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Isoflavones found in soy products are a promising class of nutrients that may have a positive effect on human health. In particular, the phytoestrogen metabolite equol is associated with a reduced risk of developing female hormone-related diseases. However, the effect of equol on estrogen remains unclear. Equol can modify blood and urinary estradiol (E2) levels. The aim of this cross-sectional study was to examine the associations between urinary estrogen levels, equol levels, and equol production status in Japanese women. We analyzed urine samples from 520 women by gas chromatography-mass spectrometry. Urinary E2 and 4-hydroxylated E2 levels were higher in equol producers (EQP) than in non-EQPs (P P=0.00112, respectively). After adjusting for age and tobacco use by analysis of covariance, the association remained significant (β = 0.299, P P P = 0.0462). Our findings suggest that equol may promote urinary E2 excretion and modify blood E2 levels in women.

Possible effects of multi-wall carbon nanotubes (MWCNTs) on immune and inflammatory responses were examined in mice. Female ICR mice were given a single intraperitoneal administration (2 mg/kg body weight) of either MWCNTs, carbon black (CB), or crocidolite (blue asbestos) and controls received a vehicle of 2% sodium carboxymethyl cellulose (CMC Na). In the peritoneal cavity of MWCNT-administered mice, the liver had changed to a rounded shape and fibrous adhesions were seen on internal organs. Peritoneal cells overexpressed mRNA for genes of T helper (Th)2 cytokines (interleukin [IL]-4, IL-5, and IL-13), Th17 cytokine (IL-17), pro-inflammatory cytokines/chemokines (IL-1β, IL-33, tumor necrosis factor α, and monocyte chemotactic protein-1), and myeloid differentiation factor 88 for at least 2 weeks after the administration of MWCNTs, while those of Th1 cytokine genes (IL-2 and interferon γ) were overexpressed several weeks later and expression levels remained high up to 20 weeks. In MWCNT-treated mice, the numbers of leukocytes, monocytes, and granulocytes in the peripheral blood and the expression of the leukocyte adhesion molecules, cluster of differentiation (CD)49d and CD54, on granulocytes were increased 1 week after administration and remained high up to week 20. Production of ovalbumin-specific IgM and IgG(1) was enhanced by MWCNTs. These changes were not observed after CB or crocidolite administration. Thus, this study showed that MWCNTs exhibited sustained stimulating effects on immune and inflammatory responses, unlike the other mineral fibers with structural similarities.

To determine the reversibility of hematological and pathological changes in spleen induced by sub-chronic administration of chlorpropham (CIPC), male F344 rats were given CIPC in the diet at 0, 600, 3000 or 15,000 ppm for 13 weeks (administration period) and then were given standard (0 ppm) diet for 10 weeks (recovery period). At 0, 1, 2, 4 or 10 weeks in the recovery period, 5 rats in each groups were examined for hematology and pathology. At the end of CIPC administration, dose-dependent and significant methemoglobinemia, anemia, splenomegaly and pathological lesions indicating hemolytic anemia were observed in all the treated groups. The hematological changes, congestion of red pulp, lymphoid atrophy, increased extramedullary hematopoiesis in spleen and hematopoietic cell hyperplasia in bone marrow were diminished during the 10 weeks recovery period. However, increased hemosiderin deposition and capsular fibrosis in spleen of the treated groups remained at the end of recovery period. The results indicated that hematological changes induced by sub-chronic administration of CIPC were reversible but hemosiderin deposition and fibrosis in spleen were not reversible in the recovery period examined, suggesting the significance of splenic lesion in CIPC-toxicity.

Male and female CD-1 mice (50 mice per group) were administered thiabendazole (TBZ) in diet at levels of 0 (control), 0.031, 0.125 and 0.5% for 78 weeks. A life time study was terminated after 78 weeks due to enhanced strain specific mortality. There were no significant differences in mortality between the control and treated groups. Mean body weights of high-dose groups showed significant decreases compared with the controls. The bladder weights of male and female mice of the 0.5% group were significantly higher than those of the control mice. Gross findings in treated mice included the renal atrophy, hydronephrosis, calculi in renal pelvis and/or bladder and ovarian atrophy. Microscopic findings in the kidneys of treated mice included the nephrosis, hydronephrosis or hyperplasia of transitional epithelium of renal pelvis or papilla. In the bladder of treated mice, hyperplasia or squamous metaplasia of transitional epithelium and one transitional cell papilloma were observed. Dose-dependent decreases in the incidence of spontaneous lesion in the male or female reproductive system were recognized. It is concluded that TBZ is not carcinogenic to CD-1 mice of both sexes. However, caution should be exercised in the long-term application of high TBZ doses.

Male and female ICR mice were given 0, 1875, 7500 or 30,000 ppm of chlorpropham (CIPC) in the diet for 13 weeks. Methemoglobin levels of male and female mice in the 7500 and 30,000 ppm groups were significantly elevated. Hemoglobin concentration, packed cell volume, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and white blood cell count of male and female mice in the 30,000 ppm group were significantly increased. Dose-dependent splenomegaly was observed in male and female mice in the 7500 and 30,000 ppm group. Congestion, increased hemosiderin deposition and increased extramedullary hematopoiesis in the spleen, hematopoietic cell hyperplasia and hemosiderin deposition in bone marrow was observed dose dependently in male and female mice in the 7500 or 30,000 ppm group. Eosinophilic granular cytoplasm of hepatocytes, sinusoidal dilatation, hemosiderin deposition, extramedullary hematopoiesis and necrosis of hepatocytes were observed in the liver of male and female mice in the 30,000 ppm group. Hemosiderin deposition was increased in the kidney of male and female mice in the 30,000 ppm group. Administration of CIPC in diet for 13 weeks caused methemoglobinemia and splenomegaly in ICR mice.

Male and female CD-1 mice (51–104 mice/group) were administered piperonyl butoxide (α-[2-(2-butoxyethoxy)ethoxy-4,5-methylenedioxy-2-propyltoluene) in the diet at levels of 0 (control), 0.6 and 1.2% for 52 weeks (1 year). Hepatocellular carcinomas were induced in treated groups in a dose-dependent manner. The incidences of hepatocellular carcinoma were 11.3 and 52.0% in male mice given 0.6 and 1.2% piperonyl butoxide, and 41.2% in female mice given 1.2%. Piperonyl butoxide is thus a hepatocarcinogen to mice as it is known to be to rats.

Chlorpropham[Isopropyl-N-(3-chlorophenyl)carbamate; CIPC] is a widely used sprout suppressant. Groups of ten male and ten female F344 rats were given 0, 7500, 15,000 or 30,000 ppm of CIPC in the diet for 13 weeks. Body weight gain of male and female rats in the 30,000 ppm-group was depressed. Spleen and liver weights of male and female rats in the treated groups were dose-dependently increased. Red blood cell count, hemoglobin concentration, hematocrit, mean corpuscular hemoglobin concentration and platelet count were decreased in male and female rats of the treated groups. Methemoglobin level, mean corpuscular volume and mean corpuscular hemoglobin were increased in male and female rats of the treated groups. Those hematological changes were dose-dependent and were marked in the 15,000 and 30,000 ppm-groups. White blood cell count of male and female rats in the 30,000 ppm-group were significantly higher than those of the control group. Congestion, increased hemosiderin deposition, increased extramedullary hemopoiesis, lymphoid atrophy and fibrosis were seen in spleen of male and female rats of all treated groups in a dose-dependent manner. Hemopoietic cell hyperplasia was marked in bone marrow of male and female rats in all treated groups. The results suggested that the erythrocyte is one of the primary targets of CIPC toxicity in rats.

The nephrotoxicity and recovery following administration of thiabendazole (TBZ) were investigated in ICR adult mice. A single oral administration of TBZ (500-2000 mg/kg body wt.) caused a dose-dependent proximal tubular necrosis in the kidney and increase in serum urea nitrogen 24 h after dosing. These changes were marked in mice of high dose groups (1000 or 2000 mg TBZ/kg body wt.). The time course of changes on kidney of mice treated with 1000 or 2000 mg TBZ/kg body weight were examined at 1, 2, 3, 5, 7 or 10 days after dosing. Light microscopy showed necrosis of proximal convoluted tubules from 1 day after dosing. Tubular necrosis was extensive 2 or 3 days after dosing. Partial regeneration from tubular necrosis was seen 3 days after dosing, and substantial regeneration had occurred from 5 days after dosing. Thus, TBZ-induced renal injury was most severe at 2 or 3 days after dosing and was followed by regeneration. Electron microscopy showed swelling of mitochondria in the proximal tubular epithelium at 1 day after dosing. The pathological changes were correlated with the changes in urinalysis, serum urea nitrogen concentration and kidney weight.

Piperonyl butoxide was administered to pregnant mice by gavage at a level of 0 (control), 1065, 1385 and 1800 mg/kg body weight only on day 9 of gestation. The animals were sacrificed on day 18 of gestation. Early and late foetal deaths were significantly increased in the higher dose groups and those effects were significantly dose-related. The average body weights of male and female foetuses were significantly reduced in a dose-related fashion. The external malformation of oligodactyly in forelimbs was significantly increased in higher treatment groups in a dose-related manner. The dose levels of piperonyl butoxide in the present study produced adverse effects on developmental parameters.

Male F344 rats were given 0, 0.6, 1.2 or 2.4% of piperonyl butoxide in the diet. at 1, 2, 4 or 12 weeks after the beginning of the experiment, liver and kidney weight and serum clinical parameters were determined and livers and kidneys were examined with light microscopy. From 1 or 2–12 weeks, distinct increase of liver weight, changes in serum clinical parameters for liver damage, oval cell proliferation, bile duct hyperplasia, single cell necrosis, enlarged and vacuolated hepatocytes, enlarged nuclei and anisonucleosis were seen in treated rats. From 4–12 weeks, cell infiltration, focal necrosis, multinucleated hepatocytes and prominent nucleoli of hepatocytes were seen in treated rats. At 12 weeks microgranulomas were seen in treated rats. Especially in rats of the 2.4% group at 12 weeks, severe enlargement of hepatocytes, severe enlargement of nuclei and multinucleated hepatocyte were seen, suggesting preneoplastic alteration. Relative kidney weights and serum urea nitrogen levels were increased in treated rats from 1 or 2–12 weeks and at 12 weeks, atrophy of proximal tubules, dilation of tubules, cell infiltration, fibrosis and accumulation of yellow-brown pigment in the proximal tubular cells were seen.

Tetrabromobisphenol A (TBBPA) is widely used throughout the world as flame retardant for electronic equipment or building materials, and is detected in air at the dismantling plant, sewage sludge, sediment or human serum samples. In the present study, we examined the effects of TBBPA on the liver when administered to mice for 14 consecutive days. Groups of 7 (control group) or 8 (treated group) Crlj:CD1 (ICR) male mice were given 0 (control), 350, 700 or 1400 mg/kg body weight/day TBBPA (99.1% pure) in olive oil for 14 days. The serum concentration of total-cholesterol in high-dose (1400 mg/kg BW) group was higher than those of the control group. Absolute and relative liver weights were dose-dependently increased, and were significantly increased in high-dose (1400 mg/kg BW) group. The histological findings showed that the slight enlargement of the hepatocytes, inflammatory cell infiltrations and focal necrosis of hepatocytes were more marked in liver of treated groups (from 350 mg/kg BW) than in control group. The present data suggest the possibility of inducing hepatic lesion by TBBPA dosing.

Male F344 rats were given 0 or 3% chlorpropham in the diet and at 2, 4, 6, 8 or 13 weeks of administration, five rats in each group were examined for hematology, plasma clinical chemistry and pathology. Marked splenomegaly and hepatomegaly were observed in treated rats at 2–13 weeks of administration. Red blood cell counts, hemoglobin concentration, packed cell volume and platelet counts were significantly decreased and methemoglobin level, mean corpuscular volume and white blood cell counts were significantly increased in treated rats at 2–13 weeks of administration. The covalent binding of m -chloraniline m-CA, (the hydrolytic metabolite of chlorpropham) was observed in hemoglobin or splenic protein of treated rats, but only small amounts of free m-CA were present in blood or spleen. Congestion, hemosiderin deposits, extramedullary hemopoiesis and lymphoid atrophy in spleen and hyperplasia of hemopoietic cells in bone marrow were observed in treated rats at 2–13 weeks and fibrosis in splenic capsule were observed in treated rats at 4–13 weeks. The pathological changes in spleen rather than hematological changes progressed during administration, suggesting splenotoxicity of CIPC in rats.

The effects of thiabendazole (TBZ) on mitochondrial function of the renal cortex were investigated in ICR mice. Mice were given 1000 or 2000 mg TBZ/kg body weight by gavage and mitochondria were isolated from the renal cortex for the measurement of respiratory rates. The state 3 and DNP-uncoupled respiratory rates of renal cortical mitochondria were dose-dependently depressed at 6 hours after dosing. The depression of these respiratory rates of renal cortical mitochondria was more marked at 16 hours after dosing. There was no depression in these respiratory rates of renal cortical mitochondria at 3 hours after dosing, although renal cortical concentrations of TBZ were higher than those at 6 or 16 hours after dosing. Histochemical examination revealed that NAD-linked isocitrate dehydrogenase, a marker enzyme of mitochondria, was inhibited in renal cortical tubules at 16 hours after dosing of 1000 or 2000 mg TBZ/kg body weight. Furthermore, renal cortical ATP level was significantly decreased at 16 hours after dosing of 1000 or 2000 mg TBZ/kg body weight. The results indicate that administration of TBZ caused mitochondrial dysfunction in renal cortical tubules of mice.

The present studies were designed to evaluate the developmental toxicity of chlorpropham in mice. The first study was conducted to determine administration time, and the second study was designed to evaluate dose-response effects. Chlorpropham was administered to pregnant mice by gavage on Days 8,8.3,9,9.3,10, and 11 of gestation at a level of 3000 mg/kg bw, and the females were killed on Day 18 of gestation. The administration on Day 8.3 of gestation induced the highest percentage of external malformations with brachyury occurring among more litters than in other groups. Chlorpropham was administered to pregnant mice by gavage at a level of 0 (control), 750,1500, and 3000 mg/kg bw on Day 8.3 of gestation, and the females were killed on Day 18 of gestation. The total resorption rate was significantly increased in the 3000 mg/kg bw group. The average fetal body weight of each sex was significantly reduced in the 3000 mg/kg treatment group. The total incidence of external malformations was significantly increased in the two highest dose groups in a dose-related manner. Again brachyury was significantly increased in the 3000 mg/kg bw group.

The subchronic toxic effects of thiabendazole (TBZ) administered in the diet at levels of 0 (control), 0.8 and 1.6% for 13 wk to male and female ICR mice were investigated. Mean body weights of male mice fed 0.8 or 1.6% TBZ showed a significant decrease compared with controls, except for wk 3 and 8 for mice fed 0.8% TBZ. Red blood cell parameters in male mice of treated groups were significantly lower than controls. Biochemistry showed increased concentrations of GOT and GPT in male and female mice of the 1.6% TBZ groups. Relative spleen or liver weights were significantly increased in male and female mice of treated groups. Relative kidney weights of treated mice tended to be increased in comparison with controls. Histological findings showed a marked haemosiderosis and extramedullary haematopoiesis in the spleen of treated mice. In the liver, sinusoidal dilatation and enlargement of liver cells were found in treated mice. In the kidney, atrophy of tubules with peritubular fibrosis, cell infiltration and some tubular necrosis were found in treated mice. Slight hyperplasia was found in the urinary bladder of treated mice. The findings in the present study indicate that TBZ caused a slight anaemia and liver or kidney injury at both levels tested, under these conditions.

Piperonyl butoxide was administered to pregnant rats by gavage at a level of 0 (control), 630, 1065, and 1800 mg/kg bw on days 11-12 of gestation. The animals were killed on day 20 of gestation. Average maternal body weight gain (gestational days 11-20) was significantly reduced in the 1065 and 1800 mg/kg bw groups. Total resorption rate was significantly increased in the 1800 mg/kg bw group and those effects were significantly dose-related. The average fetal body weight of each sex was significantly reduced in the 1065 and 1800 mg/kg bw groups. External limb deformity (oligodactyly, syndactyly, and polydactyly) was significantly increased in the 1065 and 1800 mg/kg bw groups in a dose- related manner. The dose levels of piperonyl butoxide in the present study produced limb deformities in rats.

F344 rats and B6C3F1 mice of each sex were administered 0, 1.81, 2.09 or 2.40% (for rats) and 0, 2.08, 2.50 or 3.00% (for mice) of sodium benzoate in the diet for 10 days. In male rats of the 2.4% group, relative liver and kidney weight, serum levels of albumin, total protein and gamma-glutamyl transpeptidase were significantly increased and enlarged hepatocytes with glassy cytoplasm were seen using light microscopy. In male mice of the 3.0% group, absolute liver weights and serum cholesterol and phospholipid levels were significantly increased, and enlargement, vacuolation and necrosis of hepatocytes were evident.

Piperonyl butoxide, alpha-[2-(2-Butoxyethoxy)ethoxy]-4,5-methylenedioxy-2-propyltoluene, is a pesticide synergist. F344 rats of both sex were maintained on diets containing 0, 0.6, 1.2 or 2.4% of piperonyl butoxide for 13 weeks. At the end of experimental period, they were necropsied. Selected organs were weighed and serum was analyzed by clinical chemistry. In male and female rats of the 2.4%-group, body weight gains were depressed, macroscopically, hepatomegaly was marked and liver weights were significantly higher than those of the control group. In male and female rats of all treated groups, relative kidney weights were significantly increased in a dose-dependent manner. Rats of the 2.4%-group had increased levels of albumin, cholesterol, urea nitrogen and gamma-glutamyl transpeptidase. Examination of livers of the male 2.4%-group by light microscopy showed enlarged hepatocytes with glassy cytoplasm and fatty deposition. On occasion, there was coagulative necrosis of a few hepatocytes in the periportal area and oval cell proliferation. The kidney of treated rats showed atrophy of epithelium in the proximal convoluted tubules. These results indicated that toxicity of piperonyl butoxide in rats was directed primarily to the liver and kidney.

The effects of cysteine (CYS), glutathione (GSH) and diethylmaleate (DM) on the teratogenicity of thiabendazole (TBZ) were investigated. On day 9 of gestation mice were given ip a dose of 0, 50 or 100 mg CYS/kg body weight, or 0, 400 or 800 mg GSH/kg, or 0, 0.05, 0.10, 0.15 or 0.60 DM/kg. One hr later they were dosed orally with 0, 250, 500 or 1000 mg TBZ/kg. All foetuses were removed from the uterus on day 18 of gestation, and were examined for external and skeletal anomalies. The number of malformed foetuses was increased in mice pretreated with CYS or GSH and was decreased in those pretreated with DM, in comparison with numbers in the corresponding group treated with TBZ alone GSH pretreatment enlarged the area under the curve (AUC) of TBZ and 5-hydroxyTBZ, a representative metabolite, in foetal tissue. DM pretreatment reduced the AUC of TBZ and 5-hydroxyTBZ.

The effects of thiabendazole (TBZ) on the kidneys of male and female Crj:CD-1 (ICR) mice were investigated. The mice were given 0, 250 or 500 mg TBZ/kg body weight/day by gavage (using olive oil as a vehicle) for 1, 3, 5 or 7 days. The 24-hr urine volumes of treated mice were increased, significantly so in male mice given the high dose of TBZ. Protein was present in the urine of both control and treated mice throughout the experiment but electrophoresis of the protein showed the presence of a relatively high-molecular-weight protein in the urine of the treated mice. Levels of serum urea nitrogen were decreased in treated mice, but serum creatinine levels did not differ from those of controls. Relative kidney weights tended to be dose-dependently increased in comparison with the controls. Pathological examination showed that after one dose (at either level) the kidneys of males and females were swollen and white maculae were present. Microscopic examination revealed dilation of the proximal, distal and collecting tubules with flattening and degeneration of the tubular epithelium. Tubular dilation was severe in high-dose male mice. These histological changes paralleled the alterations in the 24-hr urine volume. These data suggested that the increased urine volume may be caused primarily by the prevention of reabsorption of water in the distal and collecting tubules. Electron microscopy revealed the flattening of foot processes of podocytes and oedematous changes in the mesangium of glomeruli in TBZ-treated mice. We conclude that TBZ given by gavage in olive oil affects the kidneys of ICR mice.