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C S Aaron

Publications and source records attributed to C S Aaron.

59 records · Page 4Linked to original sources
PubMedDate not supplied

Validation of intratracheal instillation as an alternative for aerosol inhalation toxicity testing.

In collecting inhalation toxicity data for the evaluation of the health hazard from occupational exposure to the aerosols of a drug or a chemical, the determination of the inhaled dose in relation to the animal response is most desirable. Intratracheal administration is most likely to deliver an exact dose of a compound to the lungs of an experimental animal. In a series of tests, microliter (microl) quantities of a solution or a suspension of a test material were nebulized into the trachea of an anesthetized rat using an intratracheal fast instillation (ITFI) method. The dose-response in terms of the minimal effective dose (MED) and the median lethal dose (LD50) were determined. The ITFI dose-response for four drugs, five chemicals or chemical intermediates and four pesticides were compared with those obtained via inhalation (IH) and ingestion (p.o.). In addition, the dose-responses of the four pesticides were compared with two additional parameters, intranasal instillation (IN) and intravenous injection (i.v.). The MED end-points for studies via the respiratory administration route were no pharmacotoxic signs other than transient respiratory rales and/or dyspnea and no gross lesions, whereas those for the intranasal, oral and the intravenous administration routes were transient and slight body weight loss and no pharmacotoxic signs and/or gross lesions. The MED ratios between ITFI, IH and p.o. were 1 : 9.3+/-6.5 : 201.4+/-133.3, respectively, for the drugs, chemicals and chemical intermediates. The MED ratios for ITFI, IH, IN, i.v. and p.o. for the four pesticides were 1 : 2.2+/-1.4 : 2.1+/-1.3 : 1.1+/-0.7 : 1.4+/-0.9. The MED ratios for the two categories of test materials were fairly consistent between different routes of administration. Thus, the ITFI dose can be used for extrapolating the IH dose. The simplicity of the ITFI procedure and its requirement of only microliters of a compound to generate a meaningful and reliable dose-response suggests that ITFI may be an alternative method for acute inhalation toxicity evaluation of materials that may present inhalation hazards from liquid or solid aerosols.

Administration, Inhalation↗
PubMedDate not supplied

A report of the U.S. Environmental Protection Agency Gene-Tox Program. Evaluation of mutagenicity assays for purposes of genetic risk assessment.

For the vast majority of chemicals, mammalian germ-line (MG) mutation data do not exist. The question was examined of how best to utilize results of non-MG genotoxicity assays that are included in the Gene-Tox data base to provide information of the likelihood that genetic damage might be induced in and transmitted by the reproductive cells of exposed human beings. Two approaches were used to assess the relative value of different assays for genetic hazard identification. (1) Test results were weighted according to parameters by which conditions of an assay resemble those encountered in the potential induction of transmitted genetic damage in mammals. For this purpose, 35 assays were grouped into 16 categories that were assigned weights ranging from 1 to 15; there were 2367 chemicals in the data base. This system was evaluated by comparing the sum of weighted test results for each chemical with the outcome of MG-standard (MGst) tests where such had been reported. (MGst tests used were the specific-locus and heritable-translocation assays [SLT and HTT] for gene mutations and chromosome aberrations, respectively.) The weighting system produced a few false positives with respect to the MGst results. It produced no false negatives, but the available evidence is limited by the circumstance that MGst test have evidently been preferentially performed with chemicals that had already been shown to be positive in several other assays. (2) Findings from each MGst test were compared with those from each of the other assays in turn, provided that at least 10 chemicals had been tested in both of the assays. There were 11 such comparisons involving the SLT, and 14 such comparisons involving the HTT. The observed concordance was above random expectation in several comparisons, particularly those involving certain mammalian in vivo tests, but in only one case (HTT vs. unscheduled DNA synthesis in the testis) did the degree of elevation approach statistical significance.

Animals↗
PubMedDate not supplied

Comparison of the genetic activity of 5-nitroimidazole derivatives in Escherichia coli, Neurospora crassa, Saccharomyces cerevisiae and Drosophila melanogaster.

5-nitroimidazoles, including metronidazole (compound 1) and 3 analogues (compounds 2, 3 and 4) of actual or potential chemotherapeutic use were assayed for genetic activity in test systems detecting forward and back mutations in Escherichia coli K-12/343/113, forward mutations in Neurospora crassa heterokaryon 12, mitotic gene conversion in the heteroallelic diploid yeast strain Saccharomyces cerevisiae D4 and sex-linked recessive lethals in Drosophila melanogaster. Whereas metronidazole exhibits moderate mutagenic activity in E. coli, two of the analogues, compounds 2 and 3 are strongly mutagenic even at concentrations that do not inactive the colony forming ability of the cells. The analogue compound 4 does not show any effect toward E. coli under the present experimental conditions. Similar results were obtained with N. crassa, with S. cerevisiae and with Drosophila in which compound 2 exhibits the highest effect, while compound 4 is non-mutagenic in all assays. These biological effects have been partly explained on the basis of differences in the chemical structure of the compounds.

Animals↗