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Archives of Toxicology (v.72, #6)

The use of dogs as second species in regulatory testing of pesticides I. interspecies comparison by Ulrich Gerbracht; Horst Spielmann (pp. 319-329).

The relevance of studies in dogs on regulatory testing of pesticides was examined retrospectively using data of 216 pesticides (acaricides, fungicides, growth regulators and hormones, herbicides, insecticides, molluscicides, nematicides, rodenticides, synergists for insecticides) submitted for regulatory purposes during the past 40 years to the Federal Institute of Health Protection of Consumers and Veterinary Medicine (BgVV), the competent national authority in Germany. At first the relevance of the no-observed-effect levels (NOEL) for safety assessment was evaluated for each chemical in 4-week (subacute), 13-week (subchronic) and 52/104-week (chronic) toxicity studies carried out on dogs, rats and mice. After subchronic and chronic application of fungicides the sensitivity of rats and dogs to the toxic chemicals was quite similar. However, the dog was generally a more sensitive species to toxic effects of insecticides than rat and mouse. On the other hand the NOEL was lower in the rat than the dog in chronic studies on herbicides. When the lowest-observed-effect level (LOEL) was evaluated in animal species, the dog was the most sensitive in ∼15% of the studies. Mice were found to be the most sensitive species only in ∼1% of the studies on 216 pesticides. Comparison of organ specific toxicity at the LOEL in subacute studies on fungicides and herbicides revealed a poor correlation of target-specific organ toxicity across species. However, in the subchronic and chronic studies (13 and 52/104 weeks) no significant differences in species-specific organ toxicity were observed in the three species rat, mouse and dog. The only exception were haematoxic effects in chronic studies on herbicides, which were more frequent in dogs (40%) than in rats and mice (20%). The results support the established concept that studies on dogs and rats are important for the safety assessment of pesticides, while studies on mice do not provide further information, except for detection of an oncogenic potential which is a further controversial issue. Further analysis of subacute, subchronic and chronic studies in dogs should reveal if all of the studies are essential for safety assessment of pesticides.

Keywords: Key words Pesticides; Regulatory testing; NOEL; LOEL; Target organ toxicity ; Interspecies comparison

The use of dogs as second species in regulatory testing of pesticides I. interspecies comparison by Ulrich Gerbracht; Horst Spielmann (pp. 319-329).

Keywords: Pesticides; Regulatory testing; NOEL; LOEL; Target organ toxicity ; Interspecies comparison

Application of the queueing theory with Monte Carlo simulation to inhalation toxicology by Guang Wu (pp. 330-335).

Various models have been developed in modelling of inhalation toxicology. The deterministic approach, which has been used to date in most of the␣models, needs to consider numerous factors, e.g. anatomical structure, breathing frequency, humidity, metabolism rate, partition coefficients, pulmonary ventilation, perfusion rates, unidirectional/cyclic air flow, non-steady-state, steady-state, etc. In the present study, a stochastic approach was used in the modelling of inhalation toxicology, because there is a phenomenological analogy between the queueing system and respiratory system dealing with inhaled toxicants. Using the queueing theory, the amounts of toxicants in the respiratory system, the time needed to remove the accumulated amounts of toxicants from the respiratory system, etc. can be estimated. The Monte Carlo simulation of queueing process was performed to analyse cigarette smoking, and shows the potential use of the queueing theory in inhalation toxicology.

Keywords: Key words Cigarette smoking ; Inhalation toxicology ; Mathematical modelling ; Monte Carlo simulation ; Queueing theory

Induction of CYP2A5 by pyrazole and its derivatives in mouse primary hepatocytes by Anneli Kojo; Pirkko Viitala; Markku Pasanen; Olavi Pelkonen; Hannu Raunio; Risto Juvonen (pp. 336-341).

Mouse liver CYP2A5 is induced by several structurally unrelated compounds. In intact mouse liver, pyrazole (PYR) and 4-hydroxypyrazole (4-OH) induce selectively the expression of CYP2A5 while expression of other CYPs is decreased. In this study we exposed mouse primary hepatocytes to PYR, 4-OH, 4-methylpyrazole (4Me; 0.1–20 mM) and 4-iodopyrazole (4-I; 0.1–5.0 mM). PYR and its derivatives increased coumarin 7-hydroxylase activity, with 4-1 and 4-OH being the strongest inducers, by 114-fold and 41-fold, respectively. However, only 4-1 treatment increased markedly the CYP2A5 protein content. CYP2B9/10-mediated pentoxyresorufin O-deethylase activity (PROD) was decreased by 80% by 4-Me and 4-1, and by 50% by 4-OH while PYR had no marked effect. PYR and 4-Me␣increased 2- to 3-fold the CYPA1/2-mediated ethoxyresorufin O-deethylase activity (EROD) while 4-OH and 4-1 had no marked effect on this enzyme. The time of exposure markedly affected the inducibility of 4-OH such that induction was 7-fold stronger when it was added to the incubation medium 24 h after the isolation of hepatocytes compared to exposure 3 h after their isolation. Cimetidine prevented the induction of coumarin 7-hydroxylase activity by PYR and 4-OH by 46 and 74%, respectively indicating that their effects on the expression of CYP2A5 are, at least partly, mediated via their metabolites. The data demonstrate that the regulation of CYP2A5 is different from other monooxygenases and that the effects of pyrazole and its derivatives are different in vivo and in vitro. Also, the timing of exposure markedly affects the inducibility of 4-OH in hepatocytes.

Keywords: Key words CYP2A5; Coumarin 7-hydroxylase; Pyrazole; Pyrazole derivatives; Primary hepatocytes

Mutagenic properties of 1,2,3,4-tetrahydronaphthaline-1-hydroperoxide, a model compound for organic peroxides in Diesel exhaust by S. Stock; G. Esser; D. Klockow; H. M. Bolt; G. H. Degen (pp. 342-346).

The genotoxicity of the organic peroxide 1,2,3,4-tetrahydronaphthaline-1-hydroperoxide (or tetraline-1-hydroperoixde, THP) was investigated in the Ames assay without a metabolic activating system using Salmonella typhimurium strains TA 98, TA 100, and TA 102. THP served as a model compound for higher organic peroxides, which can arise from autoxidation of hydrocarbons, e.g. in Diesel exhaust. While THP induced no mutagenic response in S. typhimurium TA 98, it was directly mutagenic in strains TA 100 and TA 102. These data, along with findings on mutagenic properties of other alkyl hydroperoxides, suggest that such compounds deserve further investigation regarding their genotoxic potential and occurrence in the environment.

Keywords: Key words Tetraline-1-hydroperoxide; Peroxide; Genotoxicity; Diesel exhaust

The nephrotoxicity and hepatotoxicity of 1,1,2,2-tetrafluoroethyl-L-cysteine in the rat by Edward A. Lock; John Ishmael (pp. 347-354).

Recent studies have shown that tetrafluoroethylene is a renal and hepatic carcinogen in the rat. In this study, we have examined the ability of a single i.p. dose of 1,1,2,2-tetrafluoroethyl-l-cysteine (TFEC), a major metabolite of tetrafluoroethylene, to produce hepatic and renal injury in male and female rats. We have also examined the effect of blocking the renal organic anion transport system with probenecid and of inhibiting the activity of cysteine conjugate β-lyase with aminooxyacetic acid on the extent of renal injury produced by TFEC. Doses of ≥12.5 mg/kg TFEC produced renal tubular necrosis to the pars recta of the proximal tubules within 24 h in both male and female rats. This was associated with an increased kidney to body weight ratio and plasma urea at doses of ≥25 mg/kg. No consistent evidence of liver injury was seen at doses up to 50 mg/kg TFEC in rats of either sex, although occasional vacuolation of hepatocytes and a small dose-related increase in liver to body weight ratio was observed. Prior treatment of female rats with probenecid completely prevented the renal injury produced by either 25 or 50 mg/kg TFEC as judged by plasma urea and histopathology. However, prior treatment of female rats with aminooxyacetic acid afforded no protection against the nephrotoxicity produced by either TFEC or the cysteine conjugate of hexachloro-1,3-butadiene. Thus no major sex difference in nephrotoxicity in the rat was seen with TFEC, while accumulation of TFEC, or its N-acetyl derived metabolite, into renal proximal tubular cells via a probenecid sensitive transport system appears to be a key event in the mechanism of nephrotoxicity. The lack of protection observed with the cysteine conjugate β-lyase inhibitor, aminooxyacetic acid, may reflect the inability to completely inhibit the mitochondrial form of this enzyme and thereby prevent the formation of the reactive metabolite. Our acute studies provide no insight concerning the liver carcinogenicity of tetrafluoroethylene.

Keywords: Key words Tetrafluoroethylene; 1; 1; 2; 2-tetrafluoroethyl-l-cysteine; Renal toxicity; Probenecid; Aminooxyacetic acid

Stimulation of liver heme oxygenase in hexachlorobenzene-induced hepatic porphyria by Michael D. Stonard; Giuseppe Poli; Francesco De Matteis (pp. 355-361).

We have measured liver heme oxygenase, a heat shock protein known to be increased under conditions of oxidative stress, to obtain additional evidence for an oxidative stress mechanism in hepatic uroporphyria induced by hexachlorobenzene (HCB). We have studied heme oxygenase at different times during HCB treatment and in two strains of rats (Agus and Wistar strains), which are known to differ in their sensitivity to the porphyria-inducing properties of HCB, in order to ascertain whether the same time course and genetic differences known to exist for the induction of porphyria also apply to hepatic oxidative stress. HCB induced heme oxygenase and accumulation of porphyrins in the liver of rats of both strains; no significant difference was found between the two strains in the HCB-induced heme oxygenase activity. The increased activity of the enzyme was first detected during the early phases of treatment, when a modest increase in liver porphyrins was observed; heme oxygenase remained at induced levels for several weeks during HCB treatment, and was still raised when an increase in total liver iron content and the onset of marked porphyria were also found. In contrast to the effects of HCB, phenobarbitone sodium (given in the drinking water for up to 4 weeks) produced similar elevations of total liver cytochrome P450 as HCB, but did not stimulate heme oxygenase or increase the total liver content of either iron or porphyrins. These results are compatible with an oxidative stress mechanism in HCB-induced liver toxicity and porphyria, but also suggest the existence of successive stages in the induction of hepatic porphyria, with more than one mechanism contributing to the marked accumulation of uroporphyrin.

Keywords: Key words Heme oxygenase; Hexachlorobenzene; Hepatic porphyria

Elucidation of mitochondrial effects by tetrahydroaminoacridine (tacrine) in rat, dog, monkey and human hepatic parenchymal cells by Donald G. Robertson; Timothy K. Braden; Ellen R. Urda; Narendra D. Lalwani; Felix A. de la Iglesia (pp. 362-371).

Tetrahydroaminoacridine (tacrine) causes morphological and functional changes in the endoplasmic reticulum, ribosomes, and mitochondria in the liver of humans and animals. In order to investigate species differences as well as to understand the morphological changes, we examined the effects of tacrine on respiration and electron transport in mitochondria isolated from rat, dog, monkey, and human liver. Tacrine produced significantly decreased respiratory control ratios (RCR) in all species at concentrations ranging from 5 to 25 μg/ml. Human mitochondria were more sensitive to tacrine effects with RCR decreased 24% at 5 μg/ml while other species were unaffected at this concentration. The tacrine effects were characterized by increased hepatic mitochondrial State 4 respiration in rats and decreased State 3 respiration in humans. Mitochondria from aged rats were more sensitive to the effects of tacrine than mitochondria from young animals, with significantly decreased RCR at 10 μg/ml in aged rats while mitochondria from young rats were unaffected at this concentration. Concomitant with the respiratory changes, mitochondrial DNA synthesis was impaired. Since tacrine undergoes extensive biotransformation, we also explored the possibility that metabolites could exert detrimental effects. The ranking order of potency for decreasing RCR caused by monohydroxylated metabolites was: tacrine >4-OH and 7-OH >2-OH, 1-OH, and velnacrine with the latter group of metabolites having no effect on mitochondrial respiration at concentrations up to 50 μg/ml. In vivo administration of 20 mg/kg tacrine to rats for up to 20 days caused a paradoxical increase in RCR and P/O on Day 1 and decreased RCR on Days 9 and 20, the later findings being consistent with in vitro data. From these data we propose that tacrine does not necessarily have to be metabolized to exert effects on mitochondria at different sites in the electron transport chain that differ among species. These effects are exacerbated in mitochondria from older animals and humans appear to be more sensitive than the laboratory animals studied.

Keywords: Key words Tetrahydroaminoacridine; Tacrine hepatotoxicity; Tacrine metabolites; Mitochondrial respiration; Age-related effects

Evaluation of toxicity indicators in rat primary astrocytes, C6 glioma and human 1321N1 astrocytoma cells: can gliotoxicity be distinguished from cytotoxicity? by C. Mead; V. W. Pentreath (pp. 372-380).

A comparison was made of rat primary astrocytes, C6 glioma cells pre-treated with dibutyryl cyclic AMP, and the human astrocyte 132N1 cell line using a range of 40 compounds and the neutral red (NR) assay. The 40 chemicals included substances known to be toxic to astrocytes or neurons, to be generally cytotoxic or not thought to be toxic to nervous tissue. For those compounds which were toxic, changes in glial fibrillary acidic protein (GFAP) levels were measured in the primary and C6 cultures, and changes in vimentin and S-100 measured in the C6 cells. The number of compounds with EC₅₀ values <2000 μg/ml for the NR assay for the different cell cultures were as follows: primary astrocytes, 19; C6 cells, 15; and 1321N1 cells, 11. The log of the EC₅₀ values for the NR assay for the test compounds between the three cell types was not significantly different at the 5% level by paired Student's t-test. For the toxic substances the correlation coefficients of the EC₅₀ values between primary cells and the C6 or 1321N1 cells were r>0.5, and between the C6 and 1321N1 cells r>0.9. For GFAP there was a similar degree of correlation in EC₅₀ values between the different cell types. The GFAP, vimentin and S-100 levels showed similar EC₅₀ values for the toxicants, but were not as sensitive as the NR assay. The toxic substances caused altered morphology in the primary, C6 and 1321N1 cells, with increased branching of cell processes. The combined astrocyte systems identified 8 out of 9 substances reported to be toxic to astrocytes in vivo, together with substances which have general cytotoxic properties. A␣number of substances (including the 1 out of 9 reported gliotoxic substances), which may primarily affect neurons, which may affect nervous tissue after long-term exposure, or which are not thought to be toxic to nervous tissue, were not detected. The astrocyte systems positively identify gliotoxic and cytotoxic substances and will allow detailed mechanistic studies to be made on the different underlying mechanisms.

Keywords: Key words Astrocytes; C6 glioma; 1321N1 astrocytoma; Gliotoxicity; Cytotoxicity

Effects of vitamin A pretreatment on nickel-induced lipid peroxidation and concentration of essential metals in liver, kidney and lung of mice by Chang-Yu Chen; Yeou-Lih Huang; Te-Hsien Lin (pp. 381-386).

In the present study we report the effects of pretreatment with large doses of vitamin A (Vit A, retinol) on hepatic, renal and pulmonary lipid peroxidation, and Ni and essential metal (Fe, Cu, Zn and Ca) concentrations in mice acutely exposed to nickel. Vitamin A (250 000 IU/kg per day) was administered by oral gavage to ICR mice for 7 days. On the 8th day, NiCl₂ (5 mg Ni/kg body wt.) was injected i.p. to Vit A- or vehicle-pretreated mice. Vitamin A pretreatment alone did not alter lipid peroxidation in liver, kidney and lung. Lipid peroxidation in liver, kidney and lung was increased after treatment with NiCl₂ alone. The extent of lipid peroxidation levels in Vit A+Ni treated mice was enhanced in liver, but reduced in kidney and lung. The Ni concentration in these three organs was below the detection limit (0.09 μg/g) in control and Vit A-pretreated mice. The accumulation of Ni in Vit A+Ni treated mice was increased in liver, but decreased in kidney and lung compared to Ni-treated mice. The concentrations of Fe, Cu, Zn and Ca in these organs were significantly increased in Ni-treated mice. In Vit A+Ni treated mice, compared to Ni-treated mice, hepatic Fe was significantly increased while Cu, Zn and Ca levels were reduced, but still higher than those of control and Vit A-treated mice. In the kidney of Vit A+Ni treated mice, the increase of Cu, Fe, and Zn but not Ca, was reduced and not significantly different from control and Vit A-treated mice. Pretreatment with Vit A reduced the increased Fe, Cu, Zn and Ca concentration in the lung caused by Ni injection. We therefore conclude that the effect of Vit A pretreatment on Ni toxicity is organ-dependent.

Keywords: Key words Vitamin A; Nickel; Lipid peroxidation; Essential metals

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Archives of Toxicology (v.72, #6)