bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative chemical and biological analysis of coal tar‐based therapeutic agents to other coal‐derived materials
Authors: Wright Cherylyn W. , Later Douglas W. , Pelroy Richard A. , Mahlum D. Dennis , Wilson Bary W.
Published: October 2006

In this study, methodologies developed for the analysis of synthetic fuel products were applied to the coal tar fractions isolated from coal tar‐based pharmaceutical products. A pharmaceutical stock solution of 20% coal tar in alcohol, a 50% coal tar bath emulsion and a 4.3% coal tar shampoo were studied. The toxicology and chemical composition of the coal tar fractions isolated from these materials were compared with an industrial coal tar and with a direct‐liquefaction coal liquid product. The coal tars and coal liquid product were fractionated into chemical classes by alumina column chromatography and individual components were identified and quantitated by high‐resolution gas chromatography. The microbial mutagenicity of these materials was measured against S. typhimurium, TA 98. In addition, the industrial coal tar, coal‐liquid product, and coal tar isolate from the 20% coal tar in alcohol solution were tested for initiating activity in an initiation/promotion mouse skin painting assay for carcinogenicity. The chemical compositions of the coal tar‐based therapeutic agents, the industrial coal tar and direct‐liquefaction coal liquid were similar. With the exception of the 50% bath emulsion, the microbial mutagenicity and tumor‐initiating activity in mouse skin for those materials tested were also similar.
Effects of alcide® gel on fetal development in rats and mice. II
Authors: Gerges Samy E. , Abdel‐Rahman Mohamed S. , Skowronski Gloria A. , Hagen Stanley Von
Published: October 2006

Alcide® gel is a germicidal agent which is highly effective in killing a wide range of bacterla and fungi in vitro within 1 min. Alcide® gel consists of sodium chlorite and lactic acid, parts A and B, respectively. Chlorine dioxide is formed when sodium chlorite and lactic acid, the active ingredients of Alcide®, are mixed. The objective of this investigation was to study the teratogenic effects of Alcide® gel both in rats and in mice. The gel was administered topically in doses of 1 and 2 g per kg body weight on days 6–15 of gestation. No toxic symptoms were observed following exposure of pregnant rats and mice to Alcide® gel. Viability of the fetuses as well as weight, length and number of resorptions were quite similar compared with control groups. Fetuses were examined for external, visceral and skeletal anomalies. Some incidence of missing or incompletely ossified sternebrae, missing ribs and incomplete ossification of skull bones were observed from skeletal examination. Gastromegaly, kidney agenesis, heart displacement, interatrial septal defect, limb hyperflexion and club foot were observed from soft‐tissue examination. These defects, however, were not significantly different compared with control animals. Alcide® gel was not teratogenic at the doses tested.
Comparative cytotoxicity of naphthalene and its monomethyl‐ and mononitro‐derivatives in the mouse lung
Authors: Rasmussen Ronald E. , Do Diem Hoang , Kim Tae Sun , Dearden Lyle C.
Published: October 2006

Male Swiss‐Webster mice were exposed to napthalene, 1‐methyl‐, 2‐methyl‐, 1‐nitro‐ and 2‐nitronaphthalene by intraperitoneal injection of peanut oil solutions over a dose range of 0.5–3.0 mmol kg−1 body weight. Treated mice were killed at times from 6 hours to 14 days post‐treatment. Tissues were analyzed for cytotoxic effects by optical and electron microscopy, and for cell proliferation by autoradiography following in vitro labeling of lung slices with 3H‐thymidine. The naphthalene derivatives varied widely in their cytotoxic effects. The most toxic was 1‐nitronaphthalene with no mice surviving doses greater than 1 mmol kg−1. Naphthalene and 2‐methylnaphthalene were about equally toxic, followed by 2‐nitro‐ and 1‐methylnaphthalene, in decresing order of toxicity. In all cases the first evidence of cytotoxic effects was seen in the Clara cells of the bronchiolar epithelium, and at the highest doses, toxic effects were found in the adjacent ciliated cells. Changes could be detected at the ultrastructural level at all doses, and within 6 hours after treatment. Only slight effects were seen in other cell types. Increased cell proliferation following chemical treatment was seen only in the bronchiolar epithelium, among cells tentatively identified as Clara cells or their precursors. Cytotoxic effects of naphthalene and its 1‐ and 2‐methyl derivatives were confined to the lung, with minimal evidence of toxicity in the liver and kidney. The mononitronaphthalenes both produce small areas of centrizonal necrosis in the liver, but no discernible effects in the kidney. The experiments demonstrate the effect of small structural differences on the cytotoxicity of this group of environmental pollutants and also illustrate the sensitivity of the Clara cell as a target for xenobiotics.
The relative induction of mixed‐function oxidase specific activity to CH and CC1 bond strengths in polychlorinated derivatives of dibenzo‐p‐dioxin (PCDDs)
Authors: Brownlee L. J. , Evans C. H. , Hollebone B. R.
Published: October 2006

The structure–activity relationships between the mixed‐function oxidase (MFO) system and six polychlorinated derivatives of dibenzo‐p‐dioxin (PCDDs) were studied using Sprague Dawley rats. The study was set up in accordance with previous work in these laboratories involving monocyclic hydrocarbons. Three possible mechanisms at the MFO active site are proposed. C—H bond hydroxylation in low chlorine substituted PCDDs, and probable exposidation in the intermediate chlorinated species including 2378 tetrachlorodibenzodioxin. Benzo[a]pyrene activity induced by some PCDDs appears irrelevant to the desired metabolic result.
Alterations in prostacyclin and thromboxane formation by chronic cigarette smoke exposure: Temporal relationships and whole smoke vs. gas phase
Authors: Lubawy W. C. , Culpepper B. T. , Valentovic M. A.
Published: October 2006

Chronic cigarette smoke exposure in vivo causes decreased conversion of [14C]arachidonic acid (AA) to prostacyclin (PGI2) by isolated aortic tissue and increased conversion to thromboxane (TXA2) by isolated platelets from rats. Alterations in the PGI2/TXA2 balance may be part of the mechanism through which smoking increases the risk of cardiovascular disease. To study the influence of smoke exposure duration on this response, male rats were exposed daily to 10 puffs of freshly generated cigarette smoke. Animals were klledd after 1, 4, 14, 28 and 57 days of smoke exposure and 3, 7, 14 and 28 days after cessation of the 57‐day of smoke‐exposure regimen. Elevated carboxyhemoglobin levels during the smoke‐exposure sessions verified smoke (gas phase) inhalation. Statistically significant alterations in prostacyclin synthesis preceded those of thromboxane. A decrease of 20‐25% (P<0.05) in PGI2 production from [14C]AA in isolated aortic tissue was found beginning 28 days after smoke was initiated and quickly rebounded when smoke exposure was terminated. Increased production of TXA2 from [14C]AA by isolated platelets became statistically significant (P<0.05) on the 57th day and returned to normal 7–14 days after cessation of smoke exposure.

To determine the effect of gas phase constituents on the PGI2/TXA2 balance a second series of experiments divided male and female Sprague‐Dawley rats into sham, whole smoke and gas phase groups. Gas phase was produced by passing whole smoke through a Cambridge filter to remove particulate matter. Per cent COHb averaged 1.4 for sham, 7.8 for whole smoke and 9.4 for gas phase groups. After 8 and 12 weeks of exposure, whole smoke decreased aortic PGI2 and increased platelet TXA2 both in male and in female rats. In contrast to whole smoke exposure, 8 or 12 weeks of exposure to gas phase constituents filed to produce any statistically significant alteration in PGI2 and TXA2 formation.

It was concluded that changes in PGI2 and TXA2 formation occur readily following initiation or termination of chronic whole smoke exposure and that substances present in the particulate phase of smoke are essential to producing these changes.
The effects of chronic ozone exposure on pulmonary collagen content and collagen synthesis in rats
Authors: Filipoicz C. , McCauley R.
Published: October 2006

Male rats were exposed to 0.125, 0.25 or 0.5 ppm of ozone or clean air for up to 1 year. During this exposure period there was little evidence for collagen accumulation in the lungs. However, the rate of incorporation of tritriated proline into both lung collagen and total lung protein was accelerated. These data suggest that exposure to ozone under these conditions results in an increase in the turnover of collagen as well as other lung proteins.
Effect of donor age on the levels of activity of rat, hamster and human liver S9 preparations in the Salmonella mutagenicity assay
Authors: Raineri R. , Andrews A. W. , Poiley J. A.
Published: October 2006

Liver S9 fractions were prepared from male and female Syrian Golden hamsters and Sprague‐Dawley rats, 1, 3, 6 and 12 months of age, which were either iuninduced (corn‐oil treated) or induced with Aroclor 1254 suspended in corn oil. These preparations were compared at varying protein levels for their ability to metabolize polycyclic aromatic hydrocarbons (benzo(a)pyrene, 3‐methylcholanthrene, 7,12‐dimethylbenzanthracene), aromatic amines (N‐2‐acetyl‐aminofluorene, β‐naphthylamine, benzidine), and nitroso compounds (N‐nitroso‐diethylamine, nitrosopyrrolidine, nitrosodiethylmethylurea) to products mutagenic to Salmonella typhimurium. With 3‐methylcholanthrene or benzo(a)pyrene in the presence of S9 preparations from Aroclor‐treated male rats, the numbers of revertant colonies decreased with increasing age of the animals. Mutagenicity of aromatic amines was not affected by the age of the donor animals from which the S9 was prepared. The use of liver S9 from 1‐month‐old hamsters produced the highest number of revertant colonies with nitrosodiethylamine. This number decreased with preparations from animals of increasing age. The greatest number of revertant colonies with nitrosopyrolidine occurred with preparations from male hamsters. A decrease in numbers of revertant colonies with increasing age was observed with the S9 preparation from Arcolor‐treated male rats. Nitroso‐diethylmethylurea was mutagenic only in the presence of S9 from male or female Aroclor‐treated hamsters and the metabolic activity of the S9 preparations did not change with age.

S9 preparations from livers of 50–70‐year‐old humans were compared for their ability to produce mutagenic metabolites at a number of protein levels. Very low levels of mutagenicity with polycyclic aromatic hydrocarbons were seen with all human liver S9. Two preparations from human liver obtained shortly after death metabolized both benzidine and β‐naphthylamine (known human carcinogens) to mutagenic products. Very low or no increases in the number of revertant colonies were seen with the other human S9s. However, all of these liver S9 preparations gave a positive mutagenic response with N‐2‐acetylaminofluorene. The only nitrosamine mutagenic with human liver S9 was nitrosopyrrolidine. All of the human preparations metabolized this carcinogen at similar levels.

To obtain a positive mutagenic response with a number of these compounds, it was important that the tissue samples be obtained with minimum delay after death. The ability of S9 preparations made from tissues of older rats to metabolize chemicals to mutagenic products was diminished, and compared well with the results obtained with S9s from 50–70‐year‐old humans. These findings demonstrate the value of the Salmonella mutagenicity assay used with liver S9 preparations from humans in screening for potentially harmful agents.
Measurement of the deposition and clearance of inhaled radiolabeled particles from rat lungs
Authors: Newton Paul E. , Pfledderer Chris
Published: October 2006

Immediately after a 20 min nose only exposure to 51Cr labeled polystyrene latex microspheres (1.4 MMAD, geometric standard deviation = 1.3, 2 μg m−3), 23% of the measured radioactivity was within the trachealungs of the exposed rats, 37% was within the gastrointestinal tract, 10% was within the defurred head, and 30% was on the fur. One hour after deposition these percentages had changed to 20, 64, 5 and 11% respectively. As a result of this non‐pulmonary particle load transiting the esophagus, external thoracic radioactivity measurements did not accurately reflect excised lung measurements until 30 h post‐deposition. Consequently, it was necessary to combine excised lung ratioactivity data (0–30 h post deposition) with serial external thoracic measurements (30–934 h post‐deposition) to measure the clearance of these microspheres. Use of an annulus shaped detector sufficiently increased sensitivity to allow measurements to be made through at least 934 h post‐deposition. The lung radioactivity retention curve was biexponential with half times of 34.3 ± 2.3 and 963 ± 107 h. Simultaneous exposures to 5% CO2 increased deposition by 40% but failed to reduce deposition inhomogeneity and test variability.
Mercury–selenium interaction in workers exposed to elemental mercury vapor
Authors: Suzuki Tsuguyoshi , Himeno Sei‐Ichiro , Hongo Tetsuro , Watanabe Chiho , Satoh Hirosi
Published: October 2006

Mercury (Hg) and selenium (Se) levels were determined for erythrocytes, plasma and urine of 25 male and 29 female workers exposed to elemental mercury (Hg0) vapor. Interrelationship between the Hg levels and the Se levels was examined by the correlational analysis and the stepwise regression analysis.

Indicators of Se status (erthrocyte Se levels, plasma Se levels and urinary Se levels) were closely inter‐correlated; similary, indicators of exposure to Hg0 vapor (erythrocyte inorganic Hg levels, plasma Hg levels and urinary Hg levels) were significantly intercorrelated. Since plasma Hg level was one of the significant independent variables in determining the erythrocyte Se and plasma Se levels, Hg0 vapor exposure was though likely to influence the Se metabolism in workers. None of the Se status indicators were significant as determinants of the indicators of Hg0 vapor exposure.
Determination of rat β2‐microglobulin in urine and in serum. II. Application of its urinary measurement to selected nephrotoxicity models
Authors: Viau C. , Bernard A. , Ouled A. , Lauwerys R.
Published: October 2006

β2‐microglobulin (β2‐m) was measured in the urine of rats by a specific immunoassay based on latex particles agglutination. the excretion of this protein was compared to the excretion of the enzyme β‐N‐acetyl‐D‐glucosaminidase (NAG), albumin and amino acids in rats treated with either a single dose of sodium chromate (5 and 10 mg kg−1), repeated doses of gentamicin (5 and 20 mg kg−1), or cadmium (1 mg kg−1), and in aging rats (from 2 to 20 months). All treatments resulted in an early increased excretion of β2‐m indicative of functional alterations of the proximal tubular cells. An increased NAG excretion was observed only at the highest dose of chromate and in the cadmium model but the relative increases of β2‐m were much larger (up to 200 times the control values against four times the control values for NAG). From 2 to 20 months of age, urinary β2‐m increases by a factor of four. Aminoacids excretion showed little sensitivity in the various models. Albumin showed little variations in purely tubular or in the tubular phase of renal injury but the chronic progressive nephrosis of aging rats caused a 40‐fold increase in its excretion between 2 and 20 months of age. Therefore urinary β2‐m, albumin and albumin/β2‐m ratio provide useful tools in the assessment of nephrotoxicity and of its mechanisms in various experimental models.
Mutagenicity testing of selected analgesics in Ames Salmonella strains
Authors: Oldham James W. , Preston Robert F. , Paulson John D.
Published: October 2006

Acetaminophen (APAP), aspirin (ASA), phenacetin (PA) and ibuprofen (IB) were tested for mutagenic activity in the Ames Salmonella plate incorporation assay using strains TA98, TA100, TA1535, TA1537 and TA1538. These analgesics were tested in four separate tests: without metabolic activation, and in the presence of a rat, hamster or mouse liver post‐mitochondrial supernatant (S‐9, Aroclor 1254‐induced). Treatment of all five strains of Salmonella with APAP, ASA or IB under all four metabolic conditions did not induce any appreciable increases in revertant colony counts, as compared to the negative controls. A dose‐related increase in revertant colony counts, reaching levels twice the negative control values, were seen with PA at doses ⩾500 μg per plate. This response was only seen in strain TA100 in the presence of hamster S‐9. Therefore, these findings constitute a positive result for PA in the Ames test. APAP, ASA and IB did not show any mutagenic potential under these conditions of testing. These findings are discussed along with previously published results concerning the genotoxicity of these analgesics.
The toxicity of brass dust to the microalgaeAnkistrodesmus falcatusandSelenastrum capricornutum
Authors: Haley Mark V. , Johnson Dennis W. , Hart Gayle S. , Muse William T. , Landis Wayne G.
Published: October 2006

The toxicity of brass dust was examined by conduction 96 h growth inhibition tests. Two species of algae were used,Ankistrodesmus falcatus(EC50=0.316 mg brass/I) andSelenastrum capricrnutum(EC50=0.056 mg brass/I). Brass dissociate into two components, Cu (68.5%) and Zn (27.5%). Enhanced algal growth was exhibited at concentrations of 0.01 and 0.001 mg brass/I. Available literature on the toxicity of copper toS. capricornutum(EC50=0.047 mg Cu/I), indicate that the toxicity of brass dust is due to the ionized copper. Reported toxicities of zinc are orders of magnitude lower than copper. The ionization of the brass is dependent on pH and hardness. The literature cites cases in which copper toxicity varies with pH, clay content and dissolved organics. At present little is known of the fate and distribution of brass dust upon the release into the environment. However, the presence of heavy metals has consistently been shown to impact aquatic systems.
Combined effect of ethanol and carbon disulphide on cytochrome P‐450 monooxygenase, lipid peroxidation and ultrastructure of the liver in chronically exposed rats
Authors: Wrońska‐Nofer Teresa , Klimczak Jadwiga , Wiśniewska‐Knypl Justyna M. , Jajte Jolanta , Opalska Barbara
Published: October 2006

A 5‐month treatment of rats with ethanol (10% solution in drinking water) stimulated aniline p‐hydroxylase and the microsomal ethanol oxidizing system (MEOS) by 140 and 70%, respectively, cytochrome P‐450 by 22% and accompanied by lipid peroxidation by 40% in microsomes. It also caused smooth endoplasmic reticulum (SER) proliferation and rough endoplasmic reticulum (RER) degranulation in hepatocytes. Repeated inhalatory exposure of rats to 1.5 g/m3 of CS2, 5h daily, 5 days a week for 5 months decreased aniline p‐hydroxylase and MEOS by 70 and 55% respectively, doubled hexobarbital sleeping time and depressed cytochrome P‐450 by 30% and its conversion to cytochrome P‐420; these effects were accompanied by the appearance of cytochrome P‐420, the intensification of lipid peroxidation in microsomes and some degranulation of RER in hepatocytes. Combined exposure of rats to ethanol and CS2 resulted in a significant potentiation of the inhibitory effects of CS2 on cytochrome P‐450 mono‐oxygenase and MEOS but with enhancement of CS2 effects on the liver microsomal mono‐oxygenase, but CS2 decreased the effect of ethanol on SER proliferation. The interaction both on the biochemical and the morphological level can be explained with the ethanol‐stimulated biotransformation of CS2 to reactive electrophilic derivative(s), the subsequent destruction of cytochrome P‐450 to cytochrome P‐420 and the intensification of lipid peroxidation.
Influnce of manganese on the gastrointestinal absorption of cadmium in rats
Authors: Sarhan Mohammad J. , Roels Harry , Lauwerys Robert , Reyners Hubert , De Reyners Elva Gianfelici
Published: October 2006

Four groups of male rats were given the following oral treatment: control group (n = 20) deionized drinking water, Mn group (n = 20) deionized drinking water containing 56 ppm Mn2+ (1 mmol/l), Cd group (n = 10) deionized drinking water containing 112 ppm Cd2+ (1 mmol/l) and Cd+Mn group (n = 10) deinonized drinking water containing 112 ppm Cd2+ and 56 ppm Mn2+. Half of each group was sacrificed after 4 weeks and the other half after 8 weeks of treatment. At each time interval, the mean levels of Mn in blood, in urine and in the various tissus did not differ between the control and Mn groups. Furthermore, comparable Mn levels were found after 4 and 8 weeks of treatment. Microscopical examination of the brain failed to reveal any overt morphological alteration in the Mn group. With respect to the control group, the Cd and Cd + Mn groups exhibited increased levels of Cd in blood, urine, liver, whole kidney, kidney cortex and in brain (cortex, cerebellum, basal ganglia), but the Cd + Mn groups showed invariably lower levels than the Cd group after 4 weeks as well as after 8 weeks. These results suggest that the rate of gastrointestinal absorption of Cd is decreased by supplementation of the drinking water with a ‘non‐toxic’ dose of Mn2+.
Urinary tract effects of phensuximide in the Sprage‐Dawley and Fischer 344 rat
Authors: Rankin Gary O. , Cressey‐Veneziano Kim , Wang Ruu‐Tong , Brown Patrick I.
Published: October 2006

Phensuximide is a succinimide antiepileptic drug useful in the treatment of petit mal epilepsy. Phensuximide has been reported to be nephrotoxic in man but not in animals. In the present study, the effects of single and subacute administration for seven days of phensuximide on renal function and urinary tract morphology were evaluated in Sprague‐Dawley and Fischer 344 rats. Single administration of phensuximide (1.25 mmol/kg, ip) induced mild changes in renal function (trace hematuria, increased proteinuria and decreased p‐aminophippurate uptake). No morphological changes were observed at 24 hr. Subacute administration of phensuximide (0.6 mmol/kg/day, ip) produced diuresis in the Sprague‐Dawley rats, but little functional evidence of nephrotoxicity. Renal morphological changes in Sprague‐Dawley rats were seen primarily in distal segments of the nephrons. These changes were characterized by distensions of the basal infoldings, apical protrusions, and occlusion of some lumen. In the Fischer 344 rat, subacute phensuximide administration (0.3 or 0.6 mmol/kg/day, ip) resulted in transient hematuria and proteinuria, but no change in the other renal function parameters studied. Renal morphological changes observed in Fischer 344 rats occurred primarily in proximal tubular cells. Damaged cells were characterized by large vacuoles at the basal infoldings, accumulations of opaque granules, migration of nuclei to the lumenal membranes, occlusion of the lumen and/or loss or the brush border. Morphological damage was more widespread in Fischer 344 rats than in Sprague‐Dawley rats. Areas of focal hemorrhage were observed in ureters and bladders, especially in Fischer 344 rats given phensuximide 0.6 mmol/kg/day. However, morphological effects may be reversible with continued dosing. It was concluded that phensuximide produces mild, transient renal effects in Fischer 344 rats, and that the Fischer 344 rat is suitable model for studying phensuximide‐induced toxicity to the urinary tract.
Chemical and biological monitoring of chronic lead poisoning in the rat. Implications to the assessment of hazard of low‐level lead
Authors: Wigfield Donald C. , Chakrabarti Chuni L. , Wright Sandra C. , Eastwood Jennifer A. , Karkowska Regina , Johnson Pam M.
Published: October 2006

A studyon rats of the effects of lead on δ‐aminolevulinate dehydratase (ALA‐D) activity, and its pH‐dependent maximal enzyme activity is reported. Over a 5‐week period, the lead burden and ALA‐D activity in kidney, liver and brain are documented. Lead concentrations in the organs, expressed as μg/g protein are in the sequence kidney>liver> brain and reach essentially a constant level after 3 days of exposure. This is consistent with the existence of an efficient mechanism removing lead from these organs. Lead affects the ALA‐D in all three organs by reducing the activity and shifting the pH of maximum enzyme activity to more acidic values. In common with the lead levels, the ALA‐D activity does not deteriorate beyond the levels reached after 3 days of exposure. The existence of a mechanism removing lead from the organs is further supported in a recovery study on blood and kidney, in which both lead level and ALA‐D activity return essentially to normal values after 7 days of no exposure to lead.
The preventive effect of prednisolone on the adrenal toxicity of cadmium
Authors: Selypes A. , Lorencz R. , Serényi P.
Published: October 2006

The effects of a single dose of 3.3 mg/kg body weight i.p. or of a single dose of 0.2 mg/kg per os of cadmium and prednisolone on the adrenal weight and the thickness of the adrenal cortex were investigated in female mice. A significant increase was detected in the mean weight of the adrenals and the thickness of the adrenal cortex was signficantly higher than the control value on days 1–3 following cadmium treatment. A. dramatic decrease was observed in both adrenal weight and adrenal cortex thickness on day 4 following cadmium administration. No significant change occurred in the adrenals when prednisolone was given orally to mice following cadmium administration. This observation indicates a protective action of prednisolone on cadmium‐induced adrenal toxicity.
Studies on the mechanism of toxicity of the mycotoxin, sporidesmin. V. Generation of hydroxyl radical by sporidesmin
Authors: Munday R.
Published: October 2006

Sporidesmin, the mycotoxin responsible for ‘facial eczema’ in ruminants, has previously been shown to generate superoxide radical and hydrogen peroxide. In the present study, the formation of the third ‘active oxygen’ species, hydroxyl radical, has been demonstrated. This species is produced both during the autoxidation of the reduced (dithiol) form of the mycotoxin and in the cyclic reduction/autoxidation reaction between sporidesmin and glutathione. In view of the exceptional reactivity of the hydroxyl radical, this substance may be the proximate agent responsible for the toxic effects of sporidesmin.
Acute toxicity of the major alkaloids of cultivatedLupinus angustifoliusseed to rats
Authors: Petterson D. S. , Ellis Z. L. , Harris D. J. , Spadek Z. E.
Published: October 2006

The seed of modern cultivars ofLupinus angustifoliusnormally contain less than 0.03% alkaloids. The acute oral LD50to rats of a prorata mixture of the alkaloids ofL. angustifoliusseed was found to be 2279 mg/kg. For lupanine the LD50by oral administration was 1464 mg/kg and by intraperitoneal injection 177 mg/kg. For 13‐hydroxylupanine the LD50by intraperitoneal injection was 199 mg/kg. Since these two alkaloids comprise about 85% of the total and are known to be rapidly cleared from the body it is suggested that the alkaloids in this species do not pose a health problem for man.
Oral toxicity of trichlorobenzyl chloride and its acid derivative
Authors: Johannsen Frederick R. , Levinskas George J.
Published: October 2006

The acute rat oral LD50 of 2,4,6‐Trichlorobenzyl chloride (TCBC) was determined to be 3075 mg/kg. When male and female rats were administered 1500 and 3000 ppm TCBC in the diet for 3 weeks, marked retardation in weight gain was observed. Reductions in food consumption were noted in both groups of treated male, but not female, rats. All blood chemistry and urinalysis parameters including those indicative of liver injury, were within the range of normal limits. Gross necropsy revealed pale livers in all high‐dose rats and the majority of low‐dose animals. Gross observations correlated with observation of degenerative hepatic changes (irregularity of cell and nuclear size, cord pattern, edema and cytoplasmic alterations) following microscopic evaluation. Rats and dogs administered up to 100 ppm trichlorobenzoic acid (TCBA) in the diet for 90 days exhibited no effects considered related to treatment.
Structure‐nephrotoxicity relationships for meta‐substituted N‐phenylsuccinimides
Authors: Yang David J. , Brown Patrick I. , Lo Herng‐Hsiang , Teets Vonda J. , Rankin Gary O.
Published: October 2006

The N‐phenylsuccinimides are being evaluated as experimental agricultural fungicides. The purpose of this study was to examine the relationship between the electron withdrawing or electron donating properties of phenyl ring substituents on meta‐substituted N‐phenylsuccinimide (NPS) derivatives and the nephrotoxic potential of the corresponding fungicides. Male Fischer 344 rats were administered a single intraperitoneal injection of a succinimide (0.4 or 1.0 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg), and renal function monitored at 24 and 48 hr. Non‐halogen‐substituted NPS derivatives produced little evidence of nephrotoxicity at the doses used in this study. Among the meta‐halogen derivatives of NPS, N‐(3‐chlorophenyl)succinimide (NCPS) was the most nephrotoxic. NCPS‐induced nephrotoxicity was characterized by diuresis, proteinuria, hematuria, elevated blood urea nitrogen (BUN) concentration, decreased organic ion accumulation and proximal tubular necrosis. However, all renal effects produced by NCPS were mild to moderate. These results suggest that the electron withdrawing or donating property of a functional group is not a good predictor of the nephrotoxic potential for the corresponding fungicide. In addition, lipophilicity did not correlate with nephrotoxic potential for the meta‐substituted NPS derivatives evaluated in this study.
Effects of the exposure profile on the inhalation toxicity of carbon tetrachloride in male rats
Authors: Bogers M. , Appelman L. M. , Feron V. J. , Beems R. B. , Notten W. R. F.
Published: October 2006

To examine the effect of the exposure pattern on the inhalation toxicity of carbon tetrachloride (CCI4) two 4‐week inhalation studies with this compound were carried out in male rats at basic exposure concentrations of 63 and 80 ppm and basic exposure periods of 6 hours per day, 5 days per week. The two main variables studied were interruption of the daily 6‐hour exposures by 1.5 hours (2 × 3‐hour exposures with a non‐exposure interval of 1.5 hour), and peak loads of 5–7 times the basic concentration with or without 1.5‐hour interruption of the daily 6‐hour exposures. Adverse effects of CCI4 included abnormal activities of several enzymes in serum and liver, decreased quantity of microsomal proteins in the liver, increased relative liver weight, and hydropic and fatty degeneration of hepatocytes. As compared with uninterrupted, interrupted exposures increased more the activities of glutamic oxalacetic and glutamic pyruvic transaminase in serum; peak exposures only slightly affected these enzyme activities. Uninterrupted exposures caused less severe fat accumulation in and hydropic degeneration of liver cells than interrupted exposures with or without peak loads. In addition, uninterrupted exposure to 63 ppm CCI4 with peak loads resulted in more severe hydropic liver degeneration than uninterrupted exposure to the same concentration without peak loads. It was concluded that interruption of the daily 6‐hour exposures by 1.5 hour did not result in less severe but rather in slightly more severe hepatotoxicity, and peak loads superimposed on a fixed concentration only slightly aggravated the toxic effects of CCI4 on the liver.
The effects of cardioteratogenic doses of caffeine on cardiac function in the 3‐day chick embryo
Authors: Bruyere Harold J. , Michaud Bernard J. , Gilbert Enid F. , Folts John D.
Published: October 2006

The effects on embryonic cardiac function of caffeine administration (two non‐cardioteratogenic and two cardioteratogenic doses) to Hamburger–Hamilton stage 19 (3–3 1/2 days of incubation) chick embryos were investigated. Using microcinephotoanalysis, we have determined that caffeine (1.0–4.7 mg/egg), within the initial three hours after treatment, produced a dose‐dependent decrease in end diastolic volume, stroke volume, cardiac output, and ejection fraction. These effects were sustained for a longer period of time following dosing at a cardioteratogenic level (3.5–4.7 mg/egg). Caffeine (1.0–4.7 mg/egg) also increased cardiac rate with a maximum increase of 30% seen 60 minutes after treatment with doses of 2.7 mg and 3.5 mg. However, the increase in cardiac rate was not related to dose. At 20 hours after treatment, caffeine increased stroke volume, ejection fraction and cardiac output relative to the controls. End‐diastolic volume and cardiac rate were not changed. These results are evidence for a biphasic effect of cardioteratogenic dosing with caffeine during the first 20 hours after treatment—initially a sustained decrease in cardiac output, suggesting decreased flow through the embryonic heart, followed by an increase in ejection fraction, suggesting increased cardiac workload.
Effects of methyl mercury and cadmium on the kinetics of substrate activation of (K+)‐paranitrophenyl phosphatase
Authors: Sahib K. I. Ahammad , Moorthy K. S. , Desaiah D.
Published: October 2006

Previous studies from this laboratory have indicated that methyl mercuric chloride (CH3HgCI) and cadmium chloride (CdCI2) are potent inhibitors of K+‐p‐nitrophenyl phosphatase (K+‐PNPPase). The present studies were undertaken to study the effects of CH3HgCI and CdCI2 on the substrate activation kinetics of K+‐PNPPase to understand the mechanism of inhibition of Na+ pump by these heavy metals. Uncompetitive inhibition with regard to activation by PNPP was indicated by altered Vmax and Km values by both the heavy metals. Substrate activation kinetics of heavy metal inhibited K+‐PNPPase in the presence of 25 μM dithiothreitol and glutathione indicated mixed type of activation by altering apparent Vmax and Km. Absence of competition between PNPP site and heavy metals appear to indicate absence of reactive‐SH groups in the active site. Failure of added iodoacetate, in concentrations ranging from 5 × 10−8 to 5 × 10−5M, to inhibit K+‐PNPPase further substantiate this conclusion. The results suggest that CH3HgCI and CdCI2 inhibit Na+ pump by inducing conformational changes in the enzyme and thereby decrease catalytic velocity of dephosphorylation of the enzyme‐phosphoryl complex. Hydrolysis of PNPP was linear with time with or without either heavy metal and the inhibition exerted by CH3HgCI or CdCI2 on free or heavy metal loaded enzyme indicated absence of heavy metal interaction. The results suggest that CH3HgCI and CdCI2 inhibit K+‐PNPPase possibly by binding at two different sites.
Toxicological profile of orally administered 1,6‐hexane diamine in the rat
Authors: Johannsen Frederick R. , Levinskas George J.
Published: October 2006

The industrial chemical 1,6‐Hexane Diamine, or hexamethylenediamine (HMD), has an acute oral LD50 of 980 mg kg−1 in rats. Dietary administration of HMD to groups of rats for 3 months at dosages of 0, 50, 150, and 500 mg kg−1 resulted in a modest retardation in weight gain at the two higher test levels. No other obvious signs of toxicity or changes in the peripheral blood picture or selected clinical pathology parameters were found at any test level throughout the study. Evaluation of absolute and relative weights of 10 selected organs, as well as complete necropsies and microscopic evaluation of over 30 selected tissues and organs, revealed no changes considered related to treatment. The administration of HMD by gavage to pregnant rats at 0, 112, 184 and 300 mg kg−1 day−1 on days 6–15 of pregnancy (day 1 = day sperm detected) did not induce any teratogenic effects. Signs of maternal toxicity were observed only at 300 mg kg−1 day−1. Embryotoxicity was observed at both the 300 and 184 mg HMD kg−1 day−1 dosage levels. No treatment‐related effects were observed at 112 mg HMD kg−1 day−1.
Role of exposure parameters in toxicity of aerosolized diesel fuel in the rat
Authors: Dalbey W. , Henry M. , Holmberg R. , Moneyhun J. , Schmoyer R. , Lock S.
Published: October 2006

Sprague–Dawley rats were exposed to aerosolized diesel fuel (ADF) to determine the potential health effects in military troops during exposure to this visual obscurrant. Acute range finding studies were performed to estimate exposure conditions at which minimal (<1%) mortality would occur. This information was used in the design of a repeated exposure study to test the relative significance of the frequency of exposures, the duration of exposure, and aerosol concentration in any toxicity which might occur. Animals were exposed once or three times per week for a total of nine times to concentrations ranging from 1.3 mg ADFI−1 to 6 mg ADFI−1 and exposure durations of 2 or 6 h. Body weight and food consumption were recorded at weekly intervals during the exposure period and in animals that were retained for 2 weeks after the last exposure. Animals were used for a variety of endpoints, including neurotoxicological tests, pulmonary function tests, hematology, clinical chemistry, organ weights, and histopathology, either within 2 days of the last exposure or after the 2‐week recovery period. Animals exposed to ADF showed an initial depression in body weight followed by a slower rate of growth than the sham exposed controls. No exposure related changes were observed in any of the neurotoxicology assays. The lung was the primary site of toxicity. Focal accumulations of pulmonary free cells were observed histologically, with thickening and hypercellularity of nearby alveolar walls. The number of lavaged pulmonary free cells increased similarly. Both pulmonary wet and dry weights increased. Lung volumes were altered by exposure, including increased FRC and decreased TLC. Carbon monoxide diffusing capacity was decreased. Histologic abnormalities were not observed in any other organs. Of the exposure parameters tested, the frequency of exposure appeared to be the most significant in relation to degree of toxicity.
The combined effect of Pb2+ and Mn2+ on monoamine uptake and Na+, K+‐ATPase in striatal synaptosomes
Authors: Hussain Tahir , Ali M. M. , Chandra S. V.
Published: October 2006

Rat striatal synaptosomes (P2‐fraction) were subjected to lipoperoxidation by the addition of 120 μM Fe2+ and 200 μM ascorbic acid. This preparation (pretreated synaptosomes) was used to investigate the interaction of Pb2+ and Mn2+ on the uptake of tritiated catecholamines, Na+, K+‐ATPase activity and malondialdehyde (MDA) formation in order to understand the mechanism of enhanced neurotoxocity by concurrent exposure to these metals. The combination of Pb2+ and Mn2+ (25 μM + 100 μM, respectively) produced a significant increase in the uptake of 3H‐Dopamine only in the untreated synaptosomes. No significant effect was noted on the uptake of 3H‐Norepinephrine in either pretreated or untreated synaptosomes. However, the combination of Pb2+ and Mn2+ produced a pronounced decrease in the activity of Na+, K+‐ATPase, but the magnitude of the change was the sum of the individual metal effects. Metal interaction did not produce any significant change in the formation of MDA compared to the control (without addition of metals). These results indicate that Pb2+ and Mn2+ interaction may produce inhibition in the activity of transport ATPase in both the preparation of synaptosomes, with more pronounced effect of synaptosomes subjected to lipoperoxidation and these changes may be responsible for the disruption in the physiology of nerve impulse transmission.
Nuclear enlargement produced in mouse skin by carcinogenic mineral oils
Authors: Ingram A. J. , Grasso P.
Published: October 2006

Ten oils of differing origin, degree of refinement and carcinogenicity, were examined for their ability to produce nuclear enlargement in mouse skin following repeated topical exposure over a 3 day period. Application of the oils was made in a vehicle of methyl ethyl ketone incorporating a promoter and assessment of epidermal nuclear size was made on tissue sections using a Quantimet 720 image analyser.

One of the oils reported to be non‐carcinogenic; was examined initially and its inability to induce enlargement of nuclei beyond the size seen in hyperplastic skin was confirmed. The same oil was then examined in combination with benzo(a)pyrene (BaP) and, from the dose–response obtained, it was clear that the oil did not prevent BaP induced nuclear enlargement.

The other nine oils were examined by comparing them with the previously tested non‐carcinogenic oil. Two oils gave rise to clear nuclear enlargement; these were non‐solvent refined and gave rise to skin tumours in reported long‐term studies. One solvent‐refined oil, which gave a single papilloma in reported long‐term studies, gave borderline (non‐significant) nuclear enlargement; whereas the other solvent‐refined oils, including five reported as non‐carcinogenic and one reported as having weak (questionable) carcinogenic activity, gave no nuclear enlargement.

Further examination of the data suggested that, within the limited series of oils examined, nuclear enlargement under these test conditions correlated well with carcinogenicity and might be used for predicting the skin carcinogenicity of an oil. Studies on a further 23 oils, on which long‐term studies have been carried out but not published, support this conclusion.
Developmental toxicity studies of caprolactam in the rat and rabbit
Authors: Gad Shayne C. , Robinson Keith , Serota David G. , Colpean Barbara R.
Published: October 2006

Caprolactam was evaluated for developmental toxicity potential in both rats and rabbits by the oral route. In rats dosed on days 6–15 of gestation with 100, 500 or 1000 mg/kg/day of caprolactam, the maternal survival rate was significantly lower in the high‐dose group and implantation efficiencies were slightly lower in the 100 and 1000 mg/groups (but not the 500 mg/kg) than in the control. The incidence of fetal death was comparable for all groups, and the incidence of fetal viability was considerably lower in the high‐dose group (but not the mid or low) than in the control group. Visceral anomalies and one visceral variant were observed in one 100 mg/kg and one 500 mg/kg pup, respectively. The anomalies included exencephaly, an incomplete left eyelid, microphthalmia (right), and a protruding tongue. No skeletal anomalies were observed. It was concluded that caprolactam at levels up to at least 500 mg/kg of body weight produced no teratogenic effects in the Fischer 344 rats.

In rabbits receiving 50, 150 or 250 mg/kg caprolactam on days 6–28 of gestation, the pregnancy rate in all groups was at least 80%. The numbers of corpora lutea, live and dead fetuses, resorptions, the sex ratio and the pre‐ and post‐implantation losses were not significantly different among the test and control groans. The incidence of major malformations and of minor skeletal anomalies was unaffected by treatment with caprolactam. Maternal weights were depressed in the group receiving 250 mg/kg. Treatment of a separate group with a positive control substance (ó‐aminonicotinamide) resulted in significantly (P < 0.001) increased incidences of major malformations, minor visceral anomalies and minor skeletal anomalies. Maternal toxicity in terms of mortality was observed in pregnant rabbits treated with caprolactam at a dose of 250 mg/kg/day. Fetotoxicity was evidenced by lower fetal weights at the 150 and 250 mg/kg/day levels, and an increased incidence of thirteenth ribs was observed at the 250 mg/kg/day dose level. Neither embryotoxicity nor teratogenicity occurred at any dose level.
Decision criteria for the in vitro rat hepatocyte UDS assay
Authors: Oshiro Y. , Balwierz P. S. , Falk R. W. , Piper C. E.
Published: October 2006

The induction of unscheduled DNA synthesis (UDS) in rat primary hepatocytes is used as an in vitro screen for genotoxicity. The purpose of this study was to develop criteria for statistical evaluation of autoradiographic grain counts from the UDS assay. Based on our historical solvent control population (N = 17), we first established a predictive two‐sided symmetric tolerance interval providing 95% confidence for coverage of 99% of the distribution of the mean net nuclear grain count for a new solvent control observation. The tolerance interval was determined to run from −2.82 to 4.03 net nuclear grains. When the concurrent solvent control (C) proves admissible (−2.82 < C < 4.03), the mean net nuclear grain counts from treatment groups are compared to the concurrent solvent control value. If the difference exceeds 3.09 at two successive concentrations, the test compound is considered positive. We have tested eight carcinogens (MNNG, AFB1, 4DAB, 4NQO, DMBA, 2AAF, DEN and 2AA) utilizing these criteria. All eight were positive. Four non‐carcinogens (2AB, pyrene, anthracene and αNA) were negative. Each of these chemicals was tested twice using our standard protocol, which employs a preliminary range‐finding cytotoxicity assay. We conclude that these criteria provide adequate sensitivity and specificity to be applicable for the evaluation of the results of routine UDS assays with compounds of unknown genotoxic potential.
Alterations in urethan‐induced adenoma formation in mice exposed to selenium and nickel
Authors: Blakley Barry R.
Published: October 2006

Female Swiss mice were exposed to sodium selenite (3 μ/ml selenium content) and nickelous chloride (100 μg/ml nickel content) in the drinking water on alternate days for 15 weeks. After 3 weeks of metal exposure, the mice were administered urethan (1.5 mg/g) intraperitoneally. Pulmonary adenoma formation was evaluated 12 weeks later. Selenium exposure did not alter the tumor incidence (P = 0.059) or the tumour size (P = 0.98). Nickel exposure did not affect the tumour incidence (P = 0.25), but increased the average tumour size (P = 0.0025). Combined selenium and nickel exposure resulted in significant interactions associated with tumour size (P = 0.00075) and tumour number (P = 0.045). Urethan‐induced sleeping times were reduced by selenium exposure (P = 0.0049), but were unaffected by nickel exposure (P = 0.99). Combined metal exposure did not influence urethan‐induced sleeping times (P = 0.48).
Hepatotoxic effects elicited by n‐hexane or n‐ heptane
Authors: Goel S. K. , Rao G. S. , Pandya K. P.
Published: October 2006

Hepatotoxic effects of n‐hexane and n‐heptane administered i.p. (1 ml/kg body wt) were studied in albino rats after 1, 2, 7 and 45 days of treatment. Hepatic protein content decreased with n‐heptane and total sulphydryl content showed a significant decrease in the rats exposed to either solvent. A significant increase in lipid peroxidation was observed after 24 h and 48 h exposure to n‐hexane or n‐heptane. A marked decrease in drug metabolizing activity and an increase in pentabarbitone sleeping time was also observed. Hepatic glucose‐6‐phosphatase, a microsomal marker enzyme, showed a significant decrease.