Urinary Physiologic and Chemical Metabolic Effects on the Urothelial Cytotoxicity and Potential DNA Adducts ofo-Phenylphenol in Male Rats

Smith, Raymond A.; Christenson, W. R.; Bartels, Michael; Arnold, Lora L.; John, Margaret St.; Cano, Martín; Garland, Emily M.; Lake, Stephen G.; Wahle, B.S.; McNett, Debra A.; Cohen, Samuel M.

doi:10.1006/taap.1998.8435

Cited by 26 publications

(19 citation statements)

References 40 publications

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“…As the epithelium is merely eroded, not ulcerated, there is no hemorrhage or in ammatory reaction. This super cial cytotoxicity can be produced either directly by the administered chemical or a metabolite, as with orally administered orthophenylphenol (30), by the formation of the calcium phosphate-containing precipitate generated by administration of high doses of sodium salts to rats (31), or by the generation of various types of microcrystals (22,23). The sodium salts include such chemicals as saccharin, chloride, bicarbonate, ascorbate, glutamate, aspartate, and a variety of other chemicals which are essential to viability or are 668 COHEN TOXICOLOGIC PATHOLOGY produced as intermediary metabolites (31).…”

Section: Other Bladder Lesions In Rodentsmentioning

confidence: 99%

Comparative Pathology of Proliferative Lesions of the Urinary Bladder

Cohen

2002

Toxicol Pathol

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Bladder neoplasia in humans consists of 2 diseases, a low-grade papillary tumor that does not invade or metastasize, and a high-grade lesion that usually invades and metastasizes. Bladder carcinogenesi s in rats is most like the low-grade, papillary tumor, although it eventually does progress and invade. In the mouse, models are available that mimic each of these disease processes. Preneoplastic lesions in humans and rodents include various types of hyperplasia, proliferative cystitis, and dysplasia. These preneoplasti c and neoplastic lesions arise throughou t the urothelium, from the renal pelvis to the urethra, although most commonly in the bladder. Rarely, benign and malignant mesenchymal lesions occur in rats and mice, with a unique submucosa l mesenchyma l lesion present in some strains of mice. In addition, eosinophilic and clear inclusions in the super cial layer of urothelium in mice, which do not appear to be associated with toxicity or carcinogenesis , have been reported. An approach to evaluation of carcinogenic mechanisms involved in the urothelium is presented. It focuses on distinguishing between DNA reactive carcinogen s vs those that act by increasing cell proliferation. Although rodent models do not precisely mimic the human disease, they have provided useful models for furthering our understandin g of the carcinogenic process in the urothelium as it pertains to human diseases.

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Section: Other Bladder Lesions In Rodentsmentioning

confidence: 99%

Comparative Pathology of Proliferative Lesions of the Urinary Bladder

Cohen

2002

Toxicol Pathol

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“…A single adduct spot was found in the bladder DNA of all six treated rats but was not present in control rat DNA. However, a virtually identical 13-week study conducted by Smith et al [1998] with OPP did not find any evidence that DNA adducts were induced in F344 rat urinary bladder tissue. Kwok et al…”

Section: In Vitro and In Vivo Systems Detecting Covalent Dna Adductsmentioning

confidence: 70%

“…Both 14 C-labeling and 32 P-postlabeling methods were used to identify DNA adducts in vivo. No adducts were found in rat liver DNA [Grether et al, 1989a] or rat urinary bladder DNA [Reitz et al, 1983;Christenson et al, 1996;Smith et al, 1998;Kwok et al, 1999] following dietary or oral gavage administration of OPP up to carcinogenic dose levels. Reitz et al [1983] failed to find evidence of DNA adducts in liver tissue of Fisher rats exposed to SOPP at 500 mg/kg by oral gavage.…”

Section: In Vitro and In Vivo Systems Detecting Covalent Dna Adductsmentioning

confidence: 95%

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

Brusick

2005

Environ. Mol. Mutagen.

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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.

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“…These rats were maintained on a powdered basal diet—Oriental M (Oriental Yeast Co., Tokyo). In contrast, in a study conducted by Dow Chemical Company for regulatory submission [Wahle and Christenson, ; Smith et al, ], the rats were fed Purina Mills Rodent Lab chow 5001‐4 in “etts” form with reported urinary pH values of >7.4 in both control and OPP‐treated male F344 rats. Experiments in our laboratory have also shown that different batches of the same dietary formulation from the same distributor can produce substantial changes in urinary pH in both controls and OPP‐treated male F344 rats.…”

Section: Discussionmentioning

confidence: 99%

“…o ‐Phenylphenol (OPP), a widely used fungicide and antibacterial agent, has been found to cause cancer in the urinary bladder of male F344 rats [Hiraga and Fujii, ; Fujii et al, ; Wahle and Christenson, ; Smith et al, ] and concerns have been raised about its potential health risks to humans [USEPA, 2006]. A better understanding of OPP's mechanism of action will allow risk assessors to make more reliable estimates of its carcinogenic risks.…”

Section: Introductionmentioning

confidence: 99%

The role of urinary pH in o‐phenylphenol‐induced cytotoxicity and chromosomal damage in the bladders of F344 rats

Balakrishnan

Hasegawa

Eastmond

2016

Environ and Mol Mutagen

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o-Phenylphenol (OPP) is a widely used fungicide and antibacterial agent that at high doses has been shown to cause bladder cancer in male F344 rats. The mechanisms underlying OPP-induced bladder carcinogenicity remain unclear but it has been proposed that a non-enzymatic pH-dependent autoxidation of phenylhydroquinone (PHQ), a primary metabolite of OPP, may be a key step in OPP-induced rat bladder carcinogenesis. To investigate this mechanism and to provide insights into the potential human health relevance of OPP-induced cancer, a series of in vitro and in vivo experiments were conducted. In human lymphoblastoid TK-6 cells and rat bladder epithelial NBT-II cells, strong increases in cytotoxicity were seen at a constant concentration of PHQ by increasing the buffer pH as well as by increasing concentrations of PHQ at a constant pH. In in vivo studies, male rats were administered OPP (4,000 and 8,000 ppm) in a diet supplemented with either 1% ammonium chloride or 3% sodium bicarbonate to produce acidic and alkaline urinary pH, respectively. Significant increases in cell proliferation as detected by 5-bromo-2'-deoxyuridine incorporation and micronucleus formation were seen in the bladder cells of OPP-treated rats with neutral or alkaline urinary pH but not in animals with the acidified urine. The results from these in vitro and in vivo studies provide support for the autoxidation hypothesis of bioactivation, and provide additional evidence that urinary pH can significantly influence the genotoxicity and carcinogenicity of this important agent.

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Urinary Physiologic and Chemical Metabolic Effects on the Urothelial Cytotoxicity and Potential DNA Adducts ofo-Phenylphenol in Male Rats

Cited by 26 publications

References 40 publications

Comparative Pathology of Proliferative Lesions of the Urinary Bladder

Comparative Pathology of Proliferative Lesions of the Urinary Bladder

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

The role of urinary pH in o‐phenylphenol‐induced cytotoxicity and chromosomal damage in the bladders of F344 rats

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