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Archives of Toxicology (v.70, #9)

Exploration of an interaction threshold for the joint toxicity of trichloroethylene and 1,1-dichloroethylene: utilization of a PBPK model by Hisham A. El-Masri; John D. Tessari; Raymond S. H. Yang (pp. 527-539).

Physiologically based pharmacokinetic (PBPK) modeling and gas uptake experiments were utilized to verify the competitive inhibition mechanism of interaction between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE) and to investigate the presence of an interaction threshold between the two chemicals. Initially, gas uptake experiments were conducted on Fischer 344 rats where the initial concentrations of both DCE and TCE were 2000∶0, 0∶2000, 2000∶2000, 1000∶0, 1000∶1000, and 500∶500 ppm, respectively. When the different modes of inhibition interactions (competitive, uncompetitive and noncompetitive) were employed in the PBPK model, the model description of the competitive inhibition interaction provided the best description of the declining concentrations in the gas uptake chamber. Furthermore, to predict the range at which the interaction threshold would be found, the PBPK model included a mathematical description of the percentage of enzyme sites occupied by either chemical in the presence or the absence of the other. By comparing the percentage of occupied sites by one chemical, in the presence of the other, to those sites occupied in the absence of the latter, the PBPK model predicted a range of concentrations (100 ppm or less) of either chemical where the competitive inhibition interaction would not be observed. Consequently, gas uptake experiments were designed where the initial concentration was selected at 2000 ppm for one chemical while the other chemical was set at 100 in one experiment and 50 ppm in another. Under these conditions, the best simulation to the concentration depletion curves in the gas uptake system of the chemical in the higher concentration was obtained when the PBPK model was run under the assumption of no-interaction. This substantiated the model predictions of the presence of observable interaction only at concentrations higher than 100 ppm.

Keywords: Chlorinated hydrocarbons; Trichloroethylene; 1,1-Dichloroethylene; Pharmacokinetic; Models

Biochemical and morphological characterization of carbon tetrachloride-induced lung fibrosis in rats by Paavo Pääkkö; Sisko Anttila; Raija Sormunen; Leena Ala-Kokko; Raija Peura; Victor J. Ferrans; Lasse Ryhänen (pp. 540-552).

The short-term and long-term lung CCl₄ injuries in rats were studied by i.p. CCl₄ for 2 or 5 weeks, respectively, and the lung injury in the third progression group receiving i.p. CCl₄ for 2 weeks followed by 3 weeks without. Acute haemorrhagic interstitial pneumonia resulted from short-term injury; chronic interstitial pneumonia from long term injury, and residua of injury or advanced chronic interstitial pneumonia in the progression group. All groups also exhibited features for diffuse alveolar damage. Connective tissue stains revealed both interstitial and intra-alveolar fibrosis in short-term injury. Hydroxyproline content and the activities of prolyl hydroxylase and galactosyl-hydroxylysyl glucosultransferase were elevated. This suggests an early onset of pulmonary fibrosis. Immunohistochemistry revealed the interstitial accumulation of BM proteins. In contrast, increased type III pN-collagen could also be found in the intra-alveolar spaces. The degrees of both interstitial and intra-alveolar fibrosis, BM proteins and type III pN-collagen, and also hydroxyproline content were greater in long-term injury, while the progression group showed on average fewer fibrotic changes than did the long-term injury group, but more than the shortterm injury pointing to persistence or progression of the changes. Additionally, intra-alveolar crystallized haemoglobin was found following short-term injury. We conclude that CCl₄-induced lung injury is an useful experimental model to study pulmonary fibrosis. The mechanism of CCl₄ lung injury is not known but free radical-mediated lipid peroxidation is suggested.

Keywords: Carbon tetrachloride; Lung injury; Collagens; Crystals

Distribution and induction of aflatoxin B₁-9a-hydroxylase activity in rat liver parenchymal and non-parenchymal cells by M. Gemechu-Hatewu; K. -L. Platt; F. Oesch; P. Steinberg (pp. 553-558).

Chronic administration of aflatoxin B₁ (AFB₁) to rats gives rise to hepatocellular and cholangiocellular carcinomas without affecting Kupffer and endothelial cells. The enzymatic conversion of AFB₁ to AFB₁-8,9-epoxide is the critical step in the activation of the mycotoxin, while the conversion of AFB₁ to aflatoxin M₁ (AFM₁), catalyzed by the AFB₁-9a-hydroxylase, is considered to be a detoxication route for the toxin. In the present study the distribution and inducibility of AFB₁-9a-hydroxylase were analyzed in microsomes derived from freshly isolated liver parenchymal (PC) and nonparenchymal cells (i.e. Kupffer +endothelial cells, NPC). AFB₁-9a-hydroxylase activity was clearly measurable in NPC and similar to that of PC. In NPC the rate of formation of AFM₁ was higher (when incubating with 16 μM AFB₁) than or similar (with 128 μM AFB₁) to that of AFB₁-8,9-epoxide, while in PC it was significantly lower. Taken together, these results suggest that the AFB₁-9a-hydroxylase activity might be particularly important in NPC to protect these cells from AFB₁ by converting it to a significantly less mutagenic metabolite and by reducing the amount of AFB₁ available for epoxidation. Furthermore, it is shown that AFB₁-9a-hydroxylase activity is inducible by phenobarbital (only in PC), 3-methylcholanthrene, isosafrole and Aroclor 1254, thus indicating that in rat liver the conversion of AFB₁ to AFM₁ is catalyzed by members of the cytochrome 1A and 2B families.

Keywords: Aflatoxin B₁ ; Aflatoxin B₁-9a-hydroxylase; liver; Nonparenchymal cells; Parenchymal cells

Purification and characterization of a new glutathioneS-transferase, class δ, from human erythrocytes by Klaus R. Schröder; Ernst Hallier; David J. Meyer; Frederike A. Wiebel; Andreas M. F. Müller; Hermann M. Bolt (pp. 559-566).

A new polymorphic form of glutathioneS-transferase (GST), metabolising monohalogenated methanes, ethylene oxide and dichloromethane, has been purified from human erythrocytes and characterized. Several characteristics, such as similar elution patterns on different chromatographic matrices, K_M-values and activity towards antibodies, confirm a previous assumption that this novel GST is a class δ enzyme. Although the presence or absence of the enzyme activity in human red blood cells is parallel with the polymorphism of the human GST T1 gene, the new GST δ in red blood cells may differ from the known GST T1-1 enzyme from other tissues in terms of substrate specificity, since established GST T1-1 substrates [1,2-epoxy-3-(p-nitro-phenoxy)propane andp-nitrobenzyl chloride] are not metabolized. The substrate specifity of the new enzyme in erythrocytes resembles more closely that of GST T2-2, most likely due to a commonN-terminal modification which modifies substrate binding. The new polymorphic GST-isoform in human red blood cells therefore may be considered to represent anN-terminally modified isoform of GST T1-1.

Keywords: GlutathioneS-transferase; Erythrocytes; Human

An attempt to define a just detectable effect for airborne chemicals on the respiratory tract in mice by Lee Ann Boylstein; Jier Luo; Maryanne F. Stock; Yves Alarie (pp. 567-578).

We have attempted to define a just detectable effect (JDE) for three different types of reactions along the respiratory tract: (a) sensory irritation of the upper airways (S), (b) airflow limitation along the conducting airways (A), and (c) pulmonary irritation at the alveolar level (P1 or P). Each type of reaction, S, A, P1 or P, was recognized by analyzing the breathing pattern of unanesthetized mice held in body plethysmographs. A rule-based computer program analyzed each breath during a period of 3.75 h and classified each breath as normal (N) or falling in any of the above categories (i.e., S, A, P1 or P). Eight groups of four mice were used for sham exposures: exposed to water vapor. These data sets were used, as sham exposure data, to define the variation which can occur with time in order to define an expected range of normal variation. Once this range was established, we defined JDE values for each type of effect and used such values to evaluate the results obtained in exposed animals. Eight groups of four mice were exposed to a mixture of airborne chemicals, machining fluid G (MFG), at concentrations from 0.17 to 55 mg/m³. Data sets for individual animals and for each group of animals exposed to MFG were analyzed to determine if and when a particular effect occurred. It was possible to recognize the effects of low exposure concentrations on groups of exposed animals or individual animals within each group. This procedure will be valuable when investigating the effect of airborne chemicals and when it is impossible to generate high exposure concentrations to define concentration-response relationships.

Keywords: Sensory irritation; Pulmonary irritation; Airflow limitation; Machining fluids; Metal working fluids; Toxicity of mixtures

Determination of urinary 2-mercaptobenzothiazole (2-MBT), the main metabolite of 2-(thiocyanomethylthio)benzothiazole (TCMTB) in humans and rats by Alli Manninen; Seppo Auriola; Matti Vartiainen; Jyrki Liesivuori; Taina Turunen; Markku Pasanen (pp. 579-584).

A method for biological monitoring of urinary 2-(thiocyanomethylthio)benzothiazole (TCMTB), a wood preservative and an industrial chemical, was developed. Three different doses of TCMTB in olive oil were given to male rats by gavage for 3 weeks. Urine was collected daily and the metabolites were analysed as thioethers by derivatization with pentafluorobenzylbromide by gas chromatography-mass spectrometry. The parent chemical was not detected in urine samples, but two metabolites of TCMTB were identified. 2-Mercaptobenzothiazole (2-MBT) was the main metabolite, and its excretion varied according to the dose. The second metabolite was 2-(mercaptomethylthio)benzothiazole. The amount of 2-MBT excreted in rat urine was 66±12% (SD), 51±20% and 44±9% for TCMTB doses of 15, 75 and 150 mg/kg, respectively. Two doses, 75 and 150 mg/kg, caused diuresis in rats during the 1 week of dosing. During the 3-week TCMTB treatment, rat liver microsomal CYP enzyme profile was not significantly changed. Urine samples of sawmill workers exposed to TCMTB were collected after their work shifts for exposure assessment. TCMTB could not be detected in the urine samples of exposed workers. Most concentrations of 2-MBT were below the limit of the detection, 0.12 μmol/l, the concentrations were 0.12–0.15 μmol/l only in few cases. The determination of 2-MBT in urine, when a sample is taken immediately after a work shift, is a suitable indicator of workers’ exposure to TCMTB.

Keywords: 2-(Thiocyanomethylthio)benzothiazole; TCMTB; 2-Mercaptobenzothiazole; 2-MBT; Kemtox S 10

Effects of paraquat on mitochondrial electron transport system and catecholamine contents in rat brain by Toshinaga Tawara; Tetsuhito Fukushima; Nobumasa Hojo; Akio Isobe; Kuninori Shiwaku; Tomoichi Setogawa; Yosuke Yamane (pp. 585-589).

The effects of paraquat on rat brain were studied. Activities of complex I (NADH: ubiquinone oxidoreductase) in mitochondrial electron transport system, lipid peroxidation and the amount of catecholamines in rat brain were measured after acute paraquat exposure. Complex I activities were significantly lower and lipid peroxides were higher in the brains of a paraquat-treated group than in those of a control group. Lipid peroxide in rat serum, however, did not increase after paraquat exposure. A study of the time dependency of paraquat effects disclosed that mitochondrial complex I activities in rat brain as well as those in rat lung and liver gradually decreased prior to the appearance of respiratory dysfunction. As compared to controls, the dopamine in rat striatum was significantly lower in the paraquat-treated group. These results suggest that paraquat after crossing the blood-brain barrier might be reduced to the radical in rat brain, which may damage the brain tissue, especially dopaminergic neurons in striatum. We therefore propose that cerebral damage should be taken into consideration on paraquat exposure. Patients may therefore need to be followed up after exposure to high doses of paraquat.

Keywords: Paraquat; Central nervous system; Complex I; Catecholamine; Lipid peroxidation

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Archives of Toxicology (v.70, #9)