Analysis of genotoxicity and the carcinogenic mode of action for ortho-phenylphenol.
Ortho-phenylphenol (OPP) and its sodium salt (SOPP) are commercial products that have wide human exposure and have been shown in several studies to be rodent carcinogens. Genetic toxicology data were assessed in an attempt to understand the carcinogenic mode of action of OPP and SOPP. More than 130 studies were evaluated to determine if OPP, SOPP, or any of their enzymatic or nonenzymatic breakdown products react directly with DNA to induce mutation, changes in chromosome structure or number, DNA repair, or nonspecific DNA damage including strand breakage or covalent binding. The genotoxicity databases for OPP and SOPP are not only large but heterogeneous, requiring weight-of-evidence methods to arrive at a conclusion regarding their genotoxic properties and potential. Evidence derived from the available studies leads to the conclusion that study results showing OPP/SOPP directly interacting with DNA are equivocal. Clastogenicity was the most consistent type of genetic toxicity produced by OPP/SOPP (and their break-down products) and was consistently associated with other intracellular preneoplastic toxicity produced at super-threshold concentrations. The weight of evidence from the combined database supports the hypothesis that OPP/SOPP-induced DNA damage is a threshold-dependent response associated with target tissue toxicity, most likely induced by their breakdown products phenylhydroquinone and phenylbenzoquinone. It is possible that this threshold-dependent clastogenicity could contribute to the carcinogenic mode of action for OPP or SOPP.
Brusick
David
D
Covance Laboratories, Vienna, Virginia 22182, USA. david.brusick@covance.com
D016227:Benzoquinones; D001713:Biphenyl Compounds / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D015197:Carcinogenicity Tests; D004247:DNA / Q000187:drug effects*; D018736:DNA Adducts / Q000187:drug effects; D004249:DNA Damage; D016208:Databases, Factual; D006873:Hydroquinones; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D009154:Mutation / Q000187:drug effects; D018675:Toxicity Tests
D016227:Benzoquinones; D001713:Biphenyl Compounds; D018736:DNA Adducts; D006873:Hydroquinones; D009153:Mutagens; C029322:phenylbenzoquinone; D004247:DNA; C004369:2-phenylphenol; C066330:phenylhydroquinone