Fukuronori (Gloiopeltis furcata) extract: 90-day dietary toxicity study in F344 rats

Fukuronori extract (FE), which is mainly composed of polysaccharides, and is an extract of the seaweed Gloiopeltis furcata, is permitted for use as a food thickening agent by the Ministry of Health and Welfare, Japan. In order to study the subchronic toxicity of FE, F344 rats of both genders were administered FE at concentrations of 0% (basal diet, control group), 0.5%, 1.5% and 5.0% in basal powder diet for 90 days, and observation of general condition, recording of body weight and food consumption, examination of hematology and blood chemistry, measurement of organ weight, and pathological examination were performed. Food consumption tended to increase in both sexes given FE at 1.5% and 5.0% throughout most of the experimental period. This was, however, considered not to be a toxic effect because the differences in body weight were small. Total cholesterol and triglycerides in serum decreased significantly (p < 0.05) and not significantly, respectively, in males of the 5.0% group. These changes were considered to be related to the intake of FE, but the differences were slight and within physiological ranges. Hematological and pathological examination revealed neither any particular adverse effect nor any significant difference from the control. Hence, dietary intake of 5.0% of FE, 3,362 mg/kg/day for males and 3,594 mg/kg/day for females as mean daily intake, for 90 days was considered to be a no observable adverse effect level in rats.     

Gymnema sylvestre leaf extract: a 52-week dietary toxicity study in Wistar rats

A 52-week study of oral-repeated-dose toxicity for the extraction powder of Gymnema sylvestre (GS), Indian-native genus, Metaplexis japonica, was conducted in both genders of Wistar rats. The rats were administered a graded dose of GS at 0.01, 0.10 and 1.00% of basal powder diet, along with a group fed solely with the basal powder diet without GS, for 52 weeks. General conditions were recorded daily. Body weights and food consumptions were recorded weekly up to 12 weeks, and thereafter at longer intervals. At 26 weeks, for an intermediate examination, and 52 weeks, for the final examination, animals were subjected to hematology, serum chemistry, and pathological examination. None of the animals died in the period up to 52 weeks. No exposure-related changes in body-weight, in the food consumption, in the hematological examinations, or in the serum biochemical examinations were recognized. No histopathological alterations were seen. Thus, it was concluded that there was no toxic effect in rats treated with GS at up to 1.00% in the diet for 52 weeks. The no-observable-effect level from this study is 1.00% GS, i.e., 504 mg/kg/day for male and 563 mg/kg/day for female as mean daily intake, for 52 weeks.     

A 52-week feeding study of genetically modified soybeans in F344 rats

A chronic feeding study to evaluate the safety of the genetically modified glyphosate-tolerant soybeans (GM soybeans) was conducted using rats. F344 DuCrj rats were fed diet containing GM soybeans or Non-GM soybeans at the concentration of 30% in basal diet. Non-GM soybeans were closely related strain of GM soybeans. These two diets were adjusted to an identical nutrient level. In this study, the influence of GM soybeans on rats was compared with that of the Non-GM soybeans, and furthermore, to assess the effect of soybeans themselves, the groups of rats fed GM and Non-GM soybeans were compared with a group fed commercial diet (CE-2). General conditions were observed daily and body weight and food consumption were recorded. At the intermediate examination (26 weeks), and at the termination (52 weeks), animals were subjected to hematology, serum biochemistry, and pathological examination. There were several differences in animal growth, food intake, serum biochemical parameters and histological findings between the rats fed the GM and/or Non-GM soybeans and the rats fed CE-2. However, body weight and food intake were similar for the rats fed the GM and Non-GM soybeans. Gross necropsy findings, hematological and serum biochemical parameters, organ weights, and pathological findings showed no meaningful difference between rats fed the GM and Non-GM soybeans. These results indicate that long-term intake of GM soybeans at the level of 30% in diet has no apparent adverse effect in rats.     

A 104-week feeding study of genetically modified soybeans in F344 rats

A chronic feeding study to evaluate the safety of genetically modified glyphosate-tolerant soybeans (GM soybeans) was conducted using F344 DuCrj rats. The rats were fed diet containing GM soybeans or Non-GM soybeans at the concentration of 30% in basal diet. Non-GM soybeans were a closely related strain to the GM soybeans. These two diets were adjusted to an identical nutrient level. In this study, the influence of GM soybeans in rats was compared with that of the Non-GM soybeans, and furthermore, to assess the effect of soybeans themselves, the groups of rats fed GM and Non-GM soybeans were compared with a group fed commercial diet (CE-2). General conditions were observed daily and body weight and food consumption were recorded. At the termination (104 weeks), animals were subjected to hematology, serum biochemistry, and pathological examinations. There were several differences in animal growth, food intake, organ weights and histological findings between the rats fed the GM and/or Non-GM soybeans and the rats fed CE-2. However, body weight and food intake were similar for the rats fed the GM and Non-GM soybeans. Gross necropsy findings, hematological and serum biochemical parameters, and organ weights showed no meaningful difference between rats fed the GM and Non-GM soybeans. In pathological observation, there was neither an increase in incidence nor any specific type of nonneoplastic or neoplastic lesions in the GM soybeans group in each sex. These results indicate that long-term intake of GM soybeans at the level of 30% in diet has no apparent adverse effect in rats.     

Antioxidant effects of flavonoids used as food additives (purple corn color, enzymatically modified isoquercitrin, and isoquercitrin) on liver carcinogenesis in a rat medium-term bioassay

To clarify the effects of purple corn color, enzymatically modified isoquercitrin (EMIQ), and isoquercitrin (IQ), registered as natural food additives in Japan, on liver carcinogenesis in vivo, a medium-term bioassay was employed. A total of 100 male F344 rats were divided into 5 groups; groups 1 to 4 were given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg b.w.) on day 1. From weeks 2 to 8, they were administered basal diet purple corn color, EMIQ, or IQ as containing test chemicals at doses of 1.0% (groups 1 and 5), 0.1% (group 2), 0.01% (group 3), or 0% (group 4) (experiments 1, 4, and 5). All rats were subjected to two-thirds partial hepatectomy at week 3 and were sacrificed at week 8. Purple corn color exerted no significant modifying effects on GST-P positive foci, preneoplastic foci, development in the liver. However, serum of rats treated with purple corn color provided evidence of antioxidant power significantly by potential antioxidant (PAO) test in vivo (experiment 2). And microarray analyses showed purple corn color to induce RNA expression such as P450 (cytochrome) oxidoreductase, phosphatidylinositol 3-kinase, and phospholipase A2 (experiment 3). Higher doses of EMIQ or IQ with strong antioxidant power in vivo by PAO test treated groups were correlated with smaller numbers of GST-P positive foci, with Spearman's rank correlation coefficients of P= 0.002 and P= 0.049, respectively (experiments 4 and 5). Therefore, the tested food additives may be effective as antioxidants in vivo and have chemopreventive potential against liver preneoplastic lesion development.     

Promotion potential of madder color in a medium-term multi-organ carcinogenesis bioassay model in F344 rats

ABSTRACT:  A medium-term multi-organ carcinogenesis bioassay in rats was conducted to assess any possible tumor promoting effects of madder color extracted from the root of madder. Male F344 rats were divided into 5 groups of 20 each. All rats of groups 1 to 4 were given DMD treatment, consisted of multicarcinogens, N-nitrosodiethylamine (DEN), N-methyl-N-nitrosourea (MNU), and N-bis (2-hydroxypropyl) nitrosamine (DHPN), for 4 wk, while group 5 served as untreated control without carcinogens. The animals were then administered a basal diet containing madder color at doses of 5.0% (group 1), 2.5% (group 2 with 0.75% additional dextrin), or 0 (groups 3 with 1.5% additional dextrin, 4 without dextrin and 5) for the following 28 wk (total 32 wk). The total amount of dextrin in groups 1 to 3 diets was adjusted to 1.5% by extra dextrin because madder color powder contained dextrin. Key organs were observed histopathologically and glutathione S-transferase placental form (GST-P) positive foci of the liver were quantified. In the liver, 5.0% and 2.5% treated groups showed statistically significant dose-related increases in both number and area of GST-P positive foci, number: 2.81 ± 0.90 and 1.96 ± 0.93 (groups 1 and 2), area: 0.99 ± 2.49 and 0.37 ± 0.77, as compared with control, number: 0.87 ± 0.72, area: 0.06 ± 0.06 (group 3). In the kidneys, incidences (and numbers) of adenoma treated with 5.0% and 2.5%, 47.4% (0.20 ± 0.24), and 47.4% (0.13 ± 0.15) (groups 1 and 2) were significantly increased compared to control, 0% (0) (group 3). In conclusion, madder color demonstrated significant tumor promoting effects in the liver and kidneys in the DMD model.     

Ninety-day dietary toxicity study of mulberry leaf extract in rats

Mulberry leaf extract was studied toxicologically in male and female SD rats. The extract was administered orally at concentrations of 0% (control group), 0.1%, 0.4% and 1% in basal diet for 90 days. No remarkable change in test animals of both sexes was observed in terms of body weight gain or at necropsy. Hematology and blood chemistry revealed no abnormalities. Pathological examination revealed no toxic change in any organ observed. These findings indicate that dietary intake of 1% mulberry leaf extract for 90 days (884.5 mg/kg/day for males and 995.7 mg/kg/day for females as mean daily intake) causes no toxicological change in rats.     

Oral Toxicological Studies of Pueraria Flower Extract: Acute Toxicity Study in Mice and Subchronic Toxicity Study in Rats

Kudzu has been widely used as an herbal medicine in China. The root of the kudzu is also well known as an antipyretic and analgesic in treatment of the common cold, while its flower has been used to treat alcohol intoxication, alcohol abuse, and dysentery. Pueraria flower extract (PFE) is a hot water extract derived from the flower of the kudzu, Pueraria thomsonii Benth. (Fabaceae), oral intake of which exhibits anti‐obesity properties in mice and humans. In this study, we conducted acute and subchronic toxicity studies for an evaluation of safety. In the acute study, PFE (5 g/kg body weight) was orally administered to ddY mice. For 14 d after administration, no deaths or abnormal changes were observed in general signs, body weight (BW), or food consumption, and no abnormal findings were observed in the major organs and tissues of either males or females at necropsy. The oral LD₅₀ of PFE was therefore estimated to be higher than 5 g/kg BW. In the subchronic study, PFE was mixed into the diet in place of powdered CRF‐1 and administered at concentrations of 0% (control), 0.5%, 1.5%, and 5.0% to male and female Sprague–Dawley rats for 90 d. No mortality or toxicological changes were observed during the experimental period. Blood biochemical, hematological, and urinary parameters revealed no toxicologically significant changes. Furthermore, no anatomical or histopathological changes due to PFE were observed. The no‐observed adverse‐effect‐level of PFE was thus estimated to be 5.0% in the diet (male: 3.0 g/kg BW/d; female: 3.5 g/kg BW/d).     

Absence of adverse effects of sodium metabisulphite in manufactured biscuits: results of subacute (28-days) and subchronic (85-days) feeding studies in rats

Sulphites are extensively used in the food and drinks industry. Their toxicity has been previously evaluated by addition to the diet or drinking water of laboratory animals. Because interactions between sulphites and food constituents occur, the present work was conducted to determine the subacute and subchronic toxicity of sulphite-bound compounds in a finished product: manufactured biscuits. The studies were performed on Sprague Dawley rats for 28 and 85 days of dietary exposure. Diets were prepared from sulphited or untreated (controls) biscuits with the addition of sugar, protein, vitamins and minerals according to the nutritional requirements of the animals. Groups of 10 male and 10 female rats were administered diets containing sulphited biscuits at levels of 0, 10, 35 and 75%, corresponding to 10-15, 35-45, 150-170 and 310- 340mg S0₂/kg diet. In both studies, no death or clinical abnormalities were reported. Growth rate, food consumption and food conversion efficiency were not affected by treatment. No dose-related changes were observed for haematology, clinical chemistry, ocular examination, renal-function, urinalysis, organ weights or gross and microscopic examinations. The liver concentrations of vitamins A, B₁, C and E were not significantly changed except for an increase in vitamin E in high-dose males after 28 days' exposure. Based on these data, the no-observed-adverse-effect level (NOAEL) of sulphites in baked biscuits was judged to be 310mg SO₂/kg diet or 25mg/kg body weight/day.     

Investigations on the metabolism and potentially adverse effects of ethoxyquin dimer, a major metabolite of the synthetic antioxidant ethoxyquin in salmon muscle

The feed additive ethoxyquin (EQ) is a commonly used synthetic antioxidant preservative in animal feeds. In farmed Atlantic salmon fillets, EQ residues are present, both as the parent compound and as EQ derivatives. One of the main EQ derivates in fish muscle is an ethoxyquin dimer (EQDM), and the potential toxicity of this metabolite is not known. The aim of this study was to evaluate the metabolism and potentially toxicological effects of EQDM. A 90-day subchronic exposure study with repeated dietary exposure to EQDM at 12.5 mg/kg of body weight per day was performed with male F344 rats. Hepatic Cyp1a1 mRNA was significantly reduced to <3% of the control in rats fed EQDM, and hepatic Cyp2b1 mRNA was increased to 192%. EQDM increased Gstpi1 mRNA expression to 144% that of the control, but the activity level of this phase II enzyme was reduced. Biomarkers of liver and kidney function did indicate adverse effects of EQDM when F344 rats were fed 12.5 mg/kg of body weight per day. The present study revealed that EQDM produces responses that are comparable to those produced by the parent compound (EQ) in terms of activating the same enzyme systems.     

Butyric acid modulates activities of intestinal and renal disaccharidases in experimentally induced diabetic rats

To elucidate the effect of feeding of butyric acid on disaccharidase activities, the specific activities of the disaccharidases were measured in the intestinal mucosa and kidney cortex of control and diabetic rats. Diabetes was induced in rats using streptozotocin. Rats were fed with basal diet containing wheat bran (5%) as a source of insoluble dietary fiber and guar gum (2.5%) as a source of soluble dietary fiber. The experimental group received butyric acid at 250, 500 and 750 mg/kg body weight/day. Increased activities of intestinal maltase, sucrase and lactase in diabetic rats were significantly reduced in fiber-fed diabetic group. Supplementation of butyric acid at 500 mg/kg body weight/day showed a further decrease in their activities. The activity of disaccharidases in renal tissue was decreased in diabetic rats and was significantly improved in fiber-fed diabetic group. Butyric acid feeding at 500 mg/kg body weight/day showed further improvement in their activities.     

Establishment of animal model for elucidating the mechanism of intoxication by the poisonous mushroom Clitocybe acromelalga

Dietary intake of a poisonous mushroom, Clitocybe acromelalga, causes acromelalgia. The symptom continues for over a month. Some papers reported that treatment with nicotinic acid is effective. We have established an animal model to elucidate the mechanism of toxicity of the poisonous mushroom Clitocybe acromelalga. Diet containing Clitocybe acromelalga was fed to niacin-deficient rats for 24 hours (designated as day 0). The food intake decreased to about one-half compared with that of day before, and body weight loss was noted. Although the diet was returned to the control diet on day 1, the food intake did not recover until day 7, and body weight gain was not seen until day 6. A severe symptom resembling acromelalgia in humans started to appear on day 3. This is the first report of an animal model for the intoxication of Clitocybe acromelalga in humans. Since no similar symptom resembling human intoxication was seen in a previous rodent study, the niacin-free/tryptophan-limited diet used in the present study may have contributed to the result.     

Toxicologic evaluation of sucrose carbonic acid esters in basic subchronic feeding studies in rats. 2. Effect of sucroacetoglycerides]

Groups of male and female rats received a sucroacetoglycerides containing product (SAG) for 3 months at dietary levels of 0, 2.5, 5 and 10%. Food consumption was initially increased in females at all SAG-levels. After two weeks significant increases in food intake were observed in males and females fed 10% SAG throughout the feeding period. The serum analysis revealed significantly elevated activity in serum alkaline phosphatase at the highest SAG-level in males and females after 6 weeks and in females after 13 weeks. Histological changes related to the SAG-feeding were noted in the intestinal lymph nodes of male and female animals fed 10% SAG. The no-adverse effect level established in this subchronic feeding study was 5% SAG in the diet of rats, equivalent to a daily intake of 3.6 g/kg body weight in males and 4.0 g/kg in females.     

甜叶菊苷M的毒理学安全性评价

甜叶菊苷M是在甜叶菊中发现的糖苷类物质,已被确定为一种潜在的甜味剂。本研究依据食品安全国家标准,采用小鼠急性经口毒性试验、Ames试验、小鼠骨髓红细胞微核试验、小鼠精母细胞染色体畸变试验和28 d经口毒性试验对甜叶菊苷M进行了安全性评价。结果显示:甜叶菊苷M对雌雄小鼠急性经口MTD值均大于10000 mg/kg·bw,属实际无毒级;Ames试验、小鼠骨髓红细胞微核试验和小鼠精母细胞染色体畸变试验均为阴性;将样品以2000、1000和500 mg/kg的设计剂量掺入基础饲料中喂养大鼠28 d后,各剂量组雌雄动物的体重、摄食量、食物利用率、血液学、血生化和组织病理学等指标与对照组相比无明显异常。样品对雌、雄大鼠未观察到有害作用剂量(NOAEL)分别为2650和2421 mg/kg·bw t。研究结果表明,甜叶菊苷M未见急性毒性、遗传毒性和短期毒性,具有较高的食用安全性。     

铁摄入过量对大鼠胚胎发育影响的实验研究

目的:铁过量可使机体氧化应激水平增强,引起损伤器官组织,但对胚胎正常发育有无影响尚不明确,本文探索铁摄入过量对雌性大鼠胚胎发育的影响。方法:雌性Wistar大鼠60只随机分成5组,分别饲喂含不同剂量铁的饲料:C1组(低铁组):每天铁摄入量为约1.67mg/kg体重;C2组(正常剂量组):每天铁摄入量约为7mg/kg体重;C3组(3倍高剂量组):每天铁摄入量约为21mg/kg体重;C4组(9倍高剂量组):每天铁摄入量约为63mg/kg;C5组(27倍高剂量组):每天铁摄入量约为189mg/kg体重。6周后,雌鼠、雄鼠以2∶1比例合笼交配,次日早晨作阴道涂片,查到精子者定为妊娠第0d,怀孕雌鼠妊娠第20d称重后,麻醉、剖取胎鼠,检查胎鼠的一般状况、死胎数、吸收胎数、外观畸形数、着床数、胚胎体长、尾长、胎重,胎盘重等,制作胎鼠内脏和骨骼标本,检查内脏与骨骼的情况。结果:胎鼠出生情况检查显示,不同铁剂量组胎鼠体表颜色随铁剂量增加而逐渐变深,低铁组胎鼠颜色较苍白,正常剂量组淡红(正常),C3组较红润、C4组深红、C5组紫红;生长情况分析发现,3个高剂量组胎鼠的胎重、体长、尾长和胎盘重量随铁剂量的增加而下降;与正常剂量组比较,胎重分别降低了13.3%、16.7%和17.2%(P值均0.05);体长分别减少了3.8%、9.7%和10.0%,(P值均0.05);尾长分别降低了3.6%、7.9%和5.0%(P值均0.05);胎盘重分别降低了21.2%、23.1%和26.9%(P值均0.05);同时发现,3个高剂量组胎鼠与正常剂量组比较,吸收胎数、椎骨色黑率、内脏出血率有所增加,在9倍和27倍铁组吸收胎数增加显著(P0.05),分别升高了5.88%和5.97%;椎骨色黑率增加显著(P0.05),分别升高了12.7%和12.9%;内脏出血率3个高剂量铁组均增加显著(P0.05),分别升高了16%、27%和39%,随铁摄入量的增加而升高。结论:雌鼠摄入过量铁可使胎鼠体色变深,摄入超过正常量3倍的铁,可增加死胎、吸收胎甚至胚胎畸形的机率,因此过量铁的生殖毒性应引起关注。     

Type of cottonseed and level of gossypol in diets of lactating dairy cows: plasma gossypol,health, and reproductive performance

Objectives were to determine effects of altering gossypol intake by feeding whole linted Upland (WUP) or a 1:2 blend of WUP and cracked Pima (BUPCP) cottonseed on plasma gossypol (PG) concentrations, reproduction, and health of Holstein cows. Cows, 813, on three dairy farms were assigned to one of two diets starting at 13 +/- 11 d in milk for a 170-d experiment. Diets contained 717 and 951 mg of free gossypol/kg of dry matter from WUP and BUPCP, respectively. Concentrations of PG, as well as the proportion of total gossypol (TG) as the minus isomer were higher for cows fed BUPCP vs cows fed WUP. Conception rate at the first postpartum artificial insemination did not differ between treatments. However, cows consuming the higher gossypol diet had reduced subsequent conception rates and a lower pregnancy rate. Incidence of abortions increased in the higher gossypol diet, and cows that aborted or remained open had higher PG concentrations. Increasing PG concentrations resulted in reduced conception rates and extended days open. The probability of conception after the first artificial insemination declined at a decreasing rate as the plasma TG increased. Incidence of health disorders were unaffected by gossypol intake and PG concentrations. Similarly, gossypol intake and PG concentrations had no effect on culling or mortality. Six cows died in each diet, and none had postmortem signs compatible with gossypol toxicity. Consumption of a high gossypol diet for 170 d had no effect on health of lactating dairy cows, but it increased PG concentrations and impaired reproductive performance.     

3种功能食品原料提取物毒性研究及安全性评价

目的 研究3种功能食品原料(红景天、五味子和蜂花粉)醇/醇水提取物毒性并评价其安全性。方法 利用小鼠急性毒性实验、遗传毒性实验(小鼠骨髓细胞微核实验、雄性小鼠精子畸形实验)和大鼠30 d喂养实验对3种提取物的毒性进行考察。结果 小鼠对红景天、五味子和蜂花粉提取物的最大耐受量都大于20 g/(kg?bw);3种提取物在遗传毒性实验均呈阴性反应;给予大鼠5.0 g/(kg?bw)红景天、五味子、蜂花粉提取物(分别相当于成人日推荐量250倍、250倍、500倍)连续灌胃30 d,大鼠生长正常,无中毒症状、异常症状和死亡,各试食组动物体重、进食量、饲料利用率、血常规指标、常见血液生化指标、脏器重量以及病理组织学等指标与阴性对照组比较,无毒性反应。结论 红景天、五味子、蜂花粉提取物属无毒物质,无遗传毒性和长期毒性。本研究为以红景天、五味子和蜂花粉提取物为原料的功能食品开发和应用提供了一定的安全性依据。     

Addition of glycerol to lactating cow diets stimulates dry matter intake and milk protein yield to a greater extent than addition of corn grain

The objective of this study was to determine if the addition of glycerol to the diet of dairy cows would stimulate milk protein yield in the same manner as the addition of corn grain. Twelve multiparous lactating dairy cows at 81 ± 5 d in milk were subjected to 3 dietary treatments in a replicated 3 × 3 Latin square design for 28-d periods. The diets were a 70% forage diet considered the basal diet, the basal diet with 19% ground and high-moisture corn replacing forages, and the basal diet with 15% refined glycerol and 4% added protein supplements to be isocaloric and isonitrogenous with the corn diet. Cows were milked twice a day and samples were collected on the last 7 d of each period for compositional analysis. Within each period, blood samples were collected on d 26 and 27, and mammary tissue was collected by biopsy on d 28 for Western blot analysis. Dry matter intake increased from 23.7 kg/d on the basal diet to 25.8 kg/d on the corn diet and 27.2 kg/d on the glycerol diet. Dry matter intake tended to be higher with glycerol than corn. Milk production increased from 39.2 kg/d on the basal diet to 43.8 kg/d on the corn diet and 44.2 kg/d on the glycerol diet. However, milk yield did not differ between corn and glycerol diets. Milk lactose yields were higher on the corn and glycerol diets than the basal diet. Milk fat yield significantly decreased on the glycerol diet compared with the basal diet and tended to decrease in comparison with the corn diet. Mean milk fat globule size was reduced by glycerol feeding. Milk protein yield increased 197 g/d with addition of corn to the basal diet and 263 g/d with addition of glycerol, and the glycerol effect was larger than the corn effect. The dietary treatments had no effects on plasma glucose concentration, but plasma acetate levels decreased 27% on the glycerol diet. Amino acid concentrations were not affected by dietary treatments, except for branched-chain amino acids, which decreased 22% on the glycerol diet compared with the corn diet. The decreases in plasma acetate and branched-chain amino acid concentrations with glycerol and the larger effects of glycerol than corn on milk protein and fat yields suggest that glycerol is more glucogenic for cows than corn grain.     

Effect of a polyglucosamine on the body weight of male rats: Mechanisms of action

Polyglucosamine (PG) is a low-molecular-weight chitosan (125 kDa) mixed with vitamin C and tartaric acid in standardised proportions. The aim of this study was to determine its effect on the body weight of male rats and clarify the mechanism of action. Three groups of 12 young male rats were fed a standard diet, or a diet containing PG (1% or 2%), for nine weeks. Body weight, food and water intake, and total cholesterol and triglyceride levels were measured before and at the end of treatment; low-density (LDL) and high-density lipoproteins (HDL), the amount of faeces, and their lipid, glucose and acetate content were also measured at the end of treatment.     

Functional and proliferative effects of repeated low‐dose oral administration of furan in rat liver

Scope: Furan, a food contaminant formed during heat processing, induces hepatocellular tumors in rodents and high incidences of cholangiocarcinomas in rats even at the lowest dose (2 mg/kg b.w.) administered. Initial estimates suggested that human intake of furan may be as high as 3.5 μg/kg b.w./day, indicating a relatively narrow margin of exposure. The aim of this study was to establish dose–response data for cytotoxicity, regenerative cell proliferation and secondary oxidative DNA damage in livers of male F344 rats treated with furan at doses ≤2 mg/kg b.w. for 28 days. Methods and results: No significant signs of hepatotoxicity other than a mild, dose‐dependent increase in serum cholesterol and unconjugated bile acids, and no evidence of oxidative DNA damage were seen. Histopathological alterations and proliferative changes were restricted to subcapsular areas of the left and caudate liver lobes. Conclusion: Although statistically significant effects were only seen at the 2 mg/kg b.w. dose during the course of our study, a ～two and ～threefold increase in 5‐bromo‐2′‐deoxyuridine labeling index was observed at 0.1 and 0.5 mg/kg b.w., respectively, suggesting that chronic exposure to doses even below 2 mg/kg b.w. may cause proliferative changes in rat liver and highlighting the need to assess furan carcinogenicity at lower doses.