Neoplastic lesions of questionable significance to humans
R H Alison1, C C Capen, D E Prentice
1Department of Veterinary Pathobiology, Ohio State University, Columbus 43210.
Abstract:
Many compounds giving a positive result in animal carcinogenicity studies through mechanisms involving secondary carcinogenesis pose little or no risk to humans. This article provides an overview of current understanding, with particular reference to renal tumors in male rats with alpha 2mu-globulin nephropathy, urinary bladder neoplasia in rodents, mesovarian leiomyomas induced in rats by beta 2-receptor stimulants, carcinoid tumors in the rodent stomach induced by prolonged suppression of acid secretion, thyroid follicular cell tumors in rodents, canine mammary neoplasia due to administration of progestagens, rodent mammary neoplasia induced by estrogens, uterine endometrial carcinomas of rats induced by dopamine agonists, Leydig cell tumors in the testis of rats, and ovarian tubulostromal adenomas in mice. A positive result on a rodent carcinogenicity study should not automatically preclude further development of a compound; future progress in this field should increase the accuracy of the rodent carcinogenicity study as a tool in human safety assessment.
Insights
Many positive rodent carcinogenicity study results, driven by secondary mechanisms, pose minimal human risk. Further research can improve the accuracy of animal studies for human safety assessment.
Area of Science:
- Toxicology
- Carcinogenesis
- Risk Assessment
Background:
- Animal carcinogenicity studies are crucial for human safety assessment.
- Some positive findings in rodents result from secondary mechanisms not relevant to humans.
- Understanding these mechanisms is key to accurate risk evaluation.
Purpose of the Study:
- To review current understanding of rodent carcinogenicity studies with secondary mechanisms.
- To highlight specific examples of compounds and associated rodent tumors.
- To advocate for improved accuracy in using animal studies for human safety.
Main Methods:
- Literature review and synthesis of existing research.
- Analysis of specific cases of rodent tumors and their proposed mechanisms.
- Discussion of implications for drug development and regulatory science.
Main Results:
- Identified several compounds with positive rodent carcinogenicity results due to secondary mechanisms (e.g., alpha 2mu-globulin nephropathy, hormonal imbalances).
- Examples include renal tumors in male rats, urinary bladder neoplasia, mesovarian leiomyomas, stomach carcinoids, thyroid tumors, mammary and uterine tumors, and Leydig cell tumors.
- These findings suggest that positive rodent bioassays do not always equate to human carcinogenicity.
Conclusions:
- Positive rodent carcinogenicity findings due to secondary mechanisms often indicate low human risk.
- Compounds should not be automatically disqualified based solely on such study results.
- Enhancing the predictive accuracy of rodent carcinogenicity studies is vital for robust human safety assessment.
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