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Archives of Toxicology (v.72, #8)
Toxicokinetics of soman in cerebrospinal fluid and blood of anaesthetized pigs by Ann Göransson-Nyberg; Sten-Åke Fredriksson; Britt Karlsson; Marlene Lundström; Gudrun Cassel (pp. 459-467).
The toxicokinetics of the four stereoisomers of the nerve agent C(±)P(±)-soman was analysed in cerebrospinal fluid (CSF) and blood in anaesthetized, spontaneously breathing pigs during a 90-min period after injection of soman. The pigs were challenged with different intravenous (i.v.) doses of C(±)P(±)-soman corresponding to 0.75–3.0 LD50 (4.5, 9.0 and 18 μg/kg in a bolus injection and 0.45 μg/kg per min as a slow infusion). Artificial ventilatory assistance was given if, after soman intoxication, the respiratory rate decreased below 19 breaths/min. Blood samples were taken from a femoral artery and CSF samples from an intrathecal catheter. The concentrations of the soman isomers were determined by gas chromatography coupled with high resolution mass spectrometry. All four isomers of soman were detected in both blood and CSF samples. The relatively non-toxic C(±)P(+) isomers disappeared from the blood stream and CSF within the first minute, whereas the levels of the highly toxic C(±)P(−) isomers could be followed for longer, depending on the dose. Concurrently with the soman analyses in blood and CSF, cholinesterase (ChE) activity and cardiopulmonary parameters were measured. C(±)P(−) isomers showed approx. 100% bioavailability in CSF when C(±)P(±)-soman was given i.v. as a bolus injection. In contrast, C(±)P(−) isomers displayed only 30% bioavailability in CSF after slow i.v. infusion of soman. The ChE activity in blood decreased below 20% of baseline in all groups of pigs irrespective of the soman dose. The effect of soman intoxication on the respiratory rate, however, seems to be dose-dependent and the reason for ventilatory failure and death. Artificial ventilation resulted in survival of the pigs for the time-period studied.
Keywords: Key words Cerebrospinal fluid; Cholinesterase; Pigs; Respiration; Soman toxicokinetics
Serum and urinary boron levels in rats after single administration of sodium tetraborate by Kan Usuda; Koichi Kono; Yukio Orita; Tomotaro Dote; Kozo Iguchi; Hiroyuki Nishiura; Mika Tominaga; Teruaki Tagawa; Eita Goto; Yumi Shirai (pp. 468-474).
The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6 ± 7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t 1/2a=0.608±0.432 h; elimination half-life, t 1/2=4.64±1.19 h; volume of distribution, Vd=142.0±30.2 ml/100 g body wt.; total clearance, C tot=0.359 ± 0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (C max) was 2.13 ± 0.270 mg/l, and the time needed to reach this maximum concentration (T max) was 1.76 ± 0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication.
Keywords: Key words One compartment model; Experimental boron exposure; Volume of distribution; Total clearance; Biological half-life
Urinary excretion kinetics of 1-hydroxypyrene following intravenous administration of binary and ternary mixtures of polycyclic aromatic hydrocarbons in rat by Michèle Bouchard; Kannan Krishnan; Claude Viau (pp. 475-482).
The effect of exposure to binary and ternary mixtures of polycyclic aromatic hydrocarbons (PAHs) on the urinary excretion kinetics of 1-hydroxypyrene (1-OHP) has been examined. Male Sprague-Dawley rats were administered intravenously 5 μ mol/kg of pyrene alone or in combination with 0.5, 5 and 25 μ mol/kg of either naphthalene, benzo(a)pyrene (BaP), or both. Urine samples were collected at frequent intervals over 48 h. The kinetics of 1-OHP in urine was not altered by the presence of either naphthalene or BaP in the mixtures, at least from 4 h post-dosing. Hence, none of the injected mixtures significantly modified the first-order apparent elimination half-life of 1-OHP in urine obtained for the 12 to 42 h period post injection where mean values ranged between 6.2 and 9.6 h. However, while the presence of naphthalene or the low BaP dose of 0.5 μ mol/kg in the mixtures did not have a significant effect on the total excretion of 1-OHP, BaP doses of 5 and 25 μ mol/kg in the mixtures significantly increased the amount of 1-OHP excreted in urine. Mean percentages of the pyrene dose excreted as 1-OHP after injection of pyrene in combination with 0.5, 5 and 25 μmol/kg BaP were respectively increased 1.3, 2.2 and 2.6 times compared to the value obtained after administration of pyrene alone. The percentages determined after concomitant administration of pyrene and 0.5, 5 and 25 μ mol/kg of BaP plus naphthalene were 1.4, 1.8 and 2.4 times, respectively, the value obtained after administration of pyrene singly. The observed effect of BaP (5 or 25 μ mol/kg) on 1-OHP total excretion appears to result from BaP induction of pyrene metabolism. Lack of effect of naphthalene appears to be due to its weak P450 1A1 enzyme induction capacity. Absence of significant effect of the low BaP dose in the mixtures (0.5 μ mol/kg) suggests that 1-OHP in urine is useful as a bioindicator of occupational and environmental exposures to PAH mixtures.
Keywords: Key words 1-Hydroxyprene; Urinary excretion kinetics; Chemical mixtures; Polycyclic aromatic hydrocarbons; Pyrene
Toxicokinetics of 1,2,4-trimethylbenzene in humans exposed to vapours of white spirit: comparison with exposure to 1,2,4-trimethylbenzene alone by J. Järnberg; G. Johanson; A. Löf; B. Ståhlbom (pp. 483-491).
This study compares the toxicokinetics of inhaled 1,2,4-trimethylbenzene (124TMB) in men exposed to white spirit with that previously observed in the same individuals exposed to 124TMB alone. The appropriateness of using dimethylhippuric acid (DMHA) metabolites of 124-, 123- and 135TMB in urine as biomarkers of exposure is also addressed and the kinetics of n-decane, n-undecane and 123TMB is investigated. The toxicokinetics of 124TMB was studied in nine male, healthy volunteers exposed to solvent vapours in an exposure chamber for 2 h during a work load of 50 W. The subjects were exposed to 2 ppm (11 mg/m3) of 124TMB during exposure to 300 mg/m3 of white spirit. The 124TMB isomer was analysed in blood, urine and exhaled air by gas chromatography. The DMHA metabolites of all three TMB isomers were analysed in urine by high-performance liquid chromatography. The results were compared with previously published exposures to 2 and 25 ppm (120 mg/m3) of 124TMB vapour alone. In addition, the occurrence of acute effects was studied by means of a questionnaire. Irritation and central nervous system (CNS) symptoms were recorded by ratings on a 100 mm visual analogue scale. Blood levels of 124TMB and excretion rates of 3,4-DMHA in urine were markedly elevated both during and after exposure to white spirit compared to the same exposure level of 124TMB alone. No irritation or CNS effects were reported in the questionnaire at any exposure condition. It appears that components in white spirit interfere with the metabolic elimination of 124TMB. This should be considered in biological exposure monitoring as well as in risk assessment.
Keywords: Keywords Toxicokinetics; trimethylbenzene; n-Decane; n-Undecane-Dimethylhippuric acid
Differential alterations in levels of hepatic microsomal cytochrome P450 isozymes following intracerebroventricular injection of bacterial lipopolysaccharide in rats by Yoshinori Shimamoto; Hiroshi Kitamura; Hidenobu Hoshi; Akio Kazusaka; Yoshinori Funae; Susumu Imaoka; Masayuki Saito; Shoichi Fujita (pp. 492-498).
To investigate the effect of central inflammation due to bacterial infection, such as meningitis, on the activities of hepatic cytochromes P450 (CYPs), rats were injected intracerebroventricularly (i.c.v.) with 0.1 μ g of bacterial lipopolysaccharide (LPS). The LPS i.c.v. injection significantly decreased the total P450 contents (by 30% of the levels of control rats treated with saline i.c.v.), the contents of CYP1A (48%), 2B (54%), 2C11 (37%) and 3A (40%) and related drug metabolizing activities, 7-ethoxycoumarin O-deethylation (36%), imipramine N-demethylation (41%) and erythromycin N-demethylation (33%) in liver microsomes 24 h after the treatment. In contrast, intraperitoneal (i.p.) injection of LPS at the same dose as i.c.v. (0.1 μ g) did not significantly affect the hepatic microsomal contents of total P450 or the content of each individual CYP isozyme and its activity. CYP2D1 protein and the activity of imipramine 2-hydroxylase were not significantly decreased by LPS injection regardless of the route of administration. The inhibitory effects of 0.1 μg i.c.v. LPS on the activities of these CYPs were almost equal to those of 10 μg i.p. LPS, and 0.01 μg of i.c.v. LPS significantly decreased the activity of imipramine N-demethylase only. Therefore, the LPS i.c.v. injection resulted in CYP isozyme-selective inhibition at an ineffective dose when injected i.p.. It is suggested that a central inflammation, such as meningitis, differentially decreases the levels of hepatic CYP isozymes. A possible involvement is discussed of the central nervous system in this down-regulation.
Keywords: Key words Cytochrome P450; Drug metabolism; Intracerebroventricular; Lipopolysaccharide; Meningitis
Biomonitoring of aromatic amines V: acetylation and deacetylation in the metabolic activation of aromatic amines as determined by haemoglobin binding by Iris Zwirner-Baier; Hans-Günter Neumann (pp. 499-504).
Aromatic amines are metabolically activated by N-oxidation of either the amine or the acetamide as a first step and esterification of the resulting N-hydroxyl derivatives as a second step. Both pathways may lead to DNA-adducts and subsequently to DNA lesions and mutations. Since the accumulation of non-acetylated adducts has been associated with tumour initiating properties, the balance between acetylation and deacetylation may greatly influence the biological effect. Hydrolysable haemoglobin adducts representing the bioavailability of N-hydroxylamines and the corresponding nitroso-derivatives were analysed following oral administration to female Wistar rats of two arylamine-acetamide couples: 4-aminobiphenyl and 2-aminofluorene, and two arylamine-acetamide-diacetamide triples: benzidine and 3,3′-dichlorobenzidine. The results show that the mono-acetamides are readily deacetylated in vivo whereas the diacetamides are not. A dynamic equilibrium is indicated to exist between acetylation and deacetylation, which depends on substrate specificity, and the role of deacetylation is emphasised. In addition, acetylation polymorphism was studied with 4-chloroaniline and 3,3′-dichlorobenzidine in slow acetylating A/J and rapid acetylating C57BL/6J mice. The slow acetylator genotype was associated with significantly higher haemoglobin-adduct levels for both arylamines. The results provide additional support for the use of haemoglobin adducts in biomonitoring as a dosimeter for the biologically active dose of arylamines/arylacetamides. Moreover, biomonitoring of haemoglobin adducts may provide information about an individual's susceptibility to the toxic and carcinogenic effects of these chemicals.
Keywords: Key words Biomonitoring; Haemoglobin adducts; Aromatic amines; Acetylation; Deacetylation
Correlation of 32P-postlabelling-detection of DNA adducts in mouse skin in vivo with the polycyclic aromatic compound content and mutagenicity in Salmonella typhimurium of a range of oil products by Ewan D. Booth; Henk C. A. Brandt; Robert W. Loose; William P. Watson (pp. 505-513).
The in vivo genotoxic activities in mouse skin of the dimethyl sulphoxide (DMSO) extracts of a range of oil products [residual aromatic extract; untreated heavy paraffinic distillate aromatic extract; mildly refined light naphthenic base oil; bitumen (vacuum residue); high viscosity index base oil obtained by catalytic hydrogenation] were evaluated by 32P-postlabelling DNA analysis. The results of quantitative 32P-postlabelling analyses of epidermal DNA from mice treated with the DMSO extracts showed linear relationships with the total polycyclic aromatic compound (PAC) contents, determined by the Institute of Petroleum method IP 346 and also the 3–6 ring PAC contents, measured by on-line liquid-liquid extraction using flow injection analysis. The 32P-postlabelling data also showed a linear relationship with the mutagenicity indices of these oil products determined in S. typhimurium TA98 using the modified Ames Salmonella microsome test. The in vivo genotoxicity of the DMSO extracts from the oil products was low, judged by 32P-postlabelling analysis of DNA adducts measured in epidermal DNA of treated mouse skin, and ranging from 2 to 723 attomole/μg DNA per mg oil product. The in vivo 32P-postlabelling data from this study are consistent with these materials expressing low genotoxicity in mouse skin in vivo. The DMSO extraction procedure coupled with 32P-postlabelling DNA analysis is useful for ranking the relative genotoxic potency in vivo of a wide range of oil products. In general the trend observed is similar to rankings based on physicochemical measurements of␣total PAC contents or 3–6 ring PAC contents of the oil products.
Keywords: Key words Oil products; DNA adducts; 32P-Postlabelling; Mutagenicity; Polycyclic aromatic compound (PAC) content
Stereospecificity of the sensory irritation receptor for nonreactive chemicals illustrated by pinene enantiomers by Jukka-Pekka Kasanen; Anna-Liisa Pasanen; Pertti Pasanen; Jyrki Liesivuori; Veli-Matti Kosma; Yves Alarie (pp. 514-523).
To clarify the existence of a receptor protein for sensory irritants in trigeminal nerve endings, d- [i.e. (+)] and l- [i.e. (−)] enantiomers of α- and β-pinene as models of nonreactive chemicals were evaluated for their potency in outbred OF1 and NIH/S mice using ASTM E981-84 bioassay. All pinenes possess sensory irritation properties and also induced sedation and signs of anaesthesia but had no pulmonary irritation effects. According to the ratio of RD50 (i.e. concentration which causes a 50% decrease in respiratory rate, f ) and vapour pressure (Po), all pinenes are nonreactive chemicals. For nonreactive chemicals, P° and olive oil-gas partition (LOil) can be used to estimate their potency as sensory irritant. Thus, for enantiomers with identical physicochemical properties, the estimated RD50 values are the same. In addition, although α- and β-pinene do not have identical Po and LOil values, their estimated potencies are quite close. However, the experimental results showed that d-enantiomers of pinenes were the most potent as sensory irritants and a difference in potency also exists between α- and β-pinene. RD50 for d-enantiomers of α- and β-pinene were almost equal, 1053 ppm and 1279 ppm in OF1 strain and 1107 ppm and 1419 ppm in NIH/S strain, respectively. Values differed by a factor of ∼4 to 5 from l-β-pinene for which the RD50 was 4663 ppm in OF1 and 5811 ppm in NIH/S mice. RD50 could not be determined for l-α-pinene; this pinene was almost inactive. d-α-pinene seems to best fit the receptor because its experimental RD50 was one-half of the estimated value while for d-β-pinene those values were equal. On the contrary, l-β-pinene was about 3 to 4␣times less potent than estimated. l-α-pinene was only slightly active although it was estimated to be as potent as d-α-pinene. The remarkable difference in potency between l-enantiometers is most likely due to a structural difference between α- and β-pinene: the more flexible β-pinene can bend to fit into the receptor better than the rigid α-pinene. The results showed that the commonly used physicochemical descriptors cannot fully explain the potency of these chemicals; their three-dimensional structure should also be considered. Because of the stereospecificity of pinenes, a target site for nonreactive sensory irritants is most likely a receptor protein containing a chiral lipophilic pocket.
Keywords: Key words Sensory irritation; Stereospecificity; Enantiomers; α-Pinene; β-pinene; Chirality
The toxic mechanism and metabolic effects of atractyloside in precision-cut pig kidney and liver slices by David K. Obatomi; Nguyen T. K. Thanh; Stephen Brant; Peter H. Bach (pp. 524-530).
The toxic and cellular metabolic effects of atractyloside, a diterpenoid glycoside, which causes fatal renal and hepatic necrosis in vivo in animals and humans, have been investigated in tissue slices prepared from male domestic pig kidney and liver. Precision-cut slices (200 μm thick) were incubated with atractyloside at concentrations of 200 μM, 500 μ M, 1.0 mM and 2.0 mM for 3 h at 37 °C and changes in lipid profile and pyruvate-stimulated gluconeogenesis investigated. Lipid peroxidative changes, reduced glutathione (GSH) and ATP content, the release of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine and aspartate aminotransferase (ALT/AST) were also assessed. After 3 h of incubation, atractyloside caused a significant (P < 0.01) and concentration-dependent leakage of LDH and ALP from kidney slices. Only LDH leakage was significantly elevated in liver slices while ALT and AST leakage showed marginal increase. Atractyloside at concentrations of ≥200 μ M caused a significant increase in lipid peroxidation, but only in liver slices. However, atractyloside at concentrations of ≥200 μ M caused a marked depletion of GSH and ATP content in both kidney and liver slices. There was a marked decrease in total and individual phospholipid in kidney but not in liver slices. However, cholesterol and triacylglycerol levels were not affected by atractyloside in both kidney and liver slices. Renal and hepatic pyruvate-stimulated gluconeogenesis were significantly (P < 0.05) inhibited at atractyloside concentrations of ≥500 μM. Accumulation of organic anion p-aminohippuric acid (PAH) was also inhibited in renal cortical slices at atractyloside concentrations of ≥500 μM. These results suggest that the observable in vivo effect of atractyloside can be reproduced in slices and that basic mechanistic differences exist in the mode of toxicity in liver and kidney tissues. The data also raise the possibility that the mechanistic basis of metabolic alterations in these tissues following treatment with atractyloside may be relevant to target selective toxicity.
Keywords: Key words Atractyloside; Pig kidney and liver slices; Metabolic alterations; Energy status; Selective toxicity
Glutamine transaminase K intranephron localization in rats determined by urinary excretion after treatment with segment-specific nephrotoxicants by Andrea Trevisan; Patrizia Cristofori; Gianluca Fanelli; Fabio Bicciato; Emanuela Stocco (pp. 531-535).
Glutamine transaminase K(GTK) excretion assessed in urine and by kidney histology was evaluated in rats after single treatment with 1.0 mg/kg i.p. of mercuric chloride, 100 mg/kg i.p. of hexachloro-1:3-butadiene (both S3, pars recta, segment-specific nephrotoxicants) and 25 mg/kg s.c. of potassium dichromate (S1–S2, pars convoluta, segment-specific nephrotoxicant). The aim was to correlate segment-specific injury and enzyme excretion in order to assess, using non-vasive methods, localization of GTK along the proximal tubule. Mercuric chloride and hexachloro-1:3-butadiene produced early focal damage in the pars recta (focal necrosis was shown 10 h after treatment, and diffuse necrosis appeared later at 34 and 24 h after treatment). Changes of the pars convoluta were occasional and delayed (72 h after treatment for both substances). On the contrary, potassium dichromate induced damage of the pars convoluta (vacuolar degeneration and focal necrosis were evident 24 h and 48 h after treatment, respectively), whereas the pars recta was affected later (focal vacuolar degeneration was observed 72 h after treatment). Increase urinary GTK excretion was early after treatment with mercuric chloride and hexachloro-1:3-butadiene (significant increase was observed within 10 h), with a peak for both substances 24␣h after treatment, in agreement with the necrosis of the pars recta. Potassium dichromate induced a significant increase of enzyme excretion in urine also 24 h after injection, according to histological features showing vacuolar degeneration of the pars convoluta; the peak of excretion was reached 48 h after treatment (delay was due, probably, to s.c. administration). The results show that GTK increased in urine after treatment with S3 and S1–S2 specific nephrotoxicants; the combination of histological examination and urinary enzyme supports the evidence that the enzyme is distributed along the whole of the proximal tubule.
Keywords: Key words Glutamine transaminase K; Proximal tubule segments; Hexachloro-1:3-butadiene; Mercuric chloride; Potassium dichromate
Reduction of cisplatin toxicity in cultured renal tubular cells by the bioflavonoid quercetin by Martin K. Kuhlmann; Ernst Horsch; Gunther Burkhardt; Martina Wagner; Hans Köhler (pp. 536-540).
Quercetin (QC), a polyphenolic compound widely distributed in fruits and vegetables has recently gained interest due to its cisplatin (CP) sensitizing properties in cancer cells. It is currently unknown, whether quercetin also increases the susceptibility of the kidneys to cisplatin toxicity. We studied the effects of various bioflavonoids on CP toxicity in an in vitro model of cultured tubular epithelial cells (LLC-PK1). Viability of LLC-PK1 cells, as assessed by lactate dehydrogenase (LDH) release and MTT-test, was affected by CP (100–400 μM) in a time and dose dependent fashion. Pretreatment of cells with QC for 3 h significantly reduced the extent of cell damage. The protective activity of QC was concentration dependent, starting at 10–25 μM and reaching a plateau between 50 and 100 μM. Other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations (100–500 μM). Quercetin itself showed some intrinsic cytotoxicity at concentrations exceeding 75 μM. Our data indicate that quercetin reduces cisplatin toxicity in cultured tubular epithelial cells. The exact mechanism of protection is unclear, though scavenging of free oxygen radicals may play an important role.
Keywords: Key words Flavonoid; Quercetin; Cisplatin; Nephrotoxicity; Cytoprotection
Reduction of thyroid hormone levels by methylsulfonyl metabolites of polychlorinated biphenyl congeners in rats by Yoshihisa Kato; Koichi Haraguchi; Tomoo Shibahara; Yoshito Masuda; Ryohei Kimura (pp. 541-544).
Male Sprague-Dawley rats received four consecutive intraperitoneal doses of four kinds of methylsulfonyl (MeSO2) metabolites of polychlorinated biphenyl (PCB) congeners: 3-MeSO2-2,2′,3′,4′,5,6-hexachlorobiphenyl (3-MeSO2-CB132); 3-MeSO2-2,2′,3′,4′, 5,5′-hexachlorobiphenyl (3-MeSO2-CB141); 3-MeSO2-2,2′,4′,5,5′,6-hexachlorobiphenyl (3-MeSO2-CB149) and 4-MeSO2-2,2′,4′,5,5′,6-hexachlorobiphenyl (4-MeSO2-CB149). The congeners were major MeSO2-PCBs determined in human milk, liver and adipose tissue, and the aim was to determine their effect on thyroid hormone levels. All four tested MeSO2 metabolites (20 μmol/kg once daily for 4 days) reduced serum total thyroxine levels by 22–44% at a much lower dose than phenobarbital (PB; 431 μmol/kg once daily for 4 days) on days 2, 3, 4 and 7 after the final doses. Total triiodothyronine levels were reduced 37% by treatment with 4-MeSO2-CB149 at day 7. A 30% increase in thyroid weight was produced by 3-MeSO2-CB141 treatment. Total cytochrome P450 content was increased by 3-MeSO2-CB132, 3-MeSO2-CB141 and 3-MeSO2-CB149, but not by 4-MeSO2-CB149. Thus, it is likely that the 3-MeSO2-hexachlorobiphenyls and 4-MeSO2-CB149 could influence the thyroid hormone metabolism by different mechanism(s). The results show that tested 3- and 4-MeSO2 metabolites of PCB congeners reduce thyroid hormone levels much more than PB in rats. Our finding suggests that the metabolites may act as endocrine-disrupters.
Keywords: Key words Polychlorinated biphenyl; Methylsulfonyl metabolite; Total thyroxine; Rat