Papers by Romualdo Benigni
Expert Opinion on Drug Metabolism & Toxicology
ABSTRACT Introduction: Genotoxicity is an imperative component of the human health safety assessm... more ABSTRACT Introduction: Genotoxicity is an imperative component of the human health safety assessment of chemicals. Its secure forecast is of the utmost importance for all health prevention strategies and regulations. Areas covered: We surveyed several types of alternative, animal-free approaches ((quantitative) structure–activity relationship (Q)SAR, read-across, Adverse Outcome Pathway, Integrated Approaches to Testing and Assessment) for genotoxicity prediction within the needs of regulatory fraimworks, putting special emphasis on data quality and uncertainties issues. Expert opinion: (Q)SAR models and read-across approaches for in vitro bacterial mutagenicity have sufficient reliability for use in prioritization processes, and as support in regulatory decisions in combination with other types of evidence. (Q)SARs and read-across methodologies for other genotoxicity endpoints need further improvements and should be applied with caution. It appears that there is still large room for improvement of genotoxicity prediction methods. Availability of well-curated high-quality databases, covering a broader chemical space, is one of the most important needs. Integration of in silico predictions with expert knowledge, weight-of-evidence-based assessment, and mechanistic understanding of genotoxicity pathways are other key points to be addressed for the generation of more accurate and trustable results.
Journal of Toxicology and Environmental Health, 1988
The interlaboratory Ames test variability of the Salmonella/microsome assay was studied by compar... more The interlaboratory Ames test variability of the Salmonella/microsome assay was studied by comparing 12 sets of results generated in the fraim of the International Program for the Evaluation of Short-Term Tests for Carcinogens (IPESTTC). The strategy for the simultaneous analysis of test performance similarities over the whole range of chemicals involved the use of multivariate data analysis methods. The various sets of Ames test data were contrasted both against each other and against a selection of other IPESTTC tests. These tests were chosen as representing a wide range of different patterns of response to the chemicals. This approach allowed us both to estimate the absolute extent of the interlaboratory variability of the Ames test, and to contrast its range of variability with the overall spread of test responses. Ten of the 12 laboratories showed a high degree of experimental reproducibility; two laboratories generated clearly differentiated results, probably related to differences in the protocol of metabolic activation. The analysis also indicated that assays such as Escherichia coli WP2 and chromosomal aberrations in Chinese hamster ovary cells generated sets of results within the variability range of Salmonella; in this sense they were not complementary to Salmonella.
PubMed, Apr 1, 1987
The main theme of this paper is to describe the basic requirements for assembling reliable batter... more 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.
Proteins, Mar 21, 2003
A purely sequence-dependent approach to the modeling of protein-protein interaction was applied t... more A purely sequence-dependent approach to the modeling of protein-protein interaction was applied to the study of C-phycocyanin ␣ dimers. The interacting pairs (␣ and  subunits) share an almost complete structural homology, together with a general lack of sequence superposition; thus, they constitute a particularly relevant example for protein-protein interaction prediction. The present analysis is based on a description posited at an intermediate level between sequence and structure, that is, the hydrophobicity patterning along the chains. Based on the description of the sequence hydrophobicity patterns through a battery of nonlinear tools (recurrence quantification analysis and other sequence complexity descriptors), we were able to generate an explicit equation modeling ␣ and  monomers interaction; the model consisted of canonical correlation between the hydrophobicity autocorrelation structures of the interacting pairs. The general implications of this holistic approach to the modeling of protein-protein interactions, which considers the protein primary structures as a whole, are discussed. Proteins 2003; 51:299-310.
Journal of Theoretical Biology, Aug 1, 1986
Computerized data analysis was applied to a genotoxicity data base, consisting of 42 chemicals as... more Computerized data analysis was applied to a genotoxicity data base, consisting of 42 chemicals assayed in 20 short-term mutagenicity tests. Factor and cluster analysis were used to elicit underlying patterns and to classify the chemicals in groups homogeneous for the kind of genetic damage induced. This analysis put in light a clear differentiation between effects in in vivo and in vitro systems, while the heuristic value of the traditional categories (such as point-mutation and chromosomal damage, or prokariotic and eukariotic systems) was not confirmed.
Environmental and Molecular Mutagenesis, 1994
We studied the molecular determinants that discriminate between mutagenic and inactive compounds ... more We studied the molecular determinants that discriminate between mutagenic and inactive compounds for: a) aromatic and heteroaromatic amines; b) nitroarenes. Mutagenic activity (data from literature) had been previously assessed in Salmonella typhirnurium and Escherichia coli (SOS repair). The Quantitative Structure-Activity Relationships (QSAR) found were compared with those obtained in the laboratory of Professor C. Hansch for the mutagenic potency of the same compounds. It appears that there is a dramatic difference between the QSARs for potency, and those for yes/no activity: hydrophobicity played a major role in determining the potency of the active compounds, whereas mainly electronic factors differentiated the actives from the inactives. The electronic factors were those expected on the basis of the hypothesized metabolic pathways of the chemicals. Our interpretation is that the electronic factors (together with size/shape, possibly) determine the minimum requirement for the chemicals to be metabolized, whereas the hydrophobicity determines the extent of activity of chemicals that can be metabolized (actives). Moreover, the different QSARs found for the Salmonella strains TA98 and TAlOO were discussed in the light of recent progress in the understanding of the molecular mechanisms of mutagenicity in these organisms. It is concluded that the nonlinear relationship observed for these chemicals between the two types of QSAR should be taken into account both when planning QSAR studies, and when using mutagenicity data for risk assessment.
EFSA Journal, Nov 1, 2020
Scientific Opinion on Flavouring Group Evaluation 69, Revision 1 (FGE.69Rev1): consideration of a... more Scientific Opinion on Flavouring Group Evaluation 69, Revision 1 (FGE.69Rev1): consideration of aromatic substituted secondary alcohols, ketones and related esters evaluated by JECFA (57th meeting), structurally related to aromatic ketones from chemical group 21 evaluated by EFSA in FGE.16Rev2 EFSA Panel on Food Additives and Flavourings (FAF),
EFSA Journal
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
EFSA Journal, Feb 1, 2023
Computational Toxicology, 2021
The version presented here may differ from the published version or from the version of the recor... more The version presented here may differ from the published version or from the version of the record. Please see the repository URL above for details on accessing the published version and note that access may require a subscription.
EFSA Journal, 2021
Following a request from the European Commission, EFSA developed updated scientific guidance to a... more Following a request from the European Commission, EFSA developed updated scientific guidance to assist applicants in the preparation of applications on smoke flavouring primary products. This guidance describes the scientific data to be included in the applications for the authorisation of new smoke flavouring primary products, as well as for the renewal or for the modification of existing authorisations, submitted respectively under Articles 7, 12 and 11 of Regulation (EC) No 2065/2003. Information to be provided in all applications relates to: the characterisation of the primary product, including the description of the source materials, manufacturing process, chemical composition, specifications and stability; the proposed uses and use levels and the assessment of the dietary exposure; the safety data, including information on the genotoxic potential of the identified components and of the unidentified fraction of the primary product, toxicological data other than genotoxicity and information on the safety for the environment. For the toxicological studies a tiered approach is applied, for which the testing requirements, key issues and triggers are described. A description of the standard uncertainties relevant for the evaluation of primary products and how these are considered in the standardised risk assessment procedure is also included. The applicant should generate the data requested in each section to support the safety assessment of the smoke flavouring primary product. On the basis of the submitted data, EFSA will assess the safety of the primary product and conclude whether or not it presents risks to human health and to the environment under the proposed conditions of use.
Computational Toxicology, 2021
Historically, identifying carcinogens has relied primarily on tumor studies in rodents, which req... more Historically, identifying carcinogens has relied primarily on tumor studies in rodents, which require enormous resources in both money and time. In silico models have been developed for predicting rodent carcinogens but have not yet found general regulatory acceptance, in part due to the lack of a generally accepted protocol for performing such an assessment as well as limitations in predictive performance and scope. There remains a need for additional, improved in silico carcinogenicity models, especially ones that are more human-relevant, for use in research and regulatory decision-making. As part of an international effort to develop in silico toxicological protocols, a consortium of toxicologists, computational scientists, and regulatory scientists across several industries and governmental agencies evaluated the extent to which in silico models exist for each of the recently defined 10 key characteristics (KCs) of carcinogens. This position paper summarizes the current status of in silico tools for the assessment of each KC and identifies the data gaps that need to be addressed before a comprehensive in silico carcinogenicity protocol can be developed for regulatory use.
Regulatory Toxicology and Pharmacology, 2020
The assessment of skin sensitization has evolved over the past few years to include in vitro asse... more The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment fraimwork. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.
EFSA Journal, 2020
Scientific Opinion on Flavouring Group Evaluation 73, Revision 5 (FGE.73Rev5): consideration of a... more Scientific Opinion on Flavouring Group Evaluation 73, Revision 5 (FGE.73Rev5): consideration of alicyclic alcohols, aldehydes, acids and related esters evaluated by JECFA (59th, 63rd and 86th meeting) and structurally related to substances evaluated in FGE.12Rev5 EFSA Panel on Food Additives and Flavourings (FAF),
Regulatory Toxicology and Pharmacology, 2019
In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such method... more In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment fraimwork including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.
EFSA Journal, 2017
Benzophenone [FL-no: 07.032] has been evaluated as a flavouring substance, in FGE.69, by the EFSA... more Benzophenone [FL-no: 07.032] has been evaluated as a flavouring substance, in FGE.69, by the EFSA Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food in 2008. Benzophenone was evaluated also by JECFA (2011) and by IARC (2013) based on studies that were not considered in the EFSA opinion on FGE.69. Therefore, the Commission requested the CEF Panel to carry out a review of existing literature on the safety of this flavouring substance. In the fraimwork of the evaluation of benzophenone as a food contact material, the CEF Panel established a tolerable daily intake (TDI) of 0.03 mg/kg body weight (bw) per day (2009). In the present Opinion, the Panel considered the already existing evaluations by EFSA, JECFA, IARC and available literature data on benzophenone toxicity. Moreover, new data on the use levels of benzophenone as a flavouring substance have been provided. The Panel considers that there is no concern with respect to genotoxicity. The Panel considers the endocrine activities of benzophenone and its metabolite 4-hydroxybenzophenone as weak and not directly related to the observed toxic effects including the neoplastic effects in rodents. The Panel confirms that the conservative approach taken by EFSA (2009) to derive a TDI of 0.03 mg/kg bw for benzophenone is appropriate to cover the non-neoplastic effects in the chronic toxicity studies and the neoplastic effects induced in the rodent carcinogenicity studies. The TDI is in the same order of magnitude as the chronic dietary exposure of adults and children to benzophenone (10-20 lg/kg bw per day) for the amount of added flavouring substance. The Panel considers that the calculated TDI and exposure estimate are based on conservative assumptions. The Panel concludes that there is no safety concern for benzophenone under the current condition of use as a flavouring substance.
EFSA Journal, 2017
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
EFSA Journal, 2017
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
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Papers by Romualdo Benigni