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Archives of Toxicology (v.69, #9)

Characterization of the effects of an airborne mixture of chemicals on the respiratory tract and smoothing polynomial spline analysis of the data by Lee Ann Boylstein; Stewart J. Anderson; Randolph D. Thompson; Yves Alarie (pp. 579-589).

We expanded a previously published (Vijayaraghavan et al. 1994) computerized system to analyze the breathing pattern of unanesthetized mice in order better to recognize and quantify the effects of an airborne mixture of chemicals at three different levels of the respiratory tract. The airborne chemical mixture used was a machining fluid. Such fluids are widely used in industry and a large number of workers are exposed to these airborne mixtures. We found this mixture to be capable of inducing three types of effects on the respiratory tract: sensory irritation of the upper respiratory tract (S), airflow limitation along the conducting airways (A) and pulmonary irritation (P). Depending upon the exposure concentration, mainly S or P effects were obtained but an A effect was also identified. The three types of effects occurred at various times during the exposures and, furthermore, within a group of exposed animals some exhibited one type of effect while others exhibited another type. In order to analyze such complex data sets, two statistical methods for smoothing polynomial splines were utilized: the maximum likelihood (ML) method and generalized cross validation (GCV) method. The results indicated that previous methods used to characterize a single effect of airborne chemicals can now be extended to evaluate mixtures likely to induce multiple types of effects. However, statistical analysis methods, either the ML or GCV methods, or other appropriate methods are needed to evaluate the responses obtained due to the complex effects that a mixture can induce in comparison to single chemicals.

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

Regional differences in expression of osteonectin mRNA after administration of cadmium to rats by Myeong Jin Lee; Kiyofumi Saijoh; Eric J. Nestler; Ronald S. Duman; Kimiaki Sumino (pp. 590-595).

Osteonectin gene expression in relation to metallothionein mRNA expression was investigated in various tissues from Cd-treated rats. After a single 50 μmol/kg subcutaneous injection of CdCl₂, Cd predominantly accumulated in the liver and metallothionein gene expression significantly increased concomitantly with Cd accumulation, but no alteration of osteonectin gene expression was observed. In the kidney and lung, both metallothionein and osteonectin mRNA increased significantly but the elevation of metallothionein mRNA levels (1 h after Cd administration) preceded that of osteonectin (3 h after administration). A significant elevation of osteonectin mRNA levels was also observed in the testis after 3 h, but that of metallothionein mRNA occurred after 6 h. Not only accumulation of Cd but also increments in both osteonectin and metallothionein mRNA were minimal in the brain, but a significant increase in gene expression was observed after 1 h for osteonectin and after 3 h for metallothionein. Since, except in the testis, metallothionein gene expression preceded osteonectin gene expression, the induced metallothionein might transpose Cd and thereby affect its levels immediately, thus reducing the levels of Cd available for accumulation in other tissues. Hence, the osteonectin-Cd interaction might be secondary to the metallothionein-Cd interaction. However, the fact that osteonectin mRNA was predominantly induced by Cd administration in the target tissues of Cd toxicity, such as the lung, kidney and testis, suggests the possible involvement of osteonectin in Cd intoxication/detoxication mechanisms.

Keywords: Cadmium; Osteonectin; Metallothionein; Gene expression; Rat

Placental and lactational transfer of lead in rats: a study on the lactational process and effects on offspring by Ira Palminger Hallén; Lars Jorhem; Agneta Oskarsson (pp. 596-602).

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 measued 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.

Keywords: Lead; Neonatal exposure; ALAD-activity; Milk composition; Cross-fostering

Evidence for renal ischaemia as a cause of mercuric chloride nephrotoxicity by Guillermina Girardi; María Mónica Elías (pp. 603-607).

The present study was undertaken to investigate if the source of oxidative stress and the renal injury produced by mercuric chloride could be renal ischaemia. Verapamil Vp was used because it was described that calcium channel blockers protect cells from nephrotoxicants and from ischaemia. Vp (75 μg/kg, i.v.; 30 min before HgCl₂ injection) prevented mercuric chloride renal injury observed 1 h post-HgCl₂ injection as measured by clearance techniques. Vp also prevented the diminution of non-protein-sulfhydryls (NPSH) and the increased lipid peroxidation (LPO) induced by HgCl₂ in renal tissue. Hg²⁺ toxicokinetic alterations were not observed in Vp plus HgCl₂ treated rats, nor was Vp ability found as a free radical scavenger in renal tissue homogenates. The results described in this study give some evidence for the role of renal ischaemia in the production of oxidative stress, generating LPO and functional and morphological renal injury described in mercuric chloride treated rats.

Keywords: Mercuric chloride; Nephrotoxicity; Ischaemia; Verapamil; Oxidative stress

Neurobehavioral development of CD-1 mice after combined gestational and postnatal exposure to ozone by Giacomo Dell’Omo; Marco Fiore; Simona Petruzzi; Enrico Alleva; Giorgio Bignami (pp. 608-616).

Outbred CD-1 mice were exposed continuously to ozone (O₃, 0.6 ppm) from 6 days prior to the formation of breeding pairs to the time of weaning of the offspring on postnatal day 22 (PND 22) or to PND 26. One half of the mice in each of eight O₃ and eight control litters were subjected on PND 24 to a 20-min open-field test after IP treatment by either saline or scopolamine (2 mg/kg). The remaining mice (those exposed until PND 26) were subjected on PNDs 28–31 to a conditioned place preference (CPP) test, using a short schedule with a single IP injection on PND 29 of either d-amphetamine (3.3 mg/kg) or saline. Subsequently, the saline mice of the open-field experiment were used on PND 59 for an activity test in one of the CPP apparatus compartments after IP treatment by either d-amphetamine (same dose) or saline. In addition, the saline mice of the CPP experiment underwent a multitrial, step-through passive avoidance (PA) acquisition test on PND 59 or 60, followed 24 h later by a single-trial retention test. In the absence of effects on reproductive performance (proportion of successful pregnancies, litter size, offspring viability, and sex ratio), O₃ offspring showed a long-lasting reduction in body weight without modification of sex differences. Ozone effects on neurobehavioral development were not large and quite selective, including: attenuation of the sex differences in several responses (rearing and sniffing in the open-field, activity in the final CPP test session); a change in response choices in the final CPP test, in the absence of a main effect on conditioning; a reduction of grooming in the activity test on PND 29; and impairment of PA acquisition limited to the initial period of training.

Keywords: Ozone; Mouse; Neurobehavioral development; Spontaneous activities; Conditioned place preference

In vitro influences of alcohols on mouse synaptosomes, and structure-activity relationships by Hideji Tanii; Xiao -Ping Zhang; Takao Ohyashiki (pp. 617-623).

Little information is available on the structure-central nervous system membrane toxicity relationship of alcohols. The purpose of the present study was to study in vitro influence of alcohols (n=20) on the activity of the toxic indicator Na⁺/K⁺-adenosine triphosphatase (Na⁺/K⁺-ATPase) and acetylcholinesterase (AchE), and membrane fluidity in mouse brain synaptosomes, in terms of the structure-activity relationship. The potency of inhibition for the enzymes (IC₅₀) and the potency of increasing membrane fluidity (IC_12.5) were determined experimentally, and n-octanol/water partition coefficient (P) and the steric constant Taft Es are cited from the literature. Regression analysis revealed that log 1/IC₅₀ for Na⁺/K⁺-ATPase is a function of log P and Taft Es. The situation was true for AchE activity. The results indicate that the hydrophobicity expressed as log P and the steric effect of the alcohols play an important role in inhibiting both enzyme activities. A linear relationship between log 1/IC_12.5 for membrane fluidity and log P is shown, indicating a significant effect of the alcohols on membrane fluidity. Based on these results, it is suggested that the alcohols inhibit the Na⁺/K⁺-ATPase and AchE activity through a direct action on the enzymes and/or through changing the membrane fluidity.

Keywords: Methyl alcohol; Ethyl alcohol; n-Propyl alcohol; Isopropyl alcohol; Allyl alcohol; n-Butyl alcohol; Isobutyl alcohol; sec-Butyl alcohol; tert-Butyl alcohol; n-Pentyl alcohol; Isopentyl alcohol; sec-Pentyl alcohol; sec-Isopentyl alcohol; tert-Pentyl alcohol; 4-Methyl-2-pentyl alcohol; n-Hexyl alcohol; n-Heptyl alcohol; n-Octyl alcohol; n-Nonyl alcohol; n-Decyl alcohol; Na⁺/K⁺-ATPase; Acetylcholinesterase; Membrane fluidity; n-Octanol/water partition coefficient; Taft Es constant

Effect of bolesatine on phospholipid/calcium dependent protein kinase in vero cells and in rat thymus by R. Ennamany; O. Kretz; E. E. Creppy (pp. 624-630).

Bolesatine, a glycoprotein from Boletus satanas Lenz, has previously been shown to be mitogenic to rat and human lymphocytes at very low concentrations, whereas higher concentrations inhibit protein synthesis in vitro and in several in vivo systems. The mechanism whereby this mitogenic activity occurs was previously unknown. To elucidate this mechanism, the effects of bolesatine have been studied in a cell-free system, VERO cells in culture, and in rat thymus. Bolesatine was found to activate PKC, in vitro (cell free system), in VERO cells, and in vivo in rat thymus. In a cell-free system, bolesatine appears to be a direct effector of PKC. The activation is concentration dependent for 1–10 ng/ml. At the same time, VERO cells significantly proliferate when incubated with bolesatine (3, 5 and 10 ng/ml), since the DNA synthesis increases by 27, 48 and 59%, for respectively, 3, 5 and 10 ng/ml compared with control. Moreover, Bolesatine (5 and 10 ng/ml) induces InsP₃ release in a concentration-dependent manner (114 and 142%) as compared to control. In vivo, 24 h after oral administration of bolesatine to rats (20, 100 and 200 μg/kg), PKC activity is significantly increased in thymus. The most effective doses (100 and 200 μg/kg) give 590–620% increase in cytosolic PCK activity and 85–91% increase in total PKC activity as compared to control. This PKC activation by bolesatine in rat thymus is directly linked to the mitogenic activity observed in vivo. Bolesatine is thus capable of activating the PKC directly and/or indirectly (via InsP₃ release) during its mitogenic process.

Keywords: Bolesatine; Boletus satanas ; Rat thymus; VERO cells; Protein kinase C; Inositol triphosphate; DNA synthesis

Investigation of potential oncogenetic effects of β-cyclodextrin in the rat and mouse by Trevor Waner; Giannella Borelli; Sandro Cadel; Ido Privman; Abraham Nyska (pp. 631-639).

The results of oncogenicity studies of β-cyclodextrin in inbred Fischer 344 rats and CD-1 outbred mice are presented. Chronic feeding of β-cyclodextrin to Fischer 344 rats and CD-1 mice did not cause any treatment related carcinogenic effects. The only toxic effect was seen in mice as macroscopic distension of the large intestine with soft or fluid contents, histologically associated with the mucosa covered by mucous secretion containing exfoliated cells, and mucosal flattening and intestinal gland atrophy. Despite these observations, no differences between control and treated groups were observed concerning mortality, clinical observations or body weight and food consumption.

Keywords: β-Cyclodextrin; Oncogenicity; Rat; Mouse

Chloropropionic acid-induced alterations in glucose metabolic status: possible relevance to cerebellar granule cell necrosis by Edward A. Lock; Andrew Gyte; Peter Widdowson; Michael Simpson; Ian Wyatt (pp. 640-643).

We have examined the effect of l- and d-2-chloropropionic acid (l-CPA and d-CPA) on the concentrations of pyruvate, lactate, glucose and β-hydroxybutyrate in the blood at various times after doses which produce cerebellar granule cell necrosis. Blood pyruvate and lactate concentrations were reduced in these animals 4 h after dosing and remained below those of controls for up to 48 h. No changes were seen in concentrations of plasma glucose of β-hydroxybutyrate at any time point. Similarly, no changes in cerebellar glucose, pyruvate or lactate were seen 24 h after 750 mg/kg l-CPA. Oxidation of [¹⁴C] pyruvate or [¹⁴C] glucose to [¹⁴CO₂] by cerebellar slices from control rats was not altered by the presence of l- or d-CPA (1–10 mM for 2 h). Nor were these parameters affected in cerebellar slices from rats killed 24 h after a dose of 750 mg/kg l-CPA. We conclude that activation of the pyruvate dehydrogenase complex is unlikely to be a critical factor in the selective toxicity of CPA to the cerebellum.

Keywords: Cerebellar granule necrosis; l and d-2-Chloropropionic acid; Glucose oxidation; Pyruvate oxidation

Detection of the organophosphorus nerve agent sarin by a competitive inhibition enzyme immunoassay by Yong-xin Zhou; Qing-jin Yan; Yun-xiang Ci; Zhen-quan Guo; Kang -Tai Rong; Wen-bao Chang; Yu-fen Zhao (pp. 644-648).

Two artificial antigens, N ^αN^ε-di(O, O-diisopropyl) phosphoryl l-lysine (DIP)-bovine serum albumin (BSA) conjugate (DIP-BSA) and DIP-KLH (keyhole limpet hemocyanin), were synthesized. Antibodies against sarin (O-isopropyl methylphosphonofluoridate) were obtained after immunization of rabbits with DIP-KLH conjugate. A competitive inhibition enzyme immunoassay (CIEIA) was developed to detect the organophosphorus nerve agent sarin. The antibody solutions could be inhibited by sarin as low as 10⁻⁶ mol/l, and the standard curve was linear over 3 orders of magnitude. The coefficients of intraassay and interassay variation of this method were 5.4–6.2% (n=11) and 8.0–9.5% (n=6) at a sarin concentration range of 10⁻³–10⁻⁶ mol/l, respectively. The recovery of sarin in water samples at the concentration of 5×10⁻⁵ mol/l was in the range of 96.8–102.5%. The specificity of the antiserum was assessed by comparing the inhibition induced by sarin with soman, Vx, isopropyl alcohol and isopropyl methyl phosphonic acid. The results showed that less than 5 mmol/l soman, 2 mmol/l Vx, 16 mmol/l isopropyl alcohol and 8 mmol/l isopropyl methyl phosphonic acid did not influence the determination of sarin in water samples.

Keywords: Artificial antigen; Competitive inhibition enzyme immunoassay; Sarin; Detection

Prediction of the percutaneous penetration and metabolism of dodecyl decaethoxylate in rats using in vitro models by Clive S. Roper; Doug Howes; Peter G. Blain; Faith M. Williams (pp. 649-654).

Percutaneous absorption of a lipophilic surfactant, dodecyl decaethoxylate, can be predicted using in vitro models. In vivo, dermal penetration of dodecyl decaethoxylate was found to be 22.9% in 48h. All of the absorbed dodecyl decaethoxylate in the rat was metabolised and excreted in expired air as carbon dioxide, or in the urine and faeces. Using rat skin mounted in the unoccluded flow-through diffusion cell with MEM as receptor fluid, in vivo absorption was predicted by the percentage of the applied dose recovered in the stratum corneum, epidermis, dermis and receptor fluid at 24 h (25%). Conversely, the penetration of dodecyl decaethoxylate was over-predicted in the unoccluded static diffusion cell using aqueous ethanol (50% v/v) as the receptor fluid where 49.4% recovered in the receptor fluid at 24 h. In vitro models may be used to predict percutaneous absorption and reduce animal use, provided a suitable receptor fluid is used in which the penetrant is soluble. Dermal metabolism of dodecyl decaethoxylate was low and not considered to influence dermal absorption.

Keywords: Flow through diffusion cell; Static diffusion cell; In vitro skin; Dodecyl decaethoxylate; Occlusion

Role of cytochrome P450 in hepatotoxicity induced by di- and tributyltin compounds in mice by S. Ueno; N. Susa; Y. Furukawa; M. Sugiyama (pp. 655-658).

The role of cytochrome P450 in the induction of hepatotoxicity by butyltin compounds such as tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) was investigated in vivo. The pretreatment of mice with SKF-525A, which decreased hepatic levels of cytochrome P450, suppressed TBTC-induced hepatotoxicity, as estimated by serum ornithine carbamyl transferase activity, whereas pretreatment with phenobarbital (PB), which increased the levels of cytochrome P450, enhanced the hepatotoxicity of TBTC. In the case of DBTC, PB pretreatment enhanced hepatotoxicity, while SKF-525A had no effect. Under these experimental conditions only PB pretreatment was found to increase hepatic levels of tin in mice treated with TBTC. These results suggest that hepatic metabolism of butyltin compounds by cytochrome P450 is more closely related to the induction of hepatotoxicity by TBTC than by DBTC. The active tin compounds formed during hepatic metabolism, which are responsible for induction of hepatotoxicity, will be discussed

Keywords: Butyltin compounds; Cytochrome P450; Hepatotoxicity

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Archives of Toxicology (v.69, #9)