Exposure of mouse skin to organic peroxides: subchronic effects related to carcinogenic potential.
Screening of newly synthesized organic peroxides for tumor initiating/promoting activity would be greatly facilitated if predictive methodologies could be developed using topical exposures shorter than those required for definitive tumor assessment in mouse skin models. Nine organic peroxides [benzoyl peroxide (BZP), di-t-butyl peroxide (DTBP), t-butyl peroxybenzoate (TBPB), p-t-butyl isopropylbenzene hydroperoxide (TBIBHP), cumene hydroperoxide (CHP), dicetyl peroxydicarbonate (DPD), dicumyl peroxide (DCP), methyl ethyl ketone peroxide (MEKP) and O,O-t-butyl-O-(2-ethylhexyl) monoperoxycarbonate (TBEC)] were evaluated for their ability to increase biomarkers of tumor promotion in mouse skin, i.e. sustained epidermal hyperplasia, dermal inflammation and oxidative DNA damage. Evaluations were performed using SENCAR mice exposed topically for 4 weeks. The organic peroxides varied in their effects on these biomarkers. BZP, TBPB and TBIBHP exhibited significant increases in all three biomarkers associated with tumor promoting activity, CHP produced increases only in sustained epidermal hyperplasia and dermal inflammation, MEKP and DCP produced increases only in sustained epidermal hyperplasia and TBEC produced an increase only in dermal inflammation. DTBP and DPD had no effect on the three parameters studied. TBPB and TBIBHP were selected for further examination of their ability to produce mutations in codons 12, 13 and 61 of the c-Ha-ras protooncogene, i.e. those mutations known to be involved in the initiation of mouse skin tumors, because they were the only peroxides to exhibit significant positive results in all assays except the Ha-ras mutation following 4 weeks of exposure. Evaluations were performed using SENCAR mice dosed topically for 8 or 12 weeks in a complete carcinogenesis protocol or 16 weeks in an initiation/promotion protocol using 7,12-dimethylbenz[a]anthracene, urethane, benzo[a]pyrene and N-methyl-N'-nitro-N-nitrosoguanidine as positive controls. Neither TBPB nor TBIBHP produced detectable mutations in the c-Ha-ras protooncogene, indicating that they are not likely to possess tumor initiating or complete carcinogenic activity.
Hanausek
Margaret
M
AMC Cancer Research Center, Denver, CO 80214, USA. hanausekm@amc.org
Walaszek
Zbigniew
Z
Viaje
Aurora
A
LaBate
Michael
M
Spears
Erick
E
Farrell
David
D
Henrich
Richard
R
Tveit
Ann
A
Walborg
Earl F
EF
Slaga
Thomas J
TJ
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology*; D005260:Female; D011905:Genes, ras / Q000187:drug effects; D051379:Mice; D018632:Mice, Inbred SENCAR; D009154:Mutation; D016877:Oxidants / Q000494:pharmacology*; D010545:Peroxides / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects*
D001565:Benzoates; D002273:Carcinogens; D016877:Oxidants; D010545:Peroxides; C060534:tert-butyl peroxybenzoate