bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of the effects of inorganic and alkyllead compounds on human erythrocytic δ‐aminolevulinic acid dehydratase (ALAD) activity in vitro
Authors: Burns C. B. , Godwin I. R.
Published: October 2006

A study comprising two experiments comparing the effects of the alkyllead compounds triethyllead acetate and tetraethyllead as well as an inorganic lead compound (Pb(NO3)2) on human erythrocytic δ‐aminolevulinic acid dehydratase activity was undertaken. In Experiment 1, four human blood samples were pre‐incubated for 0 min or 60 min with increasing concentrations (0–1000 μM) of triethyllead acetate, tetraethyllead and Pb(NO3)2, and the δ‐aminolevulinic acid dehydratase activity was determined. There was no discernible inhibitory effect of tetraethyllead at any concentration, with or without pre‐incubation. Pb(NO3)2 showed a distinct effect at an addition concentration of 1 μM, with a substantial inhibition only following pre‐incubation. Triethyllead acetate showed no difference in effect with pre‐incubation. In the second experiment, the activating effects of zinc chloride (60 μM) and dithiothreitol (20 mM) on δ‐aminolevulinic acid dehydratase activity were examined on four human blood samples in the presence of varying concentrations of Pb(NO3)2 (0–50 μM) and triethyllead acetate (0–1000 μM). The addition of zinc chloride alone showed little effect on enzyme activity, while dithiothreitol alone caused a substantial activation of the enzyme at all lead concentrations. The addition of both zinc chloride and dithiothreitol caused an even greater activation of the enzyme. The data indicate that Pb(NO3)2 is a much more potent inhibitor of δ‐aminolevulinic acid dehydratase activity than triethyllead acetate (Ki values of 0.77 μM versus 130.37 μM, respectively). The use of δ‐aminolevulinic acid dehydratase activity as an indicator of exposure may be questionable in cases of alkyllead exposure. Possible causes for differences in the inhibition of δ‐aminolevulinic acid dehydratase by these compounds is also discussed.
Cardiopathic effect of 1,2,3‐trichloropropane after subacute and subchronic exposure in rats
Authors: Merrick B. Alex , Robinson Merrel , Condie Lyman W.
Published: October 2006

1,2,3‐Trichloropropane (1,2,3‐TCP) is an industrial water contaminant with potential for human exposure by the oral route. The systemic toxicology of 1,2,3‐TCP was evaluated after subacute or subchronic exposure in male and female Sprague‐Dawley rats. Animals were treated with 0.01, 0.05, 0.20 and 0.80 mmol kg−1 day−1 for 10 days and 0.01, 0.05, 0.10 and 0.40 mmol kg−1 day−1 for 90 days. Chemical exposure was by oral gavage in corn oil. Lethality did not occur in either study. Toxicity was observed primarily in the high dose group of subacute and subchronically treated rats of both sexes. Weight gain suppression occurred at a dose of 0.8 mmol kg−1 (118 mg kg−1) after 10 days. After 90 days of exposure to 0.40 mmol kg−1, the final body weights were 81% and 86% of control values for males and females, respectively. When major organ weights were normalized by body weight, liver and kidney values were generally increased relative to control in the two highest dose groups after 10‐ and 90‐day chemical exposure. Serum chemistries and histopathology indicated a mild hepatotoxic response to 1,2,3‐TCP in the high dose group of each study but did not support any renal toxicity. Thymic weight reduction due to atrophy occurred at 10 days of exposure in high dose groups but was normal in all groups after the 90‐day treatment. The primary histological finding in this study was an inflammation‐associated cardiopathy produced by 1,2,3‐TCP. Myocardial necrosis and degeneration occurred in a diffuse pattern with marked eosinophilia of affected cells. Male and female animals showed a cardiopathic response only at a dose of 0.8 mmol kg−1 1,2,3‐TCP after the 10‐day exposure. In the subchronic study, the incidence of cardiopathy was more prevalent in males than in females. In addition to cardiac effects, the 90‐day chemical exposure produced bile duct hyperplasia in 40% and 80% of males and females, respectively. This observation may be significant, since five other neoplastic and proliferative lesions were observed in rats receiving 1,2,3‐TCP subchronically. Thus, this study demonstrates that heart and liver were target organs for 1,2,3‐TCP toxicity and suggests that 1,2,3‐TCP exposure may be involved in carcinogenesis.
Four‐week inhalation exposures of rats to aerosols of three lubricant base oils
Authors: Dalbey W. , Osimitz T. , Kommineni C. , Roy T. , Feuston M. , Yang J.
Published: October 2006

Sprague‐Dawley rats were exposed to aerosols of one of three base stocks used to formulate lubricating oils. These stocks were a solvent‐refined oil (SRO), a hydrotreated and acid‐washed white oil (WTO) and a severely hydrotreated and hydrocracked oil (HBO). Exposures were for 6 h per day, 5 days per week for ca. 4 weeks. There were four groups of rats for each study (10 per sex per group). Aerosol concentrations were ca. 0, 50, 210 and 1000 mg m−3 for each material; the mass median aerodynamic diameter was ca. 1 μm. Following the last exposure, all animals were sacrificed and necropsied. Samples were taken for serum chemistry, hematology, sperm morphology, weights of seven organs and histopathology on at least nine organs. Body weights and clinical signs were not affected by exposures. The only treatment‐related changes were in the lung and associated lymph nodes. Both the wet weight of the lung and the dry/wet weight ratio increased in a concentration‐related manner. Associated with the increased weight were accumulations of foamy alveolar macrophages, particularly in alveoli close to alveolar ducts. Mild infiltration by neutrophils was observed with WTO and SRO; thickened alveolar walls were noted with the highest concentration of HBO. These mild responses to exposures at very high concentrations indicate a low degree of toxicity for these aerosols.
Ultrastructural localization of silver in rat testis and organ distribution of radioactive silver in the rat
Authors: Ernst Erik , Rungby Jørgen , Baatrup Erik
Published: October 2006

The deposition of silver after a single intravenous injection (2 μg Ag g−1 body weight) was studied in the testes of Wistar rats 24 h and 1 and 2 weeks after dosing with radiolabelled 110AgNo3 (2 μg Ag and 1.2 kBq g−1 body weight). Also, the temporal accumulation of silver during the experimental period was monitored in the blood, testes, epididymides, kidney, liver and brain.

The subcellular distribution of silver within the testes was demonstrated by using the histochemical technique of autometallography. Silver was cleared rapidly from the blood. After an initial rise, concentrations in organs remained almost stable throughout the experimental period.

Silver was especially abundant in interstitial macrophages and in the basement membrane. Deposits of silver were found in all cell types of spermatogenesis and in the lysosomes of the Sertoli cells.
Serum histamine and the elicitation of murine contact sensitivity
Authors: Kimber Ian , Cumberbatch Marie , Coleman John W.
Published: October 2006

We report that challenge of previously contact‐sensitized mice results in a significant increase in the concentration of serum histamine. In an attempt to determine whether this phenomenon might form the basis of an alternative method for the evaluation of elicitation reactions in experimental contact sensitivity, we have compared challenge‐induced increases in ear thickness with elevations in serum histamine. Challenge of sensitized mice revealed that both ear thickness changes and increases in the serum level of histamine were dependent upon the concentration of oxazolone used for sensitization. The kinetics of changes in serum histamine concentration were found to be biphasic, with a small increase measurable 2 h following challenge and the maximal response at 24 or 48 h. In contrast, increases in ear thickness were monophasic, although maximum responses were also observed at 24 h. It is concluded that, although they do not exactly parallel increases in ear thickness, changes in histamine concentration may provide a useful serological correlate of the challenge reaction in contact sensitivity.
Inhalation toxicity of furfural vapours: An assessment of biochemical response in rat lungs
Authors: Gupta Ghanshyam D. , Misra Anil , Agarwal Deepak K.
Published: October 2006

The pulmonary biochemical response, particularly the effects on mixed‐function oxidases, was investigated in rats exposed to 40 ppm furfural for 1 h daily, 5 days per week, for periods of 7, 15 and 30 days. This concentration is ca. 22% of the acute LC50 dose. Exposure to furfural increased the activities of acid and alkaline phosphatases and glutamic‐pyruvic transaminase, inhibited the activities of arginase and succinic dehydrogenases and elevated the concentration of lactic acid in the lungs. In the group of mixed‐function oxidases, the activities of aminopyrene‐N‐demethylase and aniline hydroxylase (phase I, cytochrome P‐450b specific) significantly increased and the activity of Benzo[a]pyrene hydroxylase (phase I, cytochrome P‐450c specific) decreased. The activity of glutathione‐S‐transferase (phase II component) also was increased concurrently with a decrease in the concentration of glutathione. The magnitude of biochemical alterations in most cases was related directly to the duration of exposure. Our observations indicate that furfural caused pulmonary irritation, parenchymal injury and the regenerative proliferation of type II pneumocytes. Selective (cellular and/or cytochrome P‐450 isozyme specific) enhancement of pulmonary mixed‐function oxidases by furfural appears to stimulate its own pulmonary biotransformation, and the excretion of oxidative metabolites was facilitated by their enzymatic conjugation with glutathione.
In vitro effects of organophosphorus compounds on calmodulin activity
Authors: Pala I. , Vig P. J. S. , Desaiah D. , Srinivasan A.
Published: October 2006

In vitro effects of organophosphorus compounds (OP), such as malathion (M), methyl parathion (MP) and ethyl parathion (EP), on calmodulin (CaM) activity and its active conformation were studied to understand the mechanism(s) of neurotoxicity, since CaM is known to regulate Ca2+ transport and the enzymes involved in signal transduction and nucleotide metabolism. The biological activity of CaM was assessed as a measure of phosphodiesterase (PDE) stimulation. The effect of OP compounds on the active conformation of CaM was determined by studying the binding of fluorescence probes, namely N‐phenyl‐1‐naphthylamine (NPN), and changes in dansyl‐calmodulin fluorescence. Dansylated calmodulin was also used to study the effect of OP compounds on complex formation between CaM and PDE. All three OP compounds inhibited the CaM activity and its active conformation in a concentration‐dependent manner. Malathion was less effective in comparison to EP and MP, with IC50 values of 37 μM, 34.5 μM and 32 μM, respectively, for CaM activity. EP and MP significantly altered NPN and dansyl‐calmodulin fluorescence (50 μM concentrations of OP compounds), whereas M did not show any significant effect on NPN fluorescence. All these compounds significantly affected complex formation between the dansylated CaM and PDE. These results suggest that OP compounds may be interacting with CaM, altering its active conformation, and thus may be inhibiting its biological activity.
Triorganotin inhibition of rat cardiac adenosine triphosphatases and catecholamine binding
Authors: Cameron Joseph A. , Kodavanti Prasada Rao S. , Pentyala Srinivas N. , Desaiah Durisala
Published: October 2006

Triorganotins have been reported to affect heme metabolism as well as the cardiovascular system. Our recent studies indicated that these organotins inhibit cardiac sarcoplasmic reticulum Ca2+‐transport and cAMP‐stimulated phosphorylation of specific proteins involved in Ca2+ transport, suggesting their interference with cardiac adrenergic function. The present study determines the effect of three organotins–tributyltin bromide (TBT), triethyltin bromide (TET) and trimethyltin chloride (TMT)–on rat cardiac ATPases and catecholamine binding, since these phenomena are involved in cardiac function. Cardiac membrane fraction was prepared from heart ventricles of male Sprague‐Dawley rats. All three organotins inhibited cardiac Na+,K+‐ATPase, [3H]ouabain binding, K+‐activated p‐nitrophenyl phosphatase (K+‐PNPPase) and oligomycin‐sensitive (OS) and oligomycin‐insensitive (OI) Mg2+‐ATPase in a concentration‐dependent manner. K+‐PNPPase was less sensitive to these triorganotins when compared to Na+K+‐ATPase, suggesting that triorganotins affect the Na+‐pump activity by acting on the Na+‐dependent phosphorylation process. OS Mg2+‐ATPase was more sensitive to these organotins when compared to OI Mg2+‐ATPase, confirming their potent effect on the enzymes of oxidative phosphorylation. The order of potency is TBT > TET > TMT. TET and TMT, but not TBT, inhibited [3H]norepinephrine and [3H]dopamine binding to cardiac membranes in a concentration‐dependent manner, the effect being more with TET. These results suggest that triorganotins inhibit sodium pump activity as well as ATP synthesis. Since Na+,K+‐ATPase is involved in the active transport of catecholamines, triorganotins not only inhibited the catecholamine transport but also to some extent affected catecholamine binding, thus interfering with cardiac function.
Effects of some organophosphorus compounds on the binding of a radioligand (8‐cyclopentyl 1, 3‐[3H]dipropylxanthine) to adenosine receptors in ovine cardiac membranes
Authors: Lau Wai‐Man , Szilagyi Maria , Freeman Shirley E.
Published: October 2006

8‐Cyclopentyl‐1,3‐[3H] dipropylxanthine ([3H]CPX) is a potent radioligand that specifically binds to the A1 adenosine receptors. Its high specificity makes it a suitable ligand for the characterization of A1 adenosine receptors in tissues with low receptor densities. We have demonstrated that the organophosphorus compounds soman, tabun and sarin, at relatively high concentrations, all bind to the A1 adenosine receptors in ovine cardiac membranes with Ki values of 36.7, 328 and 175 μM, respectively. The binding of soman to the receptor site was found to be totally reversible. We suggested that these organophosphorus compounds affect the mechanical responses of the heart through interaction with a potassium channel that does not seem to be closely linked to the A1 adenosine receptors.
Validation of a non‐invasive technique to assess immediate or delayed onset of airway hypersensitivity in guinea‐pigs
Authors: Pauluhn J. , Eben A.
Published: October 2006

Conscious Hartley guinea‐pigs were sensitized with trimellitic anhydride (TMA) or trimeric hexamethylene diisocyanate biuret (Des‐N) by repeated intradermal injections or by inhalation exposure. Immediate‐ and delayed‐onset pulmonary reactions were recorded during/after challenges with the hapten or protein conjugate of the hapten, respectively. The positive control was sensitized and challenged with ovalbumin (OA) by inhalation. Homocytotropic antibodies of the IgGI type were determined to correlate antibody titres and pulmonary responses. Immediate‐onset pulmonary reactions were apparent in guinea‐pigs sensitized by inhalation of TMA and OA. Animals sensitized intradermally with TMA demonstrated more vigorous immediate‐onset reactions than animals sensitized by inhalation. The measurement of breathing parameters demonstrated that the ability to detect immediate‐onset airway hyperreactivity was best when the breathing rate and tidal and minute volumes were measured. None of the measurements for delayed‐onset reactions presented conclusive results, since sensitized as well as naive guinea‐pigs demonstrated a delayed increase of breathing frequency. Antigen‐specific IgG1 antibodies were several orders of magnitude higher in intradermally sensitized animals compared with animals sensitized by inhalation. Although Des‐N‐sensitized guinea‐pigs experienced high IgG1‐antibody titres, no response of pulmonary hypersensitivity could be elicited after hapten or conjugate challenge. In summary, it would appear that pulmonary hypersensitivity depends on factors other than IgGl antibody titres. For the screening of chemicals, the dermal induction and inhalation challenge protocol was revealed to be more sensitive than the inhalation induction and inhalation challenge protocol.
Depression of iron uptake into erythrocytes in mice by treatment with the combined benzene metabolites p‐benzoquinone, muconaldehyde and hydroquinone
Authors: Guy Robert L. , Hu Peidi , Witz Gisela , Goldstein Bernard D. , Snydert Robert
Published: October 2006

Using radio‐iron uptake into erythrocytes as a measure of hematopoiesis, it was demonstrated that p‐benzoquinone (BQ) and muconaldehyde (MUC) are potent inhibitors of bone marrow function in female mice. These two benzene metabolites reduced iron uptake at dosages of <5–6 mg kg−1. The combination of MUC and hydroquinone (HQ) (100 mg kg−1) was additive, reducing iron incorporation to an extent that was the sum of the effect of each chemical given alone. The combined effect of MUC and BQ was significantly less than additive, demonstrating antagonism in the response. Multiple regression was used to study the contributions of the components of binary mixtures of the benzene metabolites (METAB). Data obtained from standard curves of METAB and their mixtures are separable in regression analysis. Thus, for zero interaction of METAB, the responses would be simply additive, while positive and negative interaction would indicate synergy and antagonism, respectively. T‐testing of the data resulted in non‐significant values for the mixture MUC+HQ, indicating zero interaction and an additive response. The negative t‐values obtained for the mixture MUC + BQ, however, indicate negative interaction or an antagonistic response. Since mutually exclusive agents share the same binding sites and occupation of a site by one agent excludes its occupation by another, they cannot interact in producing the effect; combinations of these agents show zero interaction and are simply additive. This suggests that HQ and MUC are mutually exclusive and share the same binding site. Conversely, MUC and BQ are mutually non‐exclusive and this requires the presence of at least two binding sites. These results support the hypothesis that the toxic effects of benzene are produced by several metabolites acting interactively.
Comparative studies of in vitro renal cephaloridine toxicity between normoglycemic and diabetic rats
Authors: Valentovic Monica A. , Jeffrey William , Ball John G. , Bailly Dianne , Morenas Mario , Kinder Jack
Published: October 2006

This study investigated if the attenuation in cephaloridine toxicity associated with streptozotocin (STZ)‐induced diabetes can be attributed to a direct cellular effect. Comparative studies examined the direct toxicity of cephaloridine 14 days after (35 mg kg−1, i.p.) STZ or vehicle injection of male Fischer 344 (F344) rats. In vitro cephaloridine toxicity was assessed by measuring lipid peroxidation, renal gluconeogenesis and organic ion accumulation in renal cortical slices. The in vitro toxicity of cephaloridine was reduced in the diabetic group since lipid peroxidation was not increased following a 120‐min exposure to cephaloridine. This was in contrast to a concentration‐ and time‐dependent increase in lipid peroxidation in renal tissue derived from normoglycemic animals pre‐incubated with 0–5 mM cephaloridine. Renal gluconeogenesis was inhibited in a concentration‐dependent manner in the normoglycemic group following a 15–90‐min exposure to 0–5 mM cephaloridine. Pyruvate‐stimulated gluconeogenesis was diminished in the diabetic group only after a 90‐min preincubation. Renal cortical slice accumulation of p‐aminohippurate (PAH) and tetraethylammonium (TEA) was decreased in the normoglycemic group. Accumulation of TEA, but not PAH, was decreased (P < 0.05) in the diabetic group. These results indicate that in vitro cephaloridine toxicity was attenuated by STZ‐induced diabetes.
Effects of subacute pyridostigmine administration on mammalian skeletal muscle function
Authors: Adler Michael , Deshpande Sharad S. , Foster Robert E. , Maxwell Donald M. , Albuquerque Edson X.
Published: October 2006

The subacute effects of pyridostigmine bromide were investigated on the contractile properties of rat extensor digitorum longus (EDL) and diaphragm muscles. The cholinesterase inhibitor was delivered via subcutaneously implanted osmotic minipumps (Alzet®) at 9 μg h−1 (low dose) or 60 μg h−1 (high dose). Animals receiving high‐dose pyridostigmine pumps exhibited marked alterations in muscle properties within the first day of exposure that persisted for the remaining 13 days. With 0.1 Hz stimulation, EDL twitch tensions of treated animals were elevated relative to control. Repetitive stimulation at frequencies >1 Hz led a use‐dependent depression in the amplitude of successive twitches during the train. Recovery from pyridostigmine was essentially complete by 1 day of withdrawal. Rats implanted with low‐dose pyridostigmine pumps showed little or no alteration of in vivo twitch tensions during the entire 14 days of treatment.

Diaphragm and EDL muscles excised from pyridostigmine‐treated rats and tested in vitro showed no significant alterations in twitch and tetanic tensions and displayed the same sensitivity as muscles of control animals to subsequent pyridostigmine exposures. In the presence of atropine, subacutely administered pyridostigmine protected rats from two LD50 doses of the irreversible cholinesterase inhibitor, soman. In the absence of atropine, the LD50 of soman was not altered by subacute pyridostigmine treatment.
Acute toxicity of 2‐butyne‐1,4‐diol in laboratory animals
Authors: Jedrychowski Ryszard A. , Czajkowska Teresa , Stetkiewicz Jan , Stetkiewicz Irena
Published: October 2006

Acute toxicity of 2‐butyne‐1, 4‐diol (BYD) was evaluated in laboratory animals. The evaluation involved acute oral and dermal toxicity in rats, dermal and ocular irritation in rabbits and skin sensitization in guinea pigs. The oral LD50 values for BYD were 132 mg kg−1 in male rats and 176 mg kg−1 in female rats. Post‐mortem histology showed severe damage in lungs, liver and kidneys. In surviving rats, moderate to severe degenerative changes were observed in the liver but only mild lesions in the kidneys. In acute dermal toxicity studies the test chemical was applied either as a solid substance or as 40% aqueous solution at a dose of 5 g kg−1 for 24 h. Within 48 h of application of the diluted test material, half of the rats died. Liver and kidneys were the primary targets and different stages of degeneration, including necrosis, were observed. No deaths occurred after application of the solid substance. In rabbits, BYD was slightly irritant to skin and eyes. No allergic contact dermatitis was observed in guinea pigs.
Flow cytometry, morphometry and histopathology as biomarkers of benzo[a]pyrene exposure in brown bullheads (ameiurus nebulosus)
Authors: Grady Andrew W. , McLaughlin Ronald M. , Caldwell Charles W. , Schmitt Christopher J. , Stalling David L.
Published: October 2006

Brown bullheads were given a single intraperitoneal dose of 0, 5, 25 or 125 mg kg−1 benzo[a]pyrene (BaP), a carcinogenic polycyclic aromatic hydrocarbon, and evaluated over 18 months. Flow cytometric analyses of hepatocyte DNA content indicated an increase in DNA synthesis in BaP‐exposed fish prior to day 14 post‐exposure. Thereafter, all flow cytometric variables returned to initial levels. Histopathological evaluation of livers from fish sampled at 18 months revealed significant differences among treatments in the amount of hepatic macrophage ceroid pigmentation and basophilic staining intensity. No neoplasms or changes in blood cell DNA content were detected. Significant morphometric variations existed among fish, but differences between sexes overshadowed differences attributable to dose. Flow cytometry yielded no evidence of long‐term DNA alterations from a single exposure to BaP; however, the differences detected by DNA analysis shortly after the toxic event suggest that flow cytometric cell cycle analysis may be useful for documenting continuing exposures.
Tannin content of tea and coffee
Authors: Savolainen H.
Published: October 2006

The tannin content of over‐the‐counter Indian tea, of green coffee beans and of the roasted coffee beans prepared from the same green beans was determined with a radial diffusion ‐ protein precipitation technique and with a spectrophotometric method. The green beans contained 6.6 ± 0.6 mg g−1 weight tannic acid equivalents as found by protein precipitation (n = 5, ± SD) or 6.8 ± 2.3 mg g−1 by spectrophotometry. The same figures for roasted beans were 18 ± 1.7 and 17 ± 2.7 mg g−1, respectively. Tea contained 37 ± 2.6 mg g−1 weight tannic acid equivalents as analysed by spectrophotometry and 24 ± 2.8 mg g−1 by the protein precipitation technique. The latter finding may show that the biological reactivity of tannins is variable, although no major changes in the tannin‐precipitated albumin occurred as shown by electrophoretic analysis. Both methods provide an easy analysis of the reportedly carcinogenic plant tannins.
Comparative lethality of methanol, ethanol and mixtures in female rats
Authors: Youssef Ashraf , Madkour Kadri , Cox Chris , Weiss Bernard
Published: October 2006

The lethalities of pure methanol and pure ethanol were compared to two mixtures of ethanol/methanol with the following percentages (95/5% and 65/35% v/v). This study was conducted to simulate situations of human exposure to denaturated alcohol (by 5% methanol) or adulterated alcohol (by 35% methanol). Four groups of female adult virgin albino rats were treated with the four mixtures. A fifth group was used as a vehicle control. Graded oral doses were given to eight animals per dose. Lethality over 24 h was used as an endpoint. The LD50 was calculated for each of the four treatments on a molar basis. A dose‐response function for each mixture was plotted of percentage lethality vs. mmol kg−1 equivalent to the given ml kg−1 dose. Results showed a significantly different LD50 estimates (P < 0.03) for the four mixtures. The order of lethal toxicity was as follows: 95/5% methanol/ethanol, pure methanol, pure ethanol then 65/35% methanol/ethanol. Slope comparisons indicated two pairs: 65/35% ethanol/methanol and pure ethanol yielding a steep slope, and 95/5% ethanol/methanol and pure methanol yielding a shallow slope. These data indicated that the acute lethality of ethanol/methanol mixtures is a complex unpredictable function. This toxicity presumably depends in a complicated way on the differences in the effective molecular weights of the two alcohols in each of the mixtures.
The effects of cyanide on brain mitochondrial cytochrome oxidase and respiratory activities
Authors: Pettersen John C. , Cohen Steven D.
Published: October 2006

Brain mitochondrial cytochrome oxidase and respiratory activities were compared after in vivo and in vitro exposure to cyanide. For the in vivo studies, mice were exposed to a non‐lethal (4 mg kg−1) or lethal (20 mg kg−1) dose of KCN. From these mice, purified brain mitochondria were prepared and cytochrome oxidase and respiratory activities measured. Results of these experiments revealed greater inhibition of cytochrome oxidase activity following a lethal (20 mg kg−1) than a non‐lethal (4 mg kg−1) KCN dose (57 and 45% inhibition, respectively). Respiration states 3 and 4 of brain mitochondria prepared from mice that received 4 mg kg−1 KCN were inhibted by 15 and 20%, respectively. In mice that received a lethal 20 mg kg−1 KCN dose, respiration states 3 and 4 were each inhibited by ca. 30% (P<0.05). In vitro, mitochondrial cytochrome oxidase activity was inhibited in a concentration‐dependent fashion at cyanide concentrations of 10−6–10−2 M. A biphasic inhibition of ADP‐stimulated (state 3) respiration was observed. Cyanide concentrations of 10−6–10−4 M produced only a 25% inhibition of respiration state 3, whereas 10−3 M produced 80% inhibition. Because this dramatic inhibition only occurred at cyanide concentrations that caused >50% inhibition of mitochondrial cytochrome oxidase activity, these findings suggest that a large proportion of cytochrome oxidase activity may be functional reserve and that cyanide poisoning likely involves other mechanisms in addition to inhibition of cytochrome oxidase.
Comparative study on the effects of five benzoylphenylurea insecticides on haematological parameters in rats
Authors: Tasheva Maria , Hristeva Vessela
Published: October 2006

Five benzoylphenylurea insecticides were administered to male Wistar rats for 28 days at oral doses of 100 mg kg−1 each. Elevation of methaemoglobin was found only in the diflubenzuron‐ and triflumuron treated groups. The number of reticulocytes was increased in all of the treated groups.
Possible Examples of Chemical Hormesis in a Previously Published Study
Authors: Calabrese Edward J. , Baldwin Linda A.
Published: October 2006

A re‐examination of data presented by Daston et al. provided an opportunity to assess the occurrence of chemical hormesis due to the wide dosage range tested and to the large number of treatments within the dosage range. The data revealed numerous examples of possible chemical hormesis for a variety of end‐points measured.
Texicological evaluation of mixtures of ten widely used pesticides
Authors: Chaturved Arvind K.
Published: October 2006

Toxicities of pesticidal mixtures in biological systems have not been explored adequately. Therefore, mixtures of ten widely used pesticides were evaluated for their toxicity in ICR male mice (21–24 g). Mice were given four mixtures of alachlor, aldrin, atrazine, 2,4‐dichlorophenoxyacetic acid, DDT, dieldrin, endosulfan, lindane, parathion and toxaphene, at 0.01, 0.1, 1.0 and 10 ppm of each of these pesticides, in drinking water for 90 days ad libitum. Also, two mixtures at 2.5 and 5 mg kg−1 of each pesticide in 7.5% Tween‐80 in water were administered to additional groups of mice by oral intubation daily for up to 14 days. In relation to the control, the 90‐day exposure caused a dose‐dependent increase in the liver/body weight ratio (3–44%), a decrease in the pentobarbital (60 mg kg−1, i.p.)‐induced sleep time (11–79%) and an increase in the metabolism of aniline (233–399%), amidopyrine (79–231%), phenacetin (127–318%) and benzo[aIpyrene (286–1633%)] in the 9000 g hepatic supernatants from the mixture‐treated mice. Proliferation, dilatation and fragmentation of the endoplasmic reticulum and scattering of ribosomes were noticed with mixture livers. In the 5 mg kg−1 group, 90% of the animals died by Day 8; incidence of death was considerably less in the 2.5 mg kg−1 group. The serum cholinesterase activity was inhibited by ca. 50% in the 2.5 and 5 mg kg−1 groups on either one or both of Days 8 and 15; the liver/body weight ratio increased by 24–79% and the pentobarbital‐induced sleep time decreased by 80–96%. On Days 8 and 15, the in vitro hepatic metabolism of amidopyrine, phenacetin and benzo[a]pyrene in the 2.5 or 5 mg kg−1 group was considerably increased (100–1478%). Findings from this study suggest that these mixtures have the potential to induce the xenobiotic‐metabolizing enzymes in liver; thus, exposures to the pesticidal mixtures might cause deleterious effects in other species, including humans, by enhancing the metabolism of xenobiotics.
Distribution of benzo[a]pyrene in pregnant rats following inhalation exposure and a comparison with similar data obtained with pyrene
Authors: Withey J. R. , Shedden J. , Law F. C. P. , Abedini S.
Published: October 2006

Eight pregnant rats were exposed, on the 17th day of gestation, for 95 min to a microcondensation aerosol of benzo[a]pyrene at five different atmospheric concentrations between 200 and 800 mg m−3 in a ‘head‐only’ inhalation chamber. Five rats were killed immediately following the exposure and three were killed at 6 h post‐dosing. Concentrations of the radiolabel and ‘free’ benzo[a]pyrene were measured in the individual fetuses and in the maternal blood, fat, kidney, liver and lung.

Distribution to the fetus did not appear to be related to its position on the uterine horn and the uptake of benzo[a]pyrene was non‐linear with increasing exposure concentrations, which was similar to the observations previously reported for pyrene. The levels of benzo[a]pyrene were much higher in the fetus and, especially, the lung than those observed in the pyrene study; so also were the levels of total metabolites in these tissues, which might, in part, account for the carcinogenic potency of benzo[a]pyrene.
Organ cadmium deposits in orally exposed female rats and their pups and the depleting efficiency of sodium N‐(4‐methoxybenzyl)‐D‐glucamine‐N‐carbodithioate monohydrate (MeOBDCG)
Authors: Kostial K. , Blanuša M. , Schönwald N. , Arežina R. , Piasek M. , Jones M. M. , Singh P. K.
Published: October 2006

Cadmium was given to female rats in the drinking water (50 ppm Cd) from 4 weeks before mating until weaning (a total of 10 weeks). Four weeks after the discontinuation of exposure, mothers and offspring were then given two i.p. doses of 1 mmol kg−1 sodium N‐(4‐methoxybenzyl)‐D‐glucamine‐N‐carbodithioate monohydrate (MeOBDCG) on subsequent days. Cadmium in kidneys and liver was determined in groups of mothers before mating and in mothers and pups after parturition, at the end of lactation and 4 and 5 weeks after the discontinuation of exposure. An additional measurement was made in pups in the middle of the lactation. period. Cadmium deposition rapidly increased in the two organs between the 11th and 21st day of lactation. At all times, Cd concentrations in the liver and kidneys of mothers were several orders higher than in the offspring. After the discontinuation of exposure, maternal hepatic and renal Cd contents showed a significant decrease. Treatment with the chelator depleted the hepatic Cd stores in mothers by 90% and in pups by 80%, while the corresponding renal depletions were only 23% and 12%, respectively. The liver and kidney contents of Cd (but not the concentration) increased by a higher factor during lactation than during pregnancy and exposure during lactation was also more important for pups than prenatal exposure.

The lower efficiency of the chelator in the offspring indicates that Cd accumulated during the neonatal period was less accessible to treatment with chelating agents than Cd accumulated in later life. It is more likely that with increasing Cd concentration a smaller proportion of Cd is bound to strong binding sites.
The early changes in mouse skin following topical application of a range of middle distillate oil products
Authors: Ingram A. J. , King D. J. , Grasso P. , Sharratt M.
Published: October 2006

A white spirit/naphtha, three kerosines, two gas oils and a catalytically cracked light cycle oil (LCO) were applied topically to mice, three times a week for up to 6 weeks, and skin changes were examined histopathologically at intervals.

The changes within 1 week of treatment appeared to depend on the effect that the physicochemical properties of each type of product had on their penetration through the skin surface or via hair follicles. With white spirit the most prominent change was widespread epidermal necrosis occurring after the second treatment, implying that the lowest boiling point materials penetrate mainly through the surface epidermis. The earliest effects with kerosines were within and around hair follicles with epidermal degeneration developing later, suggesting a predominance of follicular entry. Gas oils and LCO produced similar changes to kerosines within 1 week, gas oils producing a slower and less severe response and LCO a more severe response. In skin examined after 1–6 weeks of treatment with all middle distillates, repeated cycles of necrosis and healing responses were evident; this implied that once the epidermal barrier layer had been damaged, follicular entry became less important.

The severity of the skin changes observed with these middle distillates was probably sufficient for skin tumours to arise by a non‐genotoxic mechanism if a similar treatment regime was used in a long‐term skin painting study. A method of avoiding excessive skin irritation is therefore essential in such a study in order to obtain a reliable prediction of the human hazard of such materials.
Studies on the renal transport of trimethylpentanoic acid metabolites of 2,2,4‐trimethylpentane in rat renal cortical slices
Authors: Lock Edward A. , Strasser Josef , Bus James S. , Charbonneau Michel
Published: October 2006

2,2,4‐Trimethylpentane (TMP), a nephrotoxic component of unleaded gasoline in male but not female rats, undergoes oxidative metabolism to yield 2,2,4‐ and 2,4,4‐trimethylpentanol, pentanoic acid and 5‐hydroxypentanoic acid. We have examined the effect of three of these pentanoic acid metabolites on the renal transport of the organic anion p‐aminohippurate (PAH) and the organic cation tetraethylammonium (TEA) in renal cortical slices from male Fischer 344 rats. 2,4,4‐Trimethylpentanoic acid, the major urinary metabolite in rats, produced a selective decrease in the accumulation of PAH without affecting TEA accumulation. Kinetic analysis showed that 2,4,4‐trimethylpenanoic acid was a competitive inhibitor of the organic anion transport system, with a Ki of 4 mM. 2,4,4‐Trimethyl‐5‐hydroxypentanoic acid also showed selective inhibition of PAH transport, while 2,2,4‐trimethylpentanoic acid was less selective and reduced both PAH and TEA transport. Additional studies with radiolabeled 2,4,4‐trimethylpentanoic acid showed that there was a time‐and concentration‐dependent accumulation of radioactivity into slices of renal cortex. However, experiments conducted at 4°C and studies with metabolic inhibitors, or with an inhibitor of organic anion transport, indicated that little of the accumulated material was entering the cell. We conclude from these studies that the pentanoic acid metabolites formed from 2,2,4‐trimethylpentane are not actively transported by the renal organic anion transport system. In summary, in vitro the pentanoic acid metabolites appear to bind to renal cortical tissue and thereby reduce the transport of PAH.
Leakage of mitochondrial and cytosolic GOT in isolated rat hepatocytes exposed to halothane: An immunohistochemical study
Authors: Kinugawa Hiroshi , Kawahara Michio , Amakata Yoshikuni , Maeda Toshihiro
Published: October 2006

The leakage of mitochondrial (m‐) and cytosolic (s‐) aspartate aminotransferases (glutamic‐oxaloacetic transaminase: GOT) from isolated hepatocytes exposed to halothane was investigated immunohistochemically. In control isolated hepatocytes, a large number of cells were immunopositive (m‐GOT, 85%; s‐GOT, 98.5%) at various intensities. Reaction products of m‐GOT‐immunohistochemistry (m‐GOT‐I) were seen exclusively in mitochondria, while those of s‐GOT (s‐GOT‐I) were seen in the cytoplasm. When treated with low concentrations of halothane (up to 0.75%), the number of strongly m‐GOT‐I‐immunopositive cells was reduced to half, while that of s‐GOT‐I showed no noticeable change. The number of m‐GOT‐I‐immunonegative cells showed a negligible increase, while that of s‐GOT‐I increased gradually. At higher concentrations of halothane (1% or more), strongly immunopositive cells in both m‐ and s‐GOT‐I almost disappeared, while immunonegative cell numbers predominantly increased. This study showed that the isolated hepatocyte system was not homogeneous with regard to the quantity of GOT isozymes, and that halothane could induce the leakage of these isozymes from hepatocytes, along with inducing ultrastructural abnormalities, even at the lowest concentration used (0.5%). Furthermore, the data appear to indicate that the sensitivity of isolated hepatocytes to halothane is dependent on the nature of the hepatocyte itself and on the nature of both types of GOT isozymes.
Inhibitory effect of gomisi on reductive metabolism of halothane
Authors: Jiaxiang Ni , Fujii Kohyu , Sato Nobuyoshi , Yuge Osafumi
Published: October 2006

The effect of Gomisi (dried ripe fruit of schizandra chinensis) on chlorodifluoroethylene (CDE) and chlorotrifluoroethane (CTE) formation was investigated. The incubation mixtures for the measurement of reductive metabolites of halothane consisted of liver microsomal suspensions, 3 mM NADPH, extract solution of Gomisi and halothane in 0.1 M potassium phosphate buffer (pH 7.4). The production of CDE and CTE was inhibited by Gomisi in a dose‐dependent way. The production were reduced to half in the presence of 0.5% Gomisi extract in the reaction mixture. The results suggest that Gomisi can inhibit the reductive metabolism of halothane in vitro; thus it may protect against halothane‐induced hepatitis.
Modulation of hepatic glutathione system of enzymes in suckling mouse pups exposed translactationally to malathion
Authors: Chhabra Saranjit K. , Hashim Shehla , Rao A. R.
Published: October 2006

The present study examines the transmammary modulation of the glutathione system of enzymes in the F1 generation of mouse pups postnatally exposed to malathion. Lactating Swiss albino mice received either 30 or 100 mg malathion kg−1 body wt. (98% pure) for 14 or 21 days postpartum. The acid‐soluble sulphydryl content was significantly increased (P<0.001) in the liver of 14‐day‐old pups of dams that had received the higher malathion dose. A similar significant increase was seen in the 21‐day‐old male pups of dams that had received 30 mg (P<0.05) or 100 mg (P<0.01) malathion kg−1 body wt. Dams showed an enhanced hepatic glutathione S‐transferase activity following treatment with 100 mg melathion kg−1 body wt. for 14 days (P<0.02) and 21 days (P<0.001). Pups of either age groups also showed enhanced hepatic glutathion S‐transferase activity (P<0.001). A significant enhancement in glutathione reductase activity was observed with malathion treatment in livers of dams and pups (P<0.001). However, dams that had received 30 mg malathion kg−1 body wt. daily for 21 days or 100 mg malathion kg−1 body wt. for either 14 or 21 days showed significantly reduced hepatic glutathione peroxidase activity (P<0.01, P<0.001). A significant decrease in glutathione peroxidase activity was also observed in the liver of the 21‐day‐old male (P<0.01) and female (P<0.02) pups of dams that were treated with the higher dose of malathion.
Differential sensitivity of DBA/2 and C57BL/6 mice to cyclophosphamide
Authors: Anton Elsa
Published: October 2006

Early and delayed toxicity of a single dose of 300 mg kg−1 cyclophosphamide (CP) was investigated in male DBA/2 and C57BL/6 mice.

Early toxicity (up to 30 days after CP administration) resulted in 36.6% lethality in DBA/2 and no mortality in C57BL/6 mice. Delayed toxicity (after 30 days) occurred primarily in DBA/2 mice, resulting in a survival of 3% in DBA/2 and 93% in C57BL/6 mice on day 125 after CP administration.

Early modifications brought about by CP in erythrocytes and leucocytes, and spleen and liver indexes (mg organ g−1 body wt.) were rather similar in DBA/2 and C57BL/6 strains. However, CP treatment caused a profound cell depletion in DBA/2 bone marrow owing, in part, to the fact that the number of cells in bone marrow of normal DBA/2 mice was much lower than that in normal C57BL/6 mice. Furthermore, the thymus index (mg organ g−1 body wt.) decreased sooner in DBA/2 than in C57BL/6 animals and no sign of recovery was evident in the former even after 10 days, whereas recovery in the latter started on day 5 after injection.

Differential sensitivity of DBA/2 and C57BL/6 strains to CP could be due to differences in activation and/or inactivation of the drug, or to the increased effect of CP on DBA/2 bone marrow resulting in damage to pre‐T cells that normally participate in thymus recovery.
Correlation between concentrations of n‐hexane and toluene in exhaled and environmental air in an occupationally exposed population
Authors: Periago J. Francisco , Morente Antonio , Villanueva Manuel , Luna Aurelio
Published: October 2006

We determined the correlations between the concentrations of n‐hexane and toluene in exhaled and environmental air in the shoe manufacturing industry. Data were collected in 1988 and in 1992 from a total of 265 subjects. Environmental air samples were collected with personal diffusive samplers by adsorption on activated charcoal during exposure and from end‐expired air (alveolar air) on cartridges of activated charcoal after exposure. Both compounds were desorbed with carbon disulphide and analysed by gas chromatography. Linear regression analyses showed a good correlation between environmental and end‐expired air concentrations (r = 0.82 for n‐hexane and r = 0.81 for toluene). These correlations allowed us to calculate the concentrations in expired air corresponding to current environmental limit values. The calculated concentrations in end‐expired air that correspond to current environmental threshold limit values of 176 mg m−3 for n‐hexane and 377 mg m−3 for tolueneare 28 mg m−3 (95% confidencelimit, 27–29 mg m−3) and 40 mg m−3 (95% confidence limit, 39–41 mg m−3), respectively. Similar correlations were found when the data from the two study periods were analysed separately.
Interactions of αNi3S2 with Guinea pig alveolar macrophages and liberation of inflammatory mediators
Authors: Teissier E. , Shirali P. , Hannothiaux M. H. , Marez T. , Haguenoer J. M.
Published: October 2006

Our previous investigation presented evidence of interaction between αNi3S2 and membranous and cellular lipids of lung cells, resulting in significant increases in linoleic, linolenic and arachidonic acids. The present work was designed to follow the metabolic fate of arachidonic acid in αNi3S2‐exposed guinea pig alveolar macrophages (GPAM) in culture (50 μM αNi3S2 for 3 days).

The metabolites of arachidonic acid were assessed by HPLC coupled with UV or electrochemical detection. The concentrations of malondialdehyde (MDA), hydroxyeicosatetraenoic acid (HETE), leucotrienes (LT) and reduced glutathione (GSH) were measured.

In exposed cells a significant increase of MDA, a breakdown product of lipid peroxidation, was observed. In addition, the enzymatic reduction of 5‐hydroperoxyeicosatetraenoic acid (5‐HPETE) by the associated oxidation of GSH to GSSG increased 5‐HETE in GPAM cells and decreased GSH. 5‐Hydroperoxyeicosatetraenoic acid was furthermore converted to epoxides, such as leucotriene A4, and we also quantified in exposed cells a signficant increase of its subsequent catabolites LTB4, LTC4 and LTE4.

Direct measurements of MDA and other metabolites of arachidonic acid clearly show that exposure of GPAM cells to αNi3S2 enhances lipid peroxidation. This lipid peroxidation is an autocatalytic free‐radical process and could be responsible for DNA damage. Furthermore, αNi3S2 intoxication induces the release of proinflammatory products, such as leucotrienes, and the decrease of glutathione.