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Germ-free rats colonised with a human intestinal flora were fed diets containing high risk (HR) or low risk (LR) factors for colorectal cancer, and putative biomarkers were evaluated in the colonic mucosa; (i) proliferation, (ii) 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci and (iii) DMH-induced DNA damage. The HR diet was high in fat (45% of calories) and low in calcium and fibre, reflecting levels characteristic of typical western diets. The LR diet was low in fat (<5% of calories), and high in calcium and fibre. The nutrient/energy ratio of the two diets were similar. Mucosal crypt cell proliferation, assessed after microdissection, was higher on the LR diet (mean number of mitoses per crypt was 2.65 on the LR diet, and 1.62 on the HR diet; P < 0.05). Aberrant crypt foci (ACF) were assessed in the mucosa 12 weeks after DMH treatment. On the HR diet there were significantly more small ACF with 1 and 2 crypts per focus, but fewer ACF with 3, 5 and 7 or more crypts per focus. There was no significant difference in total ACF or the total number of crypts. The effect of diet on DNA damage in the colon was assessed in vivo by the comet assay. Animals were fed a HR or LR diet for 12 weeks before treatment with DMH or saline. For carcinogen-treated animals, DNA damage was significantly higher in colon cells from animals on the HR diet. On the LR diet both DNA damage and the induction of small ACF were reduced despite an increase in cell proliferation. The increase in large ACF on the LR diet may be attributable to elevated crypt cell proliferation possibly increasing crypt fission rates.

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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