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R Benigni

Publications and source records attributed to R Benigni.

At least 19 recordsLinked to original sources
PubMed1992

Rational approach to the quantification of genotoxicity.

The question of how many and which short-term tests (STT) are necessary for a satisfactory characterization of the genotoxic properties of chemicals is still open. The answer is important for both basic mutagenicity research and risk assessment. This paper, aimed at giving a rational answer to the problem, analyzes with multivariate statistical methods the data generated by the International Program for the Evaluation of Short-Term Tests for Carcinogens (IPESTTC). Although it has been found that this data base has a limited reliability for assessing the ability of STTs to predict carcinogenicity, the IPESTTC results are an important source of information on the relationships among different assays, and their ability to identify genotoxic chemicals. A scale of genotoxicity of the chemicals was established by studying with factor analysis their results in 20 IPESTTC tests. The next step of the analysis consisted in the identification of the STT batteries which are the most able to reproduce the genotoxicity scale based on the entire set of STTs. Different batteries were ranked according to their ability to quantify genotoxicity. As a general conclusion, this study indicated that an articulated range of STTs is necessary, and it is not possible to use only one assay (e.g., Salmonella) as an exhaustive indicator of genotoxicity.

Carcinogenicity Tests↗
PubMed1992

Multivariate statistical analysis of mutational spectra of alkylating agents.

A series of multivariate statistical methods were used to explore the current knowledge on the mutational spectra of alkylating agents (AA) in bacterial and mammalian cells. The data relative to lac I and gpt genes of Escherichia coli were considered. The analysis focused on the distribution of GC to AT transitions, which account for the majority of AA-induced mutations. The statistical analysis of 15 different mutational spectra obtained by various laboratories pointed to a number of biological factors involved in the mutational process. First of all, factor and cluster analyses demonstrated that the mutational profiles obtained in mammalian cells form a homogeneous cluster different from the cluster formed by the bacterial cell mutational spectra. SN1-type AAs give rise to classes of mutational spectra statistically different from the spectra induced by the SN2-type AAs. The analysis of the mutated sequences of both genes pointed to a correlation between mutation induction by SN1 AAs, which react through a positively charged alkylating intermediate, and the occurrence of mutations at guanines preceded 5' by a purine. Moreover, our statistical analysis showed that the distribution of AA-induced mutations is not affected by the transcriptional activity of the target gene, but is strongly determined by the sequence specificity of AA-induced mutagenesis and by the structure of the target proteins. The agreement of our results with the findings of previous studies indicates that the multivariate data analysis methods are a sensitive and reliable tool for exploring the mechanisms underlying complex biological processes. The novelty of the present results lies in their quantitative character, and in the clarity of the graphical displays. We propose the use of this methodological approach to explore the large bulk of information available on mutational spectra.

Alkylating Agents↗
PubMed1992

Simultaneous evaluation of genotoxicity data from different sources: a multivariate statistical approach.

A great deal of information on short-term mutagenicity assays presently exists, having been generated through individual as well as large comparative programs. The comparative programs have often examined the same tests, but with different sets of chemicals; this then gives rise to the problem of how to identify the information which is common to the different data bases, i.e., the general properties of the assays. This paper continues previous analyses of this subject, and describes a general approach by which different and heterogeneous data bases can be compared to each other. The results relative to 4 assays (Salmonella typhimurium gene mutation, mouse lymphoma L5178Y cell gene mutation, chromosomal aberrations in CHO cells, and SCEs in CHO cells) in 4 different data bases were studied. Factor analysis was used to model the different pieces of information. The analysis demonstrated a concordance between the indications of the U.S. National Toxicology Program and the International Program for the Evaluation of Short-Term Tests for Carcinogens, whereas the results of Gene-Tox and the International Program for Chemical Safety turned out to be biased, to different degrees, by their specific aims and characteristics. Moreover, the general properties--independent of the specific data bases--of the 4 assays were highlighted, and the similarities between the performances of the assays were given a quantitative measure.

Animals↗
PubMed1992

The induction of mitotic chromosome malsegregation in Aspergillus nidulans. Quantitative structure activity relationship (OSAR) analysis with chlorinated aliphatic hydrocarbons.

The biological activity of 24 chlorinated aliphatic hydrocarbons has been studied in the mold Aspergillus nidulans. The ability to induce chromosome malsegregation, lethality and mitotic growth arrest has been experimentally determined for each chemical. These data, together with those of 11 related compounds previously investigated, generated a data base which was used for quantitative structure-activity relationship (QSAR) analysis. To this aim, both physico-chemical descriptors and electronic parameters of each compound have been calculated and included in the analysis. The QSAR analysis indicated that toxic effects induced by chlorinated aliphatics in A. nidulans are mainly dependent on steric factors, as indicated by the correlation with molar refractivity (MR). Conversely, the ease with which they accept electrons, parametrized by LUMO (energy of the lowest unoccupied molecular orbital), plays a prevailing role in determining the aneuploidizing properties. An involvement of free radicals, generated by the reductive metabolism of haloalkanes, is hypothesized as an explanation of the data.

Aneuploidy↗
PubMed1992

Electrophilicity as measured by Ke: molecular determinants, relationship with other physical-chemical and quantum mechanical parameters, and ability to predict rodent carcinogenicity.

This paper analyzes electrophilicity data as measured by the Ke system for 205 chemicals including both rodent carcinogens and non-carcinogens. Multivariate statistical methods were used. The analysis identified atoms and substructures contributing to electrophilicity, and permitted to establish a theoretical method by which the Ke value (electrophilicity) of chemicals can be easily estimated. In a subset of chemicals, the Ke parameter was compared with other physical-chemical and quantum mechanical properties: Ke appeared to be mostly correlated with the energy of the lowest unoccupied molecular orbital and with the absolute electronegativity. The role of Ke in structure-activity studies was also investigated; in particular, a comparative analysis of the performance of Ke, Salmonella typhimurium and Ashby's structural alerts in predicting carcinogenicity was carried out. The Ke system performed better than the other systems. However, because of the many different mechanisms underlying carcinogenesis, the Ke system cannot predict the potential carcinogenicity of all kinds of chemicals. It is concluded that the main role of Ke in risk assessment consists in producing a probabilistic estimate of the rodent carcinogenicity of the chemicals: e.g. a chemical with Ke higher than 3.0 x 10(12) M-1S-1 has nearly 80% probability of being a carcinogen. Such a probability estimate can be used to rank the chemicals in a priority scale for subsequent and more detailed studies, either theoretical or experimental. In view of this, the role of our method for estimating Ke is particularly important: it gives rapidly and at no cost a chemical classification for risk assessment and priority setting.

Animals↗
PubMed1992

Relationships between in vitro mutagenicity assays.

This paper analyzes the mutagenicity results reported by the US National Toxicology Program (NTP), relative to 41 chemicals assayed with four in vitro short-term tests [Salmonella typhimurium (STY), Chromosomal aberrations in Chinese hamster ovary (CHO) cells (CHA), Sister chromatid exchange in CHO cells (SCE), mutation in L5178Y mouse lymphoma cells (MLY)] and puts this database in perspective with respect to other databases. It is shown that the test relationships pointed out by the experiments on the 41 chemicals are in substantial agreement with those indicated by a previous NTP report on 73 chemicals, and that the same test relationships were also indicated by the results on the International Program for the Evaluation of Short-Term Tests for Carcinogens (IPESTTC). The NTP and IPESTTC databases consistently indicated that there is a gradual increase in the sensitivity to the genotoxins in the following order: STY < CHA < SCE < MLY. On this scale, SCE and MLY show a great degree of similarity of responses to the chemicals, as does STY with CHA. The overall evidence provided by these results, and by the general pattern of IPESTTC and NTP genotoxicity profiles, does not support the notion that the genotoxic chemicals have genetic end point specificity. Moreover, a mathematical simulation analysis demonstrated that MLY and SCE--the two most sensitive assays of those studied by NTP--are not more subject to erratic results than other assays, and that they form--together with STY and CHA--a consistent family of genotoxicity assays.

Databases, Factual↗
PubMed1991

What indication is common to different genotoxicity data bases?

This paper studies the relationships among 4 in vitro assays: Salmonella mutation (STY), mouse lymphoma L5178Y cell mutation (MLY), chromosomal aberrations in CHO cells (CHA), and sister-chromatid exchanges in CHO cells (SCE), in 3 different data bases: U.S. National Toxicology Program (NTP), International Program for the Evaluation of Short-Term Tests for Carcinogens (IPESTTC), and International Program on Chemical Safety (IPCS). The analysis is performed by modeling each data base with factor analysis. With this tool, it has been possible to separate the different elements (or components) which play a role in each data base. It has also been possible to demonstrate that--together with some specificities of the data bases--there is a common effect which is independent of the data bases, and which typically represents the 'true' relationships among the assays. This element explains 69% of the information contained in NTP, 50% of that of IPESTTC, and 30% of that of IPCS. This common evidence indicates that the responses of STY and CHA to the 'universe' of chemicals are relatively similar, although STY is a bacterial mutation system and CHA is a mammalian cell test for chromosomal damage. The other similarity apparent from this analysis is the one between MLY (mutation in mouse cells) and SCE (cytogenetic evidence in hamster cells). The implication of this result is 2-fold. On the one hand, it is extremely reassuring that the 3 most important comparative studies agree and show common evidence, and this can be recognized rationally. On the other hand, this evidence implies that the scientists involved in mutagenicity research must face the task of exploring and explaining such relationships.

Animals↗
PubMed1991

The ability of short-term tests to predict carcinogenicity can be summarized in a single index.

This paper presents a new procedure aimed at quantifying the ability of short-term tests (STT) to discriminate between carcinogens and noncarcinogens. While the sensitivity, specificity, and accuracy indices provide an estimate that is not biased by the relative proportion of carcinogens and noncarcinogens of the different databases, the new index, called Relative Operating Characteristics (ROC), goes a step further, and overcomes the problem of the decision criterion bias. In fact, if the threshold--that is, minimum increase over the control above which an STT result is positive--is varied, sensitivity and other factors are also consequently affected. A similar problem occurs when the STTs are assembled in batteries: the performance of the battery in discriminating between carcinogens and noncarcinogens depends on the preliminary decision of how many and which assays should be positive for considering a chemical as positive in the battery. The ROC analysis produces a single value, which places the performance of different systems on a common, easily interpreted scale (instead of using several different indices such as sensitivity, etc.). Most importantly, this index is independent of the decision criterion bias; consequently it is the best measure of the true ability of STTs to discriminate between carcinogens and noncarcinogens. To illustrate the approach, the ROC analysis is applied to a battery composed of the four in vitro assays studied by the U.S. National Toxicology Program: the analysis confirmed the previous results, pointing to the limited ability of this battery to discriminate between carcinogens and noncarcinogens.

Animals↗
PubMed1991

Relationship between chlorofluorocarbon chemical structure and their Salmonella mutagenicity.

This paper is a quantitative analysis of the relationship between the chemical structure and the Salmonella mutagenicity of a number of chlorofluorocarbons (CFC). The molecules were characterized by both molecular orbital and physical chemical parameters. The results of the analysis indicated that the CFC mutagenicity is correlated with two parameters: the free energy of binding to biological receptors, and the energy of the highest occupied molecular orbital (HOMO). Since these are the same factors that would favor the cytochrome P-450-catalyzed metabolism, it would appear that the CFC mutagenicity is determined more by the rate of initial activation than by the rate of DNA attack.

Biotransformation↗
PubMed1991

QSAR prediction of rodent carcinogenicity for a set of chemicals currently bioassayed by the US National Toxicology Program.

A QSAR model based on the combination of two molecular descriptors--estimated electrophilic reactivity and Ashby's structural alerts--was used to predict the carcinogenicity of 44 chemicals currently bioassayed by the US National Toxicology Program. These predictions will be compared with the rodent carcinogenicity assay results as the assays are completed.

Animals↗
PubMed1991

Mathematical models for exploring different aspects of genotoxicity and carcinogenicity databases.

One great obstacle to understanding and using the information contained in the genotoxicity and carcinogenicity databases is the very size of such databases. Their vastness makes them difficult to read; this leads to inadequate exploitation of the information, which becomes costly in terms of time, labor, and money. In its search for adequate approaches to the problem, the scientific community has, curiously, almost entirely neglected an existent series of very powerful methods of data analysis: the multivariate data analysis techniques. These methods were specifically designed for exploring large data sets. This paper presents the multivariate techniques and reports a number of applications to genotoxicity problems. These studies show how biology and mathematical modeling can be combined and how successful this combination is.

Animals↗
PubMed1990

Strategies and governmental regulations.

An overview of testing strategies for the detection of genotoxins under OECD Guidelines and the EEC Directive 79/831 (VI Amendment) is outlined. The viewpoint of the Italian National Advisory Committee on Toxicology is also presented. In this context, the main issues of Genetic Toxicology (e.g., role of tests, tests recommended, classification of mutagens) are discussed.

Animals↗
PubMed1990

Rodent tumor profiles, Salmonella mutagenicity and risk assessment.

The tumorigenesis profiles of 116 chemicals, which proved to induce cancer in the NCI/NTP experimentation, were studied by multivariate data analysis methods. Three main patterns of tumor induction were evident. One chemical (benzene) was not classifiable in any of the 3 clusters of chemicals. The carcinogen classes based on patterns of tumor induction did not reflect a repartition between Ames-positive and Ames-negative chemicals. Therefore any classification of carcinogens as either 'primary' (genotoxic, hence assumed to pose a greater risk) or 'secondary' (presumably carcinogenic via non-genotoxic mechanisms) would seem to be a subject for research and speculation, and, for the present, an unsuitable basis for risk assessment.

Animals↗
PubMed1990

Inhibition of replicative DNA synthesis and induction of DNA repair in human fibroblasts by the intercalating drugs proflavine and 9-aminoacridine.

The induction of unscheduled DNA synthesis (UDS) and the alteration of semiconservative DNA replication by the structurally related intercalating agents proflavine and 9-aminoacridine were studied in MRC-5 human fibroblasts in culture. Autoradiographic determinations of both parameters were carried out simultaneously in the same culture specimens. Proflavine affected DNA synthesis, but did not elicit any UDS. 9-Aminoacridine inhibited DNA synthesis only at the highest concentration and caused UDS to a low but significant extent. These results suggest that the ability to induce UDS is not a general property of the intercalating agents and that the alterations of the DNA structure, typical of the "pure" intercalative process, are not handled by pathways involving unscheduled synthesis.

Aminacrine↗
PubMed1989

A bootstrap analysis of four in vitro short-term test performances.

The present analysis is aimed at estimating the confidence intervals of a number of association measures that describe the relationships of 4 in vitro short-term tests with rodent carcinogenicity, as well as with each other. The measures considered were: sensitivity, specificity and accuracy of the short-term tests with respect to chemical carcinogens, and performance dissimilarity indices (Hamming distances). The analysis refers to Salmonella, mouse lymphoma L5178Y cell mutation, chromosomal aberrations and sister-chromatid exchanges in Chinese hamster ovary cells, and is based on the data generated in the frame of the U.S. National Toxicology Program (NTP). It exploits the properties of a statistical technique, called bootstrap, to derive from only one sample of chemicals the variability intervals of the associations that the biological systems (mutagenicity assays and rodent carcinogenicity) would show in the 'universe' of the chemical compounds. The combination of the bootstrap technique with multivariate statistical methods pointed to a remarkable robustness and reliability of the information derived from the NTP data base, and provided descriptive insights into the data.

Animals↗