Mechanisms of Carcinogenesis of the Fungicide and Rat Bladder Carcinogen o-PhenylphenolEPA Grant Number: R826408
Title: Mechanisms of Carcinogenesis of the Fungicide and Rat Bladder Carcinogen o-Phenylphenol
Investigators: Eastmond, David A.
Institution: University of California - Riverside
EPA Project Officer: Hahn, Intaek
Project Period: May 1, 1998 through April 30, 2001
Project Amount: $404,943
RFA: Exploratory Research - Human Health (1997) RFA Text | Recipients Lists
Research Category: Health Effects , Human Health , Health
Ortho-Phenylphenol (OPP) and its sodium salt, sodium ortho- phenylphenate (SOPP) are widely used broad spectrum fungicides and antibacterial agents. For example, OPP is among the 10 most commonly used home and garden pesticides and SOPP is commonly used as a postharvest treatment for citrus fruits. Animal bioassays have shown that OPP and SOPP are highly effective in causing bladder cancer in male F344 rats. Understanding the mechanisms underlying OPP-induced bladder carcinogenesis is critical to determine whether tumors observed at high doses in rats pose significant risks to humans exposed to much lower levels. At the present time the mechanisms of reactive species formation, as well as the nature and identity of the molecular targets responsible for the initial events in urinary bladder carcinogenesis are not well understood. Furthermore, the mechanisms underlying the sex- and species differences in the carcinogenic effects of OPP are unknown. The overall objective of this program is to elucidate critical mechanisms in OPP-induced bladder carcinogenesis by (1) identifying early biochemical and genetic biomarkers relevant to rat bladder carcinogenesis, (2) determining the dose-response relationship between biomarkers and carcinogenesis, (3) studying mechanisms of reactive species generation from the primary OPP metabolite, henylhydroquinone (PHQ), and (4) determining the mechanisms underlying the sex and species differences of OPP-induced bladder cancer.
This research project will employ a number of recently developed cytogenetic techniques including the modified micronucleus assay, fluorescence in situ hybridization with DNA probes, and bromodeoxyuridine incorporation, as well as complementary analytical methods including accelerator mass spectrometry, and HPLC equipped with electrochemical detection. These endpoints will be used to study the relationships between dose and various genetic, biochemical, and chemical events relevant to the early stages of OPP-induced bladder carcinogenesis. The biomarkers developed will then be applied to determine the major mechanism(s) of reactive species formation in vivo. The role of PHQ and the relative importance of reactive species production via enzymatic and non-enzymatic oxidation of this compound will be assessed in vivo through the modulating effects of enzyme inhibitors and conditions known to affect the biochemistry and chemistry PHQ oxidation. Lastly, the sex and species differences in OPP-induced bladder tumorigenicity will be studied by comparing the critical biomarkers identified in the susceptible male F344 rats to similar biomarkers in the relatively resistant female rats and in the mouse which does not develop bladder cancer following exposure to OPP.
The experimental data obtained will provide valuable mechanistic information on OPP-induced rat bladder carcinogenesis which will allow a more accurate mechanistic based risk assessment to be performed to assess the risks associated with low level human exposure to this widely used chemical.