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Biomedical subjects

S C Gad

Publications and source records attributed to S C Gad.

34 records · Page 2Linked to original sources
PubMed1986

Carcinogenicity study with sodium dichromate in rats.

Solutions of sodium dichromate were administered to Sprague Dawley rats by intratracheal instillations over a period of 30 months. Dosage was 0.01, 0.05 or 0.25 mg/kg, five times a week, or 0.05, 0.25 or 1.25 mg/kg once a week. Each group consisted of 40 male and 40 female rats. Groups left untreated or given saline served as negative controls. The highest chromate dose proved to be within the range of the maximum tolerable amount. The main determinant of effect was the concentration of chromate instilled, not the total dose per week. Non-neoplastic pulmonary lesions, which occurred predominantly in the highest dose group, were fibrotic regions containing residual distorted bronchiolar lumens or cellular inflammatory foci containing alveolar macrophages, proliferated epithelium and chronic inflammatory thickening of alveolar septa. Fourteen rats given 1.25 mg/kg sodium dichromate had a total of 20 lung tumours (12 benign, 8 malignant). One rat given 0.25 mg/kg once a week had a malignant tumour. Tumours were generally small and were non-fatal. A comparable solution of calcium chromate, which was tested at the two highest dose levels, had virtually the same effect. The positive controls, benzo(a)pyrene and dimethylcarbamyl chloride, induced a high rate of fatal malignant tumours in the respiratory tract.

Adenocarcinoma↗
PubMed1986

Current concepts in occupational health: metals-chromium.

Chromium and its compounds have long been generally recognized as having potentially severe occupational health hazards. A brief review of the historical perspectives is provided. Failure to properly differentiate between the various valence states, which exhibit different toxicological properties and the physical state (solubility, particle size, etc.) as well as poor quantitation and characterization of exposure has led to confusion and potential error in estimating the risk inherent in working with chromium and its compounds. An overview is provided of the most recent and available data which address these issues in light of current concepts of scientific evaluation.

Carcinogens↗
PubMed1986

Phorbol diacetate inhibits superoxide anion radical production and tumor promotion by mezerein.

The ability of the non-promoter phorbol diacetate (PDA) to modulate superoxide anion radical production by the complete tumor promoter phorbol myristate acetate (PMA) or the second stage promoter mezerein was assessed. Superoxide anion radical production was measured by the superoxide dismutase inhibitable reduction of nitroblue tetrazolium (NBT) to a blue intracellular formazan precipitate. These studies demonstrated that superoxide anion radical production by murine peritoneal exudate cells (PEC) stimulated by i.p. injection with mezerein (100 ng) is inhibited in a dose-dependent manner by co-administration with PDA (1-1000 ng). There was no effect on the number of formazan-positive PEC when PDA was co-administered with PMA. In a two-stage tumor promotion bioassay in female SENCAR mice initiated with 25.6 micrograms dimethylbenz[a]anthracene (DMBA) followed by first stage promotion with PMA (4X, 2 micrograms), co-administration of mezerein (2 micrograms) with 2 micrograms or 20 micrograms PDA reduced the number of papillomas after 14 weeks by 38% and 44%, respectively, compared with mezerein treatment alone. PDA (20 micrograms) when co-administered with mezerein (2 micrograms) does not inhibit mezerein induced hyperplasia in mouse skin. These results suggest a correlation between the ability of PDA to inhibit both superoxide anion radical production and tumor promotion by mezerein.

Animals↗
PubMed1985

Toxicity of cyclohexanone oxime. I. Hematotoxicity following subacute exposure in rats.

Cyclohexanone oxime (CHO) was given po to male and female Fischer 344 rats at dose levels of 10, 25, 75, 150, and 300 mg/kg, five times a week for a period of 2 weeks. Control animals received distilled water. All animals given intermediate dose levels (10, 25, 75, and 150 mg/kg) and one half of the animals which were dosed at the high dose (300 mg/kg) as well as one half of the controls were terminated 14 days after administration of the first dose. The remaining rats received no treatment for an additional 14 days and were sacrificed on Day 28 of the study (recovery phase). Dose-related decreases in erythrocyte number, hemoglobin, and hematocrit, with an accompanying increase in reticulocytes and circulating nucleated erythrocytes, were observed in both sexes at Day 14. Methemoglobin levels, determined only at the high dose, were elevated in both sexes at this time. Splenomegaly and hepatomegaly were observed in both sexes at 14 and 28 days. Histopathological examination of the spleen and bone marrow revealed dose-related erythroid hyperplasia at 14 days which subsided by Day 28. The above effects were more pronounced in males. Erythrocyte numbers were only slightly depressed and reticulocytes mildly elevated in males at Day 28. Hematological values were not statistically different from controls in females at this time. These results suggest that CHO induces oxidative damage to the erythrocyte, resulting in a hemolytic anemia accompanied by increased erythropoiesis. The toxic effects appear reversible upon cessation of exposure.

Anemia, Hemolytic↗
PubMed1985

Toxicity of cyclohexanone oxime. II. Acute dermal and subchronic oral studies.

Dermal exposure of rabbits to cyclohexanone oxime (CHO) for 24 hr at 0, 0.8, 2, and 5 g/kg caused dose-related reticulocytosis on the day after dosing as well as a decrease in hemoglobin in the 5-g/kg females 7 days postdosing. Gavage of rats 5 days a week for 13 weeks at levels of 0, 0.25, 2.5, and 25 mg/kg resulted in a dose-related decrease in erythrocyte number, hemoglobin, and hematocrit, with an accompanying increase in circulating reticulocytes and nucleated erythrocytes, in both sexes. Also seen were corneal opacities and an increased incidence of Howell-Jolly bodies. Results suggested an increased erythropoiesis in the spleen and bone marrow. The data from satellite groups terminated at 30 and 60 days revealed no effect at the lower test level, but results from the end of the study showed a clear cumulative dose response down to the 0.25-mg/kg level. Males were affected earlier and at lower doses than females. These results, along with those of a subacute study with a recovery period, suggest that CHO induces an oxidative attack on erythrocytes which appears reversible upon cessation of exposure.

Administration, Oral↗
PubMed1985

Thirteen cationic ionophores: their acute toxicity, neurobehavioral and membrane effects.

Thirteen cationic ionophores (12-Crown-4, 15-Crown-5, 18-Crown-6, Dibenzo 18-Crown-6, Dicyclohexano 18-Crown-6, 24-Crown-8, Dicyclohexano 24-Crown-8, Lasalocid, Hexacyclen trisulfate, Chiral binapthol, Valinomycin, Monensin, and A-23187) were evaluated for acute toxicologic properties, including lethality and neurobehavioral effects in multiple species (rats, rabbits, and mice) by multiple routes, skin and eye irritation and effects on membrane permeability to physiologic cations. Attention was focused on determining minimum neurobehavioral effect levels and characterizing the spectrum of these effects at different dose levels. While LD50's followed one pattern, this was not the case with other effects. Cluster and factor analysis suggest that, though the primary mechanism of action is alteration of membrane permeability to specifi-cations (qualitative types of activity correlate with the results of membrane permeability studies), which ions are provided an increased passage varies with ring size and charge dispersion. In the intact animal absorption markedly modifies these results.

Animals↗
PubMed1984

Innovative designs and practices for acute systemic toxicity studies.

Over a four year period our laboratory has conducted 124 acute systemic toxicity studies (64 oral, 39 dermal, and 21 inhalation), altering study and program designs with the objectives of maximizing information while minimizing animal usage. By employing dose selection strategies, probes, lethality limits instead of LD50's, staggered sequential dosing, and by conducting studies in batteries, animal usage was reduced by 48% below the average number currently quoted as necessary for an LD50 study. Simultaneously, use of a neurobehavioral screen, adjunct studies and a flexible study design have led to a significant upgrading in the information generated by these studies. Additionally, the use of a decision tree approach for selecting tissues for histopathology was developed. The use of specific indicators (such as organ weights) for selecting organs for microscopic examination was also evaluated. Our efforts demonstrate that significantly more information can be generated by studies utilizing fewer animals than is now common practice.

Animals↗
PubMed1982

Statistical analysis of behavioral toxicology data and studies.

One of the areas of toxicology in which a wide variation occurs in the statistical procedures used to analyze experimental data is behavioral toxicology. Due to either limitations in statistical training in the toxicologists or to a lack of understanding of the underlying biological mechanisms on the part of the statisticians, data is frequently analyzed by methodologies which either do not have optimal characteristics of sensitivity and power or for which the underlying assumptions as to the nature of the data are not valid. To establish a firm basis for an identification of the optimal and most appropriate forms of statistical analysis of behavioral toxicology data (and to design efficient and sensitive studies), the four general types of data (observational scores, response rates, error rates, and times-to-endpoints) and one special class of data (teratology and reproduction) are examined in detail. The present practices as to statistical analysis are then reviewed and suggestions as to optimal methods (based on experience, with data sets presented as examples) are developed and presented. The underlying key to this entire process is to establish the biological and statistical nature of the data being generated and to design and analyze experiments accordingly.

Amphetamine↗
PubMed1982

Acute dermal toxicity of two quarternary organophosphonium salts in the rabbit.

Tetrabutyl phosphonium chloride and tetrabutyl phosphonium bromide were evaluated for their potential to cause primary dermal irritation and acute dermal toxicity in rabbits. Both chemicals were found to not only be severely irritating to skin, but the pure hygroscopic chemicals caused death in more than half the number of rabbits used in the primary dermal irritation tests. Further investigations revealed the single-application dermal LD50 of tetrabutyl phosphonium chloride (Bu4PCl) (using an ethylene carbonate (EC) vehicle) was 600 mg/kg for male rabbits and 500 mg/kg for female rabbits. The single-application dermal LD50 of tetrabutyl phosphonium bromide (Bu4PBr) (using the EC vehicle) was 700 mg/kg for male rabbits and 850 mg/kg for female rabbits. The dermal LD50 of pure undiluted Bu4PCl was 225 mg/kg for male rabbits. These data indicate that Bu4PCl and Bu4PBr represent a substantial acute dermal toxicity hazard.

Animals↗
PubMed1978

Cytotoxicity of butylated hydroxytoluene and butylated hydroxyanisole in cultured heart cells.

Butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) at concentrations of 100 ppm (0.45 and 0.55 mM, respectively) produced a marked leakage of lactic dehydrogenase (LDH) from cultured myocardial and endotheloid cells into the culture medium. At this concentration both BHT and BHA markedly depressed the beating rate of cultured heart cells with maximum inhibition occurring within 1 h after antioxidant exposure. Morphologically the appearance of cells in the presence of 100 ppm BHT and BHA was similar to the appearance of control cells. However, when BHT and BHA concentrations were increased to 1000 ppm (4.5 and 5.5 mM, respectively), marked cell lysis was seen after a 1 h exposure period. The results of this study suggest that both BHT and BHA, in relatively large concentrations, produce injury to myocardial cells in culture.

Animals↗
PubMed1978

Behavioral and neuropharmacological toxicology of the macrocyclic ether 18-crown-6.

18-CROWN-6 was assessed for neurologic effects in rats, mice, and rabbits by intravenous (IV) and intraperitoneal (IP) routes of administration. Male rats and mice exhibited no effects with IV doses to 20 mg/kg. Given IP doses of 20 to 160 mg/kg/day, rats and mice exhibited numerous signs, including aggression, tremors, muscle weakness and a degradation of some reflexes. All signs faded after four days when dosage levels were kept constant, but returned when the dose was doubled. All signs disappeared upon discontinuance of exposure. Treatment with PCPA (p-chlorophenylalanine) or dibenzyline caused most signs to disappear. Rabbits given 6.0 mg/kg/day IV displayed tremors, hyperactivity, unsteady gait and stereotypic behavior, with acclimation as in rats and mice. 18-CROWN-6 had no activity in isolated tissue preparations unless it was first incubated with tissues. PCPA and dibenzyline reversibly blocked the actions of incubated 18-CROWN-6 on isolated tissue. 18-CROWN-6 is hypothesized to be metabolized to a serotonergic agonist.

Animals↗
PubMedDate not supplied

A neuromuscular screen for use in industrial toxicology.

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 propionitrile) 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 differentiate between reversible (pharmacologic) and irreversible (toxicologic) sensory-neural responses. The development and validation of the procedure have involved its use in both acute and subchronic studies by the inhalation, oral, ip, and sc routes. As necessary, isolated tissue and biochemical assays have been done to verify mechanisms of action. In fact, decision-tree schemes have been developed as part of the screen. These schemes allow elucidation of mechanisms of action if such is desired and statistical evaluation of the diverse data generated.

Animals↗
PubMedDate not supplied

A functional observational battery for use in canine toxicity studies: development and validation.

The most commonly used nonrodent species in regulatory toxicity and safety assessment studies has been and remains the dog, with the beagle being the standard breed employed. Although a standard functional observational battery (FOB) or neurobehavioral screen for use in rodents (primarily rats) has been incorporated into rodent studies since the late 1980s, this is not the case in nonrodents. In the pharmaceutical area (where repeat exposure nonrodent studies are generally required to develop a drug for humans), some work has been previously conducted towards developing a similar screen in the dog but progress has been limited. Given both the differential metabolism and sensitivity of the dog compared to rodents and the extreme desirability of having as complete a set of toxicity and/or functionality measures in the same species (to simplify and improve the accuracy of dose/response metrics) as possible, the need for such a standardized and validated methodology is clear. Study data from prior work establish the susceptibility of dogs to a wide variety of neurotoxic agents, including 6-aminonicotinamide (ANA), methanol, lasalocid, metronidazole, acrylamide, clinoquinol, organo tins, and mercury. Additionally, the dog is likewise well established as a sensitive model for a wide range of peripheral and central nervous system-active pharmacologic agents, as required by recent regulatory requirements for safety pharmacology evaluations. Here we report on a robust and yet sensitive noninvasive screening methodology for detecting and providing initial quantitation and characterization of such direct and indirect neurotoxic and neuropharmacologic effects that has been developed. Additionally, an analysis and interpretation component that allows differentiation of neurotoxic from neuropharmacologic activities has also been adapted from prior work by one of the authors. Comparative species difference in sensitivity to neuroactive agents are also discussed, as well as means for integrating this evaluation screen into existing standard design. Particularly, with the recent promulgation of safety pharmacology testing requirements (the in vivo cardiovascular component of which is performed in the dog), the availability of such an evaluation paradigm presents a valuable potential addition to existing study designs without increasing animal usage.

Animals↗