Biomedical subjects

S Tamano

Publications and source records attributed to S Tamano.

At least 19 recordsLinked to original sources

PubMed2005

A ninety-day oral toxicity study of a new type of processed gum arabic, from Acacia tree (Acacia senegal) exudates, in F344 rats.

This study was designed to evaluate and characterize any subchronic toxicity of a new type of gum arabic (SUPER GUM [Acacia(sen)SUPER GUM]), a naturally processed polysaccharide exudate from gum acacia trees (Acacia senegal), when administered to both sexes of F344 rats at dietary levels of 0 (control), 1.25%, 2.5%, and 5.0% (10 rats/sex/group). During the study, the treatment had no effects on clinical signs, survival, body weights, and food and water consumption, or on findings of urinalysis, ophthalmology, hematology, or blood biochemistry. Gross pathology and histopathology exhibited no differences of toxicological significance between control and treated rats. Increased relative cecum (filled) weights, evident in both sexes of 5.0% group and females of 1.25% and 2.5% groups, were considered to be a physiological adaptation. Thus, the results indicated the toxic level of SUPER GUM to be more than 5.0%, and the no observed adverse effect level (NOAEL) was concluded to be 5.0% (3,117 mg/kg body weights/day for males, and 3,296 mg/kg body weights/day for males) from the present study.

Administration, Oral↗

PubMed2005

A 90-day oral toxicity study of beta-carotene derived from Blakeslea trispora, a natural food colorant, in F344 rats.

A subchronic oral toxicity study of beta-carotene derived from Blakeslea trispora, a natural food colorant, was performed with groups of 10 male and 10 female F344 rats fed the agent at dietary levels of 0%, 0.2%, 1.0% and 5.0% for 90 days. There were no treatment-related adverse effects with regard to body weight, food and water consumption, urinalysis, ophthalmology, hematology, serum biochemistry, and organ weight data. On clinical observation, red coloring of fur was noted in both sexes of the 1.0% and 5.0% group rats, with red feces observed in all treated group animals, and necropsy revealed all rats of the treated groups to have reddish coloration of the contents of the gastro-intestinal tract, due to the pigmentation and thus lacking toxicological significance. On histopathological examination, sporadic spontaneous lesions known to occur in this strain of rats were the only findings, with no specific relation to the test substance. Thus, the no-observed-adverse-effect-level (NOAEL) was judged to be a dietary level of at least 5.0% (3127 mg/kg body weight/day for males, 3362 mg/kg body weight/day for females) for beta-carotene derived from B. trispora under the present experimental conditions.

Animals↗

PubMed2005

Thirteen-week feeding study of thaumatin (a natural proteinaceous sweetener), sterilized by electron beam irradiation, in Sprague-Dawley rats.

This study was designed to evaluate and characterize any subchronic toxicity of thaumatin sterilized by electron beam irradiation (5.0 kGy) when administered at dietary levels of 0% (control), 0.3%, 1.0% and 3.0% to groups of 10 male and 10 female Crj: CD (SD) IGS rats for 13 weeks. Separate groups of both sexes received 3.0% non-irradiated thaumatin. There were no treatment-related clinical signs or adverse effects on the survival rate, body weight, food consumption, water consumption and urinalysis, ophthalmology, haematology, or blood biochemistry data. No treatment-related alterations in gross pathology or organ weights were found in any group. On histopathological examination, sporadic spontaneous lesions known to occur in this strain of rats were the only findings, with no specific relation to the test substance. Thus, the no-observed-adverse-effect-level (NOAEL) was judged to be a dietary level of at least 3.0% (2502 mg/kg body weight/day for males, 2889 mg/kg body weight/day for females) for electron beam irradiated thaumatin under the present experimental conditions. It was concluded that electron beam-irradiation of thaumatin does not cause changes of any toxicological significance.

Administration, Oral↗

PubMed2003

A thirteen-week oral toxicity study of annatto extract (norbixin), a natural food color extracted from the seed coat of annatto (Bixa orellana L.), in Sprague-Dawley rats.

A subchronic oral toxicity study of annatto extract (norbixin), a natural food color, was conducted. Groups of 10 male and 10 female Sprague-Dawley rats were fed annatto extract at dietary levels of 0, 0.1, 0.3 and 0.9% for 13 weeks. There were no treatment-related adverse effects on body weight, food and water consumption, ophthalmology and hematology data. Blood biochemical analysis revealed changes in rats of both sexes confined to the 0.9% and 0.3% groups, including increased alkaline phosphatase, phospholipid, total protein, albumin and albumin/globulin ratio. Marked elevation in absolute and relative liver weights was also found in both sexes of the 0.9% and 0.3% groups, but not the 0.1% group. Hepatocyte hypertrophy was evident and an additional electron microscopic examination demonstrated this to be linked to abundant mitochondria after exposure to a dietary level of 0.9% annatto extract for 2 weeks. Thus, the No-Observed-Adverse-Effect-Level (NOAEL) was judged to be a dietary level of 0.1% (69 mg/kg body weight/day for males, 76 mg/kg body weight/day for females) of annatto extract (norbixin) under the present experimental conditions.

Administration, Oral↗

PubMed2001

Pronounced inhibition by a natural anthocyanin, purple corn color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in male F344 rats pretreated with 1,2-dimethylhydrazine.

The potential of purple corn color (PCC), a natural anthocyanin, to modify colorectal carcinogenesis was investigated in male F344/DuCrj rats, initially treated with 1,2-dimethylhydrazine (DMH), receiving 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet. After DMH initiation, PCC was given at a dietary level of 5.0% in combination with 0.02% PhIP until week 36. No PCC-treatment-related changes in clinical signs, body weight and food consumption were found. Incidences and multiplicities of colorectal adenomas and carcinomas in rats initiated with DMH were clearly increased by PhIP. In contrast, lesion development was suppressed by PCC administration. Furthermore, in the non-DMH initiation groups, induction of aberrant crypt foci by PhIP tended to be decreased by the PCC supplementation. The results thus demonstrate that while PhIP clearly exerts promoting effects on DMH-induced colorectal carcinogenesis, these can be reduced by 5.0% PCC in the diet, under the present experimental conditions.

1,2-Dimethylhydrazine↗

PubMed2001

Epoprostenol sodium, a prostaglandin I2, lacks tumor promoting effects in a medium-term liver carcinogenesis bioassay in rats.

Potential modifying effects of epoprostenol sodium administration on liver carcinogenesis were investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine (DEN). Two weeks after a single dose of DEN (200 mg/kg, intraperitoneally), rats daily received subcutaneously epoprostenol sodium at doses of 0, 1, 10 and 100 microg/kg, or were fed phenobarbital sodium (PB) at a dietary level of 500 parts per million (ppm) as positive control for 6 weeks. All animals were subjected to partial hepatectomy at week 3, and were killed at week 8. Prominent flushing of extremis and signs of behavioural depression occurred after injection and lasted for 1 h in rats given 100 microg/kg epoprostenol sodium. Such clinical signs were slight in rats treated with 10 microg/kg, but not observed with 1 microg/kg. Marked decrease in body weight gain was noted in rats given 100 microg/kg. Statistically significant changes in relative liver weights were not found in any group given the test chemical. Epoprostenol sodium did not significantly increase the quantitative values for glutathione S-transferase placental form (GST-P) positive liver cell foci observed after DEN initiation, in clear contrast to the positive control. The results thus demonstrate that epoprostenol sodium lacks modifying potential for liver carcinogenesis in our medium-term bioassay system.

Animals↗

PubMed2001

Lack of chemopreventive effects of lycopene and curcumin on experimental rat prostate carcinogenesis.

The chemopreventive efficacy of lycopene and curcumin with regard to prostate carcinogenesis was investigated using 3,2'-dimethyl-4-aminobiphenol (DMAB)- and 2-amino-1-methylimidazo[4,5-b]pyridine (PhIP)-induced rat ventral prostate cancer models. Three 60 week experiments with male F344 rats were carried out. In the first DMAB was given for the first 20 weeks and lycopene or curcumin were administered concomitantly or subsequently at dietary doses of 15 and 500 p.p.m., respectively. In the second experiment lycopene and curcumin were given to rats pretreated with DMAB at doses of 5, 15 or 45 p.p.m. or 100 or 500 p.p.m. In the third PhIP was selected as an initiator for prostate carcinogenesis and administered for 20 weeks. Rats were then fed a diet containing lycopene at a dose of 45 p.p.m. or curcumin at a dose of 500 p.p.m. or both together. Chemopreventive effects of lycopene and curcumin on development of DMAB-induced ventral prostate carcinomas were observed only in the first experiment and no confirmation of inhibition potential was obtained in the following studies. Neither summational nor synergistic chemoprevention was evident. It is concluded from the present data that, overall, neither lycopene nor curcumin can consistently prevent rat prostate carcinogenesis.

Aminobiphenyl Compounds↗

PubMed2001

Organ dependent enhancement of rat 3,2'-dimethyl-4-aminobiphenyl (DMAB) carcinogenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): positive effects on the intestine but not the prostate.

In order to evaluate tumor enhancing effects of the heterocyclic carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), doses of 100 and 300 p.p.m. PhIP were given for 40 weeks to male F344 rats, which initially received 3,2'-dimethyl-4-aminobiphenyl (DMAB). DMAB shows a similar carcinogenic organ spectrum to that of PhIP, including the prostate and colon. PhIP alone at a dose of 300 p.p.m. resulted in the development of prostate and intestine cancers. Furthermore, among the DMAB-treated group, enhancement of intestinal carcinogenesis by 300 p.p.m. PhIP was observed. However, no prostate enhancement was demonstrated in the DMAB + PhIP group. Since PhIP-DNA adduct formation in the prostate epithelial cells in a satellite experiment was not affected by pre-treatment with DMAB, it is speculated that the contradictory findings between the intestine and prostate may be due to the specific biological effects of PhIP. Taking into account previous data, that PhIP clearly enhanced rat 1,2-dimethylhydrazine-initiated colon tumorigenesis, the potential of PhIP to enhance colon carcinogenesis may be initiator dependent.

Aminobiphenyl Compounds↗

PubMed2001

Beef tallow, but not perilla or corn oil, promotion of rat prostate and intestinal carcinogenesis by 3,2'-dimethyl-4-aminobiphenyl.

The modifying effects of three kinds of fat (corn oil, beef tallow or perilla oil, each at 20% in the diet) on F344 rat prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) were investigated. Non-invasive carcinomas of the ventral prostate were induced by DMAB alone and invasive carcinomas of the other prostate lobes and seminal vesicles by DMAB and testosterone propionate (TP). Eight groups of F344 rats were initiated with 50 mg / kg body weight of DMAB at 2-week intervals for the first 20 weeks, four also receiving TP, extended until week 60. The animals received basal chow powder diet or one of three high fat diets throughout the experiment (60 weeks). One further group served as a non-carcinogen-treated control maintained on basal chow powder diet. Beef tallow significantly increased the development of ventral prostate carcinomas with DMAB alone (from 15 to 45%, P < 0.05), while perilla oil reduced the incidence of prostatic intraepithelial neoplasia (PIN) in the ventral lobe of rats given DMA + TP (from 70 to 10%, P < 0.01), but not in those given DMAB alone. No other effects of high fats were observed regarding PIN or invasive cancers of the dorsolateral and anterior prostate or seminal vesicles. A satellite experiment demonstrated that all high fat diets for 4 weeks increased the 5-bromo-2-deoxyuridine (BrdU) labeling index of prostate epithelial cells, suggesting that a high fat intake, irrespective of the fatty acid composition, may accelerate cell kinetics in the prostate. Of the three high fat diets, beef tallow was also found to increase intestinal carcinogenesis. Thus, the present data revealed carcinogenesis in the prostate and intestine to be promoted by beef tallow.

Aminobiphenyl Compounds↗

PubMed2000

Inhibitory effects of low doses of melatonin on induction of preneoplastic liver lesions in a medium-term liver bioassay in F344 rats: relation to the influence of electromagnetic near field exposure.

We have previously reported that exposures of F344 male rats to both 900 MHz and 1.5 GHz electro-magnetic near fields (EMFs) results in slightly decreased numbers and areas of glutathione S-transferase (GST-P)-positive liver foci, liver preneoplastic lesions in rats, in a medium-term liver bioassay (K. Imaida, M. Taki, T. Yamaguchi, T. Ito, S. Watanabe, K. Wake, A. Aimoto, Y. Kamimura, N. Ito, T. Shirai, Lack of promoting effects of the electromagnetic near-field used for cellular phones (929.2 MHz) on rat liver carcinogenesis in a medium-term liver bioassay, Carcinogenesis 19 (1998) 311-314; K. Imaida, M. Taki, S. Watanabe, Y. Kamimura, T. Ito, T. Yamaguchi, N. Ito, T. Shirai, The 1.5 GHz electromagnetic near-field used for cellular phones does not promote rat liver carcinogenesis in a medium-term liver bioassay, Jpn. J. Cancer Res. 89 (1998) 995-1002.). In both experiments, the melatonin serum levels were significantly decreased in both 900 MHz and 1.5 GHz exposed groups as compared with sham-exposed control group values. Therefore, changes of serum melatonin levels may modify the development of preneoplastic lesions in the livers of rats exposed by EMF. In order to clarify this question, the effects of different doses of melatonin (1, 5, 10 and 20 ppm in the drinking water) were analyzed in the same bioassay system employed for our previously reported EMF exposure studies. Six-week-old male F344 rats were given a single dose of diethylnitrosamine (DEN, 200 mg/kg b.w., i.p.). Starting 2 weeks later, they were treated with 0, 1, 5, 10 and 20 ppm melatonin in their drinking water for 6 weeks. Melatonin treatment were performed only during the night (between 18:00 to 09:00) in order to maintain their circadian rhythm, since serum melatonin levels are high at midnight. At week 3, all rats were subjected to a two-thirds partial hepatectomy. At week 8, the experiment was terminated and the animals were sacrificed. Serum hormone levels of melatonin, adrenocorticotropic hormone (ACTH), corticosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone at this time point were measured, only the first being elevated, while LH and testosterone were reduced. Although clear dose dependence was not apparent, both numbers and areas of GST-P-positive foci in the liver were decreased in the melatonin treated groups, this being significant for numbers in the 10 ppm melatonin group. Comparison of the current results with the previously reported findings for EMF exposure experiments, suggests that increase in melatonin serum levels is a possible reason for the associated tendency for decreased preneoplastic hepatocyte foci development.

Adrenocorticotropic Hormone↗

PubMed2000

Lobe specific effects of testosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced rat prostate carcinogenesis.

We have previously shown that chronic administration of a pharmacological dose of testosterone propionate (TP) after treatment with the carcinogen, 3,2'-dimethyl-4-aminobiphenyl (DMAB), results in development of invasive and metastatic adenocarcinomas arising from the dorso-lateral and anterior prostate, as well as the seminal vesicles. Co-administration of ethinyl estradiol (EE) with TP increased the yield of carcinomas in the lateral and anterior lobes. In the present experiment, male F344 rats were treated with DMAB for 20 weeks and then co-administered a pharmacological dose of TP together with various doses of EE for 40 weeks. Without hormone(s) administration, carcinomas were confined to the ventral prostate and all were of intra-acinar type. TP administration suppressed development of the ventral prostate carcinomas but caused invasive carcinomas of the lateral and anterior lobes and of seminal vesicles and intra-acinar carcinomas in the dorsal prostate. The appearance of carcinomas in the lateral and anterior prostate was increased by co-administration of EE in a dose-related fashion but carcinomas of the seminal vesicles were inversely reduced. The suppressive influence of TP on ventral carcinoma development was overcome by only the highest dose of EE. It is concluded that estrogen can modify the enhancing effects of TP on induction of rat prostate and seminal vesicle carcinomas in a dose-related fashion with lobe specificity.

Aminobiphenyl Compounds↗

PubMed2000

Experimental prostate carcinogenesis - rodent models.

A number of rodent models of prostate carcinoma development have been established to study mechanisms and modifying potential. All except for transgenic mouse models need long experimental periods for generation of a high yield of cancers. Spontaneous prostate tumor models, while not practical in terms of time and tumor incidences, allow the natural course of multistep neoplasia to be followed without a need for chemical exposure. Carcinogens, especially in combination with testosterone, can induce prostate carcinomas in rats, but none are prostate-specific, so that tumor development in other organs is a complicating factor. Induction of invasive prostate carcinomas in the rat frequently requires long-term administration of a pharmacological dose of testosterone with or without application of a chemical carcinogen. While there are several transgenic mouse models, each also has strong and weak points, and it is therefore necessary to select the best model for the purpose of any experimental study.

Aminobiphenyl Compounds↗

PubMed1999

Non-carcinogenicity, but dose-related increase in preneoplastic hepatocellular lesions, in a two-year feeding study of phenobarbital sodium in male F344 rats.

Phenobarbital sodium (PB) was administered at dietary levels of 0 (control), 8, 30, 125 and 500 ppm to groups of 20 male F344/DuCrj rats for 104 weeks. There were no treatment-related clinical signs or adverse effects on survival rate, body weights, food consumption, and haematology or blood biochemistry data. Statistically significant increases of relative liver weights were found in the 500 and 125 ppm, but not the 30 and 8 ppm groups. Quantitative analysis of glutathione S-transferase placental form positive (GST-P+) hepatocyte foci/areas revealed clear increases limited to the 500 and 125 ppm groups. Western blotting revealed CYP2B1, 2C6 and 3A2 proteins to be also increased only with these high doses. In addition, significant increase of regenerative hepatocellular hyperplasias was noted in the 500 ppm group. No hepatocellular adenomas were observed, but a hepatocellular carcinoma arose in single rats of the 8 ppm and 125 ppm groups. No treatment-related changes were found in any other organs or tissues. Thus, under the experimental conditions used, the highest dose of PB (500 ppm) was not carcinogenic in male F344 rats. Furthermore, increase in putative preneoplastic proliferative hepatocytic lesions was only noted with 500 and 125 ppm.

Administration, Oral↗

PubMed1999

Organ-dependent modifying effects of caffeine, and two naturally occurring antioxidants alpha-tocopherol and n-tritriacontane-16,18-dione, on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary and colonic carcinogenesis in female F344 rats.

Modifying effects of caffeine, alpha-tocopherol, and n-tritriacontane-16,18-dione (TTAD) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary and colonic carcinogenesis were investigated in female F344 rats. Groups of 20 rats, 6 weeks old, were given 0.02% PhIP (in diet) alone, or together with 0.1% caffeine (in drinking water), 0.5% alpha-tocopherol (in diet) or 0.1% TTAD (in diet) for up to 54 weeks. Groups of 10 females receiving basal diet or one of the test chemicals without PhIP supplementation were also maintained. The final combined incidences (adenomas plus adenocarcinomas) and multiplicity (No./rat) of mammary adenomas and adenocarcinomas were significantly lowered in the PhIP plus caffeine group (10%, 0.10) as compared to the PhIP alone value (40%, (1.50). Incidences of mammary tumors in the PhIP plus alpha-tocopherol or TTAD groups tended to be decreased while their multiplicities were significantly lowered. With regard to colon tumor development, on the other hand, rats given PhIP plus caffeine exhibited an elevated incidence (75% versus 15% in the control), whereas alpha-tocopherol and TTAD had no effect. Surprisingly, metabolic activation of PhIP was inhibited by addition of caffeine in an in vitro assay. The results indicate that caffeine exerts a potent chemopreventive action against PhIP-induced mammary carcinogenesis, but acts as a co-carcinogen for PhIP-induced colonic carcinogenesis.

Adenocarcinoma↗

PubMed1999

Dose-dependent induction of carcinomas and glutathione S-transferase placental form negative eosinophilic foci in the rat liver by di(2-ethylhexyl)phthalate after diethylnitrosamine initiation.

The dose-dependence of di(2-ethylhexyl)phthalate (DEHP) hepatocarcinogenicity was investigated in male F344 rats which were initially injected with diethylnitrosamine (200 mg/kg, i.p.) and subjected to partial hepatectomy at week 3. The animals were administered DEHP in the diet at concentrations of 30, 300, 3,000, or 12,000 ppm starting 2 weeks after the DEN injection for up to 46 weeks and killed at weeks 8, 24, 48 and 52. Additional groups were given clofibrate (3,000 ppm in diet) or basal diet instead of the DEHP diet. Incidences of hepatocellular carcinomas were 75% (9/12, P < 0.01) for 12,000 ppm, 10% (1/10) for 3,000 ppm, 7% (1/14) for 300 ppm, 0% (0/13) for 30 ppm, 15% (2/13) for clofibrate, and 8% (1/13) for the basal diet group at week 52, 4 weeks after cessation of chemical feeding. Development of glutathione S-transferase placental form (GST-P) positive foci was only slightly increased by clofibrate-administration at week 52 and consistently lower than the control level in the DEHP-treated groups after 24 weeks. In contrast, GST-P negative eosinophilic foci were dose-dependently increased in the more than 300 ppm DEHP and clofibrate treated groups. At the 30 ppm dose level, however, no morphological changes were apparent in the liver. Thus, the non-observed effect level regarding the promotional activity of hepatocarcinogenesis was demonstrated at 30 ppm, the effects being predictable on the basis of development of GST-P negative eosinophilic foci.

Adenoma, Liver Cell↗

PubMed1998

Immunohistochemical demonstration of carcinogen-DNA adducts in tissues of rats given 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): detection in paraffin-embedded sections and tissue distribution.

A polyclonal antibody against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts was raised for their immunohistochemical demonstration in paraffin-embedded sections. Specificity of this antibody was confirmed by competitive ELISA. Positive signals were immunohistochemically detected in acetone-fixed but not in formalin- or ethanol-fixed sections from F344 rats treated by gavage with a single dose of PhIP at 37.5-300 mg/kg and killed at 1, 2, and 7 days thereafter. Dose-dependent positive staining was observed in almost all organs of both sexes, including the colon, prostate, and mammary gland but largely independent of the tumor response. Repair activity, judged by disappearance of adducts with time, differed according to the organ or cell type. One exception was hepatocytes, the liver incidentally being a nontarget organ. The results suggest that the generated antibody is applicable for detection of cells targeted by PhIP in paraffin-embedded sections and also for the investigation of the mechanisms of PhIP-carcinogenesis.

Administration, Oral↗

PubMed1998

Variation in susceptibility to the induction of forestomach tumours by butylated hydroxyanisole among rats of different strains.

The forestomach carcinogenicity of butylated hydroxyanisole (BHA) was compared in males of the F344, SHR, Lewis and Sprague Dawley rat strains. Groups of 30 6-wk-old animals were given a pellet diet containing 2% BHA for 104 wk. Forestomach squamous cell papillomas and hyperplasias developed in all rats given BHA, independent of the strain, but the incidences of squamous cell carcinomas (SCCs) differed considerably: F344, 26.7% (8/30) SHR, 76.7% (23/30) SD, 36.7% (1130) Lewis, 6.7% (2/30). Cytotoxic effects, reflected by inflammation, were also most severe in the SHR strain, correlating well with the development of SCCs. The present results indicate that major strain differences exist regarding BHA rat forestomach carcinogenesis and that sensitivity to cytotoxicity might be an important parameter.

Animals↗

PubMed1998

Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4-methoxyphenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi-organ carcinogenesis model.

The carcinogenicity of low dietary levels of the antioxidants butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and catechol, known to target the forestomach or glandular stomach, were examined alone or in combination in a 2-year long-term experiment and their modifying effects assessed in a medium-term multiorgan model. In the carcinogenicity study, groups of 30-31 male F344 rats were treated with 0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol either alone or in combination for up to 104 weeks and then killed. In the medium-term multi-organ model, groups of 10 to 15 male F344 rats were given diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or 0.032% were administered in the diet either alone or in combination after completion of the initiation regimen. All surviving animals were killed at the end of week 28, and major organs were examined histopathologically. In the carcinogenicity study, slightly increased incidences of forestomach papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%), catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet (0%), and a significant increase was observed with the five antioxidants in combination (42.9%, P < 0.001). In a medium-term multiorgan carcinogenesis model, incidences of forestomach papillomas and/or carcinomas were increased in each high dose group, but additive or synergistic effects were not found in the combination group. In the low dose case, the incidence of forestomach papillomas was significantly increased only in the combination group. With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group. The results indicate that even at low dose levels phenolic compounds can exert additive/synergistic effect on carcinogenesis.

Animals↗