Transgenic mouse models can serve as sensitive, short-term alternatives to traditional rodent 2-year cancer bioassays. K6ODC transgenic mice develop epidermal tumors when exposed to carcinogens via the promotional stimulus of enhanced expression of ornithine decarboxylase in keratinocytes. K6ODC mice were used in a 36-week study to test their susceptibility to oncogenesis by a plasmid expressing the human T24-H-ras gene, which was developed to evaluate risks posed by residual DNA in vaccines produced in neoplastic cell substrates. Male K6ODC and C57BL/6 mice (15 per group) were treated with H-ras plasmid (2.5, 250, 25000 ng), vector DNA, or saline on scarified skin or by subcutaneous injection. One group of K6ODC mice received a single exposure of 7,12-dimethylbenz-[a]anthracene ([DMBA], 200 nM) dermally. Microscopy of skin, heart, lung, liver, and spleen were performed after unscheduled euthanization or at study completion. DMBA-treated K6ODC mice developed superficial papillomas by 6 weeks that increased in incidence to 25 weeks (9±0.69 tumors/mouse, < 3mm, 13/15 responded). No tumors were detected in other groups in either mouse strain. Microscopy of skin sections confirmed papillomas in DMBA treated animals with dermal/sebaceous gland hyperplasia and follicular dystrophy in all skin samples, characteristic of this strain. Tissue analysis of K6ODC mice revealed amyloid deposition and neutrophilic infiltration within liver, heart, and spleen, and splenic atrophy regardless of treatment. Pathology was not detected in C57BL/6 mice.  After week 15, 94% (126/134) of the K6ODC mice developed unexpected dermal eczema (unrelated to either treatment regimen) requiring unscheduled euthanization. By week 32, six of the eight surviving K6ODC mice showed difficulty in mobility and loss of balance. In this study, the K6ODC failure to develop papillomas to oncogenic DNA, progressive adverse health, and decreased long-term survival suggest that K6ODC mice are an inadequate alternative model for oncogenic DNA and chemical carcinogenicity testing.