concentration of dietary Cd (500 mg/kg dry wt.) for 30 days to induce acclimation. A gastrointestinal dose of radiolabeled Cd (276 microg/kg wet wt.) was infused into the stomach of non-acclimated and Cd-acclimated trout through a stomach catheter. Repetitive blood samples over 24 h and terminal tissue samples were taken to investigate the gastrointestinal uptake, plasma clearance kinetics, and tissue distribution of Cd. Only a small fraction of the infused dose (non-acclimated: 2.4%; Cd-acclimated: 6.6%) was internalized across the gut wall, while most was bound in the gut tissues (10-24%) or remained in the lumen (16-33%) or lost from the fish (approximately 50%) over 24 h. Cadmium loading during pre-exposure produced a profound increase of total Cd in the blood plasma (approximately 28-fold) and red blood cells (RBC; approximately 20-fold). The plasma Cd-time profiles consisted of an apparent rising (uptake) phase and a declining (clearance) phase with a maximum value of uptake in 4 h, suggesting that uptake of gastrointestinally infused Cd was very rapid. Acclimation to dietary Cd did not affect plasma Cd clearance (approximately 0.5 ml/min), but enhanced new Cd levels in the plasma (but not in the RBC), and resulted in a longer half-life for plasma Cd. Tissue total and new Cd levels varied in different regions of the gastrointestinal tract, and overall levels in gut tissues were much greater than in non-gut tissues, reflecting the Cd exposure route. Dietary Cd, but not the infused Cd, greatly increased total Cd levels of all gut tissues in the order posterior-intestine (640-fold) > cecae (180-fold) > mid-intestine (94-fold) > stomach (53-fold) in Cd-acclimated fish relative to na?ve fish. Among non-gut tissues in the Cd-acclimated fish, the great increases of total Cd levels were observed in the liver (73-fold), kidney (39-fold), carcass (35-fold), and gills (30-fold). The results provide some clear conclusions that may be useful for environmental risk assessment of dietary Cd exposure in fish.     

Uptake and distribution of 14C during and following inhalation exposure to radioactive toluene diisocyanate

Inhalation of toluene diisocyanate (TDI) results in toxic responses ranging from pulmonary irritation to immunological sensitization. The use of radioactively labeled isocyanate has made it possible to follow the initial uptake of the compound into the bloodstream independent of the final fate of the isocyanate. This study shows that the rate of uptake into the blood is linear during exposure to concentrations ranging from 0.00005 to 0.146 ppm and that the uptake continues to increase slightly postexposure. It also demonstrates that the radioactivity clears from the bloodstream to a level corresponding to approximately a 100 nM concentration of tolyl group after 72 hr and persists at a nanomolar level even 2 weeks following the exposure. This is similar to the response previously reported by this group for radioactively labeled methyl isocyanate. The initial rate of 14C uptake is also a linear function of the concentration of TDI when expressed either as concentration (ppm) or as concentration multiplied by duration of exposure (ppm.hr). This is discussed in comparison with the toxic responses as a function of both ppm and ppm.hr. Finally, the inclusion of the data on methyl isocyanate indicates that the uptake into arterial blood is a function of exposure concentration, independent of isocyanate structure.     

EFFECTS OF RESERPINE ON THE CONTENT AND UPTAKE OF DOPAMINE AND NORADRENALINE IN RABBIT ARTERIES

1. Change with time of the content and uptake of dopamine (DA) and noradrenaline (NA) in the renal, superior mesenteric and femoral arteries and abdominal aorta of rabbit after reserpine administration was examined. Endogenous DA and NA were measured by high performance liquid chromatography coupled with electrochemical detector. 2. A single dose of reserpine (3 mg/kg, i.p.) maximally depleted the endogenous DA and NA contents in the four blood vessels 24 h after the administration; the ratios of reductions were 70–90% and approximately 90% of the normal levels, respectively. The DA contents in all four vessels recovered to the normal level within 4 days after reserpine. However, NA content did not recover to the normal levels within 30 days after reserpine except in the mesenteric artery. 3. The activity of dopamine β-hydroxylase (DBH) significantly increased in all four blood vessels 1 h after reserpine. Although the DBH activity returned to the normal level after 3 days in the mesenteric artery, it returned within 24 h in the other three vessels. 4. [³H]-Dopamine and [³H]-NA uptake were almost completely depressed 1 h after reserpine. The [³H]-NA uptake in four vessels recovered to the normal level 2–14 days after reserpine, and [³H]-DA uptake recovered after 30–45 days. Thus, the endogenous DA content in blood vessels was completely restored although DA uptake and NA content were still affected. 5. These results suggested that the recovery of stored DA after reserpine was faster than that of stored NA and the recovery of DA uptake after reserpine was slower than NA uptake. This indicates a possibility that a part of DA pool may be different from NA pool in adrenergic nerve terminals in the blood vessels.     

The effect of ethylene exposure on ethylene oxide in blood and on hepatic cytochrome p450 in Fischer rats.

Ethylene (74-85-1) is an important petrochemical and is produced endogenously. It is metabolized to ethylene oxide (EO) by cytochrome P450. We studied the inhibition of cytochrome P450 activity during exposure to ethylene, and verified that this inhibition was reflected in the concentration of EO in the blood. Male F344 rats were exposed to 1000, 600, and 300 ppm ethylene by nose-only inhalation for up to 6 h. Blood samples were obtained during exposure. On exposure to 600 ppm ethylene, blood EO concentration increased during the first hour of exposure and then decreased to approximately half of the peak blood concentration. A less pronounced decrease was observed at 300 ppm, and at 1000 ppm little change was observed between 10 min and 6 h of exposure. For the analysis of cytochrome P450 and isozyme-specific substrate activities, groups of four male F344 rats were removed for the collection of liver at various times after exposure to 300, 600, or 1000 ppm ethylene. At all concentrations, liver microsomal cytochrome P450 decreased during exposure. Of the various monooxygenase activities measured, 4-nitrophenol hydroxylase was the one most consistently altered, with maximal inhibition (approximately 50%) at 2 h of exposure to 1000 ppm ethylene, 4 h at 600 ppm, and 6 h at 300 ppm. Activity recovered to control levels by 6 h after exposure. Cytochrome P450 2E1 appears to be the major isoform of cytochrome P450 inhibited by exposure to ethylene, and this may explain in part the observed alteration in EO blood kinetics.     

Uptake of inspired propylene oxide in the upper respiratory tract of the f344 rat.

Propylene oxide (1,2-epoxypropane) is a nasal toxicant and weak site-of-contact carcinogen in the rodent. The current study was aimed at providing quantitative information on upper respiratory tract (URT) dosimetry of this vapor. Since depletion of nasal non-protein sulfhydryls (NPSH) may be important in the toxicity of this vapor and may serve as a biomarker for delivery of propylene oxide to nasal tissues, measurements of respiratory and olfactory NPSH content after propylene oxide exposure were also made. Towards these ends, uptake of this vapor was measured in the surgically isolated URT of the F344 rat at constant velocity inspiratory flow rates of 50 or 200 ml/min throughout a 60-min exposure. Immediately after exposure, nasal respiratory and olfactory tissues were removed and analyzed for NPSH content. Propylene oxide was scrubbed from the airstream with moderate efficiency in the isolated URT. Similar uptake efficiencies were observed at inspired concentrations of 25, 50, 100, and 300 ppm, averaging 25 and 11% at flow rates of 50 and 200 ml/min, respectively. After 1-h exposure to concentrations of 100 ppm or more, statistically significant depletion of nasal respiratory mucosal NPSH was observed. Nasal respiratory mucosal NPSH levels averaged approximately 90, 70, 50, 40, and 15% of control levels after 1-h exposure to 25, 50, 100, 300, or 500 ppm propylene oxide. Olfactory mucosal NPSH levels also generally decreased at 300 or 500 ppm propylene oxide, but did not demonstrate statistically significant, consistent changes after propylene oxide exposure.     

Maternal lead exposure inhibits intestinal calcium absorption in rat pups

Female rats were fed a diet containing 0.5% lead acetate for 5 weeks prior to breeding, during gestation, and through Day 17 of lactation. The effect of this exposure on the maturation of duodenal calcium absorption in 7-to 30-day-old rat pups was temporary. At Days 7 and 16, in vitro calcium uptake into duodenal tissue was low and there was no significant difference between control and exposed pups. Between Days 16 and 24, calcium absorption increased fourfold, which indicates the initiation of an active process for the uptake of calcium. Although calcium absorption increased markedly in both groups, calcium accumulation was significantly reduced in 20-day-old pups maternally exposed to lead. By Day 24, calcium absorption in lead-exposed pups was still decreased, but not significantly. Because only the mothers were fed lead, the exposure to pups ended at weaning. As a result, blood lead concentration in pups dropped to control levels at Day 30 and there was essentially no difference in calcium absorption between the groups.     

The pharmacokinetics of pyridostigmine and 3-hydroxy-N-methylpyridinium in the rat: dose-dependent effects after portal vein administration.

1 The elimination kinectis of [14C]-pyridostigmine iodine and [14-C-methyl]-3-hydroxypyridinium bromide (3-OH NMP) have been studied in the rat. 2 For pyridostigmine, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that pyridostigmine is subject to metabolism during the first passage through the liver. 3 When doses of pyridostigmine 1.25 mumol/kg and higher were injected via the portal vein, the proportion excreted in urine as unchanged drug remained constant; in contrast, the percentage of the dose eliminated as the metabolite was significantly reduced. This indicates that a dose-dependent process is involved in the urinary excretion of 3-OH NMP. 4 This conclusion was supported by studies involving the portal and systemic venous injection of 3-OH NMP at different dose levels. After 4 h, approximately85% of the lowest dose was eliminated unchanged in ug this period. The proportion of the dose eliminated in urine was not related to the route of administration. 5 After the injection of pyridostigmine into the jugular vein, the initial rate of drug excretion fell rapidly for approximately 10 min; in contrast, after injection into the portal vein, the rate of excretion of the drug rose to a maximum at 30 minutes. This suggests that the hepatoportal system behaves as a distinct region during the distribution of this drug.     

The time course of silver accumulation in rainbow trout during static exposure to silver nitrate: physiological regulation or an artifact of the exposure conditions?

The pattern of gill silver accumulation in rainbow trout during waterborne silver exposure has been reported to be unusual, reaching a peak in the first few hours of silver exposure followed by a marked decline with continued exposure. The potential causes of the pattern were investigated. Rainbow trout (1-5g) were exposed in a static system to 110mAg labeled AgNO(3) at a total concentration of 1.92microg Agl(-1) for 24h in synthetic soft water. Periodically throughout the exposure, gill and body 110mAg accumulation, gill and body 24Na uptake (from which whole body Na(+) uptake was calculated), gill Na(+)K(+)-ATPase activity, plus water silver (total and dissolved), Cl(-) and total organic carbon (TOC) concentrations were measured. Gill silver levels rapidly increased, peaked at 3h of exposure and then decreased until a plateau was reached at 12h of exposure. Body (minus gills) silver levels increased steadily over the exposure period until 18h of exposure. Whole body Na(+) uptake decreased, was maximally inhibited by 3h of exposure but recovered by 12h despite continued silver exposure. Gill Na(+)K(+)-ATPase activity was not inhibited until 5h of exposure. The water dissolved silver concentration declined by approximately 70% over the 24h exposure period and the TOC content of the water increased over three-fold during the first 2h of exposure. There was a decrease in the calculated contribution of Ag(+) (from 20.9 to 2.5%) and an increase in the calculated contribution of Ag-TOC complexes (from 77 to 97.3%) to the total water silver concentration over the first 2h of exposure. Apical silver uptake into the gills decreased over the initial 2.5h of exposure while basolateral silver export out of the gills to the body remained constant throughout the exposure. The results of this study suggest that: (1) physiological regulation of silver movement may explain the pattern of gill silver accumulation observed in rainbow trout, although not by a mechanism coupled to Na(+)K(+)-ATPase inhibition as originally proposed; (2) alternatively or additionally, a decreased bioavailability of silver, due to the static exposure conditions, may explain the pattern of gill accumulation; (3) the early inhibition of whole body Na(+) uptake observed during silver exposure occurs via a mechanism other than Na(+)K(+)-ATPase inhibition; and (4) gill silver accumulation may be an appropriate endpoint for biotic ligand modeling.     

Physiological pharmacokinetic modeling of inhaled trichloroethylene in rats

The pharmacokinetics of trichloroethylene (TCE) was characterized during and following inhalation exposures of male Sprague-Dawley rats. The blood and exhaled breath TCE time-course data were used to formulate and assess the accuracy of predictions of a physiologically based pharmacokinetic (PB-PK) model for TCE inhalation. Fifty or 500 ppm of TCE was inhaled by unanesthetized rats of 325-375 g for 2 hr through a miniaturized one-way breathing valve. Repetitive samples of the inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently during and for 3 hr following the exposures and analyzed for TCE by headspace gas chromatography. Respiratory rates and volumes were continuously monitored and used in conjunction with the pharmacokinetic data to delineate uptake and elimination profiles. Levels of TCE in the exhaled breath attained near steady-state soon after the beginning of exposures, and were then directly proportional to the inhaled concentration. Exhaled breath levels of TCE in rats were similar in magnitude to values previously published for TCE inhalation exposures of humans. Levels of TCE in the blood of the 50 ppm-exposed animals also rapidly approached near steady-state, but blood levels in the 500 ppm-exposed animals rose progressively, reaching concentrations 25- to 30-fold higher than in the 50 ppm group during the second hour of exposure. The 10-fold increase in inhaled concentration resulted in an 8.7-fold increase in cumulative uptake, or total absorbed dose. These findings of nonlinearity indicate that metabolic saturation ensued during the 500 ppm exposure. The PB-PK model was characterized as blood flow-limited with TCE eliminated unchanged in the exhaled breath and by saturable liver metabolism. The uptake and elimination profiles were accurately simulated by the PB-PK model for both the 50 and 500 ppm TCE exposure levels. Such a model may be quite useful in risk assessments in predicting internal (i.e., systemically absorbed) doses of TCE and other volatile organics under a variety of exposure scenarios.     

Calcium control of zinc uptake in rainbow trout

Water hardness is known to control the uptake and toxicity of zinc and other metals through either chemical competition, biological acclimation, or both processes. The dominant process controlling zinc uptake has not been previously elucidated, nor has the effect of calcium been investigated independently of other cations. We determined zinc uptake by rainbow trout acclimated and exposed to four calcium treatments: (1) low calcium (6.5 mg Ca/l; 160 μM) acclimation and low calcium exposure (LL); (2) low acclimation and high calcium (131 mg Ca/l; 3300 μM) exposure (LH); (3) high acclimation and low exposure (HL); and (4) high acclimation and high exposure (HH). Trout were exposed to sublethal zinc (100 μg 65Zn/l; 1.5 μM) for 24 h, and whole body and gill 65Zn levels were determined. Zinc uptake was approximately linear during the 24 h exposure period and uptake was calcium dependent. 65Zn uptake by trout was 22 μg/kg per h in the LL treatment and 4.5 μg/kg per h in the HH treatment. 65Zn uptake by trout in the LH and HL treatments was 13 and 10 μg/kg per h, respectively. 65Zn uptake in gills was also significantly reduced by calcium acclimation or exposure. Trout in the LH and HH treatments had five fold lower 65Zn concentrations than LL treatment fish. The results of this study demonstrate that calcium reduces zinc uptake through both biological acclimation and chemical processes, and that the protective effects of calcium are approximately additive.