bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of cadmium on succinate and NADH‐linked substrate oxidations in rat hepatic mitochondria
Authors: Cameron I. , McNamee P. M. , Markham A. , Morgan R. M. , Wood M.
Published: October 2006

Low concentrations of cadmium (3.3–40 μM) inhibited State 3 NADH‐linked respiration in rat hepatic mitochondria, but failed to release oligomycin (1 μM) inhibited State 3 respiration, or to significantly change the State 4 rate. In the presence of succinate, (40 μM) cadmium inhibited State 3 respiration by 89%, while concentrations between 3.3 and (13.3 μM) stimulated State 4 respiration. Higher concentrations caused marked inhibition. In the presence of succinate, cadmium released oligomycin inhibited State 3 respiration. Cadmium (0.001–1.0 mM) did not stimulate mitochondrial ATPase activity or inhibit ferricyanide reduction, but stimulated NAD+ linked mitochondrial dehydrogenase activities and NADH oxidation. These results indicate that cadmium interacts with either the NADH dehydrogenase complex or other NADH‐dependent enzymes and solely by an uncompling action.
Effect of variable versus fixed exposure levels on the toxicity of acetaldehyde in rats
Authors: Appelman L. M. , Woutersen R. A. , Fcron V. J. , Hooftman Ria N. , Notten W. R. F.
Published: October 2006

The effects of exposure pattern on the toxicity of acetaldehyde vapour were investigated in 4‐week inhalation studies. Male rats were exposed to 500 or 150 and 110 ppm for 6 h per day/5 days per week. One group of animals was exposed without interruption, the exposure of a second group was interrupted for 1.5 h between the first and second 3‐h periods, the exposure of a third group was similarly interrupted and for six 5 min periods exposure was increased sixfold.

Peak exposures of up to 3000 ppm superimposed on 500 ppm acetaldehyde caused irritation and excitation, and reduced body weight gain. No such effects occurred after interrupted or uninterrupted exposure to 500 ppm acetaldehyde without peak loads. A reduced phagocytotic index of lung macrophages was found in each of the groups exposed to 500 ppm acetaldehyde, the effect being most marked in the group with superimposed peaks of 3000 ppm. Degeneration of the nasal olfactory epithelium was observed in rats uninterruptedly exposed to 500 ppm acetaldehyde. Interruption of the exposure or interruption combined with peak exposure did not visibly influence this adverse effect on the nose. No compound‐related effects were seen in rats interruptedly or uninterruptedly exposed to 150 ppm acetaldehyde can be considered a ‘no‐toxic‐effect level’ in male rats exposed for 6 h/day, 5 days/week, during a 4‐week period.

It was concluded that the interruption of daily exposure by 1.5 h exposure‐free period or by the superimposition of six times 5 min peak exposure periods did not appreciably influence the nasocytotoxic potency of acetaldehyde. Futhermore for inhalation toxicity testing of irritants such as acetaldehyde the use of variable exposure patterns does not seem to produce more relevant toxicity data than the use of uninterrupted daily exposure to a fixed concentration.
Toxic and genotoxic action of electric‐arc welding fumes on cultured mammalian cells
Authors: Baker R. S. U. , Arlauskas A. , Tandon R. K. , Crisp P. T. , Ellis J.
Published: October 2006

Welding fumes generated by manual metal arc welding (MMAW) with an automatic welding machine were extracted with water and both the soluble and insoluble fractions were investigated for mitotic delay and for sister chromatid exchange (SCE) induction in cultured Chinese hamster Iung (Don) cells. Five flux‐coated electrodes of varying composition were chosen as representative of those available. In general, watersoluble and water‐insoluble fractions induced SCE in proportion to their chromium (VI) content, and any contribution from chromium(III), fluorides, nickel, manganese or other fume constituents was minor. However, mitotic delay could not be explained in terms of the chromium(VI) concentration alone. This indicated that other components of both the soluble and insoluble fractions of the fumes were capable of inducing mitotic delay. The activity of insoluble fume fractions, either in mitotic delay‐ or in SCE‐induction, was markedly less than than that of soluble fractions. This was presumably because of the lower, though still significant, bioavailability of ‘insoluble’ components of the fume particles.
Time development of distribution and toxicity following single toxic APAP doses in male BOM:NMRI mice
Authors: Skoglund L. A. , Ingebrigtsen K. , Nafstad I. , Jansen J. Høgset
Published: October 2006

The time development of the biodistribution and the hepatotoxicity following peroral administration of 14C‐acetaminophen (APAP 400 or 800 mg.kg−1; 1μCi) was characterized in a trial procedure using male Bom:NMRI mice. APAP (400 mg.kg−1) caused a transitory hepatic glutathione (GSH) depletion while APAP 800 mg.kg−1 maximally depleted hepatic GSH throughout the 12 h trial period. A lag time between the initial GSH depletion and the ensuing hepatic necrosis was seen. From 8 h post dosing a decrease of 14C‐APAP or its metabolites coincided with recovery of the hepatic GSH level and the regeneration of the hepatic cells caused by APAP 400 mg.kg−1. Hepatic glycogen depletion preceded centrilobular necrosis, and irrespective of APAP dose definite kidney damage was absent. Irrespective of APAP dose the biodistribution of 14C‐APAP or its metabolites was predominantly in organs associated with metabolism and excretion. After APAP (800 mg.kg−1) significant amounts of 14C‐APAP or its metabolites were present up to 24 h post dosing. The operative status of the hepatic GSH conjugative system has an important influence on the rate of elimination of toxic APAP doses. Hepatic cell necrosis with a possible effect on the circulation may play an important secondary role in the elimination of toxic APAP doses. Factors which may influence the status of the hepatic GSH conjugative system and toxicokinctics of perorally administered APAP doses are discussed.
Induction of superoxide dismutase isozymes in rabbit lung due to aniline exposure
Authors: Kakkar Poonam , Viswanathan P. N.
Published: October 2006

Single exposure of rabbits to aniline vapors caused induction of superoxide dismutase isozymes and activity as evidenced by the incorporation of radioactive amino acids and prosthetic group metals into enzymatic protein zones of electrophoreograms. Induced of a new cytosolic isozyme following aniline exposure was also evident. Xenobiotic stress indicated a close relation between free radical processes and lung biotransformation mechanisms.
Nephrotoxic effect of Tris(2,3‐dibromopropyl) phosphate on rat urinary metabolites: Assessment from 13C‐NMR spectra of urines and biochemical and histopathological examinations
Authors: Fukuoka Masamichi , Takahashi Terue , Tanaka Akira , Yamaha Tsutomu , Naito Katushi , Nakaji Yukio , Kobayashi Kazuo , Tobe Masuo
Published: October 2006

Rats received either single oral doses of 0, 25, 50, 100 and 200 mg/kg tris(2,3‐dibromopropyl)phosphate (Tris‐BP) or repeated doses of 50, 100 and 200 mg/kg/day Tris‐BP for 7 days. Urine was collected over a 24‐hr period and subjected to 13C‐NMR and biochemical examinations. Tris‐BP produced significant increases of urinary glucose and lactate. Urinary γ‐glutamyitransferase, lactate dehydrogenase and alkaline phosphatase levels were significantly elevated on the first 2 days of post‐treatment. Histopathologically, the kidney exhibited proximal tubular damage at a dose of 200 mg/kg. There was a good correlation among the histopathological, biochemical results, and the 13C‐NMR urinary metabolite fingerprints in the assessment of Tris‐BP‐induced renal damage. The abnormal patterns of metabolite excretion suggested that the lesions produced by Tris‐BP were caused by changes in the metabolic function of tubular epithelial cells. The urinary excretion of lactate, enzymes and inhibition of glucose reabsorption from the tubular lumina may be attributed to necrosis and desquamation of the tubular cell.
The effect of lead on chemical‐ and viral‐induced tumor production in mice
Authors: Blakley B. R.
Published: October 2006

Female Swiss mice were exposed to lead in the drinking water at concentrations ranging from 0 to 1000 ppm for 105 or 280 day periods of time. The effect of lead on urethan‐induced pulmonary adenoma formation was evaluated in the 105 day study. Urethan‐induced sleeping times observed following ip injection of urethan (1.5 mg/g) after 3 weeks of lead exposure were not altered by lead indicating that lead did not affect the rate of urethan elimination. Pulmonary adenoma formation was evaluated 84 days later. Lead exposure did not affect the number of tumors produced, nor did it alter the mean tumor diameter in the lead treatment groups. This suggests that the immunosuppressive activity of lead does not enhance urethan‐induced adenoma formation. In the 280 day study, the incidence of spontaneous murine lymphocytic leukemia was evaluated. Leukemia was observed in all treatment groups. Mortality was greater in the lead‐exposed mice. Mice exposed to 50 or 1000 ppm lead had 41.6% and 58.3% more deaths associated with the virus. The median survival time was also reduced in the lead‐exposed mice. It appears that the immunosuppressive effects of lead allow for increased expression of the murine lymphocytic leukemia virus.
A comparison of a sheep bioassay and a chemical assay used to estimate the toxicity of lupin stubbles infected with Phomopsis leptostromiformis
Authors: Hancock G. R. , Allen J. G.
Published: October 2006

Fifteen lupin stubble samples were tested for toxicity using a sheep bioassay and a chemical assay. A good association, in the functional form of a quadratic equation, existed between the results provided by the two assays. Only 16% of the variance of the chemical assay results was not associated with the sheep bioassay results.
The assessment of chemically induced liver injury in rats
Authors: Pritchard D. J. , Wright M. G. , Sulsh S. , Butler W. H.
Published: October 2006

The object of this investigation was to study the relationship between acute hepatic injury and blood coagulation. Most of the clotting factors are synthesised by the hepatocytes and therefore it would seem likely that hepatic injury would lead to an impairment of blood clotting.

Dimethylnitrosamine (DMN) and carbon tetrachloride (CCI4) were selected as model hepatotoxins to induce an acute hepatic lesion. Single doses of each compound were administered to male rats and groups of animals killed 3, 6, 16 and 24 h later in order to study the morphological development of the lesion and to relate this to changes in the haematological profiles. Both compounds produced a centrilobular necrosis, but with DMN there was a haemorrhagic component due to damage to endothelial cells, which contrasts with the classical coagulative necrosis produced by CCI4. After 6 h apoptosis was commonly seen in the centrilobular areas of the DMN treated rats. This process of cell death has not previously been demonstrated in chemically induced acute hepatic injury and was not seen in the CCI4 treated rats. Significantly prolonged clotting times were seen in both DMN and CCI4 treated rats and occurred in parallel with some of the early morphological changes but prior to the appearance of extensive haemorrhagic or coagulative necrosis. This preliminary data suggests that the measurement of blood coagulation times may provide a relatively specific and sensitive indicator of acute hepatic injury in rats.
Development of a reconstituted water medium and preliminary validation of the Frog Embryo Teratogenesis Assay—Xenopus (FETAX)
Authors: Dawson Douglas A. , Bantle John A.
Published: October 2006

A reconstituted water medium was developed for use in the Frog Embryo Teratogenesis Assay—Xenopus (FETAX). FETAX solution was then tested on three compounds with known mammalian teratogenicity (ethanol, caffeine, and 5‐fluorouracil) as was a non‐teratogen (saccharin). The results obtained were then compared with results from tests on these compounds in two other media that had previously been used in the assay. Saccharin was not teratogenic. Ethanol and caffeine were weak and moderate teratogens, respectively. 5‐fluorouracil was a strong teratogen. The results compare favorably with those obtained in mammalian studies. The amount of growth inhibition in embryos in the 96 h tests was positively correlated with the degree of teratogenicity of the compound. Final validation of FETAX will allow it to be used to screen and rank compounds for further testing and as a tool for studying the basic mechanisms of teratogenesis.
Studies on γ‐glutamyl transpeptidase (GGT) after Di(2‐ethylhexyl) phthalate (DEHP) exposure
Authors: Parmar Devendra , Srivastava Satya P. , Seth Prahlad K.
Published: October 2006

Administration of Di(2‐ethylhexyl)phthalate (DEHP) at doses of 250, 500, 1000 and 2000 mg/kg to adult rats was found to significantly increase the activity of γ‐glutamyl transpeptidase (GGT) in liver and serum in a dose‐dependent manner. The data indicate that DEHP can be hepatotoxic since an increase in serum GGT levels are indicative of hepatobiliary dysfunction and liver malignancy. An assay of GGT in serum of the individuals exposed to DEHP could be helpful in early detection of liver disorders due to this widely used plasticizer.
Time‐course studies of the distribution of [1–14C] acrylonitrile in rats after intravenous administration
Authors: Silver E. H. , Szabo S. , Cahill M. , Jaeger R. J.
Published: October 2006

Intravenous injection of acrylonitrile (ACN) causes adrenal hemorrhagic necrosis. ACN and its metabolites react with glutathione and bind covalently with macromolecules. Hence the purpose of this investigation was to measure the distribution and covalent binding of radiolabel derived from [1‐14C]ACN in order to detemine whether binding of ACN or its metabolites may be implicated in the pathogenesis of ACN‐induced adrenal injury. Following intravenous injections of ACN, concentrations of total radiolabel were highest in the blood, liver, duodenum, kidneys, and adrenals. Except for blood, there was a time‐dependent decrease in total radiolabel in these tissues. Compared with other major organ systems, the levels of covalently bound radiolabel were lower in the adrenal glands. These results do not support a role of covalent binding of ACN or its metabolites in the adrenal toxicity of ACN, but suggest that the initial high concentrations of total radiolabelled compounds derived from ACN could play a role in the action of ACN on the adrenal glands.
Acute inhalation toxicity of 3,3‐dimethyl‐2‐butanol in sprague‐dawley rats
Authors: James John T. , Infiesto Bernardita P. , Landauer Michael R.
Published: October 2006

Sprague‐Dawley rats were given 15, 70 and 140 min exposures to 15 mg/l 3,3‐dimethyl‐2‐butanol, pinacolyl alcohol (PA), or 6‐hour exposures to 0.2, 1.0 and 5.0 mg/l PA (1 mg/l = 240 ppm). A 50% mortality rate was obtained at the longest exposure to 15 mg/l. Sex related differences in the blood levels of PA and pinacolone were noted, and the surviving male rats failed to gain weight normally in the first week after exposure. In rats exposed to 5.0 mg/l for 6 hours, there were reductions in horizontal and vertical activity and the minute volume was 55% of controls at the end of exposure. Like many secondary alcohols, PA poses only a possible Inhalation hazard; however, male rats may be somewhat more susceptible than females.
Subchronic dermal toxicity studies of alcide Allay® gel and liquid in rabbits
Authors: Abdel‐Rahman Mohamed S. , Skowronski Gloria A. , Turkall Rita M. , Gerges Samy E. , Kadry Abdel‐Razak , Abu‐Hadeed Ali H.
Published: October 2006

Alcide® is a germicidal agent which is highly effective in killing a wide range of bacteria and fungi. 2.0 g kg−1 Allay® gel or placebo were applied once per day while 3.0 g kg−1 Allay® liquid or placebo were administered three times per day over a 30 day period to the skin of albino rabbits. Allay® gel and liquid contained either of two concentrations of sodium chlorite and lactic acid as active ingredients. The concentration of active ingredients, sodium chlorite and lactic acid, in the low dose gel was 25% of high dose gel and low dose liquid was 60% of high dose liquid. Moderate to severe erythema was observed only in the high dose gel group after 7 days of treatment, but skin appeared visibly normal by day 18. Histologically fixed skin at day 30, however, showed inflammatory changes in the high and low dose gel groups and hyperkeratosis in all gel groups. At the termination of the study, mean corpuscular hemoglobin concentration decreased significantly in the Allay® gel and liquid groups compared to an untreated control group. In all gel treatments, BUN/creatinine levels decreased significantly. Hematology and clinical chemistry parameters, however, were within the normal range of values for the gel and liquid groups, indicating no clinically significant changes due to Allay® treatment. Pancreas/body weight ratios were significantly reduced in all gel groups, while spleen, pancreas and ovary/body weight ratios were significantly higher in both liquid dosage groups. No histotogical changes were observed in any of these organs.
One‐year inhalation toxicity study of formaldehyde in male rats with a damaged or undamaged nasal mucosa
Authors: Appelman L. M. , Woutersen R. A. , Zwart A. , Falke H. E. , Feron V. J.
Published: October 2006

To study the effect of bilateral intranasal electrocoagulation damage on the susceptibility of rats to formaldehyde vapour, male Wistar rats with a damaged or undamaged nasal mucosa were exposed to atmospheres containing 0, 0.1, 1 or 10 ppm formaldehyde vapour during 6 h/day, 5 days/wk for 13 or 52 weeks.

Electrocoagulation damage was induced in the anterior third part of the nose. The repair process followed the pattern of wound healing. Loss of turbinates and perforation of the septum were common irreversible findings. After 13 weeks basal cell hyperplasia and squamous metaplasia of the respiratory epithelium, and rhinitis were still visible. After 52 weeks effects attributable to electrocoagulation were slight basal cell hyperplasia and some rhinitis. Major formaldehyde‐related adverse effects in the 10 ppm group not subjected to electrocoagulation included growth retardation, reduced urine production, and rhinitis accompanied by squamous metaplasia of the nasal respiratory epithelium. No adverse effects were seen at 0.1 or 1 ppm in rats with an intact nasal mucosa.

The principal untoward effects of formaldehyde in electrocoagulation‐treated rats seen after 13 and/or 52 weeks comprised increase in basal cell hyperplasia, squamous metaplasia of the nasal respiratory epithelium, damage to the olfactory epithelium at 10 ppm, and focal squamous metaplasia of nasal respiratory epithelium at 0.1 and 1 ppm.

Major conclusions were: (a) the rat nose damaged by electrocoagulation is more susceptible to the cytotoxic action of formaldehyde than the undamaged nose, (b) 10 ppm formaldehyde has no adverse effect on organs remote to the site of entry in rats with an undamaged nose, and (c) 1 ppm formaldehyde did not visibly affect the intact nasal epithelium.
Nucleophilic index value: Implication in the protection by indole‐3‐carbinol from N‐nitrosodimethylamine cyto and genotoxicity in mouse liver
Authors: Shertzer H. G. , Tabor M. W.
Published: October 2006

A novel assay system was developed in order to quantitate the nucleophilicity of pure chemicals or tissue extracts. This Nucleophilic Index Value (NIV) assay was based on the ability of putative nucleophiles to inhibit the methylation of cysteine by limiting concentrations of the electrophilic source, N‐methyl‐N‐nitrosourea (MNU). Efficacy of model and cellular nucleophiles was quantitated as nmol cysteine protected by the nucleophile from methylation by MNU/h/mM compound. The NIVs of the pure compounds ascorbate, glutathione, 4‐(4‐nitrobenzyl)‐pyridine (NBP) and indole‐3‐carbinol (I‐3‐C) were 2400, 1600, 3 and 0, respectively. When mice were treated with I‐3‐C by gavage at dosages of 0, 25, 50, 75 or 100 mg/kg body wt, the NIV for ethyl acetate extracts of the livers 1 h after treatment were 0, 33, 47, 52 and 92 nmol cysteine preserved/h/g tissue, respectively. The I‐3‐C enhancement of NIV was not attributable to ascorbate or glutathione, neither of which were present in the ethyl acetate extracts of liver. When mice were treated with 10 mg N‐nitrosodimethylamine (NDMA)/kg body wt 1 h after the varying dosages of I‐3‐C, the 24 h post‐NDMA plasma alanine transaminase (ALT) values were decreased by I‐3‐C pretreatment in a dose‐dependent fashion. Plasma ALT values were used in this study as an indicator of hepatotoxicity. The coefficient of determination, r2, computed from the linear least squares correlation coefficient between NIV and ALT values, was 0.80 (0–100 mg I‐3‐C/kg) and 0.97 (0–75 mg/kg). In addition to cytological protection from NDMA toxicity, I‐3‐C pretreatment significantly reduced NDMA mediated DNA single strand breakage. The degree of protection was about 60% for both NDMA mediated ALT release and DNA strand breakage. The data are consistent with the hypothesis that I‐3‐C in vivo provides protection from NDMA cyto and genotoxicity by virtue of enhancing the ability of the hepatocyte to scavenge reactive electrophiles, thus protecting cellular nucleophilic sites that are critical for normal function.
The evaluation of HBDH and LDH isoenzymes in cardiac cell necrosis of the rat
Authors: Barrett R. J. , Harleman J. H. , Joseph E. C.
Published: October 2006

The total LDH, HBDH and LDH isoenzyme activities were assessed in a number of rat tissues. HBDH did not correlate with LD1 and LD2 isoenzyme activity in tissues with high HBDH activity. HBDH therefore cannot be used as a marker for cardiac necrosis in the rat. In rats treated with isoprenaline and SK&F 94120 at doses producing myocardial necrosis, only the LD1 isoenzymes showed any significant change but only within the first 24 h of treatment. No statistically significant differences were seen in the plasma AST, CK, CK‐MB and total LDH activities.
Experimental design for the C3H/10T½ CL8 cell transformation assay
Authors: Oshiro Y. , Balwierz P. S. , Piper C. E.
Published: October 2006

The C3H/10T1/2 CL8(10T½) cell transformation assay has been used as an important in vitro tool for screening potential carcinogens. In this paper we describe an experimental design that increases the sensitivity and specificity of the assay. One half of the total dishes was allocated to the solvent control and the other half was equally subdivided into four treatment dose groups of low to high cytotoxic effects. The transformation frequency was calculated on the basis of the number of dishes with Type III foci. Each treatment group, as well as the pooled treatment groups, was compared to the solvent control using Fisher's exact test. The sensitivity of our design, as evaluated by power analyses, greatly exceeded that of a standard test design in which about 20 dishes are allocated to each of the control and treatment groups. Furthermore, our use of an expanded number of control and treatment dishes reduces the chance for both false positive and false negative responses. Our experimental design is illustrated with data from experiments in which the transforming potential of two drugs, dimenhydrinate and SC‐32006, was examined.
The effects of carbon monoxide on persistent changes in young rat heart: Cardiomegaly, tachycardia and altered DNA content
Authors: Penney David G. , Gargulinski Richard B. , Hawkins Beverly J. , Santini Ronald , Caldwell‐Ayre Theresa M. , Davidson Scott B.
Published: October 2006

Newborn rat pups that inhale 500 ppm carbon monoxide (CO) for 32 days and develop increased heart mass (i.e. cardiomegaly) show persistent cardiomegaly and elevated resting heart rate as adults. Studies were carried out to explore the relationship of these phenomena to CO concentration and initial cardiomegaly using exposures of 350, 500 and 700 ppm CO. Initial cardiomegaly was greater in the right ventricle free wall (RV) than in the left ventricle plus interventricular septum (LV+S) at all three CO concentrations, and RV mass excess increased with CO concentration. Initial RV cardiomegaly was greater at 350 and 700 ppm CO in females than in males. Persistent cardiomegaly in the RV also increased with CO concentration, and was significantly greater in the females. Persistent cardiomegaly in the RV increased with initial cardiomegaly but at a decreasing rate at the higher CO concentrations, and when expressed as a percentage of initial cardiomegaly (i.e. “efficiency”), the relative response was greatest at 500 ppm CO. For LV+S, efficiency of development of persistent cardiomegaly was greatest at 350 ppm CO. Persistent tachycardia increased with CO concentration in males but failed to do so in females, and was only weakly correlated with degree of persistent cardiomegaly. Thus, persistent cardiomegaly and persistent tachycardia (in males) are related to CO concentration. Myocardial DNA content of 32‐day‐old juveniles was significantly increased at 350 and 700 ppm CO. Adult DNA content of the RV was significantly elevated at 350 ppm CO (females) and continued to rise with CO concentration. DNA concentrations of the RV and LV were increased at 700 ppm CO. The case is argued that altered cardiac DNA content and concentration indicates persistent cellular‐level changes (i.e. ‘cellular remodeling’), also related to CO concentration.
Protection against carbon tetrachloride‐induced hepatotoxicity by protein A
Authors: Singh K. P. , Saxena A. K. , Zaidi S. I. A. , Dwivedi P. D. , Srivastava S. P. , Seth P. K. , Ray P. K.
Published: October 2006

Protection from carbon tetrachloride (CCl4)‐induced hepatotoxicity by protein A was assessed histologically in rats. Carbon tetrachloride exposure produced swollen, vacuolated and necrotic cells in the centrilobular region of the hepatocyte in rats. Animals given protein A prior to and during CCl4 treatment showed a complete absence of hepatic lesions. Our study showed that protein A, a potent immunomodulator, has the potential to reduce liver injury caused by carbon tetrachloride, a known hepatotoxin in the rat.
Assessment of the relative hazard involved with airborne irritants with additional hepatotoxic or nephrotoxic properties in mice
Authors: de Ceaurriz J. , Gagnaire F. , Ban M. , Bonnet P.
Published: October 2006

This paper deals with the conversion of the hepatotoxicity of 1,2‐dichlorobenzene (DCB), the nephrotoxicity of hexachloro‐1,3‐butadiene (HCBD) and the respiratory effects of these two toxicants into quantal data. It aims to provide some useful information on the best strategy used for safety evaluation. A reflex bradypnea indicative of irritation of the nasal cavities of mice occurred during a 15‐min oronasal exposure to each chemical. A reduction in the development of staining for liver glucose‐6‐phosphatase (G6‐phosphatase) and an increase in the number of damaged tubules in cryostat kidney sections stained for alkaline phosphatase were the measure of toxicity in mice subjected to a whole‐body 4‐h exposure to DCB and HCBD vapours, respectively. The immediate irritant responses, as well as the delayed liver and kidney responses, were measured at the peak of the chemical's action. These maximum responses were then used to establish the relationships of exposure level effects and also the median active levels of exposure (MALs). The DCB and HCBD MALs responsible for a 50% decrease in the respiratory rate of mice (RD50) were 181 and 211 ppm, respectively. The MAL required for eliciting a 50% decrease in G6‐phosphatase staining intensity in DCB‐exposed mice was 598 ppm and that associated with 50% of damaged tubules in HCBD‐exposed mice was 7.2 ppm. On the basis of these quantitative data, potency ratios indicated that irritation and kidney injury are the primary manifestations of toxicity associated with short‐term exposure to DCB and HCBD, respectively. It is suggested that profiles of acute toxicity similar to that of DCB or HCBD may be useful in assessing the relative hazard involved with airborne chemicals.
Control of nephrotoxicity in the rat during repeated cis‐platinum treatments
Authors: Jones Mark M. , Basinger Mark A.
Published: October 2006

The nephrotoxicity of cis‐platinum (CDDP) in the rat can be controlled throughout a series of weekly administrations of CDDP (each of 5 mg kg−1, i.v.) for at least three weeks by a combination of protective measures involving pretreatment with dithiocarbamates and diuretics and the administration of appropriate dithiocarbamates given 1h after the CDDP. The use of dithiocarbamates with polar substitutents is effective in removing both renal and hepatic deposits of platinum from rats subsequent to its administration and in this respect these compounds are significantly superior to meso‐2,3‐dimercaptosuccinic acid (DMSA) in the rate at which platinum is removed and in the amounts removed. The most effective of the dithiocarbamates remove ca. 70% of the platinum from the kidneys and the liver; the least effective remove ca. 50% of the platinum from these organs when given at a level of 1.57 mmol kg−1 i.p. for 6 days subsequent to the administration of CDDP. Acetazolamide was shown to be much less effective in preventing renal damage than the dithiocarbamates and was not effective in reducing renal or hepatic levels of platinum. Pretreatment with sodium diethyldithiocarbamate 12h prior to the administration of the CDDP was more effective in preventing renal damage than the administration of this compound 30 min before the cis‐platinum. Several dithiocarbamates are found to be superior to sodium diethyldithiocarbamate in reducing renal platinum burdens of rats given CDDP at the level of 6 mg kg−1, and dose—response curves for the removal of renal and hepatic platinum were determined for sodium N‐methyl‐D‐glucamine dithiocarbamate (NaG). The use of dithiocarbamates, other than sodium diethyldithiocarbamate, to control the nephrotoxicity of CDDP may possess some advantages in the clinic.
Mechanism of testicular atrophy induced by Di‐n‐butyl phthalate in rats. Part 1
Authors: Fukuoka Masamichi , Tanimoto Tsuyoshi , Zhou Yu , Kawasaki Nana , Tanaka Akira , Ikemoto Isao , Machida Toyohei
Published: October 2006

Repeated oral doses of di‐n‐butyl phthalate (DBP) to male rats caused a decrease in testicular fructose and glucose and a sloughing of the germ cells on the first day of treatment. On day 2, more severe sloughing was seen and was accompanied by decreases in testicular iron and zinc levels and increases in the level of inositol and cholesterols. The sloughing was followed by atrophy, accompanied by dissociation of the germ cells from the Sertoli cells and reduction of triglycerides, cholesterols and phospholipids containing choline and ethanolamine residues in the testis.
A versatile mercury vapour generating system suitable for long‐term inhalation experiments
Authors: Magos L. , Hudson A. R.
Published: October 2006

A mercury vapour generating system is described that is based on the reduction of HgCI2 by SnCI2 in the input airstream of the inhalation chamber. The solutions of the two chemicals are pumped by peristaltic pumps from reservoirs through a miniature mixing chamber into the upper part of a sloping glass tube (reduction chamber) through which air is sucked into the inhalation assembly. The liquid flows down the slope and through a port into a Quickfit flask. Reservoirs can be filled and the collecting flask emptied without interruption of exposure. The desired vapour concentration is achieved by varying the rate of mercury injection and the rate of airflow. Concentration in the inhalation chamber can be measured by passing air through a mercury vapour monitor or by radioactivity when 203HgCI2 is used and a known volume of air is passed through a hopcalite absorber. Operation instructions and an experimental example with mice are given.
Nasal irritation and pulmonary toxicity of aliphatic amines in mice
Authors: Gagnaire F. , Azim S. , Bonnet P. , Simon P. , Guenier J. P. , De Ceaurriz J.
Published: October 2006

The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 15‐min oronasal exposure to increasing concentrations of twenty aliphatic amines. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each test compound. Moreover, eight out of the twenty amines were tested for pulmonary toxicity in mice and for the effects of a 120‐min exposure on the respiratory rates of non‐anaesthetized, traheally cannulated mice (RD50TC). Both allylamine and diallylamine showed RD50 values of 9 ppm and 4 ppm, respectively, while the RD50 values associated with exposure to saturated amines ranged from 50 to 200 ppm. Among the eight amines tested for both upper airway irritation and pulmonary toxicity, diisopropylamine and di‐n‐butylamine showed a RD50TC/RD50 ratio of <1, indicating that the respiratory toxicity induced by these two amines would be related primarily to pulmonary effects. On the basis of prior predictions proposed for upper airway irritants, tentative standards are given for ten amines. Moreover, it is suggested that the basis of standards for industrial exposure to diisopropylamine and di‐n‐butylamine should be specified.
Transient renal impairment in rats after oral exposure to diethylene glycol
Authors: Freundt K. J. , Weis N.
Published: October 2006

Volume, specific gravity, creatinine, lactate dehydrogenase (LDH), leucine aminopeptidase (LAP), betagalactosidase (GAL), leucocytes, erythrocytes, nitrite, protein (albumin), glucose, ketone, urobilinogen, bilirubin and pH were estimated in urine of rats after single (by gavage) or repeated (via drinking water) oral administration of diethyiene glycol (DEG). Following single or repetitive doses (daily over 90 days) of 0.2 g DEG kg−1 body weight, no change in renal function was observed (no effect level). In urine of rats treated once with 0.7 g DEG kg−1 body weight, LDH activity was significantly enhanced one day after treatment. A single dose of 2.0 g DEG kg−1 body weight resulted in an additional rise in urinary GAL activity two days after treatment, a significant rise of urinary volume and a decrease in creatinine concentration and pH on the first day. One day following a single dose of 8.0 g DEG kg−1 body weight, in addition to the changes mentioned before, LAP activity was significantly elevated and the specific gravity decreased. However, in all experiments the wet weight of the kidneys remained normal as compared to controls. The results thus show dose‐dependent changes in several renal parameters, indicating a slight‐to‐moderate and reversible renal impairment.
Carboxyhemoglobin in the rat: Improvements in the spectrophotometric measurement and comparison to other studies
Authors: Verma Kuldeep , Penney David G. , Helfman C. Clough , Sutariya Bharat B.
Published: October 2006

An improved and simplified spectrophotometric method for the determination of carboxyhemoglobin (COHb) is described, which employs an equation to correct for the dissociation error during analysis. Two microliters, or less, of blood is diluted with an ammonium hydroxide solution directly in the measuring cuvette. A layer of light mineral oil overlying the diluent was found to increase measured COHb saturation of blood equilibrated with 100% CO. Sodium dithionite treatment of the oil further increased this value in one case. The measured COHb was shown to be affected directly by factors that alter hemoglobin concentration in the diluent (i.e. blood volume, hematocrit). Blood samples kept cold and under oil may be stored safely for as long as 10 days. Measurement of COHb by this method in rats exposed to 525, 900, 1800 and 2400 ppm CO produces higher values than those obtained with the 1965 spectrophotometric method of Commins and Lawther. Variations on the method of Commins and Lawther, as well as COHb values available in the literature for animals exposed to CO, are reviewed briefly.
Evaluation of the developmental toxicity of five compounds with the frog embryo teratogenesis assay: Xenopus (FETAX) and a metabolic activation system
Authors: Fort Douglas J. , James Brenda L. , Bantle John A.
Published: October 2006

The potential teratogenic hazard of five compounds was evaluated using the Frog Embryo Teratogenesis Assay—Xenopus (FETAX) and a metabolic activation system. Embryos of the South African clawed frog, Xenopus laevis, were exposed to (i) three compounds suspected to be proteratogenic in mammalian test systems—[2‐acetylaminofluorene (2‐AAF), rifampicin (RA) and benzo[a]pyrene (BP)] for 96 h; (ii) one compound unaffected by mixed‐functional oxidase (MFO) metabolism—ZnSO4; (iii) one compound thought to be inactivated by cytochrome P‐450—cytochalasin D (CD). Two separate static renewal tests were conducted with and without the presence of an exogenous metabolic activation system (MAS). The metabolic activation system consisted of Aroclor 1254‐induced rat liver microsomes. The teratogenic potential of each compound and the effects of metabolic activation were based on teratogenic indices [TI=96 h LC50/96 h EC50 (malformation)], types and severity of malformation, and effects on embryo growth. Metabolic activation increased the potential teratogenic hazard of 2‐AAF, RA and BP by TI factors of 1.3, 2.8 and 6.8, respectively. The teratogenic potential of ZnSO4 was virtually unaffected by the MAS. The MAS significantly reduced the teratogenic potential of CD by a TI factor of 2.7. These results demonstrate the utility and importance of a MAS for in vitro developmental toxicity screens such as FETAX. Consistent use of a MAS with FETAX should reduce the number of potential false‐positive and false‐negative test results.
Mutagenicity of airborne particulates in the rubber industry
Authors: Barański Boguslaw , Indulski Janusz , Janik‐Spiechowicz Ewa , Palus Jadwiga
Published: October 2006

The aim of this work was to evaluate the mutagenic activity of airborne particulate matter in the rubber industry. Air was sucked through Whatman glass‐fibre filters with Staplex pumps and adsorbed substances and fume particles were extracted with acetone or toluene for 2 h in a ultrasonic cleaner. After separation of the insoluble solid phase by filtration, solvent was evaporated at a temperature of 70°C in an argon atmosphere. The residue was stored at −20°C. Mutagenicity was determined by the Salmonella plate incorporation assay with the tester strain TA98 and activity is related either to the weight of aerosol (rev mg−1) or to the volume of atmospheric sample (rev m−3). The fumes emitted from the tyre tread line, calender feeding, and tyre vulcanizing processes, showed the highest mutagenic activity (55–211 rev mg−1, + S9). At these and at other workplaces (extruder mill, carbon black station, mixer loading), mutagenic activity related to the volume of air was in the range of 22–158 rev m−3, + S9. The results indicate the need to reduce and monitor mutagenic contamination in order to increase the safety of work in the rubber industry.
Studies on some kinetic parameters of aldolases in selected tissues of the freshwater fish (Tilapia mossambica) under the toxic impact of methyl parathion
Authors: Kodavanti Prasada Rao S. , Rao K. V. Ramana
Published: October 2006

Kinetic parameters of aldolases in muscle, gill, liver and brain tissues of the teleost Tilapia mossambica were studied at sublethal concentrations with methyl parathion (MP). The pH activity profiles were optimal at pH 7.0 and 9.0 in gill, liver and brain tissues, whereas only a single peak at pH 7.0 was observed in muscle tissue of both control and MP‐exposed fish. The pH 7.0‐specific peak was confirmed as aldolase A and the pH 9.0‐specific peak represents the tissue‐specific aldolases: aldolase B in liver, aldolase C in brain and aldolase B‐C in gill. It is further confirmed with the inhibitor sensitivity of aldolases at two peaks with 6 × 10−3 M ATP or AMP. The pH‐based substrate‐dependent kinetics of aldolases showed a variable trend. The tissue‐specific activity of pH 7.0‐specific aldolases showed low Km values for gill followed by muscle, liver and brain tissues, suggestive of its high enzyme‐substrate affinity. During MP exposure, the Vmax values of pH 7.0‐specific aldolases in muscle, gill and brain were unchanged compared to controls, but Km values were decreased. The pH 9.0‐specific aldolases of gill and liver from MP‐exposed fish showed decreased Km values with a slight increase in Vmax values. Effectors such as lysine, arginine and Ca2+ inhibited, while histidine, cysteine, aspartic acid and α‐ketoglutaric acid elevated the activity levels of aldolases. It was concluded that the considerable enhancement in the catalytic efficiency of both the pH 7.0‐ and ph 9.0‐specific aldolases during MP toxicity could be due to a change in the configuration of aldolases or due to a change in the intracellular environment.
Effects of murine cytomegalovirus on development: Lack of interactions of virus and sodium salicylate
Authors: Francis B. Magnus , Huang Yuan‐Shen , Hartig Phillip C. , Rosen Mitchell B. , Kawanishi Clinton Y. , Chernoff Neil
Published: October 2006

Interactions between exposure to xenobiotics and disease can occur during pregnancy. Few data are available on the consequences of such interactions on developmental parameters. In this study, we investigated potential interactions between murine cytomegalovirus (MCMV), which induces embryolethality, and sodium salicylate, a known teratogen. MCMV administered on Day 12 was embryotoxic over a broad range of doses from 2 × 103to 2 × 106plaque‐forming units, and also decreased postnatal weight gain. MCMV administration on Day 8 of gestation caused significant prenatal mortality regardless of salicylate. exposure. Salicylate did not cause fetal mortality or malformations at either 500 or 750 mg kg−1day−1on Days 9 and 10 of gestation. No evidence of synergistic effects of MCMV and salicylate on embryo/fetal development was seen.
Synthesis and characterization of deoxyguanosine–benzoquinone adducts
Authors: Jowa Lubow , Witz Gisela , Snyder Robert , Winkle Stephen , Kalf George F.
Published: October 2006

Benzene expresses its carcinogenic potential in humans largely in the form of acute leukemia. Because an understanding of the formation of DNA adducts by benzene metabolites may help to explain the etiologkal role they play in benzene‐induced bone marrow disease, we have synthesized, isolated and characterized adducts formed by the reaction of deoxyguanosine with hydroquinone and p‐benzoquinone, two toxic metabolites of benzene. [3H]Deoxyguanosine and [14C]hydroquinone reacted in neutral aqueous buffer containing iron to form two dual‐labeled products, which were separated using HPLC. When p‐benzoquinone was substituted for hydroquinone, the same adducts were formed in the absence of added iron. The ultraviolet and fluorescence spectra of the less polar adduct, called Adduct 2, were distinctly different from the spectra of the starting materials. NMR and mass spectrometry suggested a compound with a mass of 357 with the p‐benzoquinone moiety bound to the N‐1 and N2 positions of deoxyguanosine. Based on these data it is proposed that Adduct 2 is (3′OH)benzetheno(1,N2)deoxyguanosine. The more polar product, Adduct 1, was found to have a unique ultraviolet spectrum but did not appear to be fluorescent. Both adducts were observed after calf thymus DNA was incubated with hydroquinone and digested to its constituent nuceosides.
Chlordecone interaction of calmodulin binding with phosphodiesterase
Authors: Vig P. J. S. , Desaiah D. , Mehrotra B. D.
Published: October 2006

The effects of organochlorine (O.C.) compounds, such as aldrin, dieldrin, endrin, isodrin, chiordecone and mirex, on calmodulin (CaM) activity were investigated. Changes induced by O.C compounds on biological and physical properties of CaM were monitored in terms of phosphodiesterase stimulation and tyrosine fluorescence, respectively. None of the O.C. compounds altered tyrosine fluorescence of CaM in the presence of Ca2+. Except for chiordecone, none of the O.C. compounds inhibited CaM‐activated phosphodiesterase (PDE). Chlordecone significantly decreased (P > 0.05) CaM‐activated PDE in a concentration‐dependent manner without affecting the basal enzyme. Combination of chlordecone with W‐7 (CaM antagonist) increased the inhibitory effect of W‐7 on CaM activity. These results suggest that O.C. compounds may not be changing the tyrosine fluorescence of CaM. Among the O.C. compounds tested, chiordecone is a specific inhibitor of CaM‐activated PDE.
Effect of chronic halothane exposure on lipid peroxidation, osmotic fragility and morphology of rat erythrocytes
Authors: Toker Kamil , Kartalözer Nesrin , Yalçin A. Süha , Tüzüner Sedat , Göǧüs F. Yilmaz , Emerk Kaya
Published: October 2006

Effect of chronic halothane exposure on hepatic and erythrocyte lipid peroxidation and erythrocyte osmotic fragility and morphology were determined in rats exposed to 0.4% halothane, 8 h per day for 40 days. Hepatic lipid peroxidation was increased in the halothane‐treated group compared to controls. Lipid peroxidation was not increased by halothane exposure in erythrocytes without hydrogen peroxide, but after peroxide supplementation lipid peroxidation increased more in the erythrocytes of halothane‐exposed rats than in control rats. We have observed significant morphological changes in erythrocytes from halothane‐treated rats. In addition, erythrocytes of halothane‐treated rats were more fragile in saline solutions compared to those of controls. Our results suggest that chronic halothane exposure is not only hepatotoxic but also affects erythrocyte membrane structure and stability.
Decrease in the rat bronchial acetylcholinesterase activity after toluene diisocyanate inhalation
Authors: Brondeau M. T. , Ban M. , Simon P. , Bonnet P. , de Ceaurriz J.
Published: October 2006

Acetylcholinesterase (AChE) activity was measured in bronchial tissue homogenate and blood from rats subjected to single and repeated 4‐h daily inhalation exposure to toluene diisocyanate (TDI) or control atmospheres. A single 4‐h exposure to TDI in the concentration range of 0.7–4.3 ppm did not decrease AChE activity in bronchial tissue but a 4‐h exposure to 0.6 ppm TDI, or greater, for two consecutive days did reduce this activity (19% to 33% of the controls). Increasing the level of exposure to TDI for two consecutive days from 0.6 to 4.0 ppm and extending the length of exposure to 1.2 ppm TDI from 2 to 4, 9 or 14 days produced no further decrease in bronchial ACHE activity. Throughout these experiments, blood AChE activity remained unchanged. In rats exposed to 0.3 or 1 ppm TDI for 3 weeks, staining of the bronchial smooth muscle for AChE was reduced (36% of the controls) after exposure to 1 ppm TDI. These results support, for the first time, in vivo and localized anti‐AChE activty by TDI.
Role of mixed‐function oxidases and non‐protein sulfhydryl contentent in [14C]‐2‐chloro‐4‐acetotoluidide binding to liver and kidney in starlings
Authors: Giri Shri N. , Siegel David M.
Published: October 2006

The compound 2‐chloro‐4‐acetotoluidide (CAT) is highly toxic to many avian species, including the starling. In our earlier work, we demonstrated the covalent binding of radioactivity from [14C]‐CAT to liver and kidneys of the starling. In the present study, the effects of inducers of mixed‐function oxidase (MFO) and non‐protein sulfhydryl (NPSH) depletor on the total and covalent binding of [14C]‐CAT radioactivity to liver and kidney of the starling were examined. The total and covalently bound radioactivity from [14C]‐CAT to liver and kidney were decreased significantly in the starling pretreated with the MFO inducer, 3‐methylcholanthrene. However, pretreatment with phenobarbitaf, another inducer of MFO, had no effect. Pretreatment with the inhibitor of MFO, SKF 525‐A, reduced the covalent binding of [14C]‐CAT radioactivity to liver but not to kidney. There was no reduction in the NPSH content of liver or kidney following intravenous administration of CAT (3.5 mg kg−1). Reduction of NPSH levels in the liver or kidney following treatment with diethyl maleate caused a significant increase, in the covaient binding of [14C]‐CAT to kidney but not to liver.