ABSTRACT
Phenolphthalein (800 and 2400 mg/kg/day by gavage and 2400 mg/kg/day by diet) and bisacodyl (800-500, 4000-2000, and 8000 mg/kg/day by gavage) were administered to 15 male and 15 female and 20 male and 20 female p53(+/-) mice respectively for 26 weeks to investigate the potential carcinogenicity of each compound. Toxicokinetic analyses confirmed systemic exposure. p-Cresidine was administered by gavage (400 mg/kg/day) and served as the positive control agent in each study. Dietary phenolphthalein reduced survival in both sexes and early deaths were attributed to thymic lymphoma. No bisacodyl-related neoplasms were observed. Regardless of route of administration to p53(+/-) mice, phenolphthalein but not bisacodyl was unequivocally genotoxic, causing increased micronuclei in polychromatic erythrocytes. In the Syrian hamster embryo (SHE) cell transformation assay, phenolphthalein caused increases in morphologically transformed colonies, thereby corroborating NTP's earlier reports, showing phenolophthalein has potential carcinogenic activity. Bisacodyl was negative in the SHE assay. Results of these experiments confirm an earlier demonstration that dietary phenolphthalein causes thymic lymphoma in p53(+/-) mice and show that (1) phenolphthalein causes qualitatively identical results in this transgenic model regardless of route of oral administration, (2) phenolphthalein shows evidence of micronucleus induction in p53(+/-) mice for up to 26 weeks, (3) phenolphthalein induced transformations in the in vitro SHE assay, and (4) bisacodyl in p53(+/-) mice induces neither drug-related neoplasm, nor micronuclei in polychromatic erythrocytes, and did not induce transformations in the in vitro SHE assay.
Subject(s)
Bisacodyl/toxicity , Cathartics/toxicity , Micronuclei, Chromosome-Defective/chemically induced , Phenolphthalein/toxicity , Thymus Neoplasms/chemically induced , Animals , Bisacodyl/blood , Bisacodyl/pharmacokinetics , Carcinogens/pharmacokinetics , Carcinogens/toxicity , Cathartics/pharmacokinetics , Cell Transformation, Neoplastic , Cells, Cultured , Cricetinae , Female , Genes, p53 , Lymphoma/chemically induced , Lymphoma/pathology , Male , Mesocricetus/embryology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Micronucleus Tests , Phenolphthalein/blood , Phenolphthalein/pharmacokinetics , Thymus Gland/drug effects , Thymus Gland/pathology , Thymus Neoplasms/pathology , Tumor Suppressor Protein p53ABSTRACT
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.
Subject(s)
Mice, Transgenic , Papilloma/chemically induced , Skin Neoplasms/chemically induced , Tetradecanoylphorbol Acetate/toxicity , Administration, Cutaneous , Animals , Body Weight/drug effects , Carcinogenicity Tests , Female , Heterozygote , Longevity/drug effects , Male , Mice , Mice, Inbred Strains , Papilloma/genetics , Pharmaceutical Vehicles , Skin Neoplasms/genetics , Solvents , Tetradecanoylphorbol Acetate/administration & dosageABSTRACT
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.
Subject(s)
Benzene/toxicity , Carcinogens/toxicity , Mice, Transgenic/physiology , Skin Neoplasms/chemically induced , Tetradecanoylphorbol Acetate/toxicity , Administration, Topical , Animals , Benzene/administration & dosage , Carcinogens/administration & dosage , Female , Male , Mice , Skin Neoplasms/pathology , Tetradecanoylphorbol Acetate/administration & dosageABSTRACT
Tuberculous lesions were observed at necropsy in the liver, spleen, and intestine of five 10-month-old ringneck pheasants (Phasianus colchicus) from a flock of birds raised in captivity for breeding. Histological examination of the tissues revealed granulomas with associated acid-fast bacilli. The history and lesions are unusual in that very few bacteria were found in any given lesion, the birds were all in good flesh when necropsied, and five birds from this same group at 6 months of age were observed to have acid-fast bacteria in the small intestine. Mycobacterium avium was isolated and serotyping was attempted, but the colonies were too dry to serotype.
Subject(s)
Bird Diseases/microbiology , Birds/microbiology , Mycobacterium avium/isolation & purification , Tuberculosis, Avian/microbiology , Animals , Intestines/microbiology , Liver/microbiology , Spleen/microbiologyABSTRACT
Psittacine birds can develop severe and often fatal pneumonitis when exposed to various noxious inhalants. Toxicosis in these birds caused by inhalation of pyrolysis products produced from overheated polytetrafluoroethylene-coated cooking pans on stove tops is well known, but compounds emitted from burned foods and other materials can also be toxic. We present a case of fatal pneumonitis in 10 psittacine birds associated with the operation of an oven in the self-cleaning mode.
