Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis.

Melnick, Ronald L.; Kohn, Michael C.; Portier, Christopher J.

doi:10.1289/ehp.96104s1123

Cited by 95 publications

(56 citation statements)

References 98 publications

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“…DCB is a nongenotoxic agent (Loeser and Litchfield, 1983;NTP, 1987;Steinmetz et al, 1988), which appears to produce an additive hyperplasia in rodent liver and a regenerative hyperplasia in male rat kidney. While increased cell proliferation has been implicated in the formation of tumors in rodents by various classes of nongenotoxic carcinogens (Loury et al, 1987;Butterworth, 1991;Cohen and Ellwein, 1991;Grasso and Hinton, 1991;Ames et al, 1993;Lake, 1995;Cunningham, 1996;Lake and Grasso, 1996), a correlation between increased cell replication and carcinogenesis is not always observed (Melnick and Huff, 1993;Melnick et al, 1996). In the present study replicative DNA synthesis was increased in both species after acute DCB treatment, whereas in the NTP bioassay DCB produced liver tumors only in the mouse.…”

Section: Discussioncontrasting

confidence: 48%

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

1997

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The effects of 1,4-dichlorobenzene (DCB) have been compared in male F344 rats given 0 (corn oil control), 25, 75, 150, and 300 mg/kg DCB and male B6C3F, mice given 0 (corn oil control), 300, and 600 mg/kg DCB by daily oral gavage five days per week for 1,4, and 13 weeks. The two highest rat and both mouse dose levels were the same as those employed in a NTP bioassay, where DCB produced kidney tumors in male rats and liver tumors in mice. DCB produced significant dose-related increases in relative liver weight in both the rat and the mouse which was associated with, respectively, mild and marked centrilobular hypertrophy. Administration of DCB also produced a sustained induction of microsomal cytochrome P450 content and 7-pentoxyresorufin O-depentylase activity in both species. Western immunoblotting studies demonstrated that DCB induced CYP2B isoenzyme(s) in both rat and mouse liver microsomes. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2'-deoxyuridine in study Weeks 0-1, 3-4, and 12-13. In the rat hepatocyte labeling index values were only increased in animals given 300 mg/kg DCB for 1 week, whereas hepatocyte labeling index values were significantly increased in mice given 300 and 600 mg/kg DCB for 1 and 4 weeks. DCB treatment produced significant increases in rat renal Pi/P 2 proximal tubule cell labeling index values at all time points, whereas little effect was observed in mouse kidney. The observed species difference in DCB-induced liver tumor formation may reflect the greater sensitivity of the mouse to tumor promotion by a CYP2B inducer. For the kidney, the present data provides further evidence that while DCB-induced a 2 irglobulin nephropathy is associated with a sustained stimulation of cell replication in male rat renal proximal tubule cells, this effect is not observed in the male mouse, o 1997 Soda? of Toxicology.1,4-Dichlorobenzene (DCB; CAS 106-46-7) is a volatile organic solid used as a space deodorant, a moth repellent, and as an intermediate in organic syntheses (NTP, 1987). Studies into the metabolism of DCB have indicated that the 'To whom correspondence should be addressed. Fax: 44-(0)181-661-7029.major metabolites are the glucuronide and sulfate conjugates of 2,5-dichlorophenol (Azouz et al., 1955;Hawkins et al, 1980;Klos and Dekant, 1994). Human hepatic cytochrome P450 isoenzymes which can metabolize DCB to 2,5-dichlorophenol include CYP1A2 and CYP2E1 (Bogaards et al, 1995). Studies into the acute toxicity of DCB and its isomers have demonstrated that 1,2-dichlorobenzene is more toxic to rat and mouse liver and to rat kidney than 1,3-dichlorobenzene and DCB (Allis et al, 1992;Valentovic et al., 1993;Umemura et al., 1996).DCB is considered to be a nongenotoxic agent as demonstrated by results of a number of short-term tests for mutagenic and genotoxic potential (Loeser and Litchfield, 1983; NTP, 1987;Steinmetz et al, 1988). The carcinogenicity of DCB has been evaluated in a 2-year study in F344 rats and B6C3F, mice (NTP, 1987). DCB was administere...

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Section: Discussioncontrasting

confidence: 48%

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

1997

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“…Exposure to phenobarbital, benzene, asbestos, and arsenic even without the previous application of initiator agents leads to neoplasic development (Melnick et al 1996, Trosko 2001). This contradiction has two possible explanations: either the genotoxic effect was not identified by mutagenicity and genotoxicity assays, or the initiated cells emerged spontaneously.…”

Section: Promotionmentioning

confidence: 99%

Chemical carcinogenesis

Oliveira

Colaço

Chaves

et al. 2007

An. Acad. Bras. Ciênc.

137

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The use of chemical compounds benefits society in a number of ways. Pesticides, for instance, enable foodstuffs to be produced in sufficient quantities to satisfy the needs of millions of people, a condition that has led to an increase in levels of life expectancy. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. There are three stages involved in chemical carcinogenesis. These are defined as initiation, promotion and progression. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair -i.e. mutations in proto-oncogenes and tumour suppressing genes. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals.

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“…Increased cell proliferation, as indicated by proliferating cell nuclear antigen (PCNA) immunohistochemistry, was confirmed in the gastric mucosa of ferrets experimentally infected with H. mustelae, which mimics H. pylori gastritis in humans (31). (14), and it has been suggested that a process favoring cell proliferation and survival over cell death may drive the carcinogenic process (2 (Table I). The incidences of disease (studies with H. hepaticus-related hepatitis) in Studies A-E are given in Table I.…”

Section: Introductionmentioning

confidence: 95%

Alteration in Cell Kinetics in Control B6C3F1 Mice Infected with Helicobacter hepaticus

et al. 1997

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Implications for risk assessment of suggested nongenotoxic mechanisms of chemical carcinogenesis.

Abstract: 123-134 (1996)

Cited by 95 publications

References 98 publications

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

Comparison of the Hepatic and Renal Effects of 1,4-Dichlorobenzene in the Rat and Mouse

Chemical carcinogenesis

Alteration in Cell Kinetics in Control B6C3F1 Mice Infected with Helicobacter hepaticus

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