Abstract
Genotoxicity and carcinogenicity testing of pharmaceuticals prior to commercialization is requested by regulatory agencies. The bacterial mutagenicity test was considered having the highest accuracy of carcinogenic prediction. However, some evidences suggest that it always results in false-positive responses when the bacterial mutagenicity test is used to predict carcinogenicity. Along with major changes made to the International Committee on Harmonization guidance on genotoxicity testing [S2 (R1)], the old data (especially the cytotgenetic data) may not meet current guidelines. This review provides a compendium of retrievable results of genotoxicity and animal carcinogenicity of 136 antiparasitics. Neither genotoxicity nor carcinogenicity data is available for 84 (61.8%), while 52 (38.2%) have been evaluated in at least one genotoxicity or carcinogenicity study, and only 20 (14.7%) in both genotoxicity and carcinogenicity studies. Among 33 antiparasitics with at least one old result in in vitro genotoxicity, 15 (45.5%) are in agreement with the current ICH S2 (R1) guidance for data acceptance. Compared with other genotoxicity assays, the DNA lesions can significantly increase the accuracy of prediction of carcinogenicity. Together, a combination of DNA lesion and bacterial tests is a more accurate way to predict carcinogenicity.
Highlights
Antiparasitics are used widely throughout the world in humans and animals to kill or eliminate parasites in vivo and in vitro, and in public health to control diseases and prevent the spread of parasitism from livestock to humans
It presents the antiparasitics with results in in vitro data required by present guidelines; the number of antiparasitics that have at least one result in long-term carcinogenesis assays in rats or mice; and Principle of reference
With regard to the different types of genotoxicity assays: there were 47 antiparasitics with at least one result in tests for bacterial mutagenicity; 18 antiparasitics with at least one result in tests for gene mutation in mammalian cells; 33 antiparasitics in in vitro tests for sister chromatid exchange (SCE), chromosomal aberrations, aneuploidy, or micronucleus in animal or human cells; 15 antiparasitics with results in in vitro data required by present guidelines; 31 antiparasitics in in vivo tests for SCE, chromosomal aberrations, or micronucleus in animal or human cells; 19 antiparasitics in DNA damage or DNA repair synthesis; 17 antiparasitics in other types of genotoxicity assays; and 20 antiparasitics examined for genotoxicity in human cells
Summary
Antiparasitics are used widely throughout the world in humans and animals to kill or eliminate parasites in vivo and in vitro, and in public health to control diseases and prevent the spread of parasitism from livestock to humans. According to the present guidelines for genotoxicity testing of pharmaceuticals [12,13,14,15], a standard test battery contains: (a) a test for gene mutations in bacteria, (b) an in vitro test with cytogenetic evaluation of chromosomal damage using mammalian cells or an in vitro mouse lymphoma thymidine kinase± gene mutation assay, and (c) an in vivo test for chromosomal damage using mammalian hematopoietic cells These assays were considered the best approach for genotoxic hazard identification and potential carcinogenic risk prediction. Whose clinical use is continuous for at least 6 months or intermittent in chronic recurrent conditions, the long-term carcinogenicity studies in rats and mice using lifetime treatment are required [19] This has remained the most frequently chosen testing strategy since proposed by regulatory authorities in 1970s. Regarding the present guidelines, the equivocal results that we found in extensive research were marked as positive in this review
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