Phenolphthalein and Bisacodyl: Assessment of Genotoxic and Carcinogenic Responses in Heterozygous p53 (+/–) Mice and Syrian Hamster Embryo (SHE) Assay

Phenolphthalein (800 and 2400 mg/kg/day by gavage and 2400 mg/kg/day by diet) and bisacodyl (800–500, 4000–2000, and 8000 mg/kg/day by gavage) were administered to 15 male and 15 female and 20 male and 20 female p53+/ mice respectively for 26 weeks to investigate the potential carcinogenicity of each compound. Toxicokinetic analyses confirmed systemic exposure. p-Cresidine was administered by gavage (400 mg/kg/day) and served as the positive control agent in each study. Dietary phenolphthalein reduced survival in both sexes and early deaths were attributed to thymic lymphoma. No bisacodyl-related neo-plasms were observed. Regardless of route of administration to p53+/ mice, phenolphthalein but not bisacodyl was unequivocally genotoxic, causing increased micronuclei in polychromatic eryth-rocytes. In the Syrian hamster embryo (SHE) cell transformation assay, phenolphthalein caused increases in morphologically trans-formed colonies, thereby corroborating NTP’s earlier reports, showing phenolophthalein has potential carcinogenic activity. Bisacodyl was negative in the SHE assay. Results of these experi-ments confirm an earlier demonstration that dietary phenolphtha-lein causes thymic lymphoma in p53+/ mice and show that (1) phenolphthalein causes qualitatively identical results in this trans-genic model regardless of route of oral administration, (2) phenolphthalein shows evidence of micronucleus induction in p53+/ mice for up to 26 weeks, (3) phenolphthalein induced transformations in the in vitro SHE assay, and (4) bisacodyl in p53+/ mice induces neither drug-related neoplasm, nor micronuclei in polychromatic erythrocytes, and did not induce transformations in the in vitro SHE assay