Inhalation kinetics of C6 to C10 aliphatic, aromatic and naphthenic hydrocarbons in rat after repeated exposures.

The toxicokinetic properties of C6 to C10 n-alkanes, aromates and naphthenes have been investigated in rats during inhalation of 100 p.p.m. of the single hydrocarbons for 3 days, 12 hr/day. The concentration of hydrocarbon was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat at days 1, 2 and 3, immediately after termination of exposure and 12 hr after exposure on day 3. The main conclusions drawn from the study were: a) Aromatic hydrocarbons show high concentrations in blood and low concentrations in organs. b) Naphthenic hydrocarbons show low concentrations in blood and high concentrations in organs. c) n-Alkanes show very low concentrations in blood, relatively high concentrations in brain and a high potential for accumulation in fat with repeated exposures. d) Biological concentrations of hydrocarbons within one class increase in general with increasing molecular weight, though with specific exceptions. e) Accumulation is obviously influenced by differences in metabolism and enzyme induction potential. f) Lipid solubility is not the only parameter relevant for the evaluation of hydrocarbon accumulation.     

Accumulation and distribution of aliphatic (n-nonane), aromatic (1,2,4-trimethylbenzene) and naphthenic (1,2,4-trimethylcyclohexane) hydrocarbons in the rat after repeated inhalation

The concentrations of the C9 hydrocarbons n-nonane, 1,2,4-trimethylbenzene and 1,2,4-trimethylcyclohexane were measured in rat blood, brain and perirenal fat after exposures to 1000 p.p.m. of the individual compounds. Measurements were made by head space gas chromatography at the end of 12 hr exposures on days 1, 3, 7, 10 and 14 of the exposure periods. The relative concentrations of hydrocarbons in each organ were, brain: n-nonane "trimethylcyclohexane approximately trimethylbenzene, blood: trimethylbenzene "n-C9 greater than trimethylcyclohexane and perirenal fat: trimethylbenzene greater than n-nonane greater than trimethylcyclohexane, showing the widely different distribution properties of the different hydrocarbons. Brain/blood ratios of 11.4, 2.0 and 11.4, and fat/blood ratios of 113, 63 and 135 were found for n-nonane, trimethylbenzene and trimethylcyclohexane, respectively. A marked decrease in biological concentrations of trimethylbenzene and trimethylcyclohexane during the initial phase of exposure indicate that these hydrocarbons are capable of inducing their own metabolic conversion resulting in lower steady state levels. A special attention was made to n-nonane showing the highest concentration in brain concomitantly with a low blood concentration. This observation demonstrate that biological monitoring of occupational exposure by blood measurements not should be performed without knowledge of the distribution properties of the compounds investigated.     

Distribution of Dearomatised White Spirit in Brain,Blood, and Fat Tissue after Repeated Exposure of Rats

Abstract: Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg/l), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks'exposure. After 3 weeks of exposure the concentration of total white spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure. Two hours after the end of exposure the n-decane concentration decreased to about 25% in blood and 50% in brain. A similar pattern of elimination was also observed for n-nonane, n-undecane and total white spirit in blood and brain. In fat tissue the concentrations of n-nonane, n-decane, n-undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady-state concentrations is longer than 3 weeks. After the 3 weeks'exposure the fat tissue concentration of n-nonane, n-decane, n-undecane, and total white spirit decreased very slowly compared with the rate of decrease in blood and brain suggesting that long-lasting redistribution from fat to brain may occur. One week of exposure at 800 p.p.m. caused a statistically significant increase in whole brain dopamine concentration while the noradrenaline concentration was unaffected. Exposure at both exposure levels for 1 week caused a statistically significantly decreased concentration of 5-hydroxytryptamine in whole brain. The reduction was related to the exposure concentration. These changes in neurotransmitter concentrations were normalised after 2 and 3 weeks'exposure. In conclusion, after 3 weeks of exposure the fat:brain:blood concentration coefficients for total white spirit were approximately 250:3:1, and redistribution from fat to brain is possible. As total white spirit behaved similarly to the n-alkanes in blood, brain, and fat tissue, we suggest that the non-n-alkane white spirit components possess toxicokinetic properties similar to the n-alkanes.     

Distribution of dearomatised white spirit in brain, blood, and fat tissue after repeated exposure of rats.

Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg/1), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks' exposure. After 3 weeks of exposure the concentration of total white spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure. Two hours after the end of exposure the n-decane concentration decreased to about 25% in blood and 50% in brain. A similar pattern of elimination was also observed for n-nonane, n-undecane and total white spirit in blood and brain. In fat tissue the concentrations of n-nonane, n-decane, n-undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady-state concentrations is longer than 3 weeks. After the 3 weeks' exposure the fat tissue concentration of n-nonane, n-decane, n-undecane, and total white spirit decreased very slowly compared with the rate of decrease in blood and brain suggesting that long-lasting redistribution from fat to brain may occur. One week of exposure at 800 p.p.m. caused a statistically significant increase in whole brain dopamine concentration while the noradrenaline concentration was unaffected. Exposure at both exposure levels for 1 week caused a statistically significantly decreased concentration of 5-hydroxytryptamine in whole brain. The reduction was related to the exposure concentration. These changes in neurotransmitter concentrations were normalised after 2 and 3 weeks' exposure. In conclusion, after 3 weeks of exposure the fat:brain:blood concentration coefficients for total white spirit were approximately 250:3:1, and redistribution from fat to brain is possible. As total white spirit behaved similarly to the n-alkanes in blood, brain, and fat tissue, we suggest that the non-n-alkane white spirit components possess toxicokinetic properties similar to the n-alkanes.     

Biochemical and toxicological effects of combined exposure to 1,1,1-trichloroethane and trichloroethylene on rat liver and brain

1. Inhalation exposure of adult male rats to a mixture of 1,1,1-trichloroethane (500 p.p.m.) and trichloroethylene (200 p.p.m.) for four days 6 h daily resulted in an accumulation of 1,1,1-trichloroethane in perirenal fat. Further exposure on the fifth day caused a rapid increase in various organ contents of both solvents with secondary depression of brain RNA. 2. The four-day exposure doubled the RNA content of liver and caused a slight decline in the concentrations of glutathione in liver. 3. The amount of cytochrome P-450 in liver was increased, as well as the overall mono-oxygenase activity, measured with styrene as substrate. During continuing treatment on the fifth day, styrene mono-oxygenase activity decreased, the activity after 6 h being only about 50% of that at the beginning of the fifth day of exposure. 4. UDP-glucuronosyl transferase activity (measured in digitonin-activated microsomes) was doubled by the four-day combined exposure to 1,1,1-trichloroethane and trichloroethylene. 5. The changes during the fifth day of exposure, e.g. rapid increase in the concentrations of solvents in organs, the detection of trichloroethylene in tissues and depression of mono-oxygenase activity, obviously also occurred during the exposures on days 1 to 4 and reverted during each post-exposure period.     

The Effect of an Unusual Workshift on Chemical Toxicity: II. Studies on the Exposure of Rats to Aniline

The Effect of an Unusual Workshift on Chemical Toxicity. II.Studies on the Exposure of Rats to Aniline. KIM, Y. C, ANDCARLSON,G. P. (1986). Fundam. Appl. Toxicol. 7,144-152. Increasing numbersof workers in industry are working a novel or unusual 12-hrworkshift in which the exposure time is longer and the recoveryperiod is shorter than for a standard 8-hr workshift. Experimentswere conducted to examine the effects of altering the exposureschedule of rats from 8 hr/day for 5 days to 12 hr/day for 4days on the toxicity resulting from the inhalation of anilineat 10, 30, 50, and 150 ppm. When compared to the first day,methemoglobin (MetHb) levels, measured prior to and followingthe exposure, increased with the days of exposure at 50 ppmaniline. At 150 ppm aniline, the MetHb level determined priorto exposure to aniline increased with the days of exposure whereasthe postexposure MetHb levels appeared to plateau after thesecond exposure. The MetHb levels determined prior to exposurewere significantly different between the two groups at 50 or150 ppm aniline whereas the postexposure MetHb levels were not.A residual MetHb level higher than the nonexposed control wasobserved in the 12 hr/day exposure group after a 3-day recoveryperiod. There was an aniline concentration-dependent decreasein the hematocrit level when determined 1 week after the exposurestarted. Following a single exposure for 8 or 12 hr to 100 ppmaniline there was no difference in the maximum MetHb level,the peak aniline level in blood and fat, or the rate of anilineelimination from fat and blood. Repeated exposures to 100 ppmfor 3 days did not produce a significant difference in anilinelevel in blood or fat between the 8 and 12 hr/day exposure groupsimmediately following the last exposure. However, the anilinelevel in blood was significantly higher in the 12 hr/day exposuregroup when determined on the morning following the last exposure.These results suggest that the residual burden resulting fromprevious exposures should be considered when the exposure limitsare modified for longer workshifts in man.     

The early embryo loss caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin may be related to the accumulation of this compound in the uterus

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a reproductive and developmental toxicant that can alter endocrine status, leading to decreased fertility and altered embryonic development; however, there are limited reports on TCDD toxicity during early pregnancy. In the present study, pregnant and pseudopregnant NIH mice were exposed to TCDD orally (2, 50 and 100 ng/kg body weight) during early gestation (days 1-8), pre-implantation stages (days 1-3), and peri-implantation to early post-implantation stages (days 4-8). TCDD concentration in uterus, liver, kidney, brain and fat on day 9 of pregnancy was monitored by an aryl hydrocarbon receptor (Ah receptor, AhR)-mediated LacZ reporter system in yeast. Results showed that the number of implanted embryos was significantly reduced on day 9 of gestation by 50 and 100 ng/kg TCDD exposure. The number of implantation sites was lower for animals exposed to TCDD on days 1-3 versus those exposed during days 4-8. Decidualization in pseudopregnant mice was also inhibited by TCDD exposure. TCDD concentrations as low as 2 ng/kg significantly decreased serum progesterone levels but had no effect on serum estradiol. TCDD level in the uterus was equal to levels in the liver, but lower than the fat tissue. These results suggest that TCDD sensitivity might be attributed its local accumulation in the uterus.     

Further evaluation of the kinetics of white spirit in human volunteers

This paper gives supplementary informations on the kinetics of aliphatic white spirit in humans. Eight volunteers were exposed to 600 mg/m3 (100 p.p.m.) white spirit during 3 hrs. Calculated pulmonary uptake (dose) was 392 +/- 38 mg, residence time 47.5 hrs, volume of distribution 749 1, and total body clearance 263 ml/min. Then 7 volunteers were exposed to 600 mg/m3 white spirit 6 hrs daily in 5 consecutive days. Calculated pulmonary uptake was 3464 +/- 329 mg. A mathematic model is presented which uses the blood concentrations to calculate the tissue concentrations during repeated doses administered over an extended period. By means of this model and the measured concentrations in blood and fat, the partition coefficient fat: blood for white spirit was calculated to 47. Estimated redistribution phase of white spirit in adipose tissue was approximately 20 hrs for the first 5 exposures, and half-life in adipose tissue after redistribution 46-48 hrs. During exposure to 600 mg/m3 white spirit 6 hrs daily, 5 days a week, calculated maximum steady state concentrations were 55 mg/kg fat and 5 mg/kg brain, minimum steady state concentrations 35 mg/kg fat and 0.6 mg/kg brain. These values for half-life and steady-state concentrations are considered more correct than our previously reported values, which did not take into account the existence of a redistribution phase.     

Time-dependent tissue/organ uptake and distribution of 203Hg in mice exposed to multiple sublethal doses of methyl mercury.

Swiss-Webster mice were injected intraperitoneally with one to ten doses (2.5 mg Hg/kg) of ²⁰³Hg-labeled methyl mercury. Doses were administered at 72-hr intervals. Maximal tissue/organ Hg uptake usually occurred 72 hr postinjection and was monitored at 3 and 6 days by gamma scintillation spectrometry. Most tissues/organs required five to six doses to attain maximal Hg concentrations (the carcass required seven doses; hair and fat, eight doses; lens, nine doses). Data for hair were highly variable. Except for hair (which required seven to eight doses), maximal tissue/organ concentration factors (CF) were reached 72 hr after the first dose. Kidney, liver, and hair attained CF values > 1. Except for hair, all CF values decreased with increasing dose number. Initial rates of decrease were much greater for kidney, blood, spleen, muscle, and liver than lens, brain, and fat. Only hair exhibited a significantly higher Hg concentration at 6 days after each dose than at 3 days. With increasing dose number, blood Hg; tissue/organ Hg ratios remained relatively constant for liver, kidney, spleen, and muscle; decreased for lens and brain; and decreased for hair and fat after an initial increase.     

Distribution of lithium and its effects on electrolyte and norepinephrine metabolism in discrete areas of the rat brain]

Lithium carbonate (Li2CO3) or lithium chloride (LiCl) was administered to rats, and distribution in discrete areas of the brain as well as the effects on electrolytes in the urine, blood and whole brain were investigated. Further, the effects of Li with or without methamphetamine on electrolytes and norepinephrine (NE) metabolism in discrete areas of rat brain were examined. After a single administration of Li2CO3 (2.7 mEq/kg p.o.), the Li concentration in all regions of the brain except the hypothalamus reached the maximum level at 12 hr and decreased gradually. A relatively high concentration was observed in the hypothalamus, a short time after the administration. After repeated administration of Li2Co3 (2.7 mEq/kg/day for 5 or days p.o.), the Li concentration did not increase in any region of the brain in comparison with after a single administration and there were no marked changes in the balance of electrolytes in the plasma and brain despite significant changes in the urinary electrolytes and urine volume. Acute administration of LiCl (2.4 mEq/kg and 1.2 mEq/kgx2 for 2 hr i.p.) did not affect the levels of NE and its metabolites in any region of the brain. Subacute administration of LiCl (2.5mEq/kg X 2/day for 4.5 days i.p.) concomitant with methamphetamine increased the deaminated metabolites of NE in the hypothalamus and hippocampus, whereas no influence was observed on the concentrations of sodium and potassium in any region of the brain. From these results, it is suggested that the hypothalamus is one area where Li exerts its action.     

Regulation of ATP-sensitive K+ channels by chronic glyburide and pinacidil administration.

Treatment of rats with the K(ATP)+ channel antagonist sulfonylurea, glyburide (3 mg/kg/day, i.p., every 12 hr for 9 days), increased the Bmax value of [3H]glyburide binding to heart and whole brain total membranes by 30 and 24%, respectively. The ligand affinity was unaltered. Treatment with the K+ channel activator, pinacidil (20 mg/kg/day, i.p., every 12 hr for 9 days), did not alter the Bmax value for cardiac [3H]glyburide binding sites, but decreased the Bmax value in the brain by 21%. Chronic administration of hydralazine, which caused an acute reduction in systolic blood pressure equivalent to that of pinacidil, did not alter [3H]glyburide binding in either heart or brain. Treatment with glyburide, pinacidil or hydralazine did not alter L-type calcium channels, assessed by [3H]PN 200 110 binding, in cardiac and brain membranes or small size Ca(2+)-activated K+ channels in brain assessed by [125I]apamin binding. These studies show that the ATP-sensitive class of K+ channels can be regulated following chronic drug treatment in similar fashion to other receptor and channel systems.     

Hematopoietic effects in mice exposed to arsine gas

Arsine gas is a potent hemolytic agent. Concern about semiconductor workers prompted an in-depth study of arsine at the National Institute of Environmental Health Sciences to determine the hematopoietic effects of prolonged exposure to this gas. Female B6C3F1 mice were exposed by inhalation to 0, 0.5, 2.5, and 5 ppm arsine, 6 hr/day for 14 days. Body weights of exposed mice were comparable to those of controls, but a marked, concentration-related splenomegaly was observed. Higher level arsine exposure produced statistically significant decreases in red blood cells, hematocrit and hemoglobin, with increases in white blood cell counts and mean corpuscular volume of red blood cells. Erythropoiesis as measured by quantitation of erythroid precursors in culture revealed a marrow reduction of colony-forming unit erythroids/femur cells for all treated groups on Day 3 postexposure and only at the 5 ppm dose group on 24 days postexposure, while splenic erythropoiesis increased at higher concentrations of arsine. There was no alteration in bone marrow cellularity and a less significant effect on granulocyte-macrophage progenitors. A 12-week study of arsine at 0, 0.025, 0.5, and 2.5 ppm (6 hr/day) by inhalation showed similar effects on hematopoiesis in mice. In conclusion, arsine exposure at low concentrations produces a stress on the hematopoietic system characterized by hemolysis, which persists for a prolonged period following exposure.     

Distribution and metabolism in vivo of 14C-tetrahydrocannabinol in the rat

¹⁴C-Tetrahydrocannabinol (THC) was injected i.v. into a total of 92 adult Wistar rats. At 14 times ranging from 2 min to 48 hr afterwards, groups of animals were examined for total ¹⁴C activity and thin-layer chromatographic (TLC) pattern of ¹⁴C distribution in blood, brain, heart, kidney, liver, lung, muscle, spleen and perirenal fat. The time course of rise and fall of radioactivity in the various organs and tissues closely resembled that of thiopental and other strongly lipophilic substances. Relatively high levels persisted in fat 48 hr, but levels in brain were quite low. TLC analysis showed the early appearance of 7-hydroxy-THC in all tissues, followed by increasing amounts of more polar compounds and disappearance of THC, except in fat. Levels were much lower after i.p. injection, and whole body autoradiography showed most of the activity remaining in the peritoneal cavity.     

Studies on the effects of N,N′-dimethylformamide on ethanol disposition and on monoamine oxidase activity in rats

Pretreatment of male rats with N,N′-dimethylformamide (DMF) by oral or inhalation routes prior to ethanol administration caused marked alterations in blood ethanol and/or acetaldehyde concentrations, depending upon the DMF dose given and on the DMF-ethanol time interval. Rats were given single oral doses of DMF (2 or 20 mmol/kg or disulfiram (2 mmol/kg) and challenged with ethanol (2 g/kg po) 18 hr later. Disulfiram or DMF at equimolar doses produced peak elevations in blood acetaldehyde concentrations which were about five- and fourfold higher, respectively, than those of controls. In contrast, the 20-mmol/kg did not enhance acetaldehyde blood concentrations but resulted in approximately a twofold elevation in the peak blood ethanol concentration. Monoamine oxidase activity in brain or liver was not affected by DMF. No increases in acetaldehyde concentrations occurred when the time interval between DMF and ethanol was reduced to 3 hr. Rats were exposed to DMF by inhalation at 1000 or 6000 ppm for 3 days (4 hr/day) and given ethanol 1 hr after the last exposure. Blood acetaldehyde was increased by 46% in rats exposed to 1000 ppm of DMF when measured 30 min after ethanol. DMF exposure at 6000 ppm decreased blood acetaldehyde concentrations to 50% of control values, but increased blood ethanol concentrations by 55%. When ethanol was given 24 hr after the last DMF exposure period, marked elevations in peak blood acetaldehyde concentrations occurred at both exposure concentrations of DMF. Single oral pretreatment of rats with 2- or 20-mmol/kg doses of N-methylformamide (MF), a metabolite of DMF, 18 hr prior to ethanol also enhanced blood acetaldehyde concentrations. A similar result was obtained when rats were given 2 mmol/kg of MF only 3 hr before ethanol.     

Fluoride distribution in rats during and after continuous infusion of Na18F

Rats were given Na¹⁸F as a radiotracer for fluoride ion at varying chemical dose rates by continuous iv infusion for 3 hr. Blood fluoride was assessed six to seven times over the infusion period, at the end of which the animals were sacrificed for determination of tissue fluoride distribution. Data indicate that at sublethal dose rates blood fluoride concentration approaches a steady state proportional to the rate of fluoride infusion. Blood, kidney, and lung contained the highest fluoride concentration at doses up to 3.6 mg of F/kg/hr, but at 6 mg/kg/hr the fluoride of liver, spleen, and hollow organs increased sharply indicating this dose exceeded the amount readily processed by the fluoride excretory mechanisms of the body. Another group of animals was infused for 3 hr with 6 mg of F/kg/hr, a dose which approaches the acute LD50. Tissue fluoride distribution was determined at various intervals during both fluoride accumulation and depletion phases. During infusion the fluoride concentration of blood and other tissues was high, with highest accumulation in bone. Of soft tissues, lung contained the greatest amount of fluoride, and brain, testes, and fat pads the least. During the depletion phase, tissue fluoride concentrations decreased sharply, while bone fluoride remained constant and substantial amounts remained in lung.     

Disposition of levo-[3H]Cocaine in pregnant and nonpregnant mice

levo-[³H]Cocaine (10 mg/kg free base) was injected ip to pregnant and nonpregnant mice. Concentrations of cocaine were examined at 15 min and 1,3, and 6 hr. In all tissues, peak concentrations were attained at 15 min. In pregnant mice, the concentrations in decreasing order were: uterus, placenta, spleen, kidney, fat, liver, lung, brain, spinal cord, heart, muscle, eye, and plasma; the 15-min tissue/plasma concentration ratio for the brain was 12.4 and varied from 3 to 68 for other tissues. Fetal brain and liver, in comparison with maternal organs, accumulated much smaller amounts. In several maternal organs, cocaine declined to low concentrations at 3 hr and to negligible levels at 6 hr. The 15-min tissue concentrations in nonpregnant compared to pregnant females were significantly lower in several organs; differences were less marked at 1 and 3 hr. During the first hour, excretion of total radioactivity was higher in the urine of nonpregnant than pregnant females. Cocaine was extensively metabolized since unchanged cocaine levels as percentage of total urinary radioactivity at 1 hr were 7.8 (pregnant) and 1.5 (nonpregnant). SKF 525-A (50 mg/kg ip; 1 hr prior to cocaine) caused marked tissue elevation of unchanged cocaine at 15 min in nonpregnant and at 15 min and 3 hr in pregnant animals. These data suggest that pregnancy alters pharmacokinetics of cocaine.     

Effects of prolonged copper exposure in the marine gulf toadfish (Opsanus beta) II: copper accumulation, drinking rate and Na+/K+ -ATPase activity in osmoregulatory tissues

Gulf toadfish were exposed to sublethal levels of copper (12.8 or 55.2 microM) for 30 days. Drinking in control fish averaged 1 ml kg(-1)h(-1) but exposure to 55.2 microM copper resulted in a complex biophasic pattern with initial (3 h and 1 day) inhibition of drinking rate, followed by an elevation of drinking rate from day 3 onwards. Drinking led to copper accumulation in the intestinal fluids at levels three to five times higher than the ambient copper concentrations, which in turn resulted in intestinal copper accumulation. The gill exhibited more rapid accumulation of copper than the intestine and contributed to early copper uptake leading to accumulation in internal organs. Muscle, spleen and plasma exhibited little if any disturbance of copper homeostasis while renal copper accumulation was evident at both ambient copper concentrations. The liver exhibited the highest copper concentrations and the greatest copper accumulation of all examined internal organs during exposure to 55.2 microM. Elevated biliary copper excretion was evident from measurements of gall bladder bile copper concentrations and appeared to protect partially against internal accumulation in fish exposed to 12.8 microM copper. No inhibition of Na+/K+ -ATPase activity in either gills or intestine was seen despite copper accumulation in these organs. Calculations of inorganic copper speciation suggest that Cu(CO3)(2)2- complexes which dominate in seawater and intestinal fluids are of limited availability for uptake while the low levels of ionic Cu2+, CuOH+ and CuCO3 may be the forms taken up by the gill and the intestinal epithelium.     

Early changes to oxidative stress levels following exposure to formaldehyde in ICR mice

Formaldehyde (FA) is a commonly used chemical in everyday life and can react with many molecules in the human body. Although toxicity has been reported, exposure to FA has also been shown to have beneficial effects or no effect at all. In the present study, we examined the effect of FA inhalation on oxidative stress and inflammation in mice. Male adult ICR mice were exposed FA in gaseous form (0.1 ppm), and blood, urine, brain, lung and liver were obtained for 24 hr. Levels of 8-hydroxy-2'-deoxyguanosine (8OHdG) and NO(3)(-) were then determined by HPLC. A second group of mice were injected with 5 mg/kg lipopolysaccharide (LPS) after 24 hr of FA (3 ppm) inhalation and blood and organs were assayed for NO(3)(-) level and SOD activity. After exposure to a low dose of FA (0.1 ppm), the 8OHdG/dG ratio significantly increased in plasma. However, the ratio in urine and organs significantly decreased during 24 hr of FA exposure. The NO(3)(-) levels mirrored the 8OHdG/dG ratio. After 24 hr exposure to a high dose of FA (3 ppm), NO(3)(-) levels in plasma and liver were significantly lower than in control mice exposed to air only. The SOD activity of blood and urine were conversely increased in FA exposed animals. In the present study, we suggest that inhalation of FA at low doses influences the oxidative stress response in a tissue-specific manner. The FA may partially alleviate in some tissues like preconditioning in oxidative stress.     

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.     

Inhalation studies on the biotransformation and elimination of [C]trichlorofluoromethane and [C]dichlorodifluoromethane in Beagles

The possible biotransformation of trichlorofluoromethane (FC-11) and dichlorodifluoromethane (FC-12) was investigated in 4 male and 2 female adult Beagles after a short (6- to 20-min) inhalation. Dogs were anesthetized with ketamine and succinylcholine, intubated, and ventilated artificially. Trichlorofluoromethane (1000–5000 ppm, v/v) or dichlorodifluoromethane 38000–12,000 ppm, v/v) containing up to 180μ Ci of [¹⁴C]fluorocarbon was delivered from 110-liter Teflon bags, and all exhalations were collected via a nonrebreathing valve in similar bags for 1 hr. Venous blood samples were withdrawn at appropriate times and assayed for fluorocarbon-associated radioactivity. Exhalation bags were assayed for [¹⁴C]fluorocarbon and ¹⁴CO₂. Urine was collected for up to 3 days and assayed for ¹⁴C metabolites as nonvolatile radioactivity. In some experiments animals were sacrificed 24 hr after exposure and tissues were removed for determination of nonvolatile radioactivity. Essentially all of the administered (inhaled) fluorocarbon was recovered in the exhaled air within 1 hr. Only traces of radioactivity were found in urine or exhaled carbon dioxide. All tissues contained measurable concentrations of nonvolatile radioactivity 24 hr after exposure but together represented less than 1% of the administered dose. It is not possible to determine if these trace levels are associated with metabolites of the fluorocarbons or with the unavoidable radiolabeled impurities present in the administered gas mixture. Neither phenobarbital pretreatment (60 mg/day for 3 days) nor prolonged exposure (50–90 min) produced any alteration of these results. Thus, it can be concluded that FC-11 and FC-12 are relatively refractory to biotransformation after a short inhalation exposure and that they are rapidly exhaled in their unaltered chemical form.