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Rodent carcinogenicity and toxicity, in vitro mutagenicity, and their physical chemical determinants
1Istituto Superiore di Sanitá, Laboratory of Comparative Toxicology and Ecotoxicology, Rome, Italy.
Abstract:
In this paper, we considered rodent carcinogenicity and toxicity, and four in vitro mutagenicity systems, and we made a global comparison between their different response profiles to a common set of 297 chemicals. This analysis is complemented with a study of the physical chemical properties of active and inactive compounds in the different systems. A clearcut separation between the different classes of toxicological end-points (carcinogenicity, in vivo toxicity, in vitro carcinogenicity) was evident. The observed lack of association between carcinogenicity and toxicity supports the validity of the rodent bioassays; this is contrary to the position that the positive results obtained are due mainly to the use of excessive doses that exert cytotoxic effects. We found substantial consistency in the responses of the in vivo toxicity systems (maximum tolerated dose and LD50), but we also found that remarkable differences exist between the in vitro mutagenicity assay systems. The study of the structure-activity relationships showed that: (a) the hydrophobic-electronic properties of the chemicals influence rodent carcinogenicity, with the tendency of carcinogens to be more electrophilic and more hydrophobic than non-carcinogens; (b) steric effects are implied in in vitro mutagenicity, bulkier molecules being less mutagenic than smaller molecules; (c) no clear association between in vivo toxicity and physical chemical properties was apparent. The differences between carcinogenicity and in vitro mutagenicity may hypothetically be related to their different experimental procedures. The relatively short treatment of in vitro mutagenicity requires that chemicals penetrate easily into the cells, and are well dissolved into the aqueous medium, size and hydrophilicity thus being critical for the action of the chemicals. The size of the molecules is not critical in the long-term rodent carcinogenicity experiments, where other factors, like bioaccumulation (hydrophobicity) and electronic reactivity, become essential.
Insights
This study compared rodent carcinogenicity and toxicity with in vitro mutagenicity for 297 chemicals. Findings reveal distinct profiles and highlight structure-activity relationships influencing different toxicological endpoints.
Area of Science:
- Toxicology
- Chemical Carcinogenesis
- Mutagenicity Testing
Background:
- Rodent bioassays are crucial for assessing chemical carcinogenicity and toxicity.
- In vitro mutagenicity assays provide alternative methods for evaluating chemical safety.
- Understanding the relationship between different toxicological endpoints is essential for accurate risk assessment.
Purpose of the Study:
- To conduct a global comparison of response profiles between rodent carcinogenicity/toxicity and in vitro mutagenicity systems.
- To analyze the physical-chemical properties of active and inactive compounds across these systems.
- To investigate structure-activity relationships influencing different toxicological outcomes.
Main Methods:
- Comparative analysis of 297 chemicals across rodent carcinogenicity, in vivo toxicity, and four in vitro mutagenicity systems.
- Evaluation of physical-chemical properties (hydrophobicity, electronic, steric) of tested compounds.
- Structure-activity relationship (SAR) analysis for different toxicological endpoints.
Main Results:
- A clear separation was observed between carcinogenicity, in vivo toxicity, and in vitro mutagenicity endpoints.
- Rodent carcinogenicity is influenced by hydrophobicity and electrophilicity; in vitro mutagenicity is affected by steric bulk.
- In vivo toxicity showed consistency, while in vitro mutagenicity assays exhibited significant differences.
- No clear association was found between in vivo toxicity and physical-chemical properties.
Conclusions:
- The lack of association between carcinogenicity and toxicity supports rodent bioassay validity, refuting dose-dependent cytotoxic effects as the primary driver.
- Differences in experimental procedures likely explain variations between in vitro mutagenicity and carcinogenicity.
- Hydrophobicity, electronic, and steric properties play distinct roles in chemical interactions with biological systems, influencing specific toxicological outcomes.