Analysis of genotoxicity and the carcinogenic mode of action forortho-phenylphenol

Abstract

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.

Induction of mitosis delay, apoptosis and aneuploidy in human cells by phenyl hydroquinone, an Ames test-negative carcinogen

“…OPP and its hepatic metabolite PHQ can produce urinary bladder hyperplasia and tumors (Hiraga and Fujii, 1984) but do not cause DNA damage or gene mutations and are therefore typical of non-genotoxic carcinogens (Brusick, 2005). Many chemicals considered carcinogenic are categorized as non-genotoxic carcinogens (Duesberg and Rasnick, 2000).…”

“…PHQ does not generate γ-H2AX foci Previously, it was reported that PHQ neither binds nor cleaves DNA in vitro and in vivo (Brusick, 2005;Reitz et al, 1983). Moreover, some reports suggested that PHQ causes DNA damage (Tayama and Nakagawa, 1994;Nakagawa and Tayama, 1996;Murata et al, 1999).…”

“…The mechanism by which OPP/PHQ causes tumorigenesis remains unclear. Unlike other carcinogens, OPP and PHQ are non-mutagenic in most simple gene mutation assays (Brusick, 2005). In addition, OPP neither binds to nor cleaves DNA in vivo and in vitro (Brusick, 2005;Reitz et al, 1983), but a dose-dependent binding to protein in OPP-treated rats was observed (Reitz et al, 1984;Kwok et al, 1999).…”

“…Its widespread use means considerable potential for occupational and consumer exposure. Toxicological studies on the effects of OPP and its hepatic metabolite, phenyl hydroquinone (PHQ), showed increases in the incidence of urinary bladder tumors in rats exposed through diet (Hiraga and Fujii, 1984;Niho et al, 2002;Brusick, 2005). The mechanism by which OPP/PHQ causes tumorigenesis remains unclear.…”

“…Unlike other carcinogens, OPP and PHQ are non-mutagenic in most simple gene mutation assays (Brusick, 2005). In addition, OPP neither binds to nor cleaves DNA in vivo and in vitro (Brusick, 2005;Reitz et al, 1983), but a dose-dependent binding to protein in OPP-treated rats was observed (Reitz et al, 1984;Kwok et al, 1999). On the other hand, some reports suggested that PHQ produces oxidative DNA damage (Tayama and Nakagawa, 1994;Murata et al, 1999).…”