Biomedical subjects

R Benigni

Publications and source records attributed to R Benigni.

76 records · Page 5Linked to original sources

PubMedDate not supplied

Predicting carcinogenicity with short-term tests: biological models and operational approaches.

This paper illustrates the basic biological models that have had an influence on the development and deployment of short-term assays for carcinogens. A tentative description of such a conceptual framework is provided with the use of methods for the quantitative analysis of information. This picture is contrasted with the results of a series of statistical mathematical analyses carried out on real genotoxicity data bases. The resulting evidence indicates that the biological models derived from basic laboratory research are not adequate or sufficient to interpret the operational performances of short-term assays. Obviously these models are of great importance, but, this observed discrepancy suggests the need for articulated approaches, with particular emphasis on analytical tools able to interpret the complexity of these systems. In particular, the multivariate data analysis methods are indicated as suitable for the description of large and complex bodies of data, and the identification of typologies and regularities. A number of applications of such methods are also presented. The conclusion is that biological models and operational approaches have to interact on the same level. The operational approach should indicate whether the conceptual framework of the experimenter is adequate to describe the experimental situation and possibly point to new relationships and trends, as well as to practical solutions.

Animals↗

PubMedDate not supplied

Split-dose exposure to N-methyl-N'-nitro-N-nitrosoguanidine in BALB/3T3 C1 a31-1-1 cells: evidence of DNA repair by alkaline elution without changes in cell survival, mutation and transformation rates.

Dose fractionation of a direct-acting chemical carcinogen, the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), was studied for its concurrent effects on survival, DNA damage and repair, ouabain resistance (Ouar) mutations and neoplastic transformation, in the mouse embryo cell line BALB/3T3 C1A31-1-1. MNNG doses of 0.5, 1 and 2 micrograms/ml were added to the cells either as a single exposure or in two equal fractions separated by 1, 3 or 5 h intervals. No significant difference in cytotoxicity was found when single and split-dose treatments were compared. No recovery from sublethal damage was therefore found in this cell line by split-dose administration of MNNG, although such an effect was found when the same cell line was treated with single and split doses of X-rays. Repair of DNA damage as measured by alkaline elution was studied up to 24 h after a single MNNG exposure (0.5 micrograms/ml). DNA repair was rapid during the first 5 h after treatment and slow thereafter. DNA damage detected after split doses of MNNG at 1 and 5 h intervals was significantly lower than after a corresponding single dose. With both single and split doses, rejoining of single-strand breaks (ssb) was nearly complete after 24 h of repair time. Ouar mutation and neoplastic transformation frequencies were determined for single and split doses of MNNG with the second treatment being given during (1 h) or after (5 h) the period of rapid DNA repair. No significant differences in either effect were detected for dose splitting at any tested dose.

Animals↗

PubMedDate not supplied

Infrared spectra as chemical descriptors for QSAR models.

Infrared spectra (IR) were used as regressors for a number of QSARs and compared with both mechanistically oriented descriptors and heuristic "chemically neutral" descriptors (modified adjacency matrices eigenvalues). IR spectra usually gave results inferior to those obtained with the mechanistically driven descriptors, with one notable exception, and comparable to those obtained by adjacency matrices eigenvalues. So the IR spectra cannot be considered as an "a-priori" optimal description of molecules for QSAR. However the relation of IR with the chemicophysical bases of drug-receptor interaction suggests the use of IR spectra for elucidating mechanistic details.

Journal Article↗

PubMedDate not supplied

Which rules for assembling short-term test batteries to predict carcinogenicity?

The main theme of this paper is to describe the basic requirements for assembling reliable batteries of short-term tests for carcinogenicity prediction. For this purpose, a subset of the data base generated by the International Program for Evaluation of Short-Term Tests for Carcinogens (IPESTTC) has been studied by different data-analysis methods. Much attention has been focused on the methodological dimensions of the problem, at the level of selection of both data and statistical techniques. Twenty-one of the most widely used short-term assays were considered. An exploratory study of the data base was first performed by factor analysis, showing similarities and dissimilarities between test performances and confirming our previous results obtained by cluster analysis. In this way the assays were divided into three groups on the basis of their responses to the chemicals. The Salmonella assay was in the central group, characterized by equilibrated performances in respect to sensitivity and specificity for carcinogens. Tests complementary to the Salmonella assay for sensitivity and specificity, respectively, were identified as well. A preliminary comparison of the IPESTTC results with the Gene-Tox data base is also presented. The test performances in respect to carcinogenicity prediction were then evaluated by discriminant analysis. When the subset of data was considered as a whole, the procedure resulted in a linear discriminant function able to correctly identify 84.2% of carcinogens and 83.3% of noncarcinogens. The correctly identified carcinogens summed to about 90% when adequate batteries of tests were used. This analysis yielded a number of observations. (1) Together with the selectivity indices (such as sensitivity and specificity), the operational complementarity between test performances must be ascertained and taken into account. (2) The batteries most effective at predicting carcinogenic activity were composed of three tests, one for each group. This finding converged with the fact that the three classes of assays were clearly differentiated for sensitivity and specificity, and in this sense were complementary to each other. (3) The performances of the batteries were not improved by adding more tests, but in several cases the opposite effect occurred. (4) Estimation of the probability of the chemicals of being carcinogenic, starting from qualitative genotoxicity data, is possible.

Animals↗