Abstract
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.
Keywords
ElectrophileCarcinogenChemistryComputational chemistryBiological systemElectronegativityToxicologyOrganic chemistryBiology
Affiliated Institutions
Related Publications
A retrospective evaluation of COMPACT predictions of the outcome of NTP rodent carcinogenicity testing.
The carcinogenic potentials of 40 National Toxicology Program chemicals previously predicted by Computer Optimised Molecular Parametric Analysis for Chemical Toxicity (COMPACT),...
Animal studies addressing the carcinogenicity of TCDD (or related compounds) with an emphasis on tumour promotion
Dioxin and certain structurally related compounds increase the incidence of liver neoplasms in rodents upon chronic bioassay. Short-term studies indicate the lack of direct DNA-...
Relationships Between Descriptors for Hydrophobicity and Soft Electrophilicity in Predicting Toxicity
The toxicity of chemicals is orthogonal with individual molecular descriptors used to quantify hydrophobicity and soft electrophilicity when considering large data sets. Estimat...
Comparison of dose-effect relationships of carcinogens following low-dose chronic exposure and high-dose single injection: an analysis by the median-effect principle
Experimental dose-effect relationships of carcinogens following either acute (single dose) or chronic (time to tumor) exposure appears to conform with the median-effect principl...
Electrophilicity Index
Prompted by a recent paper by Maynard and co-workers (Maynard, A. T.; Huang, M.; Rice, W. G.; Covel, D. G. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 11578), we propose that a spec...
Publication Info
- Year
- 1992
- Type
- article
- Volume
- 13
- Issue
- 4
- Pages
- 547-553
- Citations
- 31
- Access
- Closed
External Links
Social Impact
Altmetric
PlumX Metrics
Social media, news, blog, policy document mentions
Citation Metrics
31
OpenAlex
Cite This
Romualdo Benigni,
Marina Cotta‐Ramusino,
C Andreoli
et al.
(1992).
Electrophilicity as measured by <i>K</i><sub>e</sub>: molecular determinants, relationship with other physical-chemical and quantum mechanical parameters, and ability to predict rodent carcinogenicity.
Carcinogenesis
, 13
(4)
, 547-553.
https://doi.org/10.1093/carcin/13.4.547
Identifiers
- DOI
- 10.1093/carcin/13.4.547