PubMed Health⌕ Search

Biomedical subjects

S C Gad

Publications and source records attributed to S C Gad.

At least 19 recordsLinked to original sources
PubMed1997

IRAG working group 1. Organotypic models for the assessment/prediction of ocular irritation. Interagency Regulatory Alternatives Group.

The brief of the Organotypic Models Working Group was to review data submitted to the Interagency Regulatory Alternatives Group on the use of isolated eyes and components of the eye used to predict eye irritation potential. Data submissions were received on four test systems: the isolated rabbit eye (one submission), the isolated chicken eye (one submission), the bovine cornea (eight submissions) and the cultured bovine lens (one submission). On the basis of the data submitted on each test it was concluded that the isolated rabbit eye test as performed was capable of screening for severe eye irritants, but overall was of no practical value for determining irritation potential across the full range; that the isolated chicken eye test as performed showed promise as a method of predicting eye irritation potential, but the database was too small and needed expanding; that the bovine corneal opacity test had an extensive database and overall performed reasonably at screening out severe irritants and performed well for assigning relative potencies; and that the bovine lens test should be researched further to demonstrate its utility. The overall conclusion drawn was that the isolated eye tests and the bovine corneal opacity test can be used now to screen for severely irritating materials. However, it would be unwise to rely solely on these organotypic methods to provide evidence of lack of eye irritation hazard.

Animal Testing Alternatives↗
PubMed1994

The mouse ear swelling test (MEST) in the 1990s.

The mouse ear swelling test (MEST) was developed in the early 1980s to provide a lower cost, shorter and objectively graded alternative to the existing guinea pig based tests for delayed contact hypersensitivity. In the ensuing time, the test design has been modified and its use has been extended to additional applications (phototoxicity and photosensitisation screening and as a mechanistic tool in studying tumor promoting agents) and to evaluating a broader range of test materials (treated fabrics, medical devices, environmental pollutants, specialty chemicals, drugs, etc.) in the hands of new investigators. Likewise, other murine based tests have been developed. The MEST and one other murine test (the local lymph node assay, or LLNA) have also now been included in the lists of regulatorily accepted sensitization test systems. The current version of the MEST protocol is presented here, along with the rationale for changes, a review of evaluations and interlaboratory trials and an overview of the range of uses to which it has been applied.

Allergens↗
PubMed1992

Promotional activities of the non-genotoxic carcinogen bemitradine (SC-33643).

Bemitradine (SC-33643), a diuretic antihypertensive agent, was studied for its carcinogenicity in a 2-year bioassay in Charles River CD rats via dietary admix at dosages of 50, 150 and 450 mg kg-1 for up to 97 weeks (after which they were followed for eight additional weeks without treatment). Body weights were decreased compared to controls: 5-15% in the female and 10-12% in the male dosage groups by week 105 of the study. Prolactin values were significantly increased in 150 and 450 mg kg-1 females. The compound caused significant increased incidences of liver, thyroid (both sexes) and mammary (females only) neoplasms. The metabolism of bemitradine was studied in both rats and man. Bemitradine and its primary metabolite (SC-36741; desethylbemitradine) were tested and found to be non-genotoxic in Ames, rat primary hepatocyte UDS, CHO/HGPRT, CHO cytogenetics, in vivo mouse micronucleus and mouse lymphoma TK+/- (bemitradine only) assays. Finally, in an altered hepatic foci (Y-glutamyl transpeptidase positive) promotion assay in female Charles River CD rats, bemitradine was found to be a promotor, though not as potent as phenobarbital. We concluded that bemitradine (which has been dropped from development) is a non-genotoxic carcinogen which appears to act by a hormonally modulated promotional activity in inducing tumors in the liver and mammary glands. Tumors seen in the thyroid were probably secondary to the effects of bemitradine on metabolism.

Animals↗
PubMed1992

Genetic toxicology studies of an anti-AIDS drug.

SC-48334 (N-butyldeoxynojirimycin) is an experimental anti-AIDS drug which is currently in clinical trials. This drug is an aminosugar derivative. Its biological properties have been previously published [1]. Since many antiviral agents which are nucleic acid analogs exhibit mutagenic and/or clastogenic properties, the genotoxic potential of SC-48334 was examined in the Ames Salmonella/microsome assay, the Chinese hamster ovary cell/hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT) assay and the mouse bone marrow micronucleus assay. No toxic or mutagenic effects were observed in either the bacterial or mammalian in vitro mutation assays. Likewise, no clastogenic activity was observed in the in vivo micronucleus assay. Therefore, the administration of this drug in humans is not likely to have mutagenic effects and would probably not have a carcinogenic effect.

1-Deoxynojirimycin↗
PubMed1990

An industrial perspective on a quantitative estimation of risk associated with low level exposures of humans, with acrylonitrile as a case study.

Having been presented with a set of data on acrylonitrile to be utilized as a case study, an assessment was performed of the potential risk of carcinogenesis associated with low level exposures to a material with the characteristics in the supplied data package. This study attempts to present the risk assessment process in an open manner, clearly identifying the multiple complex steps involved in the process and the uncertainty associated with each of the steps. The approach used was truly pragmatic, as the author believes that, in many cases, those performing risk assessments stand on dogma, failing to recognize that what is scientifically best in addressing uncertainty is not that which is most conservative (i.e., uses a worst case decision mode), but rather that which reduces the uncertainty the most. All available data of suitable quality should be utilized in either performing the risk assessment or in checking the result. All the mathematical steps involved in the risk assessment process have limited biological basis. As a result, any risk assessment process that results in predictions which are refuted by real data should be rejected.

Acrylonitrile↗
PubMed1990

Genetic toxicity of the benzene metabolite trans, trans-muconaldehyde in mammalian and bacterial cells.

Previous studies in our laboratory identified trans,trans-muconaldehyde (MUC), a six-carbon diene dialdehyde, as a microsomal metabolite of benzene. This ring-opened metabolite of benzene was also shown to be hematotoxic in mice in a manner similar to benzene. To further explore the role of MUC in relation to benzene toxicity, a number of test systems were utilized to determine its genotoxic potential. In B6C3F1 mice, MUC induced a highly significant increase in sister-chromatid exchange (SCE), the lowest effective dose being 3 mg/kg, but failed to induce any micronuclei (MN). In Chinese hamster ovary (CHO) cells, MUC at concentrations up to 0.8 micrograms/ml was negative in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) assay. Dose-related increases in the percentage of cells with MN were observed in CHO cells treated with 0.4-0.8 micrograms/ml MUC. MUC did not-cause unscheduled DNA synthesis in rat primary hepatocytes. Treatment of Salmonella typhimurium TA97 with MUC induced a low level of mutations at concentrations ranging from 10 to 70 micrograms/ml with or without S9 activation. MUC was inactive in strains TA1535, TA100, TA1538 and TA98. In CHO cells and rat primary hepatocytes, MUC was cytotoxic at 0.4 and 4.0 micrograms/ml, respectively. Concentrations of 100 micrograms/plate MUC were toxic for bacterial cells. The present findings indicate that MUC is nonmutagenic or minimally mutagenic in bacterial and mammalian in vitro systems. In mammalian cells, MUC is highly cytotoxic and genotoxic.

Aldehydes↗
PubMed1990

Recent developments in replacing, reducing, and refining animal use in toxicologic research and testing.

Significant progress has been made in replacing animals in toxicology/safety assessment with in vitro systems, in reducing the number of animals used, and in refining how they are used. Review of annual reports of the numbers of animals used in testing in the United States, the United Kingdom, and Japan shows a continuing reduction in the numbers for all species. Multiple in vitro systems have been developed for screening/testing for eye and skin irritation, skin sensitization, teratology, and other endpoints and a scientific consensus has been formed on requirements and process for validation. However, the use of these test systems in place of existing in vivo tests is minimal. At the same time, innovative designs have been developed (and are in wide use) for in vivo tests which reduce both the numbers and the pain and distress of animals used in testing. Progress and dialogue continue on modification of both U.S. and international requirements and guidelines for testing, and for defining an "approval" process for alternatives and innovations.

Animal Experimentation↗
PubMed1989

Acute and chronic systemic chromium toxicity.

Although chromium and compounds containing it have been recognized as having potential severe adverse effects on health for more than 160 years, understanding of the systemic toxicology and true hazard of these compounds is still not complete. A review of the current state of knowledge is attempted in this paper, with appropriate attention given to the complications of multiple valence states and solubility. Selected chromium compounds, particularly hexavalent ones, are carcinogens, corrosives, delayed contact sensitizers, and have the kidney as their primary target organ. But chromium is also an essential element for humans. The body clearly possesses some effective detoxification mechanisms for some degree of exposure to hexavalent chrome compounds. The significant features of acute and chronic chromium toxicity are presented in view of these considerations.

Air Pollutants↗
PubMed1988

The development of contact hypersensitivity in mouse skin is suppressed by tumor promoters.

The ability of tumor promoters to suppress the development of contact hypersensitivity (CHS) was assessed by the mouse ear swelling assay. Application of the complete or second stage tumor promoters phorbol-12-myristate-13-acetate (PMA, 2 micrograms), croton oil (1%), benzoyl peroxide (20 mg), mezerein (2 micrograms), or phorbol-12-retinoate-13-acetate (PRA, 2 micrograms) to the abdominal surface of CF-1 female mice for 1 week (three treatments) prior to the sensitization of the same location with 0.5% 1-chloro-2,4-dinitrobenzene (DNCB) resulted in a 50% suppression (p less than 0.05) of the CHS response to DNCB. The first stage tumor promoters 4-O-Me-PMA (80 micrograms), calcium ionophore A23187 (80 micrograms), hydrogen peroxide (15%) and the non-promoting analogs phorbol-12,13-diacetate (PDA, 20 micrograms), phorbol (80 micrograms) or acetone did not suppress the response. The suppression of the development of CHS caused by PMA was dependent on the promoter being applied at the site of induction and was inhibited by application of the phospholipase A2 inhibitor dibromoacetophenone (100 micrograms), the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 100 micrograms), or the antiinflammatory steroid fluocinolone acetonide (2 micrograms). Application of PMA or mezerein 24 h prior to challenge with DNCB, to the ears of mice previously sensitized with DNCB resulted in a significant enhancement of the ear swelling response by 60% and 110%, respectively, compared with controls. The results demonstrate that tumor promoters suppress the development of CHS, and suggest the possibility that second stage promotion may involve suppression of the development of a tumor specific immune response.

Animals↗
PubMed1988

Acute and neurotoxicity of two structurally related acetylenic compounds: 5,7,11-dodecatriyn-1-ol and 5,7,11,13-octadecatetrayne-1,18-diol.

Two structurally related acetylenic compounds, 5,7,11-Dodecatriyn-1-ol, (Compound A), and 5,7,11,13-Octadecatetrayne-1,18-Diol (Compound B), were evaluated in a tier I toxicology testing program as part of an ongoing research and development program. This battery of acute tests included acute oral, guinea pig maximization, photosensitization, dermal irritation, Ames and multiple genetic endpoint and a 2 week oral fetotoxicity study. Compound A was found to have an oral LD50 of 0.25 ml/kg, be an extreme dermal sensitizer, a mild dermal irritant (PDII of 1.7), and not mutagenic or fetotoxic in the tests employed. Compound B had an oral LD50 greater than 4 g/kg, was a moderate dermal sensitizer and mild dermal irritant (PDII of 1.4), was not mutagenic in the Ames test but weakly increased the incidence of SCEs and gene mutations in Chinese Hamster Ovary cells, and was not fetotoxic. Neither compound was found to be a photosensitizer, but during the course of the photosensitization study Compound A was found to cause neuromuscular signs (including hind limb paralysis) and a bilateral necrosis of the medulla oblongata in female guinea pigs. A similar lesion was found in female rats receiving a single oral dose of 0.25 ml/kg and in nonpregnant females dosed daily for two weeks at 0.03 ml/kg. Compound B was not found to produce any of these neurologic effects.

Alkynes↗
PubMed1988

Three-generation reproduction study with caprolactam in rats.

In a three-generation reproduction study, rats were given caprolactam in the diet of 0, 1000, 5000 and 10,000 ppm. No treatment-related effects were observed in the parental animals with respect to mortality, clinical signs, reproductive performance or gross pathology findings. Consistently lower body weights were noted in the P2 and P3 mid- and high-dose males and females. Consistently lower mean food consumption values were noted in the P2 and P3 mid- and high-dose males and the high-dose females. These differences were generally significant (P less than or equal to 0.05) in the high-dose group of both sexes. Compound-related histopathologic findings noted in the high-dose P1 males consisted of a slight increase in the severity of spontaneous nephropathies, occasionally accompanied by granular casts. The offspring data revealed no treatment-related effect with respect to gross appearance, gross pathology, survival, number of pups, percentage of male pups or kidney weight. Analysis of the offspring body weights on Days 1, 7 and 21 of lactation revealed consistently and generally significant lower mean values in the high-dose male and female animals of all filial generations. The mean body weights of both sexes in the mid-dose group were generally lower than those of the controls. The effects on mean body weight, mean food consumption and the group increases in the severity of nephropathy, accompanied by the presence of granular casts in some animals, are considered to be related to the administration of caprolactam.

Animals↗
PubMed1988

A scheme for the prediction and ranking of relative potencies of dermal sensitizers based on data from several systems.

A highly desirable use of delayed contact dermal hypersensitivity data from animal tests is an accurate prediction of the relative potency of positive agents in humans. Because of the manner in which all such animal tests are performed, the wide variety of exposure conditions and concentrations (which are generally more severe than human exposure conditions) have traditionally made prediction of potency (and therefore the extent of hazard) in humans either impossible or extremely crude. A numerical/graphical method has been developed to adjust results from suitable animal studies of all sorts for exposure conditions and allow for ranking of agents for potency and classification of relative hazards. Results from four animal test systems (MEST, EMT, GPMT and Buehler) are compared with results from human studies to show that all four test systems can generate data that are usable for a relative hazard classification process, though they may vary in their performance characteristics as screens.

Animals↗
PubMed1987

Developmental toxicity studies of caprolactam in the rat and rabbit.

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 groups. 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 (6-aminonicotinamide) resulted in significantly (P less than 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.

Animals↗
PubMed1987

Toxicity of hydroxylamine sulfate following dermal exposure: variability with exposure method and species.

The acute toxicity of hydroxylamine sulfate (HS) and phenylhydrazine hydrochloride (PHZ) were compared in the rabbit and rat following a single 24-hr dermal exposure. The test materials were applied topically and occluded under a plastic or gauze cover or were injected sc. Distilled water served as a control. HS and PHZ produced similar hematotoxic effects consisting of methemoglobin formation, anemia, and reticulocytosis. HS and PHZ proved to be more toxic to the rabbit than to the rat although both chemicals produced similar hematological effects at equivalent dose levels within the same species. HS proved strikingly more toxic when administered under plastic than under gauze despite the fact that both methods included occlusion. PHZ toxicity was less variable with exposure method. HS and PHZ were lethal to the rabbit but no deaths occurred in the rat. The results of this study indicate that HS and PHZ show similar hematotoxicity and, therefore, the clinical data available on PHZ may be useful in predicting the hematological effects of HS on humans.

Administration, Topical↗
PubMed1986

Development and validation of an alternative dermal sensitization test: the mouse ear swelling test (MEST).

Traditional predictive tests for dermal sensitization in humans use the albino guinea pig as a model. A number of factors make the prospect of an alternative attractive. Guinea pig designs are labor intensive, require significant animal, caging, and husbandry resources, and are expensive. Extensive development and validation was conducted of an alternative using swelling of mouse ears as a quantitative end point. Ten strains of mice, ten age groups, both sexes, induction forms (number, route, timing), the use of an adjuvant, different vehicles and intervals to challenge, two induction sites, and three measurement intervals were evaluated. A methodology was developed for preparing induction sites to increase test sensitivity. A small battery of standard compounds was used to evaluate these design variables and a final test design was developed. The basic process was also demonstrated to occur in rats and guinea pigs and to be dose responsive. The final mouse ear swelling test (MEST) design was used to evaluate 72 materials representing a broad spectrum of chemicals and testing problems. These included 49 known positives and 23 known negatives. Guinea pig maximization test data on 37 of these resulting by studies conducted in our laboratories, along with closed patch guinea pig and human test data on many of these compounds, are also reported here for the first time. The MEST correctly identified 71 of 72 materials as potential human sensitizers or nonsensitizers. Additionally, both the efficacy of an occluded patch induction method and the duration of responsiveness of mice were evaluated. In the studies, the MEST was found to be an accurate, sensitive, and efficient alternative test design for evaluating delayed-contact sensitization.

Age Factors↗
PubMed1986

Inhalation toxicity of hexafluoroisobutylene.

An acute study of hexafluoroisobutylene (HFIB) determined its 4-hr LC50 in rats to be 1425 ppm. In a 2-week study, all animals exposed to 215 ppm for 4 days died or were sacrificed in extremis, while those exposed to the lowest level tested, 53 ppm, showed respiratory and renal effects. Based on the results of these studies, Fischer-344 rats were exposed 6 hr a day, 5 days a week, for 13 weeks to average HFIB concentrations of 3, 10, 30, and 90 ppm. No animals died due to the HFIB exposures. However, at the highest exposure level tested there were numerous marked signs of systemic toxicity in males and females. At all exposure levels, males were more affected than females. The lungs and kidneys were clearly target organs for HFIB, the kidneys being more sensitive in this study (having increased absolute and relative weights, alterations in relevant clinical chemistry parameters, and alterations in microscopic structure). A clear dose-response pattern for the above toxic effects was evident with 10 ppm in the males being an effect level. Male rats exposed to 30 ppm of HFIB had decreased body weights and significantly increased kidney weights. A satellite group of animals was maintained for 2 weeks after the completion of exposure. These animals showed some remission from the observed toxic effects, indicating recovery could be expected in rats from at least most of the toxic effects associated with exposure to HFIB. All effects observed in 3 ppm males disappeared by the end of the recovery period.

Animals↗
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↗