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Biomedical subjects

R E Stoll

Publications and source records attributed to R E Stoll.

30 records · Page 2Linked to original sources
PubMed1975

Similarity in cns sensitivity to hexobarbital in the rat and mouse as determined by an analytical, a pharmacokinetic, and an electroencephalographic measure.

Sensitivity of the central nervous system (CNS) to the hypnotic effect of hexobarbital was assessed by analytical, pharmacokinetic, and electroencephalographic techniques in male and female rats and in mice of both sexes by the first two techniques. These experimentally and conceptually diverse measures yielded strikingly similar estimates of CNS sensitivity to hexobarbital which was independent of both species and sex, while well known species ans sex (rat) differences in duration of response to hexobarbital were demonstrated.

Animals↗
PubMedDate not supplied

Hemizygous Tg.AC transgenic mouse as a potential alternative to the two-year mouse carcinogenicity bioassay: evaluation of husbandry and housing factors.

The dermal Tg.AC transgenic mouse model has been proposed as a potential alternative to the conventional (e.g. oral, dermal, parenteral, inhalation, etc.) 2-year rodent bioassay for detecting chemical carcinogenicity. The present study was designed to address a number of technical aspects of this model as well as to augment the database being developed with the Tg.AC system at the NIEHS. Hemizygous Tg.AC mice were implanted s.c. with microchips for identification and housed individually in polycarbonate (i.e. 'plastic') or suspended stainless-steel wire-bottom (i.e. 'metal') cages. Treatment consisted of dermal application of the test or control material in treatment volumes of 200 microl of acetone. Groups of 10 males and 10 females were treated as follows: G1--shaved, no treatment; G2--acetone control seven times a week; G3--100 microl of benzene three times a week; G4--150 microl of benzene three times a week; G5--1.25 microg of phorbol ester (PMA) twice a week. The G1-G5 mice were housed in plastic caging with Alpha-dri bedding. Three additional groups were housed in stainless-steel wire-bottom caging: G6--shaved, no treatment; G7--acetone control seven times a week; G8--1.25 microg of PMA twice a week. The PMA-treated mice (G5 and G8) served as the positive controls. Mice were treated for 20 weeks followed by a 6-week recovery period prior to necropsy. The incidence of dermal papillomas in the shaved area was recorded weekly. There were no spontaneous papillomas in the target area of any of the untreated (G1) or vehicle control (G2) animals in the polycarbonate cages. One papilloma was observed in the untreated mice (G6) and one in the vehicle control group (G7) in the steel cages. This suggests that the type of caging, the shaving process, microchip implantation and daily acetone treatment for 20 weeks are all consistent with a very low background incidence of papillomas in this model. Papillomas were observed in the positive control groups as early as 4 weeks of treatment and increased both in number per mouse and number of mice affected up to a maximum average of 3.5 papillomas per mouse and 55% (11/20) mice with papillomas in G5 and 2.7 and 80% (16/20) in G8. A plateau was reached at about week 13 and the numbers of papillomas remained stable through the rest of the treatment and recovery phases. The low dose of benzene (100 microl) showed no significant effect, whereas the higher dose (150 microl) produced a moderate number of papillomas beginning at about week 11. The results of this study are comparable with earlier studies at the NIEHS and indicate reproducibility between laboratories and that the Tg.AC transgenic mouse model is suitable for use in an industrial pre-clinical safety evaluation context.

Acetone↗
PubMedDate not supplied

Dermal carcinogenicity in transgenic mice: effect of vehicle on responsiveness of hemizygous Tg.AC mice to phorbol 12-myristate 13-acetate (TPA).

The Tg.AC mouse is being evaluated for use in short-term carcinogenicity bioassays. Because the dermal test protocol necessitates dissolving test agents we determined the effects of several solvents on responsiveness of hemizygous mice to dermal applications of the classical skin tumor promoter. phorbol 12-myristate 13-acetate (TPA). Mice of both sexes received dermal applications of either acetone (negative control) or TPA in various vehicles [acetone, 100% methanol, 70% and 100% ethanol, DMSO and mixtures of acetone and ethanol (1:1), acetone and DMSO (4:1 and 1: 1). and acetone and olive oil (4:1)]. Negative control animals did not exhibit papillomas. When administered in acetone. ethanolic or methanolic vehicles TPA caused prompt and robust papillomatous responses. TPA was also tumorigenic in all nonalcoholic vehicles, except the acetone-olive oil mixture. Papilloma responses were generally delayed when TPA was applied in the nonalcoholic solvents but the distinction between TPA-dosed and negative control groups was unequivocal. These results show that choice of vehicle may affect the quantitative and qualitative nature of the response of Tg.AC mice to TPA, but 8 of 9 vehicles proved satisfactory for delivery of TPA.

Administration, Cutaneous↗
PubMedDate not supplied

Dermal carcinogenicity in transgenic mice: relative responsiveness of male and female hemizygous and homozygous Tg.AC mice to 12-O-tetradecanoylphorbol 13-acetate (TPA) and benzene.

Assessment of the carcinogenic potential of chemical agents continues to rely primarily upon the chronic rodent bioassay, a resource-intensive exercise. Recent advances in transgenic technology offer a potential resource conserving approach to carcinogen detection. Incorporation of oncogenes with known roles in the development of neoplasms into the genomes of laboratory rodents may provide new models with the potential of quickly and accurately separating carcinogenic from noncarcinogenic chemicals. The insertion of the v-Ha-ras oncogene into the genome of FVB/N mice imparts the qualities of genetically initiated skin in the transgenic mouse line designated as Tg.AC. The skin of either hemizygous (animals carrying the transgene on 1 allele) or homozygous (transgene copies on both alleles) Tg.AC mice promptly responds to the application of nongenotoxic carcinogens, such as the classical tumor promoting phorbol esters, with the development of squamous papillomas. Tumor production generally begins after 8-10 applications of 2.5 micrograms/mouse (3 times/wk) of 12-O-tetradecanoylphorbol 13-acetate (TPA). Maximal tumor response is usually in evidence within 20 wk. If this transgenic mouse line is to be useful in the identification of carcinogenic chemicals, experimental protocols must be systematically optimized. Experiments were conducted to compare the relative responsiveness of male and female hemizygous and homozygous Tg.AC mice to the dermal application of TPA and the known human leukemogen, benzene. Results revealed shipment-related variabilities in the relative responsiveness of hemizygous male and female mice to the application of the proliferative agent. Homozygous mice of both sexes were more reliable and uniform in responsiveness to both TPA and benzene. Therefore, our standard protocol for the conduct of bioassays with the Tg.AC mouse line specifies the use of homozygous males and/or females.

Administration, Topical↗
PubMedDate not supplied

Oxymetholone: II. Evaluation in the Tg-AC transgenic mouse model for detection of carcinogens.

Several rodent models are under examination as possible alternatives to the classical 2-yr carcinogenicity bioassay. The Tg.AC transgenic mouse has been proposed as a shorter term model offering the possibility of detecting nongenotoxic and genotoxic carcinogenic agents. Retrospective studies of chemicals with established carcinogenic potential have revealed a close correlation between classical bioassay results and the production of skin tumors in the Tg.AC mouse model. Oxymetholone is a synthetic testosterone derivative that is a suspected carcinogen but has shown no evidence of genotoxic activity in a comprehensive battery of genetic toxicity assays. It currently is being tested by the National Toxicology Program (NTP) in a 2-yr rat carcinogenicity bioassay. Because of its nongenotoxicity and the ongoing chronic bioassay, oxymetholone was considered an ideal candidate for a prospective evaluation of the predictive validity of the Tg.AC dermal carcinogenicity model. Consequently, a 6-mo dermal study with oxymetholone in the Tg.AC mouse model was initiated and completed prior to disclosure of the NTP rat bioassay results. In this study, male and female hemizygous Tg.AC mice, 7-8 wk old, were housed individually in suspended plastic cages. An area of dorsal skin was shaved to accommodate dermal applications of 200-microl doses of vehicle control (acetone), drug (1.2, 6.0, or 12 mg oxymetholone in dimethylsulfoxide:acetone, 20:80), or positive control (1.25 microg 12-o-tetradecanoyl-phorbol-13-acetate [TPA]) solutions. Mice received oxymetholone or acetone daily or TPA twice weekly for 20 wk followed by a 6-wk recovery period. The acetone control groups exhibited low spontaneous incidences of papillomas, whereas dermal application of oxymetholone produced dose-related increases in the numbers of papilloma-bearing mice and the numbers of papillomas per animal. Females showed a somewhat greater response to the androgen than did the males. TPA caused an unequivocal increase in papillomas, with males exhibiting a greater response than females. The results of this study indicate that this nongerotoxic androgenic compound possesses proliferative properties. The results predict that chronic systemic administration of oxymetholone will most likely be associated with increased incidences of neoplasms.

Anabolic Agents↗
PubMedDate not supplied

Oxymetholone: III. Evaluation in the p53+/- transgenic mouse model.

Oxymetholone has been identified as a suspected nongenotoxic carcinogen and has recently completed testing in a conventional National Toxicology Program (NTP) 2-yr rodent bioassay program. As a synthetic androgen with a limited historical database in toxicology, oxymetholone is an ideal candidate for prospective examination of the performance of short-term transgenic mouse models in the detection of carcinogenic activity. In the present series of 3 articles, studies are described where oxymetholone was evaluated prior to disclosure of the results of the NTP 2-yr bioassay. The accompanying articles provide evidence showing that oxymetholone is devoid of mutagenic activity yet elicits a positive carcinogenic response in the Tg.AC transgenic mouse model. In the present study, oxymetholone was administered by oral gavage to p53 heterozygous male and female mice for 26 wk at doses of 125, 625, and 1,250 mg/kg/day. The vehicle was 0.5% aqueous methylcellulose. Positive controls consisted of mice treated daily by oral gavage with 200 or 400 mg/kg/day of p-cresidine in corn oil. The oxymetholone-treated females showed significantly increased body weight gain and clitoral enlargement attributable to drug treatment. In addition, significant alterations in kidney, liver, and testis weights were attributable to oxymetholone. However, there were no neoplastic lesions that were attributable to oxymetholone in either sex. p-Cresidine produced unequivocal bladder neoplasms in both sexes at the high dose and in males at the lower dose. The absence of a neoplastic response with oxymetholone is consistent with the selectivity of the p53-/- mouse model for detecting carcinogens that act by genotoxic mechanisms.

Anabolic Agents↗
PubMedDate not supplied

Transponder-induced sarcoma in the heterozygous p53+/- mouse.

Heterozygous p53+/- transgenic mice are being studied for utility as a short-term alternative model to the 2-yr rodent carcinogenicity bioassay. During a 26-wk study to assess the potential carcinogenicity of oxymetholone using p-cresidine as a positive control, glass/polypropylene microchips (radio transponder identification devices) were subcutaneously implanted into male and female p53+/- mice. During week 15, the first palpable mass was clinically observed at an implant site. This rapidly growing mass virtually quadrupled in size by week 25. Microscopic examination of all implant sites revealed that 18 of 177 animals had a subcutaneous histologically malignant sarcoma. The neoplasms were characterized as undifferentiated sarcomas unrelated to drug treatment, as indicated by the relatively even distribution among dose groups, including controls. An unusual preneoplastic mesenchymal change characterized by the term "mesenchymal dysplasia" was present in most groups and was considered to be a prodromal change to sarcoma development. The tumors were observed to arise from dysplastic mesenchymal tissue that developed within the tissue capsule surrounding the transponder. The preneoplastic changes, including mesenchymal dysplasia, appeared to arise at the transponder's plastic anchoring barb and then progressed as a neoplasm to eventually surround the entire microchip. Capsule membrane endothelialization, inflammation, mesenchymal basophilia and dysplasia, and sarcoma were considered unequivocal preneoplastic/neoplastic responses to the transponder and were not related to treatment with either oxymetholone or p-cresidine.

Anabolic Agents↗