Showing papers in "Journal of Toxicology and Environmental Health in 1982"
TL;DR: Treatment with DEHP did not affect survival rates for rats or mice, nor did it alter the amount of food consumed, but chronic inflammation of the kidney and seminiferous tubular degeneration and hypertrophy of cells in the anterior pituitary were observed in male rats and male mice.
Abstract: Groups of 50 male and female Fischer 344 rats and male and female B6C3Fl mice were fed diets containing 6000 or 12,000 (rats) or 3000 or 6000 (mice) mg di(2‐ethylhexyl) phthalate (DEHP)/kg feed for 103 consecutive wk. Concurrent controls (50 of each sex and species) were fed diet without the addition of DEHP. Treatment with DEHP did not affect survival rates for rats or mice, nor did it alter the amount of food consumed. Mean body weight gains of treated male rats (6000 and 12,000 mg/kg), female rats (12,000 mg/kg), and female mice (3000 and 6000 mg/kg) were less than those of the corresponding controls. Seminiferous tubular degeneration and hypertrophy of cells in the anterior pituitary were observed in male rats at 12,000 mg/kg, and chronic inflammation of the kidney and seminiferous tubular degeneration were observed in male mice at 6000 mg/kg. Neither clinical signs of toxicity nor nonneoplastic lesions were detected in the other treated groups at incidences greater than in the corresponding controls....
215 citations
TL;DR: Twenty-eight compounds of known teratogenic potential were assayed by an in vivo screening procedure and four chemicals known to produce only fetal toxicity were tested and the screen successfully identified those that reduced weight.
Abstract: Twenty-eight compounds of known teratogenic potential were assayed by an in vivo screening procedure. Postnatal growth and viability of prenatally exposed offspring was used as a measure of developmental toxicity. Gravid CD-1 mice were administered maximum tolerated doses of the compounds for up to 5 consecutive days during the period of major organogenesis. The dams were allowed to give birth, and litter size and weight on postpartum d 1 and 3 were recorded and compared with concurrent controls. All 15 compounds that were teratogenic by standard teratology test criteria exhibited some form of developmental toxicity. Four chemicals known to produce only fetal toxicity (reduced weight or supernumerary ribs) were tested and the screen successfully identified those that reduced weight. Finally, of the 9 compounds that show no effect in standard tests, 6 were also negative in the screen and 3 demonstrated either reduced viability or weight.
132 citations
TL;DR: The technique has been designed for and utilized as modular additions in a large number and variety of toxicity studies performed on industrial compounds including macrocyclic ethers, aldehydes, urethane foam catalysts, and others.
Abstract: A short objective screening technique has been developed to identify those agents that have peripheral and/or central nervous effects in small laboratory rodents (when utilized as a feature in routine testing protocols). The technique initially utilizes a series of simple quantitative and qualitative measures of various aspects of sensory and motor function. The methodology has been designed for and utilized as modular additions in a large number and variety of toxicity studies performed on industrial compounds including macrocyclic ethers, aldehydes, urethane foam catalysts, and others. It is shown to be a more sensitive early Indicator of toxicity than such classical measures as body weight or clinical chemistry in those cases (such as the macrocyclic ethers and amino proprionitrile) where the nervous or muscular system are the ultimate target organs. It is also a noninvasive and relatively inexpensive methodology. The second phase (a series of isolated tissue assays) establishes the ability to differen...
116 citations
TL;DR: Eleven metals were examined for their potential to induce forward mutations at the thymidine kinase locus in L5178Y mouse lymphoma cells and weak positive responses were seen with HgCl 2, NaAsO2, Na2HAsO4, and Pb(NO3)2.
Abstract: Eleven metals were examined for their potential to induce forward mutations at the thymidine kinase locus in L5178Y mouse lymphoma cells. The materials tested included AlCl3, CdSO4, HgCl2, K2CrO4, K2Cr2O7, MgCl2, MnCl2, NaAsO2, Na2HAsO4, NaCl, and Pb(NO3)2. Strong positive responses at survivals greater than 10% were observed with CdSO4, K2CrO4, K2Cr2O7, and MnCl2. Weak positive responses, yielding 2- to 3-fold increases in mutation frequency above the solvent control at greater than 10% survival, were seen with HgCl2, NaAsO2, Na2HAsO4, and Pb(NO3)2. Negative responses were obtained with MgCl2, NaCl, and AlCl3.
102 citations
TL;DR: Most of the toxic effects were reversible, but testicular atrophy was not in rats allowed a 4-wk recovery period after treatment, suggesting a cumulative toxicity.
Abstract: The short‐term oral toxicity of 2,4,6‐trinitrotoluene (α‐TNT) was determined in dogs, rats, and mice. Single‐dose oral LD50s for α‐TNT in corn oil were 1320 and 794 mg/kg in male and female rats, respectively, and 660 mg/kg in both male and female mice. For multiple‐dose studies, dogs were dosed daily for up to 13 wk with α‐TNT at 0, 0.2, 2.0, or 20 mg/kg by capsule; rats received 0, 0.002, 0.01, 0.05, or 0.25% and mice received 0, 0.001, 0.005, 0.025, or 0.125% α‐TNT in their diets over the same period. All species receiving the highest doses exhibited anemia, with reduced erythrocytes, hemoglobin, and hematocrit. Alterations were observed in organ weights, including enlarged spleens (accompanied by hemosiderosis) and livers, and depressed body weight and/or body weight gain (temporary in dogs and mice). Alterations in clinical chemistry values included elevated cholesterol and depressed serum glutamic‐pyruvic transaminase activity in dogs and rats; no effect on serum glutamic‐oxaloacetic transaminase ac...
74 citations
TL;DR: Female reproductive development was delayed by Mn treatment, as measured by testes weight, sperm count, and serum follicle-stimulating hormone and testosterone concentrations, and fertility was reduced in the group exposed to 3500 ppm Mn with a diet containing sufficient Fe.
Abstract: Long-Evans rats were chronically exposed to dietary Mn3O4 beginning on d 1 of gestation and continuing through 224 d of age. Dietary concentrations of Mn, as Mn3O4, were 350, 1050, and 3500 ppm and were applied in either a normal Fe 240 ppm) or a low-Fe (20 ppm) basal diet. General toxic effects were apparent in young animals at a dietary dose of 3500 ppm Mn and were enhanced by concomitant Fe deficiency. Fertility was reduced in the group exposed to 3500 ppm Mn with a diet containing sufficient Fe. Male reproductive development was delayed by Mn treatment, as measured by testes weight, sperm count, and serum follicle-stimulating hormone and testosterone concentrations.
73 citations
TL;DR: Studies of the rat and rabbit indicated that MEHP has no teratogenic effects and in plasma there is an equilibrium between MEHP absorbed to albumin and in free solution, whereas DEHP is bound to lipoproteins.
Abstract: The literature dealing with monoethylhexyl phthalate (MEHP), the principal metabolite of di (2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, is discussed. MEHP has been shown to be moderately toxic and, following oral administration, undergoes omega- and omega- 1 oxidation to yield the same metabolites as does DEHP. In plasma there is an equilibrium between MEHP absorbed to albumin and in free solution, whereas DEHP is bound to lipoproteins. Studies involving orally administered MEHP revealed the mild hepatic changes occurred but there was no bioaccumulation of the monoester. Studies of the rat and rabbit indicated that MEHP has no teratogenic effects.
69 citations
TL;DR: A comprehensive scheme is described for isolating amosite asbestos and ferruginous bodies from fixed and unfixed human lung tissue and sputum, and the procedure avoids many of the problems associated with previous isolation techniques and illustrates the advantages of brief bleach digestions.
Abstract: A comprehensive scheme is described for isolating amosite asbestos and ferruginous bodies from fixed and unfixed human lung tissue and sputum. This qualitative procedure avoids many of the problems associated with previous isolation techniques and illustrates the advantages of brief bleach digestions. The samples are digested in prefiltered Wright laundry bleach (9.2% sodium hypochlorite), collected on 0.2‐μm Nuclepore filters by vacuum filtration, rinsed with distilled water and absolute ethanol, and examined visually for excessive residue. If organic residues are suspected or are known to occur, the sample is treated sequentially with 2% potassium permanganate, 8% oxalic acid, and 9.2% sodium hypochlorite, and rinsed with distilled water and absolute ethanol. The ethanol, potassium permanganate, and oxalic acid steps can be repeated as often as needed until the desired sample volume has been filtered. The entire procedure allows large volumes to be filtered and yields filters that have extremely clean b...
66 citations
TL;DR: The data indicate that the substantially elevated blood Pb concentrations that are evident at partum in pups prenatally exposed to Pb might be responsible for the postnatally observed delay in synaptogenesis.
Abstract: Pregnant rats were exposed to drinking water with lead (Pb) concentrations of 0, 30, or 200 mg/l. The resultant pups were sacrificed at 11, 75, and 21 d of postnatal age for the determination of synapses/mm^ in parietal cortex. Synoptic counts from electron micrographs of ethanol phosphotungstic acid stained cortical slices were counted by four observers who were blinded as to treatment (control or 200 mg Pb/l drinking water). A greater than fourfold increase in synoptic counts was observed in layers I, II, and III of rat pups parietal cortex between II and 21 d of age. Pb treatment depressed synoptic counts maximally at 15 d of age. However, Pb‐exposed pups displayed essentially the same synoptic counts us controls by 21 d of age. In a cross‐fostering design, it was shown that prenatal exposure to Pb completely accounted for the delays in synaptogeneis. No significant depression of synoptic counts was observed in pups exposed only during the postnatal period. Blood lead concentrations (Pb'B) were determi...
65 citations
TL;DR: The results suggest that the ability of the enzyme systems in lungs to protect against NO2 fluctuated in a complex manner and the activities of the protective enzymes varied inversely with lipid peroxidation.
Abstract: This work was done to clarify the relation between the change of lipid peroxidation and the protective systems in lungs after NO 2 exposure. JCL:Wistar 8‐wk‐old male rats were exposed continuously to 10 ppm NO 2 for 2 wk. Lipid peroxidation, measured by ethane exhalation in the breath of the rats and by the reaction of thiobarbituric acid with lung homogenates, increased to a maximum at 3 d after a decline at 1 d, and then returned to the initial level (of d 0). Activities of glutathione peroxidase (GPx), glutathione reductase (GR), glucose‐6‐phosphate dehydrogenase (G6PDJ, 6‐phosphogluconate dehydrogenase (6PGD), disulfide reduciase (DSR), and Superoxide dismuiase, (SOD) in the 105,000 × g supernatant of lung homogenates were depressed slightly at 1 d. Thereafier, they increased significantly to their maximum levels from 5 to 10 d, and these maximum levels were maintained until d 14. The pattern of change of these protective enzymes was symmetric to that of lipid peroxidation after 3 d. The order of the ...
63 citations
TL;DR: Evaluation of the immune function may be helpful for the diagnosis of PCB poisoning and the suppression of cellular immunity was correlated with the severity of the disease.
Abstract: Polychlorinated biphenyl (PCB) poisoning causes many physiological abnormalities including immune suppression Cellular immunity was studied in 30 PCB-poisoned patients and 50 normal human subjects PCB poisoning caused suppression of cellular immunity such as the delayed-type skin response to streptokinase and streptodornase The suppression of cellular immunity was correlated with the severity of the disease Thus evaluation of the immune function may be helpful for the diagnosis of PCB poisoning
TL;DR: Tritiated thymidine cytocide of spleen colony-forming cells was generally increased in exposed animals, perhaps indicating a compensatory response to the reduction of circulating cells.
Abstract: Effects of benzene inhalation on mouse pluripotent hematopoietic stem cells have been evaluated. Male mice 8–12 wk old were exposed to 400 ppm benzene for 6 h/d, 5 d/wk, for up to 9½ wk. A t various time intervals exposed and control animals were killed, and cardiac blood was evaluated for changes in white blood cell (WBC) and red blood cell (RBC) content. In addition, femora and tibiae were evaluated for total marrow cellularity, stem cell content (as measured by the spleen colony technique), and the percent of stem cells in DNA synthesis (as determined by the tritiated thymidine cytocide technique). Exogenous spleen colonies grown from marrow of exposed animals were counted, identified, and scored by histological type. Exposure to benzene caused significant depressions of RBCs and WBCs throughout the exposure period, which continued for at least 14 d after exposure. Bone marrow cellularity and stem cell content were also depressed in exposed animals throughout the study. Tritiated thymidine cytocide of ...
TL;DR: It is suggested that perhaps the best approach to an experimental situation where lipid peroxidation is thought to be of central importance is measurement of both parameters, TBA reactants and ethane concentrations.
Abstract: There is some controversy about which method of assessment of lipid peroxidation in isolated hepatocytes is most appropriate. The present study was undertaken primarily to compare measurement of concentrations of thiobarbituric acid (TBA) reacting substances with measurement of ethane concentrations in the gas phase of the incubation flask as indicators of lipid peroxidation. Four metal salts, FeCl 2 , NaVO 3 , CdCl 2 , and MnCl 2 , were selected as agents that interact with the lipid peroxidation process. Furthermore, reduced glutathione (GSH) concentrations and enzyme leakage were assayed to determine whether there was a consistent pattern of interaction between lipid peroxidation and change In GSH concentrations and enzyme leakage. The effects of the metal ions on the concentration of TBA reactants estimated in the whole cell suspension and on the gaseous ethane concentration were similar. However, the assessment of TBA reactants was a little more sensitive, and ethane concentrations continued to climb...
TL;DR: Preference binding of CD by albumin and HDL may explain its unusual tissue distribution compared to other organochlorine pesticides such as aldrin and dieldrin, which bind preferentially to VLDL and LDL and distribute preferential to fat tissues.
Abstract: The preferential distribution of the relatively nonpolar pesticide chlordecone (CD) to liver rather than to fat tissues in humans suggests that it may be transported in plasma differently from other organochlorine pesticides. The plasma binding of [14C] CD was investigated in vitro in human, rat, and pig plasma and in vivo in rat plasma. Protein and lipoprotein fractions were separated by serial ultracentrifugation. Heparin-manganese precipitation and agarose gel electrophoresis were also carried out to determine whether separation techniques altered CD binding to plasma components. In human plasma, the distribution of [14C] CD among proteins and high density, low density, and very low density lipoproteins (HDL, LDL, and VLDL) was 46, 30, 20, and 6%, respectively. The distribution of cholesterol in the same plasma fractions was 4, 20, 63, and 7%, respectively. In the pig and rat the order of binding was similar to that in humans, with protein greater than or equal to HDL greater than LDL greater than or equal to VLDL. Separation by heparin-Mn precipitation confirmed the results obtained by ultracentrifugation. The distribution of [14C] CD in rat lipoprotein was similar whether the CD was administered in vivo or incubated with plasma in vitro, with approximately 80% bound to HDL, 11% to LDL, and 9% to VLDL in either case. Agarose gel electrophoresis of plasma-bound [14C] CD indicated that albumin was the major component of the protein fraction responsible for CD binding. Preferential binding of CD by albumin and HDL may explain its unusual tissue distribution compared to other organochlorine pesticides such as aldrin and dieldrin, which bind preferentially to VLDL and LDL and distribute preferentially to fat tissues.
TL;DR: It is concluded that MT induced by low doses of DMBA arise more rapidly in yellow mice than in nonyellow littermates, and this experimental system suitable for development of an assay to efficiently test the carcinogenic potential of low dose levels of chemical substances.
Abstract: Latent periods and cumulative incidence of mammary carcinomas (MT) up to 50 wk after initial gavage with 7.12‐dimethylbenz[a]anthracene (DMBA) were determined in virgin yellow (Avy/A) and agouti (A/a) (BALB/cStCrlfC3Hf/Nctr X VY/WffC3Hf/ Nctr‐Avy) F 1 hybrid female mice. When subcutaneous masses reached 5–10 mm in diameter, the mice were killed and necropsied, and the tissues examined histologically. No MT were found in control mice. Cumulative MT incidence in the 1.5‐mg DMBA group (A) was 43% (41/95) among yellow mice, and 33% (32/96) among agoutis. In the 6.0‐mg DMBA group (B), corresponding MT incidences were 86% (83/96) and 71% (67/95). In group A, the first percentile of MT detection was 13.0 wk after initial carcinogen treatment in yellow mice; it was 18.0 wk in agoutis. Corresponding latent periods for the 20th percentile were 34.3 and 47.0 wk. In group B, latencies for the first percentile were 8.3 and 9.0 wk. Corresponding latencies for the 20th percentile were 15.3 and 16.0 wk. Within genotypes ...
TL;DR: Cell lines derived from three widely distributed species of freshwater fish have the capacity to metabolize BaP to a form that is a proximate carcinogen in rodents and to produce a water-soluble conjugate of this metabolite.
Abstract: Benzo[a]pyrene (BaP) metabolism was studied in cell lines derived from rainbow trout (RTG‐2), bluegill fry (BF‐2), and fathead minnow (FHM). Confluent cultures were exposed to 3 H‐BaP (0.5 nmol/ml), and, after various exposure times, metabolites were extracted from the media with an organic solvent and analyzed by high‐pressure liquid chromatography. BF‐2 and RTG‐2 cells converted 63% of the BaP to water‐soluble metabolites within 24 h, while FHM cells converted only 12%. BF‐2 and RTG‐2 cells metabolized more than 90% of the BaP by 48 h, while only 67% of the BaP was converted to water‐soluble metabolites by FHM cells after 96 h. The major organic‐solvent‐extractable metabolites in all three cell lines were 9,10‐dihydroxy‐9,10‐dihydrobenzo[a]pyrene and unidentified polar metabolites. Of the water‐soluble metabolites formed by BF‐2, FHM, and RTG‐2 cells, 67, 42, and 19%, respectively, were converted to ethyl‐acetate‐extractable metabolites by treatment with β‐glucuronidase. All three cell lines formed a gl...
TL;DR: Chronic dietary Mn3O4 resulted in dose-related increases in Mn accumulation, and a concomitant Fe deficiency promoted Mn accumulation; the addition of substantial amounts of Mn to either diet depressed tissue Fe levels.
Abstract: Sprague‐Dawley rats were chronically exposed to particulate Mn 3 O 4 through two generations. At specific ages, observations were made of growth, tissue content, and distribution of Mn and Fe as affected by chronic exposure to Mn through an Fe‐sufficient diet and an Fe‐deficient diet. Chronic dietary Mn 3 O 4 resulted in dose‐related increases in Mn accumulation, and a concomitant Fe deficiency promoted Mn accumulation. In general, the addition of substantial amounts of Mn to either diet depressed tissue Fe levels.
TL;DR: Fetuses fathered by alcoholic male rats were malformed: 55% had soft-tissue anomalies and average pups weights were also reduced by paternal ethanol consumption, and no recovery in reproductive function was evident over the 21-d post-ethanol mating period.
Abstract: Ten male Long‐Evans rats were given 20% v/v ethanol in the drinking water for 60 consecutive days. Ten other males were given distilled water and served as controls. Each male was then allowed to mate with three virgin female Long‐Evans rats, once per week for three consecutive weeks. The males were necropsied after the third mating, the females were killed on d 20 of gestation, and the offspring were examined for parameters of fetal growth, skeletal ossification, and soft‐tissue anomalies. Ethanol caused testicular weight reductions and gross testicular atrophy in 1 of 10 males. Five matings of alcoholic male rats proved infertile. Total embryonic deaths (resorptions and preimplantation loss) were increased by ethanol, while implantations and litter size were significantly decreased. Fetuses fathered by alcoholic male rats were malformed: 55% had soft‐tissue anomalies (microcephalus, microphthalmia, cranial fissure, and hydronephrosis). Litter weight and average pups weights were also reduced by paternal...
TL;DR: Pyruvate azine was much less toxic than the parent hydrazine on a molar basis, although some fatty vacuolation was detectable in midzonal hepatocytes, and Pretreatment of animals with phenobarbital or piperonyl butoxide reduced and increased the severity of the fatty liver.
Abstract: The pathogenesis and factors affecting hydrazine‐induced fatty liver have been investigated in rats using histological and ultrastructural examination. A dose of 20 mg hydrazine/kg caused the accumulation of lipid, swelling of mitochondria, and the appearance of microbodies in both periportal and midzonal hepatocytes and in the proximal tubular cells of the kidney. These changes were detectable by light or electron microscopy 24 h after dosing with hydrazine. A dose of 60 mg/kg was the highest dose tolerated for 24 h, but the severity of the fatty liver was similar to that after a dose of 40 mg/kg. The accumulation of lipid droplets and the swelling of mitochondria were detectable by electron microscopy 30 min after dosing, but the accumulation of fat could not be detected by light microscopy until 4 h after dosing. Pretreatment of animals with phenobarbital or piperonyl butoxide respectively reduced and increased the severity of the fatty liver. Pyruvate azine was much less toxic than the parent hydrazin...
TL;DR: The selective phagocytosis of alpha NiS accounts for both high intracellular particle accumulation and high levels of soluble Ni relative to the surrounding medium, which may represent an activation step in carcinogenesis.
Abstract: The intraceliular fate of particulate crystalline αNiS, an inducer of neoplastic transformation which is readily phagocytized by cultured cells, was compared with that of particulate amorphous NiS, which does not have these properties. Amorphous and crystalline NiS both dissolve slowly in complete medium; phagocytized αNiS particles remain in the cytoplasm, where they dissolve more rapidly than extracellular particles. Thus the selective phagocytosis of aNiS accounts for both high intraceliular particle accumulation and high levels of soluble Ni relative to the surrounding medium. Since phagocytized aNiS particles do not enter the nucleus, dissolution in the cytoplasm may represent an activation step in carcinogenesis, forming soluble Ni which diffuses into the nucleus. Dissolution products from phagocytized aNiS were detected in subcellular fractions isolated from treated cells; the highest levels were found in the nuclei, mitochondria, and lysosomes. That the Ni in the subcellular fractions was dissolve...
TL;DR: It is concluded that xylene (mixed isomers) is teratogenic to the CD-1 mouse at 2.4 and 3.0 ml/kg.d, doses approaching lethal levels.
Abstract: Pregnant outbred albino (CD‐1) mice received (gavage, three times a day in cottonseed oil) a xylene mixture (60.2% m‐xylene, 9.1% o‐xylene, 13.6% p‐xylene, and 17.0% ethyl benzene) on d 6–75 of gestation (d 1 being the day vaginal plugs were observed). The mice were killed on d 18, the general and reproductive health of the dams evaluated, and the fetuses examined and processed to characterize external, visceral, and skeletal malformations. At 3.6 ml/kg·d, xylene killed 12 of 38 dams and caused a significantly (p < 0.05) smaller average weight gain during pregnancy than did the vehicle (cottonseed oil). Fetuses from dams treated with xylene at 2.4 ml/kg·d and higher doses had average fetal weights significantly lower than that of the control fetuses. However, the percent of resorptions for xylene was significantly greater than for the control only at 3.6 ml/kg·d. At 2.4, 3.0, and 3.6 ml/kg·d xylene produced a significantly (p < 0.07) greater average percent of malformed fetuses than did the control. Cleft...
TL;DR: The decrease in lung biochemical parameters and increased mortality in 7- and 24-d-old neonatal rats suggest that they are more susceptible to O3 stress than infant and adult rats.
Abstract: The influence of age on O3 effects in the lung was studied in 8 groups of Sprague-Dawley rats: 7, 12, and 18 d of age (neonatal); 24, 30, and 45 d of age (infant); and 60 and 90 d of age (adult). Lung weight, total lung protein and DNA contents, and a series of marker enzyme activities in lung tissue were determined. After exposure of rats from each group to 0.8 ppm (1568 microgram/m3) O3 continuously for 3 d, a biphasic effect was noted. The biochemical parameters, expressed per lung, in O3-exposed rats relative to their corresponding controls decreased in the 7- and 12-d-old groups, increased or remained unchanged in the 18-d-old group, and increased in the 24- to 90-d-old groups. However, the increases were much greater for 60- to 90-d-old rats than for 24- to 30-d-old rats. The increase in lung biochemical parameters is thought to occur in response to lung injury and subsequent repair processes, and greater increases in the lungs of older rats suggest that they are more responsive to O3 exposure than younger rats. The decrease in lung biochemical parameters and increased mortality in 7- and 24-d-old neonatal rats suggest that they are more susceptible to O3 stress than infant and adult rats.
TL;DR: A statistical structure-activity equation has been developed for the estimation of carcinogenic potential for chemicals that have not been subjected to carcinogenesis assays, based on substructural fragments and molecular weight obtained for 343 compounds.
Abstract: A statistical structure‐activity equation has been developed for the estimation of carcinogenic potential for chemicals that have not been subjected to carcinogenesis assays. This discriminant equation is based on substructural fragments and molecular weight obtained for 343 compounds. The data base used for the design of the equation was obtained from the monographs of the International Agency for Research on Cancer. The accuracy of classification for the carcinogens in the model is between 87 and 91%, and for noncarcinogens between 78 and 80% in the presence of between 5.5 and 10.2% of the compounds not being classifiable. The false negative rate ranges between 4 and 5%; the false positive rate is near 11%.
TL;DR: Results suggest that although hydrazine is metabolized via several routes, the hepatotoxicity may well be due to the parent compound rather than a metabolite.
Abstract: Hydrazine causes a dose-related increase in liver triglycerides and in liver weight and causes a decrease in hepatic glutathione. The threshold dose for the toxic effect is around 10 mg/kg, and the optimal effect is seen after a dose of 40 mg/kg. The effect of hydrazine on liver weight and glutathione was detectable within 30 min of dosing, but the elevation of hepatic triglycerides was not detectable until 4 h after dosing. At 24 h after a dose of 60 mg hydrazine/kg, hepatic reduced glutathione was approximately 50% of the control value and triglycerides were about 7 times the normal level. In vitro studies indicated that hydrazine is metabolized by rat liver microsomal enzymes, this being dependent on NADPH and oxygen. Pretreatment of animals with phenobarbital or piperonyl butoxide respectively decreases and increases the hepatotoxicity. Prior depletion of hepatic glutathione by administration of diethyl maleate had no effect on the toxicity. Pyruvate azine, a probable metabolite of hydrazine, is much less toxic than hydrazine itself on a molar basis. These and other results suggest that although hydrazine is metabolized via several routes, the hepatotoxicity may well be due to the parent compound rather than a metabolite.
TL;DR: The excretion of 14CO2 was correlated with the expected level of microsomal metabolism of trichloroethylene to an electrophilic intermediate capable of binding to glutathione or macromolecules and the ability of trICHloro methylene to interact with DNA in vivo was observed to be very slight.
Abstract: Male Sprague-Dawley rats and male B6C3F1 mice excreted 5-15% of a tracer dose of [14C]trichloroethylene as 14CO2 within 24 h after ip injection of a single dose in a corn-oil vehicle. The proportion of the dose excreted as CO2 was greater in mice than in rats, but increased in the rats after starvation or pretreatment with phenobarbital. As the dose was increased toward the LD50 level, the proportion excreted as 14CO2 decreased slightly, but this was largely due to increased loss of unchanged trichloroethylene. The excretion of 14CO2 was thus correlated with the expected level of microsomal metabolism of trichloroethylene to an electrophilic intermediate capable of binding to glutathione or macromolecules. Liver protein labeling was observed to be relatively high (10,000-23,000 cpm/mg in the mouse), while DNA labeling was consistently observed to be very low, not allowing identification of any adducts by high-performance liquid chromatography (HPLC). Also, no effect on DNA fragmentation was seen by alkaline sucrose gradient centrifugation after injection of an LD50 dose of trichloroethylene. The ability of trichloroethylene to interact with DNA in vivo was thus observed to be very slight.
TL;DR: The dose-dependent profile of EG metabolism argues against the use of very high chronic doses in studies intended to estimate health risks of long-term, low-level exposure to EG.
Abstract: A dose‐dependent change was observed in the disposition of 14 C‐labeled ethylene glycol (EG) after iv administration of 20, 200, 1000, and 2000 mg/kg to Fischer 344 rats. The part of the dose expired as CO 2 decreased from 39% at 20 and 200 mg/kg to 26% at 1000 and 2000 mg/kg, while urinary excretion of radiocarbon increased from 35 to 56%. The increase in urinary 14 C was almost entirely attributable to [ 14 C] glycolate, which comprised 20% of the dose in 24 h at the two higher dose levels and only 2% at the lower doses. High doses of EG limited the processes responsible for glycolate metabolism, supporting the idea that this acid is a major contributing factor to the acute toxicity of EG. Compensatory urinary excretion of glycolate resulted in minimal dose‐dependent effects on 14 C blood clearance. Blood clearance of 14 C occurred in an initial rapid phase (half‐life, 3–5 h), when plasma was comprised predominantly of ethylene glycol, that persisted for 12 h at 20 mg/kg EG and 30 h at 2000 mg/kg. The d...
TL;DR: The hypothesis that Ca plays a ubiquitous role in the death of liver cells is not supported as the toxic effects due to Cd or Cu were not ameliorated on omission of Ca from the incubation medium.
Abstract: Recent evidence has renewed interest in the hypothesis that Ca plays a central role in cell death. It was previously found that Cd and CuCl2 cause loss of viability of isolated hepatocytes. It was therefore of interest to determine whether Ca was intimately involved with the toxic effect of these metals. Some of the chemicals that were previously shown to be toxic through a mechanism involving Ca (amphotericin B, lysolecithin, and Ca ionophore A23187) were also included in the study. Hepatocytes were incubated with one of these chemicals and samples taken at various time points up to 120 min for estimation of cell viability (intracellular K+ and leakage of aspartate aminotransferase) and lipid peroxidation. The toxic effects due to Cd or Cu were not ameliorated on omission of Ca from the incubation medium. Furthermore, of the other three chemicals investigated, only the toxic properties of the Ca ionophore were effectively blocked by incubation in a Ca-free medium. The results of this study do not support the hypothesis that Ca plays a ubiquitous role in the death of liver cells.
TL;DR: Findings indicate that measures of metabolic integrity of cultured hepatocytes are more sensitive indices of early cadmium cytotoxicity than are routine, nonspecific measures such as cellular protein content and dye-exclusion viability tests, which detect the later stages of cell injury, i.e., cell death.
Abstract: Primary cultures of rat hepatocytes served as an experimental model to evaluate the cytotoxicity of cadmium chloride. Cellular injury was assessed by a series of enzymatic and functional indices in 24-h-old cultures exposed for 1 h to concentrations of cadmium chloride ranging from 50 to 400 muM. In cultures that were evaluated immediately after the 1-h exposure to cadmium, little evidence of toxicity was observed as evaluated by total cellular protein content and cell viability. In similarly treated cultures, leakage of lactate dehydrogenase from the hepatocytes into the culture medium was increased in a dose-dependent manner. The most sensitive indicators of cadmium toxicity proved to be two parameters of metabolic activity: lactate-to-pyruvate (L/P) ratios, and intracellular levels of urea. Cadmium exposure produced substantial increases in L/P ratios and decreases in urea content in the cultured liver cells. If the cultures were allowed to recover by replacing the cadmium-containing medium after 1 h of exposure with fresh medium for 24 h, cellular protein content and cell viability were shown to decrease by 40%. These findings indicate that measures of metabolic integrity of cultured hepatocytes are more sensitive indices of early cadmium cytotoxicity than are routine, nonspecific measures such as cellular protein content and dye-exclusion viability tests, which detect the later stages of cell injury, i.e., cell death.
TL;DR: The results suggest that NPSH play an important role in Hg uptake and subsequent development of Hg toxicity.
Abstract: The effect of lowering renal cortical sulfhydryl concentration on development of acute renal failure (ARF) was evaluated in rats receiving HgCl 2 (15 mg/kg body weight, im). Within 90 min after HgCl 2 injection urine flow rate and fractional excretion of sodium (FENa) were significantly elevated above control levels, and they remained elevated throughout the 3‐h experimental period. Urine flow rate and FENa were not significantly elevated above control levels in animals injected with diethyl maleate (3 mmol/kg, ip) 30 min before and 90 min after HgCl 2 (DEM/HgCl 2 ). Administration of DEM alone did not alter renal function. Although lower than control levels, concentrations of protein‐bound sulfhydryl groups (PBSH) were comparable in HgCl 2 ‐ and DEM/HgCl 2 ‐treated animals. In contrast, concentrations of nonprotein sulfhydryl groups (NPSH) were 62% lower in DEM/HgCl 2 animals than in those treated with HgCl 2 alone. Similarly, Hg accumulation was 54% lower in DEM/HgCl 2 ‐treated animals than in animals t...
TL;DR: The results indicate that albumin and low density lipoprotein bind HCB effectively and suggest that plasma proteins may play a role in its distribution to peripheral cells.
Abstract: The mechanism of transport of polychlorinated biphenyls (PCBs) to and from peripheral cells is not known. Plasma proteins, which bind a variety of compounds including hydrophobic molecules, are most likely to be involved in PCB transport. In order to study the role of lipoproteins in the transport and distribution of PCBs to cells, an assessment of the nature and extent of the interaction and binding of PCBs to plasma proteins is necessary. In this report a simple filter assay procedure for the analysis of binding of 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) by low density lipoproteins and serum albumin is described. The method allowed compete recovery of the PCBs, and reduced errors due to nonspecific binding to the apparatus to insignificant values. Low density lipoprotein bound HCB at several noninteractive sites (number of binding sites n = 30; binding constant K = 2.7 x 10(5); dissociation constant Kd = 7.2 x 10(-6) M). Bovine serum albumin bound HCB at one noninteractive site (n = 0.53; K = 5.1 x 10(5); Kd = 1.9 x 10(-6) M). The results indicate that albumin and low density lipoprotein bind HCB effectively and suggest that plasma proteins may play a role in its distribution to peripheral cells.