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Archives of Toxicology (v.70, #3-4)

Effects of benzene metabolite treatment on granulocytic differentiation and DNA adduct formation in HL-60 cells by C. C. Hedli; N. R. Rao; K. R. Reuhl; C. M. Witmer; R. Snyder (pp. 135-144).

Reactive metabolites of benzene (BZ) play important roles in BZ-induced hematotoxicity. Although reactive metabolites of BZ covalently bind to DNA, the significance of DNA adduct formation in the mechanism of BZ toxicity is not clear. These studies investigated the covalent binding of the BZ metabolites hydroquinone (HQ) and 1,2,4-benzenetriol(BT) using the DNA [³²P]postlabeling method and explored the potential relationship between DNA adduct formation and cell differentiation in human promyelocytic leukemia (HL-60) cells, a model system for studying hematopoiesis. Maturation of HL-60 cells to granulocytes, as assessed by light and electron microscopy, was significantly inhibited in cells that were pretreated with HQ or BT prior to inducing differentiation with retionic acid (RA). The capacity of RA-induced cells to phagocytose sheep red blood cells (RBC) and to reduce nitroblue tetrazolium (NBT), two functional parameters characteristic of mature, differentiated neutrophils, was also inhibited in cells pretreated with HQ or BT. These BZ metabolite treatments induced DNA adduct formation in HQ- but not in BT-treated cells. These results indicate that whereas HQ and BT each block granulocytic differentiation in HL-60 cells, DNA adducts were observed only following HQ treatment. Thus DNA adduct formation may be important in HQ but not in BT toxicity.

Keywords: Benzene; Metabolite; Granulocytic differentiation; DNA adducts; HL-60 cells

Induction of peroxisomal β-oxidation and P-450 4A-dependent activities by pivalic and trichloroacetic acid in rat liver and kidney by U. Zanelli; P. Puccini; D. Acerbi; P. Ventura; P. G. Gervasi (pp. 145-149).

The influence of pivalic acid (PIV), a compound often used to make pro-drugs, and of the structurally related trichloroacetic acid (TCA), on several hepatic and renal enzymes was investigated in Sprague-Dawley rats, following a 4-day treatment period. The PIV and TCA treatments resulted in a similar and selective induction (2–3 times) of peroxisomal palmitoyl-CoA oxidase and the cytochrome P-450 4A dependent microsomal (ω)- and (ω-1)-lauric acid activities, both in liver and kidney. Western blot analysis of liver and kidney microsomes from PIV- and TCA-treated rats, using antibody to the P-450 4A1, revealed induction of members of the P-450 4A subfamily. These results suggest that PIV, like TCA, is a renal and hepatic peroxisome proliferator in rats, and further support the previously indicated close association between the peroxisomal fatty acid β-oxidation enzymes and microsomal P-450 4A subfamily enzymes.

Keywords: P-450 4A induction; Palmitoyl-CoA oxidase induction; Pivalic acid; Trichloroacetic acid

Inhibition of microsomal and mitochondrial Ca²⁺-sequestration in rat cerebellum by polychlorinated biphenyl mixtures and congeners by P. R. S. Kodavanti; T. R. Ward; J. D. McKinney; H. A. Tilson (pp. 150-157).

Recent studies from our laboratory indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed signal transduction mechanisms including cellular Ca²⁺-homeostasis and protein kinase C translocation. We have now investigated the structure-activity relationship (SAR) of three PCB mixtures, 24 PCB congeners and one dibenzofuran for their effects on microsomal and mitochondrial Ca²⁺-sequestration in rat cerebellum. Ca²⁺-sequestration by these intracellular organelles was determined using radioactive ⁴⁵CaCl₂. All three mixtures studied, Aroclor 1016, Aroclor 1254 and Aroclor 1260, were equally potent in inhibiting microsomal and mitochondrial Ca²⁺-sequestration with IC₅₀ values of 6–8 μM. 1,2,3,7,8-Pentachlorodibenzofuran had no effect on Ca²⁺-sequestration by these organelles. The SAR among the congeners revealed: (1) congeners with ortho-/meta- or ortho-, para-chlorine substitutions were the most potent in inhibiting microsomal and mitochondrial Ca²⁺-sequestration (IC₅₀=2.4–22.3 μM); (2) congeners with only para- but without ortho-substitutions were not effective in inhibiting Ca²⁺-sequestration by microsomes and mitochondria; (3) increased chlorination was not related to the effectiveness of these congeners. The present SAR studies indicate that the effects of most PCB congeners in vitro may be related to an interaction at specific sites having preference for low lateral substitution or lateral content (meta- or para) in the presence of ortho-substitution.

Keywords: Polychlorinated biphenyls; Calcium sequestration; Cerebellum; ⁴⁵Ca²⁺-uptake; In vitro; Structure-activity relationships

Calcium dynamics in cardiac myocytes as a target of dichloromethane cardiotoxicity by P. Hoffmann; S. P. Müller; K. Heinroth; E. Büchner; D. Richards; M. Toraason (pp. 158-163).

The purpose of the present study was to determine if cardiac actions of dichloromethane (DCM) in vivo correlate with in vitro alterations of Ca²⁺ dynamics in cardiac myocytes. Neonatal rat ventricular myocytes were obtained from 2- to 4-day-old rats, and electrically induced fluctuations of cytosolic free Ca²⁺ concentration ([Ca²⁺]_i) in single cardiomyocytes were investigated using spectrofluorometric analysis of fura-2-[Ca²⁺]_i binding. In cultured myocytes, cumulative exposure to 0.64–40.96 mM DCM resulted in a concentration-dependent and reversible decrease in the magnitude of [Ca²⁺]_i transients with IC₁₀ and IC₅₀ values of 7.98 and 18.82 mM, respectively. Total inhibition of [Ca²⁺]_i transients and cessation of beating were observed at 40.96 mM DCM. Suffusion with DCM for 40 min did not cause morphological alterations of the myocytes. In a urethane-anesthetized rat model, left ventricular pressure was measured by introducing a tip catheter via the carotid artery into the left ventricle, the ECG was recorded by two needle electrodes applied subcutaneously to the chest wall, and arterial pressure was measured via the femoral artery. Oral administration of 3.1–12.4 mmol DCM/kg resulted in DCM blood concentrations between 1.0 and 1.6 mM, accompanied by a dose-dependent decrease in contractile force and heart rate without influencing blood pressure and ECG tracings. Moreover, DCM treatment provided significant protection against arrhythmia development due to CaCl₂-infusion. In spite of the slight discrepancy between DCM blood concentrations and in vitro concentrations of DCM for [Ca²⁺]_i transient inhibition, present data are consistent with the view that cardiac effects after DCM exposure are mediated by alterations of Ca²⁺ dynamics during excitation-contraction coupling.

Keywords: Dichloromethane; Cardiotoxicity; [Ca²⁺]_i transients; Myocardial contraction; Cardiac arrhythmia

Effects of sub-chronic exposure to SO₂ on lipid and carbohydrate metabolism in rats by M. R. Lovati; C. Manzoni; M. Daldossi; S. Spolti; C. R. Sirtori (pp. 164-173).

Sulfur dioxide (SO₂) is a ubiquitous air pollutant, present in low concentrations in the urban air, and in higher concentrations in the working environment. While toxicological reports on SO₂ have extensively dealt with the pulmonary system, essentially no data are available on the effects of chronic exposure to this pollutant on intermediary metabolism, although some biochemical changes in lipid metabolism have been detected. The present investigation was aimed at evaluating the effects of sub-chronic exposure to SO₂ on concentrations of serum lipids/lipoproteins and on glucose metabolism, in animal models of hypercholesterolemia and diabetes. A specially designed controlinert atmosphere chamber was used, where male Sprague-Dawley rats fed on either standard or cholesterol enriched (HC) diets, as well as streptozotocin diabetics, were exposed to SO₂ at 5 and 10 ppm, 24 h per day for 14 days. In rats, both on a standard diet and on a HC regimen, SO₂ exposure determined a significant dose-dependent increase in plasma triglycerides, up to +363% in the 10 ppm HC exposed animals. This same gas concentration significantly reduced HDL cholesterol levels. In contrast, exposure of diabetic animals to 10 ppm SO₂ resulted in a fall (−41%) of plasma and liver triglycerides and in a concomitant increase (+62%) of plasma HDL cholesterol. This discrepancy could apparently be related to diverging effects of SO₂ exposure on plasma insulin levels in the different animal groups. Kinetic analyses of triglyceride synthesis carried out in rats on a standard diet revealed, in exposed animals, a significant reduction in the secretory rate, in spite of the concomitant hypertriglyceridemia. These findings suggest that SO₂ exposure can markedly modify major lipid and glycemic indices, also indicating a differential response in normo/hyperlipidemic versus diabetic animals.

Keywords: Sulfur dioxide; Apolipoproteins; Hyperlipidemia; Atherosclerosis; Diabetes

Impairment of schedule-controlled behavior by pre- and postnatal exposure to hexachlorobenzene in rats by H. Lilienthal; C. Benthe; B. Heinzow; G. Winneke (pp. 174-181).

Hexachlorobenzene (HCB) is still frequently found at elevated levels in human adipose tissue and breast milk. As intoxication with HCB causes neurological disturbance in human beings, the purpose of the present study was to examine neurobehavioral functions in rats after pre- and postnatal exposure. Female rats were fed diets with 0, 4, 8, or 16 mg HCB/kg diet. Exposure started 90 days prior to mating and was continued throughout mating, gestation, and lactation. Thereafter, the offspring were given the same diets as their respective mothers. HCB levels were determined in the brain, the liver, and in the adipose tissue from virgin rats, dams, and the offspring. Concentrations on a lipid basis were found to decline in the order adipose > liver > brain. The exposure levels chosen did not cause gross toxic effects in dams or offspring. There were dose-related increases in liver-to-body-weight ratios in exposed dams, but not in unmated females treated alike. Behavioral testing was conducted in the offspring. Examination of open-field activity on PND 21, and of active avoidance learning on PND 90 failed to reveal significant differences between groups. Training of operant behavior started at the age of 150 days in the offspring from the control, the 8-mg group, and the 16-mg group. Animal were trained on a fixed interval schedule of 1 min (FI-1). On this schedule, responses were reinforced by a food pellet every time 1 min had elapsed after the preceding reinforcement. There were dose-dependent reductions in the post-reinforcement pause, e.g. the time between each reinforcement and the first reaction emitted after it. In addition, the index of curvature, which describes the efficiency of performance on the FI-1 schedule, was decreased in a dose-dependent fashion.

Keywords: Hexachlorobenzene; Rat; Operant behavior; Gestation; Liver

Effects of psoralen on the structural integrity of cultured osteoblasts by George I. Malinin; William J. Vornberger; Francis J. Hornicek; Theodore I. Malinin (pp. 182-188).

The 72-h dark interaction of cultured osteoblasts with 0.5–1.0 μg/ml 8-methoxypsoralen (8-MOP) resulted in the accumulation of cytoplasmic lipid droplets (steatosis) in target cells. These methanol-extractable lipid droplets and 8-MOP, however, had no microscopically detectable effect on the organization of α-actin and β-tubulin-containing filaments. On the ultrastructural level, psoralen effects ranged from negligible to unambiguous structural alterations of target cells. The latter consisted of blebbing, segmental deletions of the nuclear envelope, and structural unraveling of nucleoli. Moreover, the dilatation of the rough endoplasmic reticulum, the decrease in the number of ribosomes, and the extensive vacuolation of cytoplasm constituted yet another hallmark of the 8-MOP effect in the absence of light. Whereas psoralen has induced a number of structural alterations in some, but not in all osteoblasts, more than 95% of the target cells have, nonetheless, remained viable. Taken together, our results suggest that the dark reaction of psoralen with osteoblasts results mainly in transient structural alterations of affected cells.

Keywords: Psoralen; Dark reaction; Osteoblasts; Structural alterations; Microscopy

Enhanced liver injury in acatalasemic mice following exposure to carbon tetrachloride by Da-Hong Wang; Kunihiko Ishii; Li-Xue Zhen; Kazuhisa Taketa (pp. 189-194).

The hypothtical involvement of hydrogen peroxide (H₂O₂) in carbon tetrachloride (CCl₄)-induced acute liver injury and the potential preventive effect of catalase on hepatotoxicity have been studied in acatalasemic (C3H/AnLC_s ^bC₂ ^b) mice and compared with normal (C3H/AnLC_s ^aC_s ^a) mice. A single intraperitoneal injection of CCl₄ (20% in olive oil/g body weight) caused increases in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in both mouse groups, but the extents of increases did not show significant differences between the two mouse groups until 12 h. The variation in increases of serum AST and ALT levels in acatalasemic and normal mice turned to be distinctly different from 12 h. At 18 h (peak point for ALT) and 24 h (peak point for AST), the serum enzyme levels in acatalasemic mice were nearly two-fold higher than those in normal ones, the difference being statistically significant (p <0.01). The liver malondialdehyde (MDA) level in acatalasemic mice was also higher than that in normals at 18 h (p <0.05). The extent of the centrilobular necrosis was histologically more severe in acatalasemic mice. The catalase activity in livers of acatalasemic mice was one-third to one-fifth those of normal mice (p <0.05) before and after treatment. The decreased catalase activity in acatalasemic mice might increase tissue or cellular levels of H₂O₂ during the later phase of the acute liver injury. From these findings, we conclude that H₂O₂ breakdown in liver would account for the difference in the later stages of the acute liver damage between the two groups of mice, and catalase is important in inhibiting hepatotoxicity of CCl₄ in the later stage.

Keywords: Carbon tetrachloride; Acute liver injury; Acatalasemic mice; Hydrogen peroxide

Respiratory effects of a synthetic metalworking fluid and its components by Katherine A. Detwiler-Okabayashi; Michelle M. Schaper (pp. 195-201).

A synthetic metalworking fluid, MWF “A”, and its major components were evaluated using a previously developed mouse bioassay. This fluid and its components evoked sensory (S) and pulmonary (P) irritation in mice. For MWF “A” and each of its components, a concentration-response relationship was developed on the basis of respiratory frequency (f_R) responses. From such relationships, the concentration capable of evoking a 50% decrease in mean f_R was determined for MWF “A” and each component (RD₅₀). RD₅₀S or RD₅₀P was used to distinguish decreases in f_R that were due to sensory irritation (S) from those due to pulmonary irritation (P). From RD₅₀P values, it was concluded that the fatty acid alkanolamide condensates, tolutriazole, and triazine-type biocide components were similar in potency to one another and similar in potency to MWF “A”. By examining potency and fractional composition, it was concluded that the fatty acid alkanolamide condensates and the triazine-type biocide largely contributed to the irritancy of MWF “A”. From RD₅₀P values, occupational exposure limits were proposed for MWF “A” and each of its components. The current Threshold Limit Value of 10 mg/m³ established by the American Conference of Governmental Industrial Hygienists for “particulates not otherwise classified” (PNOC) would be inadequate to protect workers from the irritating properties of MWF “A” and most of its components.

Keywords: Respiratory effects; Metalworking fluid; Mouse bioassay

Induction and suppression of renal and hepatic cytochrome P450-dependent monooxygenases by acute and chronic streptozotocin diabetes in hamsters by T. L. Chen; S. H. Chen; T. Y. Tai; C. C. Chao; S. S. Park; F. P. Guengerich; T. H. Ueng (pp. 202-208).

The acute and chronic effects of streptozotocin diabetes on kidney and liver microsomal monooxygenases were studied using hamsters 2 days and 6 weeks following treatment with the diabetogen, respectively. Acute diabetes increased aniline hydroxylation and N-nitrosodimethylamine demethylation, decreased pentoxyresorufin O-dealkylation, without affecting benzo(a)pyrene hydroxylation and 7-ethoxycoumarin O-deethylation in kidney and liver microsomes. The effects of chronic diabetes on the microsomal monooxygenases were similar to the effects of acute diabetes, except that the chronic diabetic condition markedly decreased benzo(a)pyrene and 7-ethoxycoumarin oxidations in kidney microsomes. Total cytochrome P450 content and NADPH-cytochrome P450 reductase activity in kidney and liver microsomes of the diabetic hamsters were similar to the controls. Gel electrophoresis of microsomes from control and streptozoptocin treated hamster tissues revealed that diabetes enhanced the intensity of protein band(s) in the P450 molecular weight region. Immunoblotting of microsomal proteins showed that acute and chronic streptozotocin diabetes induced proteins immunorelated to P450s 2E1 and 1A in kidney and liver. In marked contrast, the acute and chronic diabetic conditions decreased the level of a P450 2B-immunorelated protein(s) in kidney and liver. The present study demonstrates that acute and chronic streptozotocin diabetes has the ability to induce P450 2E1 and 1A and suppress P450 2B in hamster kidney and liver and that the hamster monooxygenase responds to diabetes differently from the rat enzyme.

Keywords: Diabetes; Cytochrome P450; Monooxygenase; Hamster; Streptozotocin

Influences of gender, development, pregnancy and ethanol consumption on the hematotoxicity of inhaled 10 ppm benzene by M. Corti; C. A. Snyder (pp. 209-217).

The hematotoxic effects of benzene in both humans and animals are well documented. Current estimates concerning the risks associated with benzene exposure are usually based on adult, male cohort studies; however, there are indications that females may respond differently than males to benzene and that fetuses may respond differently than adults. Another factor to be considered in risk estimates is the impact of personal habits. In experimental animals, ethanol consumption is known to increase the hematotoxicity of benzene; therefore, alcohol consumption may also alter the potential risk of individuals exposed to benzene. To address some of the factors that may confound risk estimates for benzene exposure, a series of experiments were performed. Age-matched male as well as pregnant and virgin female Swiss Webster mice were exposed to 10 ppm benzene for 6 h a day over 10 consecutive days (days 6 through 15 of gestation for the pregnant females). Half of the animals also received 5% ethanol in the drinking water during this period. On day 11, bone marrow cells from the adults and liver cells from the fetuses were assayed for the numbers of erythroid colony-forming units (CFU-e). CFU-e assays were also performed on bone marrow cells isolated from 6-week postpartum dams exposed during gestation and from in utero-exposed 6-week old males and females. Gender differences were clearly observed in the responses to the various exposure protocols. Depressions in CFU-e numbers were only seen in male mice while elevations in CFU-e numbers were only seen in female mice. Male mice exposed as adults for 10 days to benzene (B), ethanol (E) or benzene+ ethanol (B+E) exhibited depressed CFU-e levels as did male fetal mice exposed to B in utero. In addition, adult male mice which had been exposed in utero to either B or to E individually displayed depressed CFU-e levels. In contrast, none of the groups of female mice exhibited any depressions in CFU-e numbers after any of the exposures. Elevations in CFU-e numbers were observed among pregnant females exposed to E and among adult females exposed to B+E in utero. In summary, a majority (6/9) of the exposure protocols produced depressions in the CFU-e numbers of male mice, whereas a majority (7/9) of the exposure protocols produced no changes in the CFU-e numbers of female mice. Those changes that were observed in females consisted of elevations of CFU-e numbers. These results suggest that the male erythron is more susceptible than the female erythron to the hematotoxicants benzene and ethanol, regardless of whether exposures occur in utero or during adulthood.

Keywords: Benzene; Toxicity; Intrinsic; Extrinsic factors

Acute and subacute inhalation toxicity of dichlorosilane in male ICR mice by H. Nakashima; K. Omae; T. Takebayashi; C. Ishizuka; H. Sakurai; K. Yamazaki; M. Nakaza; T. Shibata; M. Kudo; S. Koshi (pp. 218-223).

Using male ICR mice, the LC₅₀ and acute and subacute inhalation toxicity of dichlorosilane (SiH₂Cl₂, DCS) and the fate of DCS released into the air were investigated. DCS resolved and minute particles including silicon and chloride were observed, when DCS was released into the air. Most particles were under 1 micron in diameter. The CL₅₀ of DCS at 4-h exposure was 144 ppm (nominal concentration). In the acute inhalation study, ten mice in each group were exposed to 64 ppm (nominal concentration) DCS for 1, 2, 4 or 8 h. Body weight loss, wheezing and piloerection were observed in mice exposed for 2 h or more. Histopathologically, injury to the nasal mucosa and trachea were observed in all exposed mice. Mice exposed to 32 ppm (nominal concentration) DCS for 2 or 4 weeks also exhibited depression of body weight gain, wheezing and piloerection. Squamous metaplasia of the nasal mucosa and tracheal epithelium was observed in both 2- and 4-week exposure groups. Exposure to DCS was irritant or corrosive to the respiratory tract with both acute and subacute inhalation. Apart from silane (SiH₄), toxic effects of DCS seem to be characterized by chloride compounds derived from DCS.

Keywords: Dichlorosilane; Semiconductor; Inhalation toxicity; Respiratory tract; Squamous metaplasia; Mouse

Alterations of the renal function in the isolated perfused rat kidney system after in vivo and in vitro application of S-(1,2-dichlorovinyl)-L-cysteine and S-(2,2-dichlorovinyl)-L-cysteine by O. Ilinskaja; S. Vamvakas (pp. 224-229).

The nephrotoxic effects of the two isomers S-(1,2-dichlorovinyl)-l-cysteine (1,2-DCVC) and S-(2,2-dichlorovinyl)-l-cysteine (2,2-DCVC) were investigated comparatively in the isolated perfused rat kidney with two different treatment regimens. In the first approach, the kidneys were exposed to the test compounds dissolved in the perfusion media after removal from the animal. In the second approach the test compounds were administered to rats in vivo and the nephrotoxicity was assessed in the isolated perfused kidney 6 h and 18 h post-treatment. The vicinal isomer 1,2-DCVC produced concentration- and time-dependent nephrotoxicity with both treatment regimens, as indicated by the impairment of glucose reabsorption, the increase of protein excretion and of γ-glutamyltransferase and alkaline phosphatase activities in urine. In contrast to the marked toxicity observed after in vivo and in vitro administration of 1,2-DCVC, the geminal isomer, 2,2-DCVC, was not nephrotoxic at all concentrations (0.5 and 2.5 mM in vitro, 40 and 70 mg/kg in vivo) investigated.

Keywords: 1,1,2-Trichloroethene; S-(1,2-Dichlorovinyl)-l-cysteine; S-(2,2-Dichlorovinyl)-l-cysteine; Isolated perfused rat kidney; Nephrotoxicity

Interaction of rat alveolar macrophages with pulmonary epithelial cells following exposure to lipopolysaccharide by Seishiro Hirano (pp. 230-236).

Because both alveolar macrophages and pulmonary epithelial cells are primary target cells of inhaled endotoxin, it is of interest to study the interaction of alveolar macrophages with epithelial cells following exposure to lipopolysaccharide (LPS). Repeated bronchoalveolar lavage suggested that rat alveolar macrophages became adhesive to epithelial cells in response to intratracheally instilled LPS at 0.5 h post-exposure in vivo. Adherence of alveolar macrophages to SV40T2 (rat type II pulmonary epithelial cells transformed by SV40) was also increased following 0.5-h stimulation with LPS in vitro. The adherence was increased with dose and reached a plateau at 2 μg/ml LPS. The transepithelial resistance of the SV40T2 monolayer was decreased by coculture with macrophages in the presence of LPS for 4 h. The transepithelial resistance was not changed by exposure of SV40T2 alone to LPS or conditioned medium obtained from LPS-stimulated macrophages, suggesting that the intercellular interaction between alveolar macrophages and epithelial cells or unstable products of LPS-exposed alveolar macrophages was associated with the decrease in Transepithelial resistance. Following the decrease in transepithelial resistance, lysis of SV40T2 was observed in the LPS-exposed coculture system. However, the lysis of SV40T2 did not occur until 12 h after the addition of LPS, indicating that the junctional change of the monolayer preceded cell death in SV40T2. Cytotoxicity of LPS-stimulated macrophages was significantly reduced by N ^G-monomethyl-l-arginine (NMMA), an inhibitor of nitric oxide synthase, but NMMA did not reduce the decrease in transepithelial resistance. These results suggest that the greater adherence of alveolar macrophages to epithelial cells, the junctional change of the epithelial monolayer and the lysis of epithelial cells occur in this order in the LPS-exposed alveolar macrophage-SV40T2 coculture system, and the greater adherence of alveolar macrophages may play a role in LPS-induced inflammation in the rat lung.

Keywords: Alveolar macrophage; Pulmonary epithelial cell; Lipopolysaccharide; Adhesion; Transepithelial resistance; Nitric oxide

Distribution of lead in lactating mice and suckling offspring with special emphasis on the mammary gland by Ira Palminger Hallén; Leif Norrgren; Agneta Oskarson (pp. 237-243).

The distribution of lead in lactating mice and suckling offspring was studied with whole body autoradiography at 4 and 24 h after a single intravenous injection of ²⁰³Pb (50 nmol Pb/kg) to the dams. In the lactating mice on day 14 of lactation, the highest uptake of radioactivity at 4 h after administration was recorded in renal cortex, skeleton and liver. A high uptake was also evident in the mammary gland. At 24h after administration, the radioactivity had decreased in most organs except in the skeleton. In the suckling pups, exposed to lead only via dams’ milk for 24 h, the highest level of radioactivity was present in the intestinal mucosa and a much lower level of radioactivity was present in the skeleton. The mammary glands from mice given three daily intravenous injections of 240 μmol Pb/kg were examined with X-ray microanalysis. At 4 h after the last injection, lead was found associted with casein micelles both inside the alveolar cell and in the milk lumen, indicating that lead is excreted into the milk, bound to casein, via the Golgi secretory system.

Keywords: Lead; Autoradiography; Sucklings; Mammary gland; X-ray microanalysis

Protection by indomethacin and aspirin against genotoxicity of ochratoxin A, particularly in the urinary bladder and kidney by S. Obrecht-Pflumio; Y. Grosse; A. Pfohl-Leszkowicz; G. Dirheimer (pp. 244-248).

Ochratoxin A (OTA) is a ubiquitous nephrotoxic mycotoxin which was shown to be carcinogenic to laboratory animals and may be responsible for kidney pelvis, ureter and urinary bladder tumors associated with Balkan endemic nephropathy in man. Previous evidence from this laboratory demonstrated that OTA exposure results in adduct formation on kidney, testicles, liver and spleen DNA. We show in this study that after a single oral administration of OTA to mice (2 mg/kg body weight) a high level of DNA adducts (150 per 10⁹ nucleotides) is also detected in the urinary bladder. The metabolic pathway of OTA leading to genotoxic compounds is not yet known. We demonstrate here that two inhibitors of the prostaglandin H synthase, indomethacin and aspirin, administered to mice before OTA treatment, dramatically reduce the amounts of DNA adducts, particularly in the urinary bladder and kidney. This suggests a role of protaglandin H synthase in the metabolism of OTA leading to active metabolites which react with DNA.

Keywords: Ochratoxin A; Mycotoxin; DNA-adducts; Prostaglandin H synthase; Balkan endemic nephropathy

Apoptotic cell death following exposure to fluoride in rat alveolar macrophages by Seishiro Hirano; Mitsuru Ando (pp. 249-251).

Since inhaled fluoride is implicated in the acute respiratory failure, cytotoxic effects of fluoride on alveolar macrophages, primary target cells of inhaled toxicants, were investigated. The LC₅₀ of sodium fluoride was estimated to be 0.41 mM, while 1 mM sodium chloride, bromide and iodide had virtually no effects on the viability of alveolar macrophages. Photomicroscopic observation revealed that nuclei of the fluoride-exposed alveolar macrophages were fragmented. The ladder formation was observed when DNA isolated from fluoride-exposed alveolar macrophages was electrophoresed in agarose gel. These results suggest that cytotoxicity of fluoride is associated with apoptosis in rat alveolar macrophages.

Keywords: Fluoride; Alveolar macrophages; Cytotoxicity; Apoptosis; DNA fragmentation

Suppression of agonist induced Ca²⁺ oscillations in cultured hepatocytes by nafenopin: possible involvement of protein kinase C by E. Leibold; A. Stampfl; L. R. Schwarz (pp. 252-255).

The alpha₁-agonist phenylephrine (5 μM) induces an increase in the free cytosolic Ca²⁺ concentration, followed by repetitive transients of the cytoplasmic Ca²⁺ concentration, in single Fura-2 loaded hepatocytes. The tumor promoting, hypolipidemic drug nafenopin suppressed the cellular Ca²⁺ response to phenylephrine. The effect of nafenopin on the Ca²⁺ increase and Ca²⁺ oscillations was largely prevented by the specific protein kinase C inhibitor Gö 6976. This finding suggests involvement of protein kinase C in the action of nafenopin on phenylephrine induced Ca²⁺ mobilization.

Keywords: Ca²⁺ oscillations; Nafenopin Hepatocytes; Protein kinase C

Effect of dietary paraquat on a rat mutant unable to synthesize ascorbic acid by K. Minakata; O. Suzuki; S. Saito; N. Harada (pp. 256-258).

To obtain some insight into the toxicity of paraquat (PQ) in humans, PQ dichloride at 250 ppm in the diet was administered to both normal (NO) rats and ODS-od/od (OD) rats which are unable to synthesize ascorbic acid (AsA). Firstly, OD rats and NO rats treated with PQ were compared with untreated NO rats (CO). Only OD rats displayed several symptoms of PQ poisoning such as anorexia, hypokinesia, diarrhea, epistaxis, tremor and their pili became rough about 9 days after. Their cysteine proteinase inhibitor level in plasma and lung increased to 2- and 6-fold, respectively, of CO. In contrast, NO rats treated with PQ resembled CO rats, and their cysteine proteinase inhibitor levels were unchanged until 11 days. After this period they began to display symptoms. Secondly, OD rats fed with different amounts of AsA were compared. Excess AsA delayed the onset of symptoms by only 1 day. Thirdly, the day of onset of symptoms was found to be influenced with the weight of rats.

Keywords: Paraquat; Cysteine proteinase inhibitor; Ascorbic acid; Rat mutant

Preexistence of chronic tubular damage in cases of renal cell cancer after long and high exposure to trichloroethylene by T. Brüning; K. Golka; V. Makropoulos; H. M. Bolt (pp. 259-260).

Substantially more cases of tubular damage were found among renal cell carcinoma patients who had been exposed to high levels of trichloroethylene over many years than among renal cell carcinoma patients who had not been exposed to trichloroethylene. This supports the hypothesis (Goeptar et al. 1995) that chronic tubular damage may be regarded as a necessary precondition for trichloroethylene to exert a nephrocarcinogenic effect. The findings also indicate that the urine protein patterns identified with SDS-PAGE may represent a valuable parameter for effect biomonitoring of persons exposed to high levels of trichloroethylene over many years.

Keywords: Trichloroethylene; Renal cell cancer; Tubular damage

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