Chemical Carcinogenesis
Toxicology and Risk Assessment
Surgical Pathology
Urologic Pathology

Professor 
Havlik-Wall Professor of Oncology
Director of Pathology Residency Program

Research
My research involves several aspects of carcinogenesis, with an emphasis on the urinary bladder as a model system in rodents and extrapolation between rodent models and the human disease.

We have postulated that agents increase cancer risk by either directly interacting with DNA or increasing cell proliferation in appropriate target cells in a tissue allowing for more opportunity for spontaneous mutations to occur during DNA replication.

Genotoxic chemicals, such as nitrofurons, nitrosamines, and acrolein, are evaluated for metabolic activation, DNA adduct formation, and mutagenesis.

Numerous nongenotoxic chemicals have been identified as enhancing rat bladder carcinogenesis by increasing urothelial cell proliferation, including arsenic, sodium salts, amino acids, calculus-forming chemicals, and phenolic chemicals. Increased proliferation occurs either by direct mitogenesis, such as by high doses of propoxur, or by cellular toxicity and consequent regenerative hyperplasia, such as occurs with formation of calculi by chemicals like uracil, or by processes involving more subtle cytotoxicity, such as following high doses of sodium saccharin or arsenic. We successfully demonstrated the mode of action of sodium saccharin and related sodium salts. Based on our investigations, it is unlikely that these pose a carcinogenic hazard to humans. Studies with these salts involve various aspects of toxicology, basic chemistry, cell kinetics, electron microscopy, pathology, in vitro and in vivo bioassays, renal physiology and molecular biology. These findings led to the delisting of saccharin from the National Toxicology Program's List of Carcinogens.

More recently we have investigated the bladder carcinogenicity of dimethylarsinic acid (DMA), an organic arsenical, in a rat model and in cell culture. DMA and its metabolites are non-DNA reactive, but DMA in the diet produces urothelial necrosis with consequent regeneration. Urotholial cytotoxicity is produced in vitro at less than 1 mM concentration of arsenite and 1 mM DMAIII. Urinary levels of DMAIII following carcinogenic doses of DMA suggest that it may be critical to the urothelial toxicity in vivo. The relationship to growth factors, receptors, and cell cycle control mechanisms is being evaluated.

Education and Training

National Activities