Our environment is a sea of chemicals composed of hundreds and thousands of chemicals with great diversity of pharmacological function and structure. Human populations are therefore generally exposed simultaneously to numbers of toxicants, including complex mixtures of chemicals of unknown and variable origin at low doses, some of which are carcinogens and some of which are non-carcinogens. Exposure may occur in different ways and interactions between multiple chemicals acting simultaneously or sequentially in humans are a very important issue for carcinogenic risk assessment and management. Experimental data demonstrate that at very low doses, summation or synergistic enhancement of carcinogenesis is unlikely, particularly in cases of non-genotoxic carcinogens. In this review, we would like to present published data on summation and/or synergistic effects of carcinogens, dependent on the dose applied.

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T-2 toxin is a cytotoxic fungal secondary metabolite produced by various species of Fusarium. This paper reviews the reported data about the development and/or mechanisms of T-2 toxin-induced apoptosis in the hematopoietic, lymphoid and gastrointestinal tissues, dorsal skin and fetal tissues of mice and rats. Apoptosis occurs earlier in hematopoietic tissues than in lymphoid tissues, and moreover there is a difference among lymphocyte populations in the susceptibility to T-2 toxin. C-fos plays an important role in the early phase of T-2 toxin-induced apoptosis in hematopoietic and lymphoid tissues through mobilization of [Ca²⁺]_i and the PKC-dependent pathway, but not through Fas/Fasligand or p53-related pathways. In the gastrointestinal tract, apoptosis develops earlier in the small intestine than in the stomach, and is more prominent in the small intestine than in the large intestine. In the dorsal skin topically treated with T-2 toxin, epidermal basal cell proliferating activity is first suppressed due to the elevated TGF-β₁ expression, and then basal cell apoptosis develops concomitantly with the elevation of c-fos, c-jun and TNF- α mRNAs expression. In the fetuses, T-2 toxin-induced apoptosis is mainly observed in the central nervous and skeletal systems. In the fetal brain, T-2 toxin induces oxidative stress, followed by activation of the MAPK-JNK-c-Jun pathway, finally resulting in apoptosis. The TNF receptor pathway may also be involved in T-2 toxin-induced apoptosis in the fetal brain. Thus, the development and mechanisms of T-2 toxin-induced apoptosis differ somewhat depending on the tissues affected.

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To examine potential variations in sensitivity of F344 rats from different breeders to carcinogens, groups of forty 6-week-old males from CLEA Inc., SLC Co., USA Charles River Co., and Japan Charles River Co. were initially given a single dose (200 mg/kg) of diethylnitrosamine (DEN) i.p., and 2 weeks later, they were given phenobarbital (PB) at a dose of 500 ppm. in the diet for 6 weeks and then sacrificed; all rats being subjected to two-thirds partial hepatectomy (PH) at week 3. Numbers and areas per cm² of preneoplastic lesions, glutathione S-transferase placental form (GST-P) positive foci in the liver in this Ito test, were increased significantly in PB treated rats from all breeders compared with the corresponding control groups given DEN alone. The number of GST-P positive foci in animals from CLEA Japan, however, increased more than in rats from the other breeders. Assessment with Affymetrix Rat Genome 230 2.0 cDNA microarrays, revealed common changes in expression of genes between treated and control group rats from all sources. Hierarchical cluster analysis revealed the gene expression pattern to be quite similar for rats from USA Charles River Co. and Japan Charles River Co. Although the differences are very subtle, sensitivity of F344 rats to carcinogens may vary depending on breeders.

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Epidemiological studies have shown a significant inverse association between intake of COX inhibitors and the risk of colorectal cancer. The present study was conducted to determine whether SC560 (a COX-1 selective inhibitor), NS398 (COX-2 selective), SC58125 (COX-2 selective), nimesulide (COX-2 selective) and indomethacin (COX non selective), might exert chemopreventive influence on diethylnitrosamine (DEN) initiated hepatocarcinogenesis in a medium-term liver carcinogenesis bioassay in F344 male rats. Contrary to expectation, in the SC58125 treated group, the numbers and areas of glutathione S-transferase placental form (GST-P) positive liver cell foci were increased significantly, along with liver weights. In the other groups no significant changes were evident. Histopathologically, liver cells of SC58125 treated rats showed hypertrophy similar to cases with phenobarbital treatment. For further clarification, Experiment 2 was performed. After 2 weeks on test chemicals and basal diet, animals underwent histopathological, microarray and quantitative RT-PCR assessment. CYP 2B1 and 3A1 were found to be induced, again similar to phenobarbital cases. Although COX-2 selective inhibitors are clearly good candidates for chemoprevention, it is necessary to examine them carefully for any adverse toxic effects at the whole body level before considering their application as chemopreventive agents.

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Exposure to theophylline, a phosphodiesterase (PDE) inhibitor, increases the basophilic basal part and conspicuous nucleoli in salivary acini. These histological findings imply increased gene expression. The purpose of this study was to examine the effect of theophylline on the expression of representative genes in the salivary glands which are regulated by cyclic AMP. Male F344 rats received saline or theophylline (50 mg/kg) intraperitoneally. Parotid and submaxillary glands were isolated from rats at 4, 8, and 24 h post-administration, and gene expression for the principal secretory proteins, amylase 1 (AMY1) and cystatin S (CysS), dominant PDE subfamilies 3A and 4D, and a water channel, aquaporin 5 (AQP5) were quantified by RT-PCR. The cyclic AMP concentration was determined by enzyme-immunoassay. Theophylline exposure resulted in a transient increase in mRNA expression for AMY1 in the parotid gland, CysS in the submaxillary gland, and PDE3A in both salivary glands. The cyclic AMP concentration was elevated in both glands. PDE4D and AQP5 gene expressions were not altered in either gland. Our results suggest that theophylline induces cyclic AMP signals through PDE inhibition, leading to enhanced gene transcription and subsequent histological changes.

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Sequential changes in the levels of DNA synthesis in urinary bladder epithelium following administration of a rat tumor promoter, sodium L-ascorbate (Na-AsA) for 8 weeks were examined. Male 6-week-old F344 rats were allocated into 4 groups, and given powdered basal diet containing Na-AsA at concentrations of 0 (control), 1.25, 2.5 or 5.0%. The 5-bromo-2'-deoxyuridine (BrdU) labeling index in bladder epithelium in the treated groups increased at week 1, but returned to low levels between weeks 2 and 6, and increased at week 8 once again, essentially with dose dependency. The epithelium of the urinary bladder appeared normal at weeks 1 and 2, but slight simple hyperplasia was observed at weeks 4, 6 and 8 with a dose-dependent response. Our results demonstrate that the early DNA synthesis induced in the rat bladder epithelium by Na-AsA is biphasic in nature.

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