benzofurans and 2-3-4-7-8-pentachlorodibenzofuran

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin) and dioxin-like compounds (DLCs) induce numerous toxicities, including developmental, endocrine, immunological, and multi-organ carcinogenic, in animals and/or humans. Multiple studies completed by the National Toxicology Program (NTP) focused on the effects caused in Harlan Sprague-Dawley rats by specific DLCs, among them the prototypical dioxin, TCDD. Because humans are exposed daily to a combination of DLCs, primarily via ingestion of food, the Toxic Equivalency Factor (TEF) was developed in order to evaluate health hazards caused by these mixtures. Herein we review the pathological effects reported in humans exposed to TCDD; 3,3',4,4',5-pentachlorobiphenyl (PCB 126); and 2,3,4,7,8,-pentachlorodibenzofuran (PeCDF) and compare them to similar changes seen in NTP murine studies performed with the same compounds. While there were differences in specific pathologies observed, clear consistency in the target organs affected (liver, oral cavity, cardiovascular system, immune system, thyroid, pancreas, and lung) could be seen in both human studies and rodent toxicity and carcinogenicity investigations.

Topics: Animals; Benzofurans; Digestive System; Endocrine Glands; Female; Genitalia, Female; Genitalia, Male; Humans; Immune System; Male; Mice; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Species Specificity

In June 2005, a World Health Organization (WHO)-International Programme on Chemical Safety expert meeting was held in Geneva during which the toxic equivalency factors (TEFs) for dioxin-like compounds, including some polychlorinated biphenyls (PCBs), were reevaluated. For this reevaluation process, the refined TEF database recently published by Haws et al. (2006, Toxicol. Sci. 89, 4-30) was used as a starting point. Decisions about a TEF value were made based on a combination of unweighted relative effect potency (REP) distributions from this database, expert judgment, and point estimates. Previous TEFs were assigned in increments of 0.01, 0.05, 0.1, etc., but for this reevaluation, it was decided to use half order of magnitude increments on a logarithmic scale of 0.03, 0.1, 0.3, etc. Changes were decided by the expert panel for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.3), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF) (TEF = 0.03), octachlorodibenzo-p-dioxin and octachlorodibenzofuran (TEFs = 0.0003), 3,4,4',5-tetrachlorbiphenyl (PCB 81) (TEF = 0.0003), 3,3',4,4',5,5'-hexachlorobiphenyl (PCB 169) (TEF = 0.03), and a single TEF value (0.00003) for all relevant mono-ortho-substituted PCBs. Additivity, an important prerequisite of the TEF concept was again confirmed by results from recent in vivo mixture studies. Some experimental evidence shows that non-dioxin-like aryl hydrocarbon receptor agonists/antagonists are able to impact the overall toxic potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds, and this needs to be investigated further. Certain individual and groups of compounds were identified for possible future inclusion in the TEF concept, including 3,4,4'-TCB (PCB 37), polybrominated dibenzo-p-dioxins and dibenzofurans, mixed polyhalogenated dibenzo-p-dioxins and dibenzofurans, polyhalogenated naphthalenes, and polybrominated biphenyls. Concern was expressed about direct application of the TEF/total toxic equivalency (TEQ) approach to abiotic matrices, such as soil, sediment, etc., for direct application in human risk assessment. This is problematic as the present TEF scheme and TEQ methodology are primarily intended for estimating exposure and risks via oral ingestion (e.g., by dietary intake). A number of future approaches to determine alternative or additional TEFs were also identified. These included the use of a probabilistic methodology to determine TEFs that better describe the associated levels of uncertainty

Topics: Animals; Benzofurans; Dioxins; Endpoint Determination; Humans; Mice; Polychlorinated Biphenyls; Probability; Risk Assessment; World Health Organization

In breastmilk of 14 Dutch mothers and 5 Polish mothers the content of dioxins and furans is measured. The study in Dutch mothers is started to relate the level of these xenobiotics to bleeding in the perinatal and late neonatal period. Interference with coagulation is hypothesized in analogon to phenobarbital. A relation is seen between bleeding in four babies and the mean content of 2, 3, 7, 8 TCDD (= tetrachloordibenzodioxin) (P = 0.02) in their breastmilk. This relation however is not found for the content of 2, 3, 4, 7, 8 PnCDF (= pentachloordibenzofuran) or the total amount of toxic equivalents. The fact that the prenatal gradient from mother to baby is different for T4CDD and PnCDF, respectively 2:1 and 10:1, may be an explanation for the dissociation between T4CDD on one side and PnCDF and total amount of toxic equivalents on the other side. Polish breastmilk was significantly lower (about four times) for dioxins and furans than Dutch breastmilk. This means that for these chemicals pollution in Holland is much higher than in Poland.

Topics: Adult; Air Pollutants; Animals; Benzofurans; Female; Hemorrhage; Humans; Infant, Newborn; Male; Milk, Human; Netherlands; Poland; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Pregnancy; Prenatal Exposure Delayed Effects; Rats

Topics: Animals; Benzofurans; Charcoal; Cholestyramine Resin; Feces; Paraffin; Polychlorinated Biphenyls; Squalene; Stimulation, Chemical

Thirty-five years have been passing since the outbreak of Kanemi rice oil poisoning, namely, Yusho in the western Japan. However, even now the patients with Yusho have been still suffering from several objective and subjective symptoms. In order to improve or, if possible, to cure the such symptoms, the most important therapeutic treatment is considered to actively excrete the most toxic causative PCDFs/DDs congeners, that is, 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) and 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD) from the bodies of the patients and to reduce their body burdens. In rats, dietary fiber and chlorophyll have been shown to promote the fecal excretion of dioxins and to reduce their levels in rat liver. In this study, we examined whether such kinds of effect were also observed by FBRA, which was the health food and relatively rich with dietary fiber and chlorophyll in nine married Japanese couples. As a result, concentrations of PenCDF and HxCDD on the lipid weight basis in the blood of the FBRA-intake group in which they took 7.0 to 10.5 g of FBRA after each meal and three times a day for one year were more lowered than those in the blood of the non-intake group; Blood levels of PenCDF and HxCDD in the FBRA-intake group were decreased by 30.5 and 33.9%, respectively, and those decreases were 22.0 and 24.5% in the non-intake group. Their total body burdens just before and one year after the study were calculated on the assumptions that the body fat was also contaminated with these congeners at their blood levels on the lipid weight basis and the content of body fat was 20% of the body weight. Then, we computed the average amounts in excretion of PenCDF and HxCDD from the body in both the FBRA-intake and non-intake groups. Consequently, the amounts of excretion of PenCDF and HxCDD in the FBRA-intake group were 2.1 and 1.9 times, respectively, greater than those in the non-intake group. Therefore, FBRA seemed to promote the fecal excretion of PenCDF and HxCDD, the main causative PCDFs/DDs congeners of Yusho, from the human body. We also expect FBRA to reduce their body burdens of patients with Yusho and to improve some objective and subjective symptoms of Yusho patients.

Topics: Adult; Aspergillus oryzae; Benzofurans; Body Burden; Dietary Fiber; Female; Food Contamination; Food, Organic; Humans; Japan; Male; Middle Aged; Oryza; Plant Oils; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Time Factors

It has been intensively documented that there are species-differences in the sensitivity to dioxin-like compounds (DLCs) in mammalian and avian. However, this issue is still unclear in fish. This study aimed at evaluating the differential sensitivities to DLCs in fish larvae. Here, larvae of Tg(cyp1a:gfp) medaka and Tg(cyp1a:gfp) zebrafish were tested with 2,3,7,8-Tetrachlorodibenzodioxin (TCDD), polychlorinated biphenyl 126 (PCB 126) and 2,3,4,7,8,-Pentachlorodibenzofuran (PeCDF). Comparative analyses were performed on induction of GFP fluorescence, expression of endogenous cyp1a mRNAs and EROD activity between the two species after exposure to these chemicals. We found that PCB 126 and PeCDF exposure at high concentrations induced strong GFP expression in multiple organs (liver, head kidney and gut) in both medaka and zebrafish larvae. Moreover, the expression of endogenous cyp1a mRNA was significantly elevated in the zebrafish larvae exposed to TCDD, PCB 126 and PeCDF at different concentrations. Likewise, almost all the exposure conditions could cause prominent elevation of EROD activity in the zebrafish larvae, while the EROD activities were just slightly elevated in the medaka larvae exposed to 1 nM and 0.5 nM of TCDD as well as to 1.5 nM and 15 nM of PeCDF, but not in the medaka larvae exposed to PCB 126. Taken together, zebrafish was proved to be more sensitive than medaka to PCB 126 and to PeCDF in this study. The findings suggested species-specific sensitivity to DLCs in fish and will facilitate choosing a sensitive and reliable fish model or tool to evaluate the risk of dioxins and DLCs exposure.

Topics: Animals; Animals, Genetically Modified; Benzofurans; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Larva; Liver; Oryzias; Polychlorinated Biphenyls; RNA, Messenger; Zebrafish

Dioxins and dioxin-like compounds (DLCs) are potent toxicants to most vertebrates. Sensitivities to DLCs vary among species. In the present study, the sensitivities of avian species (chicken [Gallus gallus], ring-necked pheasant [Phasianus colchicus], and Japanese quail [Coturnix japonica]) to some polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) were determined by using species-specific, in vitro, transactivation assays based on a luciferase reporter gene under control of species-specific aryl hydrocarbon receptors. In ring-necked pheasant and Japanese quail, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was not the most potent inducer of toxic effects. Especially for Japanese quail, the relative potency values of most of 9 PCDD/Fs tested were greater than for TCDD. The rank order of avian species sensitivities to DLCs was chicken > ring-necked pheasant > Japanese quail. Effects of binary mixtures of TCDD, 2,3,7,8-tetrachlorodibenzofuran, and 2,3,4,7,8-pentachlorodibenzofuran were strictly additive. Moreover, we also found that the primary DLCs that were responsible for most of the potency of the DLC mixtures can be deduced by using ordination in a multidimensional space defined by the avian species sensitivities. Overall, the relative potency and the species sensitivities of these chemicals could guide risk assessments to wild species when exposure to mixtures of DLCs in the environment.

Topics: Animals; Benzofurans; Chickens; Coturnix; Dioxins; Dioxins and Dioxin-like Compounds; Galliformes; Genes, Reporter; Luciferases; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Species Specificity; Transcriptional Activation

Half-lives of blood levels of 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) are varied in Yusho patients. The objective was to evaluate a relationship between half-lives of PeCDF levels and types of SNP rs10249788 of aryl hydrocarbon receptor (AHR) gene in 93 Yusho patients. Based on physical symptoms, age, sex, body mass index and other factors, we set up suitable calculation formulas to fit the actual PeCDF levels thorough rates of change in PeCDF. We found that patients with C/T SNP had longer half lives than patients with C/C and T/T SNPs. Patients with T/T SNP are known to express higher amount of AHR mRNAs. However, detailed analysis could not be carried out in T/T group due to a limited number of patients (n = 11). Further research is warranted to determine the cause of the longer half-lives in C/T patients.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Female; Half-Life; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Porphyrias; Receptors, Aryl Hydrocarbon

The effect of cynaropicrin that is the major component of an edible plant, artichoke (Cynara scolymus) on 2,3,4,7,8-pentachlorodibenzofuran (PenCDF)-induced toxicity in mice was studied. We evaluated the effect of cynaropicrin on the wasting syndrome and oxidative stress elicited by PenCDF. However, the PenCDF dose-response relationship on the wasting syndrome has been superficial. Therefore, we determined the dose which causes wasting syndrome in C57BL/6J mice, a responsive strain to dioxins. Since 2,3,7,8-tetrachlorodibenzo-p-dioxin (0.1 mg/kg, p.o.) induces hepatic ethoxyresorfin O-deethylase (EROD) activity in mice, we set the doses of PenCDF at 0.3, 1.0, 3.0, 5.0 and 10 mg/kg (once, p.o.) on the basis of its toxic-eqivalency factor (0.3). The wasting syndrome was evaluated by measuring the daily changes of body weight. Thiobarbituric acid-reactive substances were used as an index of oxidative stress. Of PenCDF doses examined, wasting syndrome and oxidative stress took place most markedly in 5 mg/kg. In disagreement with this, EROD activity which is the marker of the aryl hydrocarbon receptor-dependent induction of cytochrome P450 1a1 was elevated most abundantly at 0.3 mg/kg. Then, we examined the effect of cynaropicrin on the wasting syndrome and oxidative stress provoked by PenCDF at 5 mg/kg. However, this compound up to 20 mg/kg (p.o.) did not attenuate PenCDF-induced wasting syndrome. On the contray, PenCDF-induced oxidateive stress was suppressed by cynaropicrin at the highest dose (20 mg/kg), although EROD activity was increased rather than reduced by cynaropicrin at lower doses. Thus, it is suggested that cynaropicrin has an ability to reduce oxidative stress caused by PenCDF.

Topics: Animals; Benzofurans; Dose-Response Relationship, Drug; Lactones; Mice; Mice, Inbred C57BL; Oxidative Stress; Sesquiterpenes; Wasting Syndrome

Dioxins and dioxin-like compounds have half-lives typically between 7.2 years and 15 years. Our previous study of patients poisoned by extremely high concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) in the 'Yusho incident' in 1968 found that in some the half-life of blood 2,3,4,7,8-PeCDF tended towards infinity. This suggests that there are two groups of Yusho patients, those with 2,3,4,7,8-PeCDF half-lives around 10 years, and those with half-lives near infinity. We sought to establish the proportions of each in a cohort of 395 Yusho patients, and whether the proportions were changing over time.. We undertook longitudinal measurement of the blood concentration of 2,3,4,7,8-PeCDF in our cohort between 2002 and 2010. We estimated the change in concentration for each patient using linear regression for measured 2,3,4,7,8-PeCDF concentration, then compared the distribution of changes in concentrations with our previous study.. In patients in whom the blood concentration of 2,3,4,7,8-PeCDF exceeded 50 pg/g lipid, the proportion 8.0% of patients exhibiting half-lives less than 13.3 years fell compared with our previous study (28.2%), while the proportion with near infinity half-lives increased.. The prolongation of the half-lives was likely a consequence of age-related factors.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Environmental Pollutants; Female; Food Contamination; Half-Life; Humans; Japan; Male; Middle Aged; Young Adult

Risk assessment for mixtures of dioxin-like compounds uses the toxic equivalency factor (TEF) approach. Although current WHO-TEFs are mostly based on oral administration, they are commonly used to determine toxicity equivalencies (TEQs) in human blood or tissues. However, the use of "intake" TEFs to calculate systemic TEQs in for example human blood, has never been validated. In this study, intake and systemic relative effect potencies (REPs) for 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), 2,3',4,4',5-pentachlorobiphenyl (PCB-118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB-156) were compared in rats. The effect potencies were calculated based on administered dose and liver, adipose or plasma concentrations in female Sprague-Dawley rats 3 days after a single oral dose, relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Hepatic ethoxyresorufin-O-deethylase activity and gene expression of Cyp1a1, 1a2, 1b1 and aryl hydrocarbon receptor repressor in liver and peripheral blood lymphocytes were used as endpoints. Results show that plasma-based systemic REPs were generally within a half log range around the intake REPs for all congeners tested, except for 4-PeCDF. Together with our previously reported systemic REPs from a mouse study, these data do not warrant the use of systemic REPs as systemic TEFs for human risk assessment. However, further investigation for plasma-based systemic REPs for 4-PeCDF is desirable.

Topics: Administration, Oral; Animals; Benzofurans; Body Weight; Cytochrome P-450 CYP1A1; Dioxins; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Lymphocytes; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Tissue Distribution

Results of recent studies showed that 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are equipotent in domestic chicken (Gallus gallus domesticus) while PeCDF is more potent than TCDD in ring-necked pheasant (Phasianus colchicus) and Japanese quail (Coturnix japonica). To elucidate the mechanism(s) underlying these differences in relative potency of PeCDF among avian species, we tested the hypothesis that this is due to species-specific differential binding affinity of PeCDF to the aryl hydrocarbon receptor 1 (AHR1). Here, we modified a cell-based binding assay that allowed us to measure the binding affinity of dioxin-like compounds (DLCs) to avian AHR1 expressed in COS-7 (fibroblast-like cells). The results of the binding assay show that PeCDF and TCDD bind with equal affinity to chicken AHR1, but PeCDF binds with greater affinity than TCDD to pheasant (3-fold) and Japanese quail (5-fold) AHR1. The current report introduces a COS-7 whole-cell binding assay and provides a mechanistic explanation for differential relative potencies of PeCDF among species of birds.

Topics: Animals; Benzofurans; Birds; Cell Line; Chlorocebus aethiops; COS Cells; Dioxins; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Species Specificity

World Health Organization (WHO) toxic equivalency factors are used to calculate toxic equivalent (TEQ) concentrations of complex mixtures of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls (PCBs), for mammals, fish and birds. The TEQ concept assumes that all species of a taxa respond with similar sensitivity to individual DLCs, but several reports do not support this assumption for birds. Our laboratory is conducting research to attempt to uncover the fundamental mechanism(s) underlying the reasons why avian species differ in sensitivity to DLCs. The present study determined concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on ethoxyresorufin-O-deethylase (EROD) activity in primary cultures of northern bobwhite quail (Colinus virginianus) hepatocytes. Bobwhite quail were studied because (1) this species is used in the laboratory for toxicity testing and (2) the amino acids at all locations within the ligand binding domain (LBD) of aryl hydrocarbon receptor 1 (AHR1) in bobwhite quail and ring necked pheasant (Phasianus colchicus) are identical. Because earlier work indicated the importance of the identity of amino acids at key sites within the AHR1 LBD, we hypothesized that bobwhite quail and ring necked pheasant hepatocytes should have similar sensitivity to EROD induction by DLCs. ECthreshold-based relative sensitivity of the bobwhite quail compared to chicken for TCDD, PeCDF and PCB 126 was 0.11, 0.17 and 0.02, respectively. The rank order of potency was PeCDF > TCDD > PCB 126. The results confirm that bobwhite quail and ring-necked pheasant hepatocytes have similar sensitivity to EROD induction by TCDD, PeCDF and PCB 126.

Topics: Animals; Benzofurans; Cells, Cultured; Colinus; Cytochrome P-450 CYP1A1; Enzyme Induction; Hepatocytes; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

The effect of 2,3,4,7,8-pentachlorodibenzofuran (PnCDF) on the fetal pituitary-gonad axis was compared with that produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Wistar rats. Maternal treatment at gestational day (GD) 15 with PnCDF and TCDD reduced the fetal expression at GD20 of pituitary luteinizing hormone (LH) and the testicular proteins necessary for steroidogenesis. The relative potencies of PnCDF ranged from 1/42nd to 1/63rd of the TCDD effect. While PnCDF, at a dose sufficient to cause a reduction in fetal LH, provoked defects in sexual behavior at adulthood, a dose less than the ED50 failed to produce any abnormality. There was a loss of fetal body weight following in utero exposure to PnCDF, and the effect of PnCDF was also much less than that of TCDD. The disturbance in fetal growth was suggested to be due to a reduction in the level of fetal growth hormone (GH) by dioxins. The disorder caused by PnCDF/TCDD in the fetal pituitary-gonad axis occurred at doses less than those needed to cause wasting syndrome in pubertal rats. The harmful effect of PnCDF relative to TCDD was more pronounced in fetal rats than in pubertal rats. These lines of evidence suggest that: 1) PnCDF as well as TCDD imprints defects in sexual behavior by disrupting the fetal pituitary-gonad axis; 2) these dioxins hinder fetal growth by reducing the expression of fetal GH; and 3) the fetal effects of PnCDF/TCDD are more sensitive than sub-acute toxicity during puberty, and the relative effect of PnCDF varies markedly depending on the indices used.

Topics: Animals; Benzofurans; Dose-Response Relationship, Drug; Environmental Pollutants; Female; Fetal Development; Fetus; Luteinizing Hormone; Male; Maternal Exposure; Pituitary Gland; Polychlorinated Dibenzodioxins; Pregnancy; Rats; Rats, Wistar; Sexual Behavior, Animal; Testis

Novel methods that predict the sensitivity of avian embryos to the toxic effects of dioxin-like compounds (DLCs) using either (1) knowledge of the identity of amino acids at key sites within the ligand binding domain of aryl hydrocarbon receptor 1 (AHR1) or (2) a luciferase reporter gene assay that measures AHR1 activation were recently reported. Results from both methods predict that European starling (Sturnus vulgaris) and domestic chicken (Gallus gallus domesticus) embryos have similar sensitivity to the biochemical and toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 2,3,7,8-tetrachlorodibenzofuran (TCDF). Chicken embryos are highly sensitive to DLC toxicity, and the prediction that starlings are equally sensitive is surprising given their widespread distribution and large population size. In an attempt to learn more about starling sensitivity to DLCs, we determined concentration-dependent effects of TCDD, PeCDF and TCDF on cytochrome P4501A4 and 1A5 (CYP1A4 and 1A5) mRNA levels in primary cultures of hepatocytes prepared from embryonic European starlings. It has been demonstrated that the sensitivity of avian hepatocytes to CYP1A4/5 induction is well correlated with LD50 values of DLCs for several avian species. The results of the present study indicate that European starling hepatocytes are indeed as sensitive as chicken hepatocytes to CYP1A4/5 induction after exposure to TCDD. However, starling hepatocytes are less sensitive than chicken hepatocytes to CYP1A4/5 induction by PeCDF and TCDF.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Avian Proteins; Benzofurans; Cell Survival; Cells, Cultured; Chick Embryo; Chickens; Genes, Reporter; Hepatocytes; Lethal Dose 50; Luciferases; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Risk Assessment; RNA, Messenger; Starlings

In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long.. To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood.. Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression.. A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy.. Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF.

Topics: Acne Vulgaris; Adult; Aged; Aged, 80 and over; Benzofurans; Erythrocyte Count; Fatigue; Female; Half-Life; Humans; Japan; Male; Middle Aged; Porphyrias; Rhinitis, Allergic, Seasonal

Using a proteomic approach, a study was conducted for determination of the effects of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PCDF) on proteins secreted by HepG2 cells. Briefly, HepG2 cells were exposed to various concentrations of 2,3,4,7,8-PCDF for 24 or 48h. MTT and comet assays were then conducted for determination of cytotoxicity and genotoxicity, respectively. Results of an MTT assay showed that 1nM of 2,3,4,7,8-PCDF was the maximum concentration that did not cause cell death. In addition, a dose- and time dependent increase of DNA damage was observed in HepG2 cells exposed to 2,3,4,7,8-PCDF. Therefore, two different concentrations of 2,3,4,7,8-PCDF, 1 and 5nM, were selected for further analysis of proteomic biomarkers using two different pI ranges (4-7 and 6-9) and large two dimensional gel electrophoresis. Results showed identification of 32 proteins ( 29 up- and 3 down-regulated) by nano-LC-ESI-MS/MS and nano-ESI on a Q-TOF2 MS. Among these, the identities of pyridoxine-5'-phosphate oxidase, UDP-glucose 6-dehydrogenase, plasminogen activator inhibitor I precursor, plasminogen activator inhibitor-3, proteasome activator complex subunit 1, isoform 1 of 14-3-3 protein sigma, peptidyl-prolyl cis-trans isomerase A, 14-3-3 protein gamma, protein DJ-1, and nucleoside diphosphate kinase A were confirmed by western blot analysis. The differential expression of protein DJ-1, proteasome activator complex subunit 1 and plasminogen activator inhibitor-3 was further validated in plasma proteins from rats exposed to 2,3,4,7,8-PCDF. These proteins could be used as potential toxicological biomarkers of 2,3,4,7,8-PCDF.

Topics: Animals; Benzofurans; Biomarkers; Cell Proliferation; Cell Survival; Comet Assay; DNA Damage; Electrophoresis, Gel, Two-Dimensional; Environmental Pollutants; Hep G2 Cells; Humans; Intracellular Signaling Peptides and Proteins; Male; Oncogene Proteins; Proteasome Endopeptidase Complex; Protein C Inhibitor; Protein Deglycase DJ-1; Proteome; Proteomics; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization; Up-Regulation

This study assessed the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8 tetrachlorodibenzofuran (TCDF) on the incidence of jaw lesions and on hepatic cytochrome P4501A (CYP1A) endpoints in mink (Mustela vison). Adult female mink were assigned randomly to one of 13 dietary treatments (control and four increasing doses of TCDD, PeCDF, or TCDF) and provided spiked feed for approximately 150 d (60 d prior to breeding through weaning of offspring at 42 d post-parturition). Offspring were maintained on their respective diets for an additional 150 d. Activity of hepatic CYP1A enzymes in adult and juvenile mink exposed to TCDD, PeCDF, or TCDD was generally greater compared with controls, but changes in other CYP1A endpoints were less consistent. Histopathology of the mandible and maxilla of juvenile mink suggested a dose-related increase in the incidence of jaw lesions. The dietary effective doses (ED) for jaw lesions in 50% of the population (ED50) were estimated to be 6.6, 14, and 149 ng/kg body weight (bw)/d for TCDD, PeCDF, and TCDF, respectively. The relative potencies of PeCDF and TCDF compared with TCDD based on ED10, ED20, and ED50 values ranged from 0.5 to 1.9 and 0.04 to 0.09, respectively. These values are within an order of magnitude of the World Health Organization toxic equivalency factor (TEF(WHO)) values of 0.3 and 0.1 for PeCDF and TCDF, respectively.

Topics: Animals; Benzofurans; Cytochrome P-450 CYP1A1; Diet; Endpoint Determination; Female; Gene Expression; Incidence; Jaw; Liver; Male; Mink; Polychlorinated Dibenzodioxins; Toxicity Tests, Chronic

Egg injection studies were performed to confirm a proposed model of relative sensitivity of birds to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this model, species are classified as belonging to one of three categories of sensitivity based on amino acid substitutions in the ligand-binding domain of the aryl hydrocarbon receptor. Embryo lethality and relative potencies of 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) were compared with TCDD for Japanese quail (Coturnix japonica; least sensitive), Common pheasant (Phasianus colchicus; moderately sensitive), and White Leghorn chicken (Gallus gallus domesticus; most sensitive). Doses ranging from 0.044 to 37 pmol/g egg (0.015-12 ng/g egg) were injected into the air cell of eggs prior to incubation. LD(50) (95% confidence intervals) values, based on rate of hatching for TCDD, PeCDF, and TCDF, were 30 (25-36), 4.9 (2.3-9.2), and 15 (11-24) pmol/g egg for the quail, 3.5 (2.3-6.3), 0.61 (0.28-1.2), and 1.2 (0.62-2.2) pmol/g egg for pheasant, and 0.66 (0.47-0.90), 0.75 (0.64-0.87), and 0.33 (0.23-0.45) pmol/g egg for chicken, respectively. LD(50)-based relative potencies of PeCDF and TCDF were 6.1 and 2.0 for quail, 5.7 and 2.9 for pheasant, and 0.88 and 2.0 for chicken, respectively. TCDD was not the most potent compound among the species tested, with PeCDF and TCDF being more potent than TCDD in the quail and pheasant. TCDF was the most potent in chicken. Species sensitivity was as expected for TCDD and TCDF, whereas for PeCDF, the chicken and pheasant were similar in sensitivity and both were more sensitive than the quail. Results from companion in vitro studies are generally similar to those reported here with a few exceptions.

Topics: Animals; Benzofurans; Chick Embryo; Chickens; Coturnix; Embryo, Nonmammalian; Galliformes; Lethal Dose 50; Models, Biological; Ovum; Polychlorinated Dibenzodioxins; Species Specificity; Toxicity Tests

An egg injection study was conducted to confirm a proposed model of relative sensitivity of three avian species to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like chemicals. It was previously reported that the order of species sensitivity to in ovo exposure to TCDD, 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or 2,3,7,8-tetrachlorodibenzofuran (TCDF) at doses ranging from 0.044 to 37 picomoles (pmol)/g egg was the chicken (Gallus gallus domesticus), common pheasant (Phasianus colchicus), and Japanese quail (Coturnix japonica) based on embryo mortality and hepatic enzyme induction. In the present study, the incidence of developmental deformities, changes in body and relative organ masses, and organ pathology of hatchlings as additional indicators of species sensitivity were assessed; in addition, embryo mortality in the three species was categorized by stage of development. Embryo mortality varied temporally with significant increases generally occurring after organogenesis and just prior to hatching. A significant increase in the percentage of developmental deformities was observed only in Japanese quail exposed to TCDF. Body and relative organ masses of quail, pheasants, and chickens dosed in ovo with TCDD, PeCDF, or TCDF were not consistently affected. Chemical-related pathology occurred only in livers of quail at the greatest doses of each compound. These results indicated that the incidence of developmental deformities, changes in body and relative organ masses and organ pathology could not be used as indicators of species sensitivity or chemical potency.

Topics: Animals; Benzofurans; Body Size; Brain; Chick Embryo; Coturnix; Embryo, Nonmammalian; Embryonic Development; Enzyme Induction; Galliformes; Liver; Myocardium; Organ Size; Ovum; Polychlorinated Dibenzodioxins; Spleen

The aryl hydrocarbon receptor (AHR) mediates the toxic effects of halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TCDF). Non-traditional activators, including omeprazole (Omp), are thought to regulate AHR action through phosphorylation rather than binding to the receptor. In this study, we examined the ability of these compounds to induce AHR-dependent regulation of cytochrome P450 1A1 (CYP1A1) and CYP1B1 in T-47D human breast cancer cells. The role of Y322, a residue implicated in Omp-dependent activation of AHR was also investigated. All four compounds induced CYP1A1 and CYP1B1 mRNA expression, with Omp differing from the HAHs. Chromatin immunoprecipitation assays revealed ligand- and gene-selectivity in the recruitment patterns of AHR coactivators. We also found that residue Y322 of human AHR was important for maximum activation of AHR by 2,3,7,8-TCDD and 2,3,4,7,8-PeCDF, but required for 2,3,7,8-TCDF and Omp in an AHR-deficient MCF-7 human breast cancer cell line. In summary, this study provides evidence for context- and ligand-selective differences in coactivator recruitment in AHR-regulated gene expression and reveal an important role of Y322 in AHR activation.

Topics: Aryl Hydrocarbon Hydroxylases; Basic Helix-Loop-Helix Transcription Factors; Benzofurans; Cell Line, Tumor; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Gene Expression Regulation, Enzymologic; Humans; Ligands; Omeprazole; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Tyrosine

Yusho is an incidence of food poisoning caused by rice bran oil in 1968. Its main causal agent is considered as 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF). The patients have been suffered by the various symptoms, and their blood concentration of PeCDF is still higher than the general population.. The purpose of this study is to estimate the change rate of PeCDF concentration among the examinees of annual health examination of Yusho patients.. PeCDF concentration of 118 men and 140 women who received the health examination four times or more from 2001 to 2008 was statistically analyzed. The estimated annual change rate of the PeCDF concentration was low; 1.43% reduction and 1.03% increase were observed, respectively, for men and women who have low PeCDF concentration, and 3.6% and 3.7% reductions, respectively, for men and women who have high concentration of PeCDF. The reduction rate was associated with age and smoking habit in men, and drinking habit in women.

Topics: Adult; Benzofurans; Female; Food Contamination; Humans; Male; Oryza; Physical Examination; Plant Oils; Polychlorinated Biphenyls

Toxicogenomics was used to examine mRNA expression profiles obtained from primary rat hepatocytes treated for 24h with 0.01 or 1.0 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), 0.02 or 2.0 nM 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) and 0.1 or 10nM 2,3,7,8-tetrachlorodibenzofuran (2,3,7,8-TCDF). The concentrations of 2,3,4,7,8-PeCDF and 2,3,7,8-TCDF were chosen to be equivalent to 2,3,7,8-TCDD's concentration based on the toxic equivalency factor/toxic equivalent (TEF/TEQ) method for estimating biological potency. 2,3,7,8-TCDD at 1.0 nM altered the expression of 533 genes; 2,3,4,7,8-PeCDF at 2.0 nM altered 182 genes, and 2,3,7,8-TCDF at 10nM altered 154 genes. Of these, 57 genes were affected by all three congeners. Agglomerative hierarchical clustering revealed distinct congener-dependent gene subclusters. Principal components analyses of the microarray data revealed that these congeners cluster independently of one another. Data presented here demonstrate that equivalent TEQ concentrations of 2,3,7,8-TCDD, 2,3,4,7,8-PeCDF and 2,3,7,8-TCDF, while altering the expression of a small battery of genes in common, also produce substantial congener specific alterations in gene expression.

Topics: Animals; Benzofurans; Female; Gene Expression Regulation; Hepatocytes; Multigene Family; Oligonucleotide Array Sequence Analysis; Polychlorinated Dibenzodioxins; Principal Component Analysis; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon; RNA, Messenger

Relative potencies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) were determined in vitro in primary hepatocyte cultures of chicken (Gallus gallus), ring-necked pheasant (Phasianus colchicus), and Japanese quail (Coturnix japonica) embryos. Concentration-dependent effects on ethoxyresorufin O-deethylase (EROD) activity and expression of cytochrome P4501A4 and cytochrome P4501A5 (CYP1A4 and CYP1A5) messenger RNA (mRNA) were determined in hepatocytes exposed to serial dilutions of TCDD, PeCDF, or TCDF for 24 h. In chicken hepatocytes, the three compounds were equipotent inducers of EROD activity and CYP1A4/CYP1A5 mRNA expression. However, in ring-necked pheasant and Japanese quail hepatocytes, PeCDF was more potent than TCDD (3- to 5-fold in ring-necked pheasant and 13- to 30-fold in Japanese quail). Among species, the rank order of sensitivity (most to least) to EROD and CYP1A4/CYP1A5 mRNA induction for TCDD and TCDF was chicken > ring-necked pheasant > Japanese quail. In contrast, the three species were approximately equisensitive to EROD and CYP1A4/CYP1A5 mRNA induction by PeCDF. It has generally been assumed that TCDD is the most potent "dioxin-like compound" (DLC) and that the chicken is the most sensitive avian species to CYP1A induction by all DLCs. This study indicates that PeCDF is more potent than TCDD in ring-necked pheasant and Japanese quail hepatocytes and that ring-necked pheasant, Japanese quail, and chicken hepatocytes are equally sensitive to CYP1A induction by PeCDF.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Birds; Cells, Cultured; Chickens; Coturnix; Cytochrome P-450 CYP1A1; Enzyme Induction; Galliformes; Hepatocytes; Polychlorinated Dibenzodioxins; RNA, Messenger

Ethoxyresorufin O-deethylase (EROD) activity was measured in primary cultures of ring-necked pheasant (Phasianuscolchicus) and Japanese quail (Coturnix japonica) embryonic hepatocytes exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 2,3,7,8-tetrachlorodibenzofuran (TCDF) for 12, 24, 36 and 48 h. In ring-necked pheasant hepatocytes there was a significant time-dependent increase in the EROD-inducing potency of TCDD, PeCDF and TCDF (i.e. decrease of the EC50). In Japanese quail hepatocytes there was no time-dependent change in the EROD-inducing potency of TCDD, PeCDF and TCDF. There was no time-dependent change in the relative potency of PeCDF and TCDF (i.e. compared to the potency of TCDD) in ring-necked pheasant hepatocytes and of PeCDF in Japanese quail hepatocytes. The results indicate that the relative potencies of these compounds at 24h are representative of their relative potencies between 12 and 48 h. However, in Japanese quail hepatocytes, the relative potency of TCDF decreased in a time-dependent manner (up to 3.6-fold difference). These results suggest that the effect of time on the EROD-inducing potency of TCDD, PeCDF and TCDF in ring-necked pheasant and Japanese quail hepatocytes is compound- and species-specific, but experimental conditions could also be involved in the differences observed.

Topics: Animals; Benzofurans; Cells, Cultured; Coturnix; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Enzyme Induction; Galliformes; Hepatocytes; Polychlorinated Dibenzodioxins

The concentration dose response for aryl hydrocarbon receptor (AHR)-mediated CYP1A1 and CYP1A2 messenger RNA (mRNA) induction and enzyme activity was determined in primary cultures of rat and human hepatocytes for 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 2,3,7,8-tetrachlorodibenzofuran. Eleven different congener concentrations from 0.00001 to 100 nM were used, thus spanning seven orders of magnitude. The Hill model was used to obtain values of EC(x) and maximal response from the individual data sets. No-observed effect concentration values were derived using several statistical methods including Dunnett's test, the Welch-Aspin test, and step-down bilinear regression. Thresholds were estimated using baseline projection methods and a "hockey stick" fitting method. Human hepatocytes were less responsive and less sensitive with respect to CYP1A1 activity and mRNA induction than rats. On the other hand, the human CYP1A2 response was more robust than the response in rats but generally less sensitive. These data allow an evaluation of relative species sensitivities for developing interspecies toxicodynamic adjustment factors, for assessing AHR activation thresholds, and for evaluating relative congener potencies. Overall, these data support the position that humans are less sensitive than rats to these AHR-dependent end points and support the use of a data-derived adjustment factor of 1.0 or less for extrapolating between rats and humans.

Topics: Animals; Benzofurans; Cells, Cultured; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Dose-Response Relationship, Drug; Environmental Pollutants; Enzyme Induction; Gene Expression Regulation, Enzymologic; Hepatocytes; Humans; No-Observed-Adverse-Effect Level; Polychlorinated Dibenzodioxins; Rats; Receptors, Aryl Hydrocarbon; Risk Assessment; Species Specificity

Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls that have toxic equivalency factors (TEFs) were measured in serum of 946 subjects in five Michigan counties. The study was motivated by concerns about human exposure to dioxin-contaminated sediments in the Tittabawassee River (TR). Most of the toxic equivalency in TR sediments is from two furan congeners, 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-pentaCDF).. The individual with the highest adjusted (for age, age squared, and body mass index) serum level of 2,3,4,7,8-pentaCDF in the study (42.5 ppt) reported a unique history of raising cattle and vegetables in the floodplain of the TR. Interviews and serum samples were obtained from the index case and 15 other people who ate beef and vegetables raised by the index case. 2,3,4,7,8-pentaCDF in beef lipid was estimated to have been more than three orders of magnitude greater than background (1,780 vs. 1.1 ppt). The mean, median, and 95th percentile for serum 2,3,4,7,8-pentaCDF in the study control population were 6.0, 5.4, and 13.0 ppt, respectively, and were 9.9, 8.4, and 20.5 ppt among beef and vegetable consumers, respectively. Back extrapolation for the index case suggests that his increase in serum concentration of 2,3,4,7,8-pentaCDF above background may have been as high as 146 ppt.. Consumption of beef and/or vegetables raised on dioxin-contaminated soil may be an important completed pathway of exposure. RELEVANCE TO PUBLIC HEALTH PRACTICE: Animals and crops should not be raised for human consumption in areas contaminated with dioxins.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Benzofurans; Cattle; Humans; Michigan; Middle Aged; Soil Pollutants; Young Adult

Concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 2,3,7,8-tetrachlorodibenzofuran (TCDF) on cytochrome P4501A (CYP1A) induction were determined in primary cultures of embryonic herring gull (Larus argentatus) hepatocytes exposed for 24 h. Based on the concentration that induced 50% of the maximal response (EC50), the relative potencies of TCDD and TCDF did not differ by more than 3.5-fold. However, also based on the EC50, PeCDF was 40-fold, 21-fold, and 9.8-fold more potent for inducing ethoxyresorufin-O-deethylase (EROD) activity, CYP1A4 mRNA expression, and CYP1A5 mRNA expression than TCDD, respectively. The relative CYP1A-inducing potencies of PeCDF and of other dioxin-like chemicals (DLCs) in herring gull hepatocytes (HEH RePs), along with data on concentrations of DLCs in Great Lakes herring gull eggs, were used to calculate World Health Organization toxic equivalent (WHO-TEQ) concentrations and herring gull embryonic hepatocyte toxic equivalent (HEH-TEQ) concentrations. The analysis indicated that, when using avian toxic equivalency factors (TEFs) recommended by the WHO, the relative contribution of TCDD (1.1-10.2%) to total WHO-TEQ concentration was higher than that of PeCDF (1.7-2.9%). These results differ from the relative contribution of TCDD and PeCDF when HEH RePs were used; PeCDF was a major contributor (36.5-52.9%) to total HEH-TEQ concentrations, whereas the contribution by TCDD (1.2-10.3%) was less than that of PeCDF. The WHO TEFs for avian species were largely derived from studies with the domestic chicken (Gallus gallus domesticus). The findings of the present study suggest that it is necessary to determine the relative potencies of DLCs in wild birds and to re-evaluate their relative contributions to the biochemical and toxic effects previously reported in herring gulls and other avian species.

Topics: Animals; Benzofurans; Cells, Cultured; Charadriiformes; Cytochrome P-450 CYP1A1; Environmental Pollutants; Enzyme Induction; Hepatocytes; Polychlorinated Dibenzodioxins; RNA, Messenger

As part of an ongoing effort to understand aryl hydrocarbon receptor (AhR) mediated toxicity in mink, cDNAs encoding for CYP1A1 and the CYP1A2 mixed function monooxygenases were cloned and characterized. In addition, the effects of selected dibenzofurans on the expression of these genes and the presence of their respective proteins (P4501A) were investigated, and then correlated with the catalytic activities of these proteins as measured by ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-deethylase (MROD) activities. The predicted protein sequences for CYP1A1 and CYP1A2 comprise 517 and 512 amino acid residues, respectively. The phylogenetic analysis of the mink CYP1As with protein sequences of other mammals revealed high sequence homology with sea otter, seals and the dog, with amino acid identities ranging from 89 to 95% for CYP1A1 and 81 to 93% for CYP1A2. Since exposure to both 2,3,7,8-Tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) resulted in dose-dependent increases of CYP1A1 mRNA, CYP1A2 mRNA and CYP1A protein levels an underlying AhR-mediated mechanism is suggested. The up-regulation of CYP1A mRNA in liver was more consistent to the sum adipose TEQ concentration than to the liver TEQ concentration in minks treated with TCDF or PeCDF. The result suggested that the hepatic-sequestered fraction of PeCDF was biologically inactive to the induction of CYP1A1 and CYP1A2.

Topics: Animals; Benzofurans; Blotting, Western; Cloning, Molecular; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Environmental Pollutants; Enzyme Induction; Female; Kinetics; Liver; Mink; Oxazines; Phylogeny; Receptors, Aryl Hydrocarbon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sequence Analysis, DNA; Sequence Analysis, Protein; Sequence Homology, Amino Acid; Substrate Specificity

In 2005, the World Health Organization (WHO) - International Programme on Chemical Safety reevaluated the toxic equivalency factors (TEFs) for dioxin-like compounds and made changes that affect the calculation of the total toxic equivalent (TEQ). The impact of these changes on the TEQs for human blood and abiotic matrices such as soil and household dust has not been widely assessed or reported.. Using a major exposure study which examined blood, household dust, and soil levels of dioxin-like compounds in several regions of Michigan, we found the mean total TEQ was significantly reduced by 26%, 12% and 14% for serum, household dust, and soil, respectively, when the TEQ was based on the 2005 TEFs compared to the 1998 TEFs. The decrease in the serum total TEQ was largely due to the down-weighting of the TEFs for the majority of mono-ortho PCBs. In contrast, the decrease in the soil total TEQ was mostly due to the down-weighting of the TEF for 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (1998 TEF=0.5, 2005 TEF=0.3). For household dust, the decrease in total TEQ was not due to any single TEF but was due to small changes in a number of compounds. There was a dramatic decrease (-88%) in the mean and 95th percentile for mono-ortho PCB TEQ due to the 2005 TEFs.. These findings suggest that comparisons between studies based on the TEQ-WHO(98) and TEQ-WHO(05) may need to consider an appropriate conversion factor to assure comparability. Furthermore, the changes in TEFs may have impact in locations where regulations of soil contamination are triggered by specific TEQ levels.

Topics: Benzofurans; Dioxins; Dust; Environmental Exposure; Environmental Pollutants; Humans; Soil; World Health Organization

Since 1968, when the Yusho poisoning incident occurred, annual physical, dermatological, dental, and ophthalmological and laboratory examinations, collectively called Yusho health checks, have been conducted for Yusho patients. The Yusho incident was a health hazard caused by intake of rice-bran oil contaminated with PCB and PeCDF; therefore, since 2001 the levels of dioxins such as PeCDF in the blood have been measured in applicants. Here, we investigated correlations among findings from various medical examinations and those between those findings and PeCDF, PCB, and PCQ.. Subjects were Yusho patients who underwent Yusho annual health checks and had their levels of PeCDF measured between 2001 and 2004. The results of 4 years of health checks of those who underwent the health checks for 2 years or longer were aggregated to extract representative inspection items by principal component analysis. We also investigated the presence or absence of correlations among these items and PeCDF, PCB, and PCQ levels in blood.. Using 49 variables extracted by principal component analysis as objective variables, we determined that there were correlations between the following combinations: arthralgia, A/G ratio and PeCDF level, ophthalmological symptoms such as excessive eye discharge and PCB level, and total cholesterol, inferior gingival pigmentation and PCQ level.

Topics: Benzofurans; Dioxins; Food Contamination; Humans; Hydrocarbons, Chlorinated; Japan; Polychlorinated Biphenyls

The half-life of 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) in the Yusho patients has been reported to be approximately seven years. In the present study, we estimated the half-life of PeCDF using data from the medical check-ups of more than 300 Yusho patients. We performed linear regression analysis with a binary logarithm of PeCDF blood level in Yusho patients as the dependent variable, and the measurement year as the independent variable. Our results showed that there were many patients who had shown no reduction of their blood PeCDF level for several years. This result contradicts the previously reported half-life period. Therefore, we believe that a more complicated excretion model needs to be established to explain the discrepancy we found. We hypothesized that there might be two mechanisms of PeCDF assimilation in human digestive tract. In the present study, we also used our hypothesis to simulate PeCDF excretion in Yusho patients.

Topics: Benzofurans; Dioxins; Food Contamination; Half-Life; Humans; Models, Theoretical; Polychlorinated Biphenyls

While it has been reported that the blood level of dioxins and polychlorinated biphenyls in humans may be decreased by treatment with colestimide, the effects of the agent are still obscure. To address this issue, we examined the effect of Cholebine, a cholesterol lowering agent containing colestimide as an active ingredient, on the excretion of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) in rats. In a short term study, male Wistar rats (5 weeks-old) were given chows including 3% Cholebine (PenCDF/Chol group) or control chows (PenCDF group) for 7 days after administration of 14C-labeled PenCDF (0.5 mg/kg body weight, p.o.). On day 1, the fecal excretion of PenCDF in the PenCDF/Chol group was greater by 15% compared to that of the PenCDF group. Although some increases were also observed during day 2 and day 7, Cholebine did not exhibit any marked effect on the fecal excretion of PenCDF. The tissue concentrations of PenCDF at day 7 in the PenCDF/Chol group showed a 20%-30% decrease compared with those of the PenCDF group, except that the level in the brain was comparable between the two groups. The fecal excretion of PenCDF in a long term study (Cholebine treatment for 28 days) demonstrated the same tendency as that of short-term study. However, in long-term study, the Cholebine had no effect on the tissue concentration of PenCDF except for brain. An increase in PenCDF excretion by Cholebine seems to be due to the binding of Cholebine to bile acids as lipid carriers. This is because no binding of Cholebine to 14C-PenCDF was detected. These results suggest that Cholebine has little effect on the reabsorption of dioxin, whereas it reduces substantially the first absorption of dioxin.

Topics: Animals; Anticholesteremic Agents; Benzofurans; Bile Acids and Salts; Dioxins; Feces; Male; Rats; Rats, Wistar

Yusho (oil disease) is the name given to a food poisoning incident caused by rice bran oil that occurred in west Japan in 1968. The causative agents of Yusho are currently considered to be polychlorinated biphenyls (PCBs) and their by-products, such as dioxin like compounds. The levels of 2,3,4,7,8-penta-cholorodibenzofuran (PeCDF) are measured in the blood of Yusho patients who attend medical check-ups. The objectives of this study were to determine the half-life of PeCDF in these patients. Linear regression analysis was performed with the binary logarithm of PeCDF blood levels in Yusho patients as the dependent variable and the measurement year as the independent variable. The linear coefficient determined in this analysis is the reciprocal of the half-life. The half-life of PeCDF varied among patients. Among patients with PeCDF blood levels of 50pgg(-1) or higher, there were two groups: one showing a half-life of approximately 7 years and the other showing no reduction in PeCDF levels over time. The results indicate that there is a group of patients whose PeCDF levels are maintained at a high level. Our study suggests that a more complicated model is required to explain PeCDF excretion in humans.

Topics: Benzofurans; Female; Foodborne Diseases; Half-Life; Humans; Male; Polychlorinated Biphenyls

Results from previously published animal studies suggest that prenatal and postnatal exposure to dioxin and dioxin-like compounds (DLCs) may profoundly affect the reproductive system of both sexes via endocrine disruption. In the present work, we evaluate the toxicity and carcinogenicity of various DLCs, with an emphasis on their effect on the reproductive organs, induced by chronic exposure of female adult Harlan Sprague-Dawley rats. This investigation represents part of an initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For fourteen, thirty-one, or fifty-three weeks or for two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); 2,3',4,4',5-pentachlorobiphenyl (PCB118); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and PCB118. The ranges of treatment-related changes in the reproductive system included chronic active inflammation in the ovary that occurred in the 1,000 and 3,000 microg/kg core groups (two-year exposure) of PCB153 and in the 300 ng/3,000 microg/kg core group of binary mixture of PCB126 and PCB153. Increases in the incidence of acute and/or chronic active inflammation of the uterus were observed in all dosed groups, including the stop-exposure group (withdrawal after thirty-week exposure) of PeCDF and the 1,000 microg/kg and/or higher group dosed with PCB153. The incidence of cystic endometrial hyperplasia was marginally increased in the 92 PeCDF ng/kg group at two years. The incidence of squamous metaplasia was significantly increased in the 44 ng/kg and higher dose group, including the stop-exposure group. The incidence of uterine squamous cell carcinoma was significantly or marginally increased in the 6 ng/kg core and 100 ng/kg stop-exposure groups of TCDD and in the 300 ng/300 microg/kg core group that received the binary mixture of PCB126 and 153. The incidence of uterine carcinoma was marginally increased in the 92 ng/kg PeCDF group at two years and clearly increased in the 1,000 and 4,600 microg/kg PCB118 core group and the 4,600 microg/kg stop group. In the studies of PCB 126, the tertiary mixture, and the binary mixture of PCB126 and PCB118, no increased incidence of any change occurr

Topics: Administration, Oral; Animals; Benzofurans; Carcinogens; Carcinoma, Squamous Cell; Dioxins; Endometrial Hyperplasia; Female; Metaplasia; Ovary; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests; Uterine Neoplasms; Uterus

Wild mink (Mustela vison) living along the Tittabawassee River in central Michigan exhibit elevated hepatic and dietary polychlorinated dibenzofuran (PCDF) concentrations exceeding mink-specific, literature-reported toxicity reference values (TRVs) on a toxicity equivalents basis. However, no apparent effects on individuals or population are evident, suggesting that available TRVs may overpredict risk for the site-specific mix of congeners. To investigate this discrepancy, a 180-day spiked feed study was conducted to assess: (1) the dosages of key congeners necessary to achieve liver concentrations bracketing those observed in wild mink, (2) time to achieve steady-state concentrations, and (3) effect of coadministration of 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) on the toxicokinetics and distribution of each congener. Adipose and hepatic PCDF concentrations were measured at 0, 90, and 180 days. PCDF concentrations in mink scat were determined at several time points and indicated nearly complete absorption of both TCDF and 4-PeCDF from the diet. Elimination half-times of TCDF were < 15 h and were inversely proportional to dose, while those for 4-PeCDF were approximately 7-9 days with no clear dose dependency in the tested dose range. Coadministration of 4-PeCDF and TCDF accelerated clearance of TCDF compared to administration of TCDF alone. Clearance of 4-PeCDF was not affected by TCDF coadministration. Distribution of 4-PeCDF, but not TCDF, demonstrated increased hepatic sequestration with increasing dose. 4-PeCDF toxicokinetics were described using a previously published two-compartment model. Overall, the toxicokinetic information gathered here illustrates the impact of CYP1A1 induction on bioaccumulation and toxicity potential of TCDF and 4-PeCDF. This information may provide insight into why the current TRVs do not appear to correctly characterize the risk for these two congeners when they are the primary components of an environmental mixture.

Topics: Adipose Tissue; Animals; Benzofurans; Ecology; Female; Liver; Mink; Models, Biological

Cancer potency estimates were derived for 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) using data collected from the recently published National Toxicology Program bioassay in female Sprague-Dawley rats. By using a toxicokinetic model for 4-PeCDF, the dose-response relationship for combined liver tumors (hepatocellular adenomas and cholangiocarcinomas) in rats was assessed in terms of lifetime average liver concentration and lifetime average adipose concentration with data from both the lifetime and the stop-exposure components of the bioassay. Benchmark dose modeling was performed to estimate tissue concentrations at two points of departure (EC(10) and EC(01) and their 95% upper and lower confidence limits). The same toxicokinetic model with human input values was then used to back-extrapolate human equivalent doses that corresponded to the internal tissue concentration measures at the points of departure. Information regarding the cancer mode of action was used to support the development of several toxicity criterion values based on a nonlinear method, e.g., reference dose or tolerable daily intake. Nonlinear estimates of toxicity criteria based on observed noncancer toxic events as possible precursors to tumor formation were also derived and were similar in value to those based on combined liver tumors. For comparison purposes, linear estimates of cancer potency were also derived.

Topics: Animals; Benzofurans; Carcinogens; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms, Experimental; Rats; Rats, Sprague-Dawley

Polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins, and poly-chlorinated dibenzofurans adversely affect the health of humans and various animals. Such effects might be partially exerted through the thyroid hormone (TH) system. We previously reported that one of the hydroxylated PCB congeners suppresses TH receptor (TR)-mediated transcription by dissociating TR from the TH response element (TRE). However, the binding site of PCB within TR has not yet been identified.. We aimed to identify the functional TR domain responsible for the PCB-mediated suppression of TR action by comparing the magnitude of suppression using several representative PCB/dioxin congeners.. We generated chimeric receptors by combining TR and glucocorticoid receptor (GR) and determined receptor-mediated transcription using transient transfection-based reporter gene assays, and TR-TRE binding using electrophoretic mobility shift assays.. Although several PCB congeners, including the hydroxylated forms, suppressed TR-mediated transcription to various degrees, 2,3,7,8-tetrachlorodibenzo-p-dioxin did not alter TR action, but 2,3,4,7,8-pentachlorodibenzofuran weakly suppressed it. The magnitude of suppression correlated with that of TR-TRE dissociation. The suppression by PCB congeners was evident from experiments using chimeric receptors containing a TR DNA-binding domain (DBD) but not a GR-DBD.. Several nondioxin-like PCB congeners and hydroxylated PCB compounds suppress TR action by dissociating TR from TRE through interaction with TR-DBD.

Topics: Benzofurans; Cell Line; In Vitro Techniques; Polychlorinated Dibenzodioxins; Receptors, Thyroid Hormone

It usuallytakes a few weeks to analyze dioxin concentrations and dioxin-TEQ (toxicity equivalency quantity) in fluegases from municipal solid waste (MSW) incinerators by a standard method provided by Japanese industrial standard (JIS 0311). To reduce the required time for analysis, we have developed a new on-line measuring system for furans homologues. This system is composed of a sensitive and robust vacuum ultraviolet (VUV) single-photon ionization (SPI) ion trap (IT) time-of-flight mass spectrometer (VUV-SPI-IT-TOFMS) and automatic sampling/concentrating process. In this work, pentachloro-dibenzofuran (P5CDF) was selected as an index homologue in chlorinated dibenzo-p-dioxin/ furan homologues (DXNs) because its concentration and I-TEF (international toxicity equivalency factor), which are 2,3,4,7,8-P5CDF is 0.5 and 1,2,3,7,8-P5CDF is 0.05, are high and the concentration correlates closely with the total amount of dioxin-TEQ. The lowest detectable limit, 1 pg (0.001 ng-TEQ/m3 N) was demonstrated by laboratory tests. This system underwent a field test at several actual MSW plants and the tests revealed the following: (a) This system is applicable for dioxin-TEQ evaluation from actual MSW incinerators. (b) It can continuously monitor P5CDF in a fluegas for 7 months. (c) The frequency of the measurements is once every 2-6 h, depending on the concentration of P5-CDF.

Topics: Benzofurans; Calibration; Incineration; Mass Spectrometry; Online Systems; Waste Products

Kanemi Yusho is the name given to a 1968 food poisoning incident resulting from the ingestion of PCB contaminated rice bran oil that had been used as a heating medium. At the time, victims presented with mainly cutaneous manifestations and various other symptoms such as of the eyes and teeth, general fatigue, headaches, and paresthesia of the extremities. The characteristic symptoms then resolved with time. Yusho patients have been followed from immediately after the incident. Blood levels of dioxins such as PeCDF have been measured for those who wishing to since 2001.. The presence or absence of relationships between blood PeCDF level and various examination items/symptoms was investigated in 359 subjects whose blood levels of PCB-related chemical compounds such as PeCDF were measured in the Yusho related examinations between 2001 and 2003. Characteristic symptoms were also compared with the results of examinations done 15 years previously.. The average blood 2,3,4,7,8-PeCDF level in designated Yusho patients was 177.50 pg/g lipids; showing a markedly higher value than that of the normal control group (15.2 pg/g lipids). As well, the blood PeCDF level was related to PCB level, hexachlorobiphenyl level, urinary sugar, erythrocyte sedimetation rate (ESR) (2-hour), thymol and Na. There were also relationships with cutaneous findings (acneiform eruption and comedones), mucosal findings (oral pigmentation), constipation, numbness in the extremities, body weight loss, and abnormal abdominal ultrasonography. Symptoms seen in the skin and eyes in 2001 and 2003 had decreased compared with those in seen 1988. However, PCB and blood PeCDF levels remained high. Patients are continuing to present with mucosal and subjective symptoms as chronic conditions.

Topics: Benzofurans; Eye Diseases; Fatigue; Food Contamination; Headache; Humans; Japan; Oryza; Paresthesia; Plant Oils; Polychlorinated Biphenyls; Skin Diseases; Time Factors; Tooth Diseases

In the Yusho medical checkup, measurement of dioxin has been performed since 2001. Although the time trend of dioxin concentrations in blood from 2001 to 2005 has been reported for the whole measurement candidate, details in the trend are not known. Therefore, to verify the trend, we divided the Yusho patients into four quatertile groups based on the dioxin concentrations. About 39 years have passed since Yusho occurred, and it is said that a big change in the concentrations of 2,3,4,7,8-PeCDF in blood is now no longer seen. However, when the Yusho patients were divided into the four groups, a downward tendency was even now found in the higher dioxin groups, but not in the lower dioxin groups.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Female; Food Contamination; Humans; Japan; Male; Middle Aged; Oryza; Plant Oils; Polychlorinated Biphenyls; Time Factors

Kanemi Yusho was a food poisoning incident caused by rice bran oil that occurred in western Japan, particularly in northern Kyushu, in 1968. It is difficult to determine the symptoms in patients after many years since the occurrence. Techniques for measuring blood dioxins have advanced recently. More accurate data measurement has now become possible, and techniques for mass data analysis, such as data mining, have also advanced. It has also become possible to find unknown characteristics, even in an object group with elusive characteristics, by checking all the combinations in all the patients.. There are already several reports on the incidence of symptoms in Yusho patients. These reports are limited to symptoms in a single period, and there has been no analysis taking into account the time that has elapsed. Here, we evaluated the relationship between recent and past symptoms and 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) levels in the same subject patient, in order to demonstrate the correlation between PeCDF levels and symptoms at a time point close to the incident.. Subjects were examined for symptoms of Yusho and had blood PeCDF levels measured, both recently and in the past. Combinations were extracted using association analysis of data mining technique for comparison, which had strong correlations between the presence or absence of symptoms in the medical examination, tests including blood test, dermatological examination, dental examination and ophthalmologic examination in recent years (2001-2004) and the blood PeCDF levels and those between the presence or absence of past (1986-1989) symptoms and recent blood PeCDF levels.. Subjects with higher PeCDF levels were more likely to present with pigmentation, a symptom included in the diagnostic criteria for Yusho. Pigmentation was a commonly found symptom in the past. Past pigmentation was a common symptom in the present.. PeCDF levels were measured recently and therefore should not be compared directly with past symptoms. However, among the symptoms included in the diagnostic criteria, past symptoms tended to have a stronger relationship with PeCDF levels than did recent symptoms. We suggest that the present PeCDF level is strongly related to the past symptoms since the present PeCDF level is correlated with the past PeCDF level due to constant emission rate. More specifically, if the past PeCDF level is strongly related to the past symptoms, it can indirectly be concluded that the present PeCDF level is also strongly related to the past symptoms. Thus, the present PeCDF level cannot be related to the past symptoms directly but can indirectly.. Combining recent and past symptoms further demonstrated that clinical symptoms are strongly related to PeCDF toxicity. This may have resulted from the increase in symptoms with aging, however, it was demonstrated that the symptoms of each patient were relieved and become obscure.

Topics: Benzofurans; Biomarkers; Female; Food Contamination; Humans; Japan; Male; Oryza; Pigmentation Disorders; Plant Oils; Time Factors

A nation-wide questionnaire survey on the past history of diseases and symptoms was conducted in 2005. The questionnaire was administered by mail to the 1258 registered Yusho patients, inguiring about the past incidence of 15 regions of malignant neoplasm, 42 diseases, and 5 symptoms. Out of the 717 patients responded to the questionnaire, 34 patients born after the Yusho outbreak were excluded, leaving 683 patients as the study subjects. Their mean age (SD) was 62.7 (14.0) years, ranging from 39 to 97 years old. Seven percent of the patients acknowledged the past history of malignant neoplasm in one or more regions. More than 40% admitted the past history of dental diseases, pain of joints, numbness of limbs, fatigue, headache, cough and sputum. Osteoporosis and myoma of the uterus, respectively, were reported by 22.8% and 15.6% of women. 14.2% of men reported prostatic hypertrophy. Logistic regression analysis was performed to estimate the association of the past history of diseases with the blood lipid level of 2,3,4,7,8-pentachlorodibenzofuran adjusting for sex and age. In the whole study subjects, 306 patients were measured the PeCDF level once or more in the years from 2001 to 2005. We found statistically significant elevation of the proportion of the patients with the past history of prostatic hypertrophy with increasing blood lipid level of 2,3,4,7,8-PeCDF (P = 0.03). The marginally significant positive association between the proportion of the patients with the past history of hypertension and 2,3,4,7,8-PeCDF was observed (P = 0.06).

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Biomarkers; Comorbidity; Female; Food Contamination; Humans; Incidence; Japan; Lipids; Logistic Models; Male; Medical History Taking; Middle Aged; Neoplasms; Oryza; Plant Oils; Polychlorinated Biphenyls; Prostatic Hyperplasia; Stomatognathic Diseases; Surveys and Questionnaires

We measured the concentrations of polychlorinated dizenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and non-ortho coplanar polychlorinated biphenyls (non-ortho PCBs) in blood collected from 242 Yusho patients and 74 Yusho-suspected persons in 2004 and 237 Yusho patients and 114 Yusho-suspected persons in 2005. The sums of toxic equivalents (TEQ) concentrations of PCDDs, PCDFs, and non-ortho PCBs in the blood of Yusho patients in 2004 and 2005 were 126.1 and 124.2 pg TEQ/g lipid, respectively, and the concentrations were 3.4 and 3.3 times higher than those of normal controls that had been previously reported, respectively. Those of the Yusho-suspected persons were about 0.8 and 1.0 times higher than those of normal controls, respectively. Although the TEQ concentrations of PCDDs and non-ortho PCBs among Yusho patients, Yusho-suspected persons, and normal controls were nearly the same, the PCDFs levels of Yusho patients were about 9.8 and 9.5 times higher than those of normal controls in 2004 and 2005, respectively. The concentration of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF), which was the highest among PCDFs congeners for Yusho patients, was about 10. 6 and 10.2 times higher than that of the normal controls in 2004 and 2005, respectively. In the case of Yusho-suspected persons, the concentrations were 0.9 and 1.4 times higher than those of normal controls, respectively. However, some of the Yusho-suspected persons showed a high concentration of 2,3,4,7,8-PeCDF that was approximately 15 times greater than concentrations in normal controls. Of 74 Yusho-suspected persons measured in 2004, 7 persons were officially registered as Yusho patients based on the "New Diagnostic Criteria" that officially became the diagnostic criteria for Yusho exposure on September 29, 2004, which included a concentration of 2,3,4,7,8-PeCDF in the blood, and in 2005, 14 persons of 114 Yusho-suspected persons were officially registered as Yusho patients.

Topics: Benzofurans; Food Contamination; Humans; Japan; Oryza; Plant Oils; Polychlorinated Biphenyls; Time Factors

Dioxin and dioxin-related compounds have been associated with high incidences of pulmonary dysfunctions and/or cancers in humans. To evaluate the relative potencies of effects of these compounds, the National Toxicology Program completed a series of two-year bioassays which were conducted using female Harlan Sprague-Dawley rats. The rats were treated orally for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and a ternary mixture of TCDD, PCB126 and PeCDF. In addition to treatment-related effects reported in other organs, a variety of pulmonary lesions were observed that were related to exposure. Pulmonary CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was increased in all dosed groups. The most common non-neoplastic lesions, which occurred in all studies, were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm which occurred in all studies. A low incidence of squamous cell carcinoma was associated only with PCB126 treatment. Potential mechanisms leading to altered differentiation and/or proliferation of bronchiolar and alveolar epithelia may be through CYP1A1 induction or disruption of retinoid metabolism.

Topics: Administration, Oral; Animals; Benzofurans; Cytochrome P-450 CYP1A1; Female; Lung; Metaplasia; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Time Factors

The recent National Toxicology Program (NTP) cancer bioassays for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) permit a reevaluation of the current TEF value of 4-PeCDF. The data also allow for the derivation of relative potency factors (RPFs) for cancer, which are based not only on administered dose but also on potentially more informative dose metrics, such as liver concentration, area under the liver concentration curve, and lifetime average body burden. Our analyses of these data indicate that chi-squared tests of observed versus predicted liver tumor incidence for 4-PeCDF reject the current TEF value of 0.5 value as too high. 4-PeCDF RPFs were derived using estimation methods that either did or did not assume parallelism of the 4-PeCDF and TCDD dose-response curves. The resulting parallelism-based RPFs for administered dose, liver concentration at terminal sacrifice, liver concentration AUC, and lifetime average body burden are 0.26, 0.014, 0.021, and 0.036, respectively. The administered dose RPF estimate is approximately one-half the current TEF value of 0.5. However, the use of administered dose fails to take into account pharmacokinetic differences between congeners and the generally acknowledged belief that body burden or some other measure of cumulative dose is more appropriate for estimating the health risk posed by persistent chemicals. The other three dose metrics do account for these important factors, and the corresponding RPFs are at least 10-fold lower than the current TEF for 4-PeCDF. In summary, our analyses support an administered dose TEF no greater than 0.25 and one in the 0.05-0.1 range for internal dose metrics such as lifetime average liver concentration or body burden.

Topics: Area Under Curve; Benzofurans; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Monte Carlo Method; Tumor Cells, Cultured

Recent National Toxicology Program (NTP) cancer bioassay data for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and a mixture of these three compounds offer opportunities to assess the accuracy of current World Health Organization (WHO) 1998 toxic equivalency factors (TEFs) for these compounds under a variety of assumptions. An evaluation of the current TEF values for these compounds using body burden in nanograms per kilogram as the dose metric is presented. Average lifetime body burdens were estimated for all compounds at all dose groups based on measured tissue concentrations at 4 time points during the 2-yr NTP studies. Poly-3 adjusted tumor incidences for hepatocellular adenomas, cholangiocarcinomas, and the two tumors combined were modeled using a quantal multistage model and the Hill model with lifetime average body burden as the dose metric. Benchmark doses for a 10% response (BMD10) for each compound and the mixture were estimated. With TCDD as the reference standard, relative potency (REP) estimates were derived from ratios of the BMD10 estimates for PCB 126, 4-PeCDF, and for the toxic equivalent (TEQ) mixture. On a body-burden basis, PCB 126 and 4-PeCDF were 2- to 3-fold and 10- to 12-fold less potent than predicted based on the WHO TEFs, respectively, while the TEQ mixture was approximately 3- to 5-fold less potent than predicted by the TEFs. The current WHO TEF values, which were derived from data on noncancer endpoints evaluated on an administered dose basis, overpredict the carcinogenic potency of these compounds on a body-burden basis compared to TCDD.

Topics: Adenoma, Liver Cell; Adipose Tissue; Animals; Benzofurans; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Body Burden; Carcinogenicity Tests; Cholangiocarcinoma; Digestive System Neoplasms; Humans; Liver; Liver Neoplasms; Lung; Models, Biological; Organ Size; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Risk Assessment

DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in human tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) is not manufactured commercially other than for scientific research purposes. The main sources of PeCDF releases into the environment are from combustion and incineration sources. PeCDF was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. While one of the aims of the dioxin TEF evaluati

Topics: Animals; Benzofurans; Carcinogens; Female; Rats; Rats, Sprague-Dawley; Thyroid Hormones; Tissue Distribution

DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized, they accumulate in body tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) are not manufactured commercially other than for scientific research purposes. The main sources of TCDD and PeCDF releases into the environment are from metal smelting, refining, and processing; combustion and incineration sources; chemical manufacturing and processing; biological and photochemical processes; and existing reservior sources that reflect past releases. PCB mixtures were commercially produced and used in the electric power industry as dielectric insulating fluids in transformers and capacitors and used in hydraulic fluids, plastics, and paints. TCDD, PeCDF, and PCB 126 w

Topics: Administration, Oral; Animals; Benzofurans; Carcinogens; Female; Polychlorinated Biphenyls; Rats; Rats, Sprague-Dawley

We evaluated gingival toxicities induced by chronic exposure of female Harlan Sprague-Dawley rats to dioxin and dioxin-like compounds (DLCs) and compared them to similarly induced oral lesions reported in the literature. This investigation represents part of an ongoing initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and 2,3',4,4',5-pentachlorobiphenyl (PCB118); control animals received corn oil-acetone vehicle (99:1) alone. A full complement of tissues, including the palate with teeth, was examined microscopically. In the groups treated with TCDD and the mixtures of TCDD, PCB126, and PeCDF; PCB126 and 153; and PCB126 and 118, the incidences of gingival squamous hyperplasia increased significantly. Moreover, in the groups treated with TCDD, PCB126, and the mixture of PCB126 and 153, squamous cell carcinoma (SCC) in the oral cavity increased significantly. This investigation constitutes the first report documenting that chronic administration of dioxin-like PCBs can induce gingival SCC in rats. These results indicate that dioxin and DLCs target the gingiva of the oral cavity, in particular the junctional epithelium of molars.

Topics: Administration, Oral; Animals; Benzofurans; Carcinogenicity Tests; Carcinoma, Squamous Cell; Dioxins; Dose-Response Relationship, Drug; Drug Synergism; Female; Gingiva; Gingival Neoplasms; Hyperplasia; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Time Factors

Multimedia fate and multipathway human exposure models are widely adopted in assessments of toxicological risks of chemical emissions at the regional scale. This paper addresses the question of how much spatial detail is necessary in such models when estimating the intake by the entire population in large, heterogeneous regions such as Europe. The paper presents a spatially resolved multimedia fate and multipathway exposure model for Western Europe, available as IMPACT 2002. This model accounts for relationships between the location of food production and drinking water extraction as well as where population cohorts live relative to where chemical emissions occur. The model facilitates estimation of environmental concentration distributions, related levels of contaminants in foods, and the fraction of a chemical release that will be taken in by the entire human population (the intake fraction) at the regional scale. To evaluate the necessary spatial resolution, the paper compares estimates of environmental concentrations and the intake fraction from the spatially resolved model with the results of a consistent clone without spatial resolution. An evaluation for disperse emissions of PeCDF (2,3,4,7,8-pentachlorodibenzofuran, CAS# 5120731-4) suggests reasonable agreement with monitoring data for most impact pathways with both versions of the model, but that the generic vegetation models for estimating contaminant concentrations in agricultural produce require improvement. A broader comparison for a range of organic chemicals demonstrates that the nonspatial models are likely to be appropriate in general for assessing dispersed sources of emissions. However, it is necessary to include generic compartments in such nonspatial models to account separately for emissions that enter lakes with long residence times versus rivers that feed directly into seas. For assessing an emission source in a specific location, using models that are not spatially resolved can result in underestimation, or overestimation, of the population's intake by at least 3 orders of magnitude for some chemicals.

Topics: Benzofurans; Data Collection; Environmental Exposure; Environmental Monitoring; Europe; Forecasting; Humans; Models, Chemical; Multimedia; Organic Chemicals; Water Pollutants, Chemical

We employed DNA microarray to identify unique hepatic gene expression patterns associated with subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other halogenated aromatic hydrocarbons (HAHs). Female Harlan Sprague-Dawley rats were exposed for 13 weeks to toxicologically equivalent doses of four different HAHs based on the toxic equivalency factor of each chemical: TCDD (100 ng/kg/day), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF; 200 ng/kg/day), 3,3',4,4',5-pentachlorobiphenyl (PCB126; 1,000 ng/kg/day), or 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153; 1,000 microg/kg/day). Global gene expression profiles for each exposure, which account for 8,799 gene probe sets contained on Affymetrix RGU34A GeneChips, were compared by principal components analysis. The aryl hydrocarbon receptor (AhR) ligands TCDD, PeCDF, and PCB126 produced very similar global gene expression profiles that were unique from the nonAhR ligand PCB153, underscoring the extensive impact of AhR activation and/or the resulting hepatic injury on global gene expression in female rat liver. Many genes were co-expressed during the 13-week TCDD, PeCDF, or PCB126 exposures, including classical AhR-regulated genes and some genes not previously characterized as being AhR regulated, such as carcinoembryonic-cell adhesion molecule 4 (C-CAM4) and adenylate cyclase-associated protein 2 (CAP2). Real-time reverse-transcriptase polymerase chain reaction confirmed the increased expression of these genes in TCDD-, PeCDF-, and PCB126-exposed rats as well as the up- or down-regulation of several other novel dioxin-responsive genes. In summary, DNA microarray successfully identified dioxin-responsive genes expressed after exposure to AhR ligands (TCDD, PeCDF, PCB126) but not after exposure to the non-AhR ligand PCB153. Together, these findings may help to elucidate some of the fundamental features of dioxin toxicity and may further clarify the biologic role of the AhR signaling pathway.

Topics: Administration, Oral; Animals; Benzofurans; DNA Primers; Female; Gene Expression Profiling; Gene Expression Regulation; Hydrocarbons, Halogenated; Liver; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA

In human breast tissue, estrone (E(1)) and estradiol (E(2)) are mainly hydroxylated by cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) to 2-hydroxyestrogens (2-OHE(1/2)) and 4-hydroxyestrogens (4-OHE(1/2)), respectively. Several studies show that 4-OHE(1/2), but not 2-OHE(1/2), may act as a carcinogen and a high estrogen 4-/2-hydroxylation ratio appears to be a marker for the presence of neoplasms. In this study, we investigated the effects of several dioxin-like compounds on estrogen 2- and 4-hydroxylation in a malignant (MCF-7) and a nontumorigenic (MCF-10A) human mammary epithelial cell line. 2- and 4-methoxyestrogen (MeOE(1/2)) formations were used as measures of the 2- and 4-hydroxylation pathways, respectively. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), and 3,3'4,4',5,5'-hexachlorobiphenyl (PCB 169) concentration dependently induced 2-MeOE(1/2) formation and ethoxyresorufin-O-deethylation (EROD) activity through induced CYP1A1 expression in MCF-7 and MCF-10A cells. 2,3',4,4',5-pentachlorobiphenyl (PCB 118) had no such effect. Effects on CYP1B1 expression and 4-MeOE(1/2) formation were less pronounced; only TCDD caused an induction, whereas PCB 169 was a potent and selective inhibitor of 4-MeOE(1/2) formation (IC(50) 0.7 and 2.2 nM PCB 169 in MCF-7 and MCF-10A cells, respectively). MCF-10A cells were less responsive toward dioxin-like compounds and the apparent EC(50) values for CYP1A1 and CYP1B1 induction in this study were 10-100 fold higher than in MCF-7 cells. The constitutive 4-/2-MeOE(1/2) ratios were 2.99 +/- 0.78 and 0.93 +/- 0.40 in MCF-7 and MCF-10A, respectively. Incubation with dioxin-like compounds resulted in a concentration-dependent decrease in the 4-/2-MeOE(1/2) ratio, but an increase in potentially carcinogenic estrogen metabolites in both MCF-7 and MCF-10A cells. This indicates that even though the 4-/2-OHE(1/2) ratio may be used as indicator for the presence of neoplasms, it is readily lowered by dioxin-like compounds and its value as a prognostic parameter for cancer risk should be further examined.

Topics: 2-Methoxyestradiol; Aryl Hydrocarbon Hydroxylases; Benzofurans; Biomarkers, Tumor; Breast; Breast Neoplasms; Cell Line; Cell Survival; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Dioxins; Dose-Response Relationship, Drug; Epithelial Cells; Estradiol; Female; Humans; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (PCDF) are widespread environmental pollutants. TCDD is well known for its adverse effects on female reproduction when administered acutely to immature or adult rats. It is also known that fetal/neonatal exposure to this compound alters reproductive parameters. It is unknown whether exposure to PCDF causes similar adverse effects in offspring. The objectives of the study were to investigate the effects of in utero and lactational (IUL) exposure to TCDD and PCDF on subsequent growth, estrous cycles, and ovulation. Additionally a gonadotropin-primed immature rat model was used to investigate possible direct effects on the ovary after IUL exposure to TCDD (2.5 microg/kg) by evaluating 1) ovarian morphometrics and 2) serum estradiol concentrations. Body weights were reduced in animals with IUL exposure to TCDD and PCDF relative to those in controls at 10 days of age (P < 0.05 for each), and this difference was maintained until termination of the experiment at 125-165 days of age (P < 0.05). Exposure to TCDD or PCDF also disrupted regular estrous cycles and inhibited ovulation rate. On Day 23 (before eCG stimulation), ovaries from animals exposed to TCDD contained the same number of primordial, primary, secondary, preantral, and antral follicles as ovaries from control animals. On Day 25 (48 h after eCG stimulation), ovaries from TCDD-exposed rats had significantly fewer large preovulatory follicles when compared with ovaries from controls. The numbers of smaller follicles (both antral and small antral) were not different. Serum estradiol was significantly lower in TCDD-exposed animals 48 h after eCG stimulation.

Topics: Animals; Benzofurans; Chorionic Gonadotropin; Environmental Pollutants; Estradiol; Estrous Cycle; Female; Growth; Lactation; Ovarian Follicle; Ovary; Ovulation; Polychlorinated Dibenzodioxins; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Reproduction; Weight Loss

The abilities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB126), and mixtures of these xenobiotics (toxic equivalents, TEQs) to induce oxidative stress in hepatic and brain tissues of rats have been investigated after chronic (30 wk) exposure to these congeners. TCDD, PeCDF, PCB126, and TEQs were administered daily to groups of rats at doses that corresponded to their toxic equivalency factors (TEFs), and the biomarkers of oxidative stress, including the production of superoxide anion, lipid peroxidation, and DNA single-strand breaks (SSBs), were determined in hepatic and brain tissues at the end of the exposure period. The three chemicals caused similar dose-dependent increases in the production of superoxide anion, lipid peroxidation, and DNA SSBs, which plateaued at certain dose ranges, followed by secondary increases at the higher dose levels. Similar effects were also produced by the TEQs; however, the dose-dependent increases in the biomarkers of oxidative stress were continuous and never achieved plateau levels. Except for PCB126, where statistical analyses revealed greater productions of superoxide anion and lipid peroxidation in brain tissues as compared with hepatic tissues, no significant differences were revealed between the two tissues in response to the other xenobiotics or the TEQs. Nonsignificant differences were also revealed when comparing the effects induced by the TEQs with those induced by the individual chemicals.

Topics: Animals; Benzofurans; Brain; Dose-Response Relationship, Drug; Environmental Pollutants; Estrogen Antagonists; Female; Liver; Oxidative Stress; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley

The abilities of single doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce oxidative stress in hepatic and some extra-hepatic tissues of animals, are well documented. In this study we have investigated the induction of oxidative stress in hepatic and brain tissues of rats after subchronic (13 weeks) exposure to TCDD and two of its congeners, namely 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 3,3',4,4',5-pentachlorobiphenyl (PCB126). TCDD, PeCDF and PCB126 were administered daily to groups of rats at various doses, for 13 weeks, and biomarkers of oxidative stress, including the production of superoxide anion, lipid peroxidation and DNA-single strand breaks (SSBs), were determined in the hepatic and brain tissues at the end of the exposure period. The three congeners caused dose-dependent increases in the production of superoxide anion, lipid proxidation and DNA-SSBs, with maximal effects achieved at doses ranging between 10-100, 20-92, and 300-550 ng/kg per day for TCDD, PeCDF and PCB126, respectively. The doses that produce 50% of maximal responses by each of the xenobiotics in the hepatic and brain tissues were found to be within the ranges of 7-34, 13-32, and 137-400 ng/kg per day for TCDD, PeCDF and PCB126, respectively. The results of the study suggest that subchronic exposures to TCDD, PeCDF and PCB126 induce significant oxidative damage in the hepatic and brain tissues of rats, with more damage observed in the brain as compared to the hepatic tissues. Also, as inducers of oxidative stress in the hepatic and brain tissues, TCDD is the most potent among the three congeners and PCB126 being the least potent.

Topics: Animals; Benzofurans; Brain; Dose-Response Relationship, Drug; Female; Lipid Peroxidation; Liver; Oxidative Stress; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rats; Rats, Sprague-Dawley

The ubiquitous and persistent nature of polychlorinated aromatic hydrocarbons (PCAHs) in our environment and the risk of exposure to PCAHs have provoked concern over their potential toxicity. In humans, exposure to PCAHs is aimed chiefly at epithelial cells residing in the intestinal mucosa, because oral intake of contaminated food is a major source of PCAHs. The purpose of this study, therefore, was to examine the effects of chronic exposure to various PCAHs [i.e. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), and 2,2'4,4'5,5'-hexachlorobiphenyl (PCB-153)], given alone or as mixtures, on intestinal cholecystokinin (CCK) peptide and messenger RNA levels. We show that chronic PCAH treatment significantly lowers intestinal levels of stored CCK peptide. Intestinal CCK messenger RNA levels are not affected. In addition, 3,3',4,4',5-pentachlorobiphenyl treatment increased intestinal insulin-like growth factor-binding protein-3 levels in a dose-related manner. Acute 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment of intestinal CCK cells lowered levels of CCK-processing enzymes (i.e. prohormone convertase-1 and -2). Together, these data indicate that PCAHs may decrease intestinal levels of stored CCK peptide by affecting the intestinal insulin-like growth factor system and CCK processing.

Topics: Animals; Aspartic Acid Endopeptidases; Benzofurans; Cell Line; Cholecystokinin; Chromogranin A; Chromogranins; Duodenum; Female; Hydrocarbons, Aromatic; Hydrocarbons, Chlorinated; Insulin-Like Growth Factor Binding Protein 3; Intestinal Mucosa; Intestines; Mice; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Proprotein Convertase 2; Proprotein Convertases; Rats; Rats, Sprague-Dawley; RNA, Messenger; Subtilisins

The hepatic tumor-promoting activity of a mixture of polyhalogenated aromatic hydrocarbons (PHAHs) was studied in a medium term two-stage initiation/promotion bioassay in female Sprague-Dawley rats. The PHAH mixture contained 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,4,7, 8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118), 2,3,3',4,4', 5-hexachlorobiphenyl (PCB 156), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) and covered >90% of the total toxic equivalents (TEQ) present in Baltic herring. To determine possible interactive effects of di-ortho-substituted PCBs, the PHAH mixture was tested with (PHAH+) and without (PHAH-) PCB 153. Rats were initiated by a diethylnitrosamine injection (30 mg/kg body wt i.p.) 24 h after a partial 23 hepatectomy. Six weeks after initiation, the PHAH mixtures were administered once a week by subcutaneous injections for 20 weeks. Treatment with the PHAH mixtures caused liver enlargement and an increased activity of the hepatic cytochrome P4501A1/2 and P4502B1/2. All PHAH exposure groups exhibited an increased occurrence of hepatic foci positive for the placental form of glutathione-S-transferase. In the PHAH-group dosed 1 microgram TEQ/kg body wt/week, the volume fraction of the liver occupied by foci was significantly lower compared to the TEQ equivalent dosed TCDD group (3.8 vs 8.7%). The volume fraction was significantly increased in the groups treated with 0.5, 1, or 2 micrograms TEQ/kg body wt/week of the PHAH+ mixture (4.5, 5.2, and 6.6%, respectively) compared to the corn oil group (2.0%), but to a lower extent than expected on basis of the TEQ doses. Overall, the TEQ-based administered dose overestimated the observed tumor-promoting effects of this PHAH mixture. The applicability of the toxic equivalency factor concept, the role of differences in toxicokinetic properties and interactive effects of PCB 153 on hepatic deposition of the dioxin-like congeners are discussed.

Topics: Animals; Benzofurans; Cytochrome P-450 Enzyme System; Enzyme Induction; Female; Liver; Liver Neoplasms, Experimental; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Precancerous Conditions; Rats; Rats, Sprague-Dawley

Hepatic microsomes derived from Cypla2(-/-) knockout (KO) and parental strains of mice, C57BL/6N and 129Sv, were used to examine the specificity of methoxyresorufin and acetanilide as substrates for CYP1A2 activity. In addition, animals from each group were exposed to CYP1-inducing compounds. As expected, microsomes from untreated 1a2 KO mice did not have immunodetectable CYP1A2 protein; however, methoxyresorufin-O-demethylase (MROD, 25.5+/-6.1 pmol/min/mg protein) and acetanilide-4-hydroxylation (ACOH, 0.64+/-0.04 nmol/min/mg protein) activities were still present. Furthermore, induction of ethoxyresorufin-O-deethylase (EROD) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 1a2 KO mice was accompanied by a greater than 70-fold increase in MROD activity. In contrast, ACOH was only induced 2-fold by TCDD. As with 1a2 KO mice, the parental strains exposed to TCDD or 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) showed substantial EROD and MROD induction, whereas ACOH activity was induced to a lesser degree. PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) resulted in low levels of both EROD and MROD induction. Results indicate that both substrates are subject to metabolism by non-CYP1A2 sources, and the apparent contribution of CYP1A1 activity to methoxyresorufin metabolism makes MROD unsuitable for differentiating CYP1A1 and CYP1A2 activities in the mouse.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Enzyme Induction; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Microsomes, Liver; Oxazines; Oxidoreductases; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Substrate Specificity

We have been already contaminated with various chemicals including highly toxic organochlorine compounds such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 2, 3, 4, 7, 8-pentachlorodibenzofuran (PenCDF) and 3, 4, 5, 3', 4'-pentachlorobiphenyl (Co-PenCB). In this study, in order to evaluate the genotoxicity of the three chemicals, we have examined their effects on the induction of sister chromatid exchanges (SCEs), which has been frequently utilized as an indicator of biological and genetic damage due to exposure to carcinogens or mutagens, in cultured human lymphocytes in the absence or presence of 7, 8-benzoflavone (ANF) and the following results were obtained. 1) TCDD, PenCDF and Co-PenCB significantly increased the frequency of SCEs with almost the same dose-dependent manner in terms of the concentration of TCDD toxic equivalent. 2) 8 x 10(-5) MANF significantly enhanced the frequency of SCEs and the simultaneous treatment of ANF and either of TCDD, PenCDF or Co-PenCB seemed to exert an additive effect as SCEs inducer. 3) TCDD, PenCDF and Co-PenCB were considered to be very potent inducers of SCEs, because their 50% effective concentration in SCEs enhancement were only 5 to 10 times higher than the level of the adipose tissue in healthy Japanese, namely, 70ppt as TCDD. Consequently, the respective TCDD toxic equivalency factors of 0.5 and 0.2 for PenCDF and Co-PenCB seemed to be reasonable so far as the induction of SCEs was employed as an indicator of the genotoxic potency.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Benzofurans; Cells, Cultured; Female; Humans; Lymphocytes; Sister Chromatid Exchange

We investigated the cell toxicity of polychlorinated biphenyls (PCBs) and 2, 3, 4, 7, 8-pentachlorodibenzofuran (PCDF) as indicators of the optical density (280nm) which is total protein in HeLa cells. Furthermore, the reductive action of cytoactivator and antilipemic agents on the PCBs and PCDF toxicity were evaluated. The quantity of total cellular protein increased to 20% with the addition of sodium dextran sulfate (2.5%) at the presence of PCBs, and 25% in the case of PCDF. However, the slope of the curve of cell proliferation of HeLa cells at the presence of PCBs or PCDF became to overlap with a control group at the presence of any other drugs except for sodium dextran sulfate. These results mean that PCBs and PCDF cell toxicity were suppressed a little by sodium dextran sulfate, but the case of other cytoactivator and antilipemic agents did not.

Topics: Benzofurans; Cell Division; Cells, Cultured; Dextran Sulfate; HeLa Cells; Humans; Hypolipidemic Agents; Polychlorinated Biphenyls

Conditions have been established for H4IIE rat hepatoma cell cultures in which effects of cytochrome P-450 induction on the metabolism of a munitions wastestream pollutant can be studied. Under these conditions, the polychlorinated hydrocarbon 2,3,4,7,8-pentachlorodibenzfuran (PCDBF) induced cytochrome P-450 (1A1) aryl hydrocarbon hydroxylase (AHH) activity over a wide range of concentrations without significant cytotoxic effects. The munition pollutant 2,4-dinitrotoluene (2,4-DNT) did not induce AHH activity itself, but its metabolism was considerably altered when applied to PCDBF induced cultures. Production of amino nitrotoluene isomers was greatly enhanced in induced cultures as compared to uninduced controls, as was the conversion of radiolabeled 2,4-DNT to relatively more polar metabolites. To some extent, the results with H4IIE cells parallel those reported for animals exposed to 2,4-DNT after induction of cytochrome P-450 AHH activity. The preliminary findings suggest that with further development and validation, H4IIE cultures could be of use in characterizing metabolites that result from exposure to chemical mixtures involving a P-450 (1A1) inducer.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Carcinoma, Hepatocellular; Cell Survival; Cytochrome P-450 Enzyme System; Dinitrobenzenes; Enzyme Induction; Liver Neoplasms; Luminescent Measurements; Mutagenicity Tests; Oxidation-Reduction; Rats; Spectrophotometry, Ultraviolet; Tumor Cells, Cultured

Children secondarily exposed through their mothers to a toxic rice oil containing PCDFs and PCBs in the Yu-cheng incident have shown developmental delay even a decade after the incident. Forty-five serum samples were collected from these children in February 1991 ad small amounts analyzed for their contaminant content using sample enrichment and isotope dilution mass spectrometry. In about one-half the samples, detectable levels of PCDFs and PCBs could still be determined with average values for 2, 3, 4, 7, 8-PnCDF and 1, 2, 3, 4, 7, 8-HxCDF of 300 and 620 ng/kg serum lipid, respectively. The mean of the total PCBs on a whole weight basis was 7.5 micrograms/kg. These concentrations of PCDFs and PCBs are still 10 to 25 times higher than those from a matched control population. Although the serum levels did not correlate with developmental delays, those for the two PCDFs but not the total PCBs correlated with duration of breast feeding indicative of postnatal exposure. The results of this study suggest that estimation of past prenatal exposure of children to PCDFs is best carried out using current mother and not current child blood concentrations.

Topics: Adult; Benzofurans; Child; Cohort Studies; Female; Food Contamination; Gas Chromatography-Mass Spectrometry; Humans; Oryza; Plant Oils; Polychlorinated Biphenyls; Pregnancy; Prenatal Exposure Delayed Effects

The potency of 2,3,4,7,8-pentachlorodibenzofuran (P5CDF) and of three defined 2,3,7,8-TCDD-free mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs) to induce cleft palates in NMRI mice was studied. The data were compared with a dose-response curve for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The slope of the dose-response curve for P5CDF was the same as for TCDD. However, application of the International-TCDD-Toxic-Equivalency (I-TE) factor (NATO/CCMS 1988) of 0.5 overestimated the potency of the pentachlorinated congener about 2.5-fold under these experimental conditions, suggesting 0.2 as a TE factor. When assessing the cleft palate frequency on the basis of I-TEs and the weight of the substances, the potencies of the two PCDF mixtures studied were also clearly overestimated. This result was not substantially changed when using the TE factor of 0.2 for P5CDF. For the PCDD mixture studied, the cleft palate-inducing potency found largely agreed with the prediction when applying the I-TE factors. According to our data, the use of TE factors as calculated by the UBA/BGA (1985) or the NATO/CCMS (1988) are both conservative when attempting to assess the cleft palate incidence induced by PCDF mixtures in mice.

Topics: Animals; Benzofurans; Cleft Palate; Dose-Response Relationship, Drug; Drug Combinations; Female; Liver; Mice; Organ Size; Polychlorinated Dibenzodioxins; Polymers; Pregnancy; Risk Factors; Teratogens; Weight Gain

Our human bodies have already been contaminated with various chemicals including highly toxic organochlorine compounds such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 2, 3, 4, 7, 8-pentachlorodibenzofuran (PenCDF) and 3, 4, 5, 3', 4'-pentachlorobiphenyl (PenCB). In this study, in order to evaluate the genotoxicity of these three chemicals, we examined their effects on the induction of micronuclei, which has frequently been utilized as indicator of biological and genetic damage due to exposure to carcinogens or mutagens, in cultured human lymphocytes in the absence or presence of alpha-naphthoflavone (ANF) and the following results were obtained. 1)4 x 10(-5) M ANF alone significantly enhanced the frequency of micronuclei and the combination of ANF and either of TCDD, PenCDF or PenCB seemed to be additive as micronuclei inducers. 2) TCDD, PenCDF and PenCB significantly increased the frequency of micronuclei with almost the same dose-dependent manner in terms of the concentration of TCDD toxic equivalent. 3) TCDD, PenCDF and PenCB were considered to be very potent inducers of micronuclei, because their values of 50% effective concentration in micronuclei enhancement were around only 10 times higher concentration than that in healthy people, namely, 70ppt as TCDD. Consequently, the respective TCDD toxic equivalency factors of 0.5 and 0.2 for PenCDF and PenCB seemed to be reasonable so far as the induction of micronuclei was employed as an indicator of their genotoxic potency.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Benzoflavones; Benzofurans; Cells, Cultured; Humans; Lymphocytes; Micronucleus Tests; Mutagens; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

We investigated the cell toxicity of polychlorinated biphenyls (PCBs) and 2,3,4,7,8-pentachlorodibenzofuran (PCDF) as two kinds of indicator of the quantity of secreting protein, which is an HBV surface antigen (HBsAg) in PLC/PRF/5 cells, and the DNA of those cells was counted the radioactivity for dot hybridization method, respectively. Furthermore, the reductive action of ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on the PCBs and PCDF toxicity was investigated. HBsAg titer increased to 10 to 15% with the addition of CDCA at the concentration of 0.02 x 2(-6)%. However, the slope of the curve of DNA synthesis of HeLa cells at the presence of PCDF was gradually increased at the concentration of 0.02 x 2(-4)% of UDCA and CDCA, and it became to overlap with a control group while PCBs did not. These results mean that PCDF cell toxicity was suppressed a little by UDCA and CDCA, but the case of PCBs did not.

Topics: Benzofurans; Cell Division; Chenodeoxycholic Acid; DNA; HeLa Cells; Hemoglobin, Sickle; Humans; Polychlorinated Biphenyls; Ursodeoxycholic Acid

The polychlorinated biphenyls (PCBs) mixture, Aroclor 1254, is a weak inducer of aryl hydrocarbon hydroxylase (AHH) activity in rabbit lung. In contrast, 2,3,4,7,8-pentachlorodibenzofuran (PCDF), like 3-methylcholanthrene (3-MC), caused a 3-fold increase in pulmonary AHH activity. An important finding of the present studies was that AHH activity, whether assayed by the flourometric or HPLC methods, was dependent on the buffer used in the incubation mixture. The metabolism of benzo(a)pyrene (BP) to its oxidative metabolites, as assayed by HPLC, revealed that PCBs, PCDF and 3-MC pretreatments caused greater than 15-fold and about 3- to 4-fold increase in the formation of the tumorigenic metabolites 9,10- and 7,8-dihydrodiols, respectively. In contrast to 3-MC and PCDF, PCBs caused a 75% decrease in the formation of the K-region metabolite, BP-4,5-dihydrodiol. These studies strongly suggest that the catalysis of BP metabolism is mediated by more than one isoform of cytochrome P450 (P450).

Topics: Animals; Aroclors; Aryl Hydrocarbon Hydroxylases; Benzo(a)pyrene; Benzofurans; Chlorodiphenyl (54% Chlorine); Chromatography, High Pressure Liquid; Cytochrome P-450 Enzyme System; Lung; Male; Methylcholanthrene; Microsomes; Rabbits

Histologic changes in extraembryonic and embryonic tissues induced by 3 or 6 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin/kg (TCDD) or 80 micrograms 2,3,4,7,8-pentachlorodibenzofuran/kg/day (4-PeCDF) were studied 24 h after the last of four daily doses administered orally to C57BL/6N mice on days 10-13 of pregnancy. Both test compounds ruptured (1) the embryo-maternal vascular barrier in the labyrinth, which resulted in hemorrhage of embryonic blood into the maternal circulation, (2) the visceral yolk sac membrane with the embryonic blood from the vitelline vessels escaping into the uterine, exocelomic and amniotic cavities, and (3) the maternal vascular spaces of the placental periphery resulting in hemorrhages into the interconceptal space. The role of the hemorrhagic lesions in the induction of cleft palate and hydronephrosis by the two compounds remains to be investigated. The presence of embryonic nucleated erythroblasts that hemorrhaged into the maternal lacunar network allowed the identification of maternal venous channels in the placenta. It revealed that (1) the labyrinth could be tentatively divided into two caudocranially oriented zones, an arterial and a venous zone; (2) the maternal blood in the labyrinthine lacunae circulated from the arterial to the venous zone, somewhat parallel to the uterine axis; and (3) the largest maternal vessels in the center of the placenta hitherto named the "central maternal artery," was in fact, venous.

Topics: Animals; Benzofurans; Embryo, Mammalian; Erythroblasts; Erythrocytes; Female; Fetomaternal Transfusion; Liver; Maternal-Fetal Exchange; Mice; Mice, Inbred C57BL; Placenta; Polychlorinated Dibenzodioxins; Pregnancy

We investigated the cell toxicity of polychlorinated biphenyls (PCBs) and 2,3,4,7,8-pentachlorodibenzofuran (PCDF) as an indicator of the quantity of m-RNA, which synthesizes the HBV core antigen region, and secreting protein, which is an HBV surface antigen in PLC/PRF/5 cells. The determination of m-RNA was conducted according to the methods of reverse transcriptase and polymerase chain reaction. Furthermore, the reductive action of ursodeoxycholic acid, shou-saiko-to and inchin-gorei-san on the PCBs and PCDF toxicity was investigated. The cell number of 1 x 10(5)/ml and concentrations of 200 micrograms/ml for PCBs and 500 microM for PCDF were used in these experiments. The titer of HBsAg was gradually increased from 1 in 1 x 10(3)/ml of cell numbers to 100 in 1 x 10(6)/ml of cell numbers. The curve became a plateau in 1 x 10(6)/ml of cell numbers. The cell number of 1 x 10(5)/ml was used in the experiments. The titer of HBsAg decreased following in the increase of concentration of PCBs. The HBsAg, even in the PCBs concentration of 1000 micrograms/ml showed a titer of 22.5%. However, the highest concentration of PCDF in this study, that is, 500 microM of PCDF, did not show any decrease of HBsAg activity. The concentrations of 200 micrograms/ml for PCBs and 500 microM for PCDF were used in the investigation of drug effects. A high titer HBsAg was observed in high concentrations of shou-saiko-to in comparison with a control group. Ursodeoxycholic acid and inchin-gorei-san exhibited a similar tendency.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Benzofurans; Cell Division; Cell Line; Drugs, Chinese Herbal; In Vitro Techniques; Polychlorinated Biphenyls; Ursodeoxycholic Acid

An effect of 2,3,4,7,8-pentachlorodibenzofuran (PCDF) as a promoter on a course of experimental skin carcinogenesis in mice by chemicals 20-methylcholanthrene (MC) has been proved by our previous studies. Details of ultrastructural epidermal alterations induced by MC and PCDF were observed and an attempt to differentiate benign tumor from malignant one in which a combined application of MC and PCDF on mice skin resulted was done electron microscopically. Four significant findings as follows were detected. First of all even the epidermal cells without tumor had some atypicality. Secondly both of benign tumor and normal-appeared skin without tumor had giant and round-shaped keratohyalin granules (KHGs) which show a tendency of less keratinization. Thirdly cytoplasmic projections of epidermal cells increased in number and sparse tonofilaments scattered in the cytoplasm of benign tumor. This is also an appearance of mucous metaplasia of keratinocytes as well as the form of KHGs mentioned above. Finally benign tumor had thick horny cells including numerous lipid droplets, and that is a sign of acceleration of epidermal turn over. Since epidermal cells have little chance to be exposed to carcinogens when they quickly keratinize, they rarely form a cancer. When epidermal cells have such tendency as less keratinization or more keratinization, they are supposed to be less sensitive to any stimuli of carcinogens, and consequently they incline to be benign tumor instead of malignant one.

Topics: Animals; Benzofurans; Methylcholanthrene; Mice; Skin; Skin Neoplasms

Previous studies showed that 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) could produce tumors in the liver and subcutaneous tissues of rats by subcutaneous administration. The present study has examined the carcinogenicity of the same compounds in rats by oral administration. Wistar strain male rats were sacrificed at two years after oral administration (0.2 mg/rat) of 2,3,4,7,8-PenCDF or 1,2,3,4,7,8-HCDF. Among rats given 2,3,4,7,8-PenCDF, a cholangiohepatoma and a osteosarcoma were revealed in a rat each. Moreover, a few hepatic nodules were found in two rats in each experimental group. These results suggest that these compounds of polychlorinated dibenzofurans have a tumorigenic potency by oral administration.

Topics: Administration, Oral; Animals; Benzofurans; Male; Neoplasms, Experimental; Rats; Rats, Inbred Strains

Treatment of 25-day-old female Sprague-Dawley rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly lowered constitutive uterine peroxidase activity and decreased uterine wet weights in a dose-response fashion. In cotreatment studies with 17 beta-estradiol, 2,3,7,8-TCDD antagonized the increase in uterine peroxidase activity and uterine wet weights, and these effects persisted for up to 156 hr. In the rat uterus, the antiestrogenic affects of two potent Ah receptor agonists, 2,3,7,8-TCDD and 2,3,4,7,8-pentachlorodibenzofuran, were comparable at a dose of 80 micrograms/kg, whereas the weaker Ah receptor agonist, 1,2,4,7,8-pentachlorodibenzo-p-dioxin, was relatively inactive at this dose. These results show that 2,3,7,8-TCDD antagonizes a well-characterized estrogen-induced response (uterine peroxidase activity), and the structure-activity data suggest that the Ah receptor is involved in mediating the antiestrogenic responses in target cells/organs.

Topics: Animals; Benzofurans; Dioxins; Estradiol; Estrogen Antagonists; Female; Kinetics; Organ Size; Peroxidase; Polychlorinated Dibenzodioxins; Rats; Rats, Inbred Strains; Receptors, Aryl Hydrocarbon; Receptors, Drug; Structure-Activity Relationship; Uterus

2,3,7,8-Tetrachlorodibenzo-p-dixoin 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are highly toxic members of a class of environmental contaminants, the polychlorinated aromatic hydrocarbons (PCAH), which exhibit a similar and highly characteristic spectrum of toxic effects. For purposes of risk assessment, it is important to be able to make accurate estimates of the relative potency of these and related compounds. Previous investigations have indicated that, in acute exposure or in vitro studies, PCDF is approximately 0.1 times as toxic and HCDF is approximately 0.01 times as toxic as TCDD. In this study, we compared the relative toxicity and tumor-promoting abilities of TCDD, PCDF, and HCDF in hairless mouse skin. Female hairless mice (HRS/J hr/hr) were treated dermally with the initiator MNNG, then dosed twice weekly for 20 weeks with acetone, TCDD (2.5-10 ng/mouse/dose), PCDF (25-100 ng/mouse/dose), or HCDF (250-1000 ng/mouse/dose) as promoter. TCDD, PCDF, and HCDF were all potent promoters for the induction of squamous cell papillomas. There was, however, no difference in the incidence or multiplicity of papilloma formation between groups. The same doses of the three PCAH, in the absence of initiator, induced no skin papillomas. TCDD produced a significant increase in liver:body weight ratio (p less than 0.001) at all doses and a decrease in thymus:body weight ratio at a dose of 10 ng (p less than 0.001). Mice treated with PCDF and HCDF had marked thymic and splenic involution, liver hypertrophy, mucous cell hyperplasia in the fundic portion of the glandular stomach, and loss of body weight. PCDF and HCDF produced a greater incidence and severity of dermatotoxic effects than TCDD. Based on data for dermal toxicity and changes in body weight and organ weights, PCDF is estimated to be 0.2 to 0.4 times, and HCDF 0.08 to 0.16 times, as toxic as TCDD following repeated dermal exposure. Therefore, toxic equivalence factors generated using data from acute and/or in vitro studies may underestimate the risk from repeated low-dose exposures to these compounds.

Topics: Animals; Benzofurans; Carcinoma, Squamous Cell; Dioxins; Female; Hypertrophy; Liver; Mice; Mice, Hairless; Papilloma; Polychlorinated Dibenzodioxins; Skin; Skin Diseases; Skin Neoplasms

Changes in the structure and function of aged skin may alter percutaneous absorption of environmental compounds such as the halogenated aromatic hydrocarbons. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and 2,3,4,7,8-penta-chlorodibenzofuran (4PeCDF) were previously found to be poorly absorbed in 3 months male Fischer 344 rats within 3 days after dermal administration. In order to examine age-related changes in dermal absorption and changes in potential for systemic exposure, the absorption, distribution, and elimination of TCDD and 4PeCDF were examined in male Fischer 344 rats of various ages (TCDD: 10, 36, and 96 week; 4PeCDF: 10, 36, 64, 96, and 120 week). Each compound was applied at a dose of 0.1 mumol/kg and/or 0.04 mumol in 60 microliters acetone to a preclipped region of the back and covered with a stainless-steel perforated cap. Rats were housed in individual metabolism cages for 3 days. Dermal absorption of both compounds was decreased in older age groups compared to 10 week rats. The major tissue depots for both compounds were liver, adipose, skin, and muscle and in comparable age groups, the liver:fat ratio was greater in 4PeCDF-treated animals. Age-related changes in the distribution of the administered dose and the absorbed dose varied with the compound as well as the depot. Elimination of TCDD and 4PeCDF was limited at all ages. Results indicate that percutaneous absorption of these compounds is decreased in older animals, suggesting that systemic bioavailability may be decreased in older organisms following dermal exposure to TCDD or 4PeCDF.

Topics: Aging; Animals; Benzofurans; Body Composition; Dioxins; Feces; Male; Polychlorinated Dibenzodioxins; Rats; Rats, Inbred F344; Skin Absorption; Tissue Distribution

Two forms of cytochrome P-450 (P-450) from liver microsomes of hamsters treated with 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), which possesses the potent acute toxicity and 3-methylcholanthrene (MC)-type inducing ability of liver microsomal monooxygenases in animals, were purified and characterized. These P-450 forms, designated as hamster P-450H and hamster P-450L, had the molecular masses of 52 and 50 kDa, respectively, and showed the absorption maximum of CO-reduced difference spectra at 446 nm. The absolute spectra of their oxidized forms indicated that hamster P-450H was in high-spin state and hamster P-450L was in low-spin state. A part of PenCDF injected into hamster was tightly bound to purified hamster P-450H at a ratio of 0.107 nmol PenCDF/nmol P-450. In a reconstituted system, both hamster P-450H and hamster P-450L showed relatively low catalytic activities for 3-hydroxylation of benzo[a]pyrene and O-deethylations of both 7-ethoxyresorufin and 7-ethoxycoumarin, while they both catalyzed 7 alpha- and 2 alpha-hydroxylations of testosterone effectively to a similar extent. Addition of cytochrome b5-to a reconstituted system accelerated the formation of 7 alpha-hydroxytestosterone 5.3-fold with hamster P-450L and 2.2-fold with hamster P-450H. In addition, hamster P-450H catalyzed estradiol 2-hydroxylation at a high rate but hamster P-450L did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Animals; Benzofurans; Cricetinae; Cytochrome P-450 Enzyme System; Enzyme Induction; Isoenzymes; Male; Mesocricetus; Microsomes, Liver; Molecular Sequence Data

Fischer 344 rats were exposed acutely to 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) during the organogenic period to evaluate its potential as an inducer of teratogenic and embryolethal effects. All dams were treated by gavage with a single dose of 0, 30, 100, or 300 micrograms 4-PeCDF/kg body wt on gestation Day (gd) 8, 10, or 12. An additional treatment group was included on gd 12 and administered 10 micrograms 4-PeCDF/kg body wt po. All animals were killed on gd 20 and maternal and fetal toxicities were assessed. Determination of embryotoxicity involved both soft tissue and skeletal examinations. 4-PeCDF induced a dose-related decrease in corrected maternal weight gain following treatment on gd 8 and 10, as well as resulted in a concomitant increase in the liver/body weight ratios, first evident at 30 micrograms/kg for all 3 days of exposure. The maternal thymus weight decreased relative to body weight compared with those of controls. Embryo-fetal toxicity was evident from the high mortality (greater than 80%) observed at 300 micrograms/kg for all 3 days of exposure. Mean fetal weight, a sensitive indicator of fetal toxicity, decreased compared to that of controls at 30, 100, and 300 micrograms/kg following treatment on either gd 8, 10, or 12.4-PeCDF induced cleft palate in survivors at a dose of 300 micrograms/kg for all 3 days of exposure. In conclusion, 4-PeCDF is maternally and fetally toxic regardless of the gestation day of exposure, but induced terata only at doses where overt maternal and fetal toxicity were observed, in contrast to previously reported studies in the mice where teratogenic effects were observed at nonfetotoxic dose levels. Thus, the mouse may be a more sensitive model for evaluating specific toxic responses induced prenatally following exposure to the structurally related polyhalogenated aromatic hydrocarbons which include the dioxins, furans, biphenyls, and naphthalenes.

Topics: Animals; Benzofurans; Body Weight; Female; Fetus; Gestational Age; Male; Organ Size; Pregnancy; Rats; Rats, Inbred F344; Teratogens

2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are environmental contaminants which mimic many of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Like TCDD, these polychlorinated dibenzofurans (PCDFs) induce hepatic benzo[a]pyrene hydroxylase activity (BPH) and possess high affinity for the Ah receptor. Another similarity of these PCDFs to TCDD is their ability to induce teratogenic effects such as cleft palate and hydronephrosis in mice. Recent studies have shown that TCDD modifies the equilibrium binding kinetics of the rat liver cytosolic glucocorticoid receptor (GRc) and the hepatic plasma membrane epidermal growth factor (EGF) receptor. To gain a better understanding of the action of halogenated hydrocarbons on these cytosolic and membrane-bound receptor systems during pregnancy, we investigated the biochemical effects of PeCDF and HCDF on the binding kinetics of maternal mouse liver GRc and EGF receptors and the induction of BPH activities. Pregnant C57BL/6N mice were treated once daily on gestation Days 10 through 13 with PeCDF (0-30 micrograms/kg) or HCDF (0-300 micrograms/kg). Hepatic [3H]dexamethasone and [125I]EGF equilibrium binding studies indicated that all doses of PeCDF tested (10, 20, and 30 micrograms/kg) significantly reduced the GRc and EGF receptor maximum binding capacities but did not affect the binding affinities of these receptors when compared to corn oil-treated control pregnant mice. Similar effects were observed for doses of HCDF greater than or equal to 100 micrograms/kg. These data suggest that the dibenzofuran-mediated decreases in GRc and EGF receptor binding capacities are similar to those caused by TCDD. Although the mechanism of action is not yet clear, our results indicate that halogenated aromatic compounds in addition to TCDD have profound effects on both steroid and growth factor receptor systems.

Topics: Animals; Benzofurans; Dose-Response Relationship, Drug; ErbB Receptors; Female; Liver; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Pregnancy; Receptors, Glucocorticoid

The hamsters have been known to be the least sensitive mammalian species to the acute toxicity of highly toxic polyhalogenated hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. In the present study, the tissue distribution, inductive effect of liver enzymes and acute toxicity of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) in male Golden Syrian hamsters were examined. The highest content (about 48% of dose) of PenCDF was found in the liver 5 days after a single i.p. dose of 1.0 mg/kg. The amount ranging about 5 to 10% of dose was also distributed to mesentery, skin and muscle. In liver, the distribution of PenCDF was just parallel to that of cytochrome P-450 (P-450), marker enzymes of liver endoplasmic reticulum, suggesting that PenCDF binds to P-450. The mode of inductive effects of PenCDF in hamsters was 3-methylcholanthrene-type as reported previously in rats. However, the typical enzymes such as benzo(a)pyrene 3-hydroxylase and DT-diaphorase were induced to a relatively less extent than did in rats. In hamsters pretreated with PenCDF at a dose of 0.5 mg/kg, the potent atrophy of thymus and the 3-fold increase of liver lipid peroxide were observed, whereas the body weight gain was not suppressed at all. These results suggest that the induction of liver enzymes and the atrophy of thymus might not be the direct cause of PenCDF-induced lethality in hamsters.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Benzopyrene Hydroxylase; Cricetinae; Cytochrome P-450 Enzyme System; Enzyme Induction; Liver; Male; Mesocricetus; Tissue Distribution

Two isomers of polychlorinated dibenzofurans, 2,3,4,7,8-pentachlorodibenzofuran or 1,2,3,4,7,8-hexachlorodibenzofuran, both of which are present in the yusho patients, were subcutaneously administered to rats in a single non-lethal dose to examine acute or subacute toxicity. Maximal inhibition of increase in body weight and decrease in daily locomotor activity were observed in the rats treated with 370 micrograms/kg of these compounds at 3 to 4 weeks after treatment, especially with 2,3,4,7,8-pentachlorodibenzofuran. Histopathologically, hypertrophy of the liver and atrophy of the thymus were noted at 4 weeks after treatment with this dose, while bile duct hyperplasia in the liver was observed at 40 weeks after treatment with 250 micrograms/kg of these compounds.

Topics: Animals; Benzofurans; Body Weight; Dose-Response Relationship, Drug; Liver; Male; Motor Activity; Rats; Rats, Inbred Strains; Time Factors

In order to examine the carcinogenicity of 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran, these two chemicals were subcutaneously administered to Wistar strain male rats at the dose of 80 micrograms, 40 micrograms or 4 micrograms per rat. At sacrifice in two years after the start of the experiment, tumors were observed in the subcutaneous tissue and the liver. Although the number of the rats used is small, the tumor occurrence showed some tendency to relate with the dose of the chemicals given.

Topics: Animals; Benzofurans; Fibroma; Fibrosarcoma; Lipoma; Liver Neoplasms, Experimental; Male; Rats; Rats, Inbred Strains; Skin Neoplasms

To ascertain whether 2,3,4,7,8-pentachlorodibenzofuran (PCDF) has the possibility of cocarcinogen, three different concentrations of 0.5, 1 and 5 ppm PCDF was evaluated in the course of experimental carcinogenesis in mice. Concerning the difference of total number of tumors occurred among the groups of mice with various treatments, the mice treated with 0.5 ppm PCDF and 20-methylcholanthrene (MC) have produced twice as many tumors as those of the other groups. Then the adequate concentration of PCDF to be a promoter was supposed to be 0.5 ppm. Two kinds of tumors were seen in mice which were treated by MC with or without PCDF, and there was no difference of tumors between the groups by appearance and pathologically. One is a benign papilloma, and the other is a squamous cell carcinoma which tends to keratinize and looks like a keratoacanthoma. The latter had a tendency to arise much more four weeks after the treatments had been done, even though the number of the former increased gradually. There was no evidence that PCDF of these concentrations could permeate through the skin and could be toxic. Furthermore PCDF seemed to neither stay nor act directly on the follicular epithelium, since there was no acne formation on the back skin of mice. One of the possible factors to cause malignant changes of epidermal cells was supposed to be a prolonged inflammation of the skin.

Topics: Animals; Benzofurans; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Methylcholanthrene; Mice; Skin Neoplasms

Polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs) are toxic environmental contaminants which have the potential to accumulate in human tissues. In order to examine the potential for systemic exposure following dermal exposure, the absorption, distribution, and elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1PeCDF), and 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) were evaluated in male F344 rats. TCDD (0.00015, 0.001, 0.01, 0.1, 0.5, and 1.0 mumol/kg) and the three PCDFs (0.1, 0.5, and 1.0 mumol/kg) were applied to a preclipped region on the back of the rat and covered with a perforated cap. The rats were held in individual metabolism cages for 3 days. In animals administered 0.1 mumol/kg, the absorption of TCDF was greater than that of 4PeCDF, 1PeCDF, and TCDD. Relative absorption (percentage of administered dose) declined with increasing dose while the absolute absorption (microgram/kg) increased nonlinearly with dose. Absorption of TCDF at 0.1 mumol/kg was 48% of the administered dose which was significantly greater than that of the other compounds. At this dose, absorption of 4PeCDF was greater than that of TCDD. Absorption at the higher doses was similar for all four compounds. Maximum relative absorption of TCDD (approximately 40% of the administered dose) was obtained at 0.001 and 0.00015 mumol/kg. Major tissue depots for these four chemicals included liver, adipose, skin, and muscle tissue; however, the liver:fat ratio for 4PeCDF was approximately fourfold higher than that for the other three compounds. When normalized to 100% of dose absorbed, the distribution of 4PeCDF-derived radioactivity in liver and adipose tissue was similar to that previously observed after oral and iv administration. In animals administered 0.1 mumol TCDF or 1PeCDF/kg, 56 and 32% of the respective absorbed dose was excreted as polar metabolites within 3 days. Very little of the absorbed dose of either TCDD (approximately 10%) or 4PeCDF (approximately 2%) was eliminated. Results indicate that the dermal absorption of these compounds is incomplete and that systemic toxicity following acute dermal exposure to levels found in the environment is unlikely.

Topics: Administration, Cutaneous; Animals; Benzofurans; Dioxins; Dose-Response Relationship, Drug; Environmental Pollutants; Feces; Industrial Waste; Male; Polychlorinated Dibenzodioxins; Polymers; Rats; Rats, Inbred F344; Skin Absorption; Tissue Distribution

1,2,3,7,8-Pentachlorodibenzofuran (1PeCDF) is one of several toxic polychlorinated dibenzofurans (PCDFs) which are ubiquitous environmental contaminants. Related in structure and toxicity to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), PCDFs have been detected in municipal and industrial effluents, PCB mixtures, and in a variety of antiseptics and preservative solutions. The objective of this study was to evaluate the distribution and elimination of 1PeCDF in the rat and to compare these parameters with that of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) and 2,3,7,8-tetrachlorodibenzofuran (TCDF). After iv administration of 0.1 mumol [3H]1PeCDF/kg, 1PeCDF was rapidly cleared from the blood and distributed to the liver, muscle, skin, and adipose tissue in a manner similar to that for other dibenzofurans. The initial pool sizes of 1PeCDF-derived radioactivity in the liver, muscle, skin, and adipose tissue were 43,35,10, and 7% of the administered dose, respectively. In all cases, loss of radioactivity from these tissues could be described by exponential decay and the initial half-lives for these tissues were 1.36, 0.03, 13, and 1 day, respectively. After redistribution from the muscle, skin, and adipose tissues to the liver, 1PeCDF was metabolized to a polar metabolite(s) and excreted from the body via the bile into the feces. No parent compound was detected in the bile and fecal excretion was the major route of elimination. Most of the radioactivity in the urine was excreted within the first day, after which less than 0.5% of the dose/day was detected. More than half of the administered dose was excreted in the urine and feces within 2 days. The whole-body half-life of related compounds is 4PeCDF much greater than 1PeCDF greater than or equal to TCDF. Therefore, persistence appears to be inversely related to the metabolism of these compounds and metabolism is inhibited by chlorine-substituted carbon atoms adjacent to the oxygen atom in the dibenzofuran ring.

Topics: Animals; Benzofurans; Bile; Environmental Pollutants; Feces; Lethal Dose 50; Male; Rats; Rats, Inbred F344; Structure-Activity Relationship; Tissue Distribution

Polychlorinated dibenzofurans are ubiquitous environmental pollutants which have great potential for human exposure. To characterize the toxicity of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), male F344 rats were administered a single oral dose of 0, 100, 250, 500, 1000, or 2000 micrograms 4PeCDF/kg. A progressive and dose-dependent loss of body weight was evident by 3 days after treatment. Signs of toxicity included piloerection, hair loss, hypoactivity, morbidity, and death. Death occurred as soon as 14 days after treatment and continued throughout the 35-day observation period. The LD50/35 was estimated to be 916 micrograms/kg with a 95% confidence interval of 565-1484 micrograms/kg. Dose-dependent increases were observed in serum cholesterol, triglyceride, and bile acid concentrations and in sorbitol dehydrogenase and aspartate aminotransferase activities. The hematocrit, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentrations were depressed in a dose-dependent fashion. Hepatic ethoxyresorufin-O-deethylase (EROD) activity was increased in all treatment groups approximately 25 times above that of control animals. Lymphoid depletion in the thymus and spleen was observed in the three highest doses and thymic atrophy was present at all dose levels. Absolute liver weight and the liver:body weight ratio were significantly increased above controls. Hepatotoxicity was dose-dependent and was characterized by lipid accumulation resulting in hepatocytomegaly. Epithelial hyperplasia and focal ulcerations of the forestomach was observed in animals administered 500 micrograms 4PeCDF/kg. Spontaneous cardiomyopathy was exacerbated by treatment with 2000 micrograms/kg. Since 4PeCDF and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produce a similar spectrum of toxic effects, the biochemical mechanism(s) of toxicity for these chemicals may be similar.

Topics: Animals; Benzofurans; Bile Acids and Salts; Body Weight; Cholesterol; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Lethal Dose 50; Liver; Macaca mulatta; Male; Organ Size; Oxidoreductases; Rats; Rats, Inbred F344; Triglycerides

The toxicity and disposition of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), a ubiquitous and acutely toxic environmental contaminant, was examined in three adult male Rhesus monkeys administered a single iv dose of 34 micrograms (0.1 mumol)/kg. Within 20 min, 4PeCDF was eliminated from the blood and was distributed to the liver, skin, adipose, and muscle tissues. Excretion occurred primarily via the feces with a minimum whole body half-life approximately 38 days. Within 7-14 days after administration, the packed cell volume and serum triglyceride and bile acid concentrations were significantly increased while serum cholesterol, protein, and albumin concentrations were decreased relative to pretreatment levels. Thyroid hormone levels were also altered with an increase in TSH and a decrease in T3 and T4 concentrations. After 28 days, two monkeys began exhibiting alopecia, hyperkeratinization of the toe and finger nails, facial chloracne-like lesions, and loss of body weight. They subsequently died 40 and 48 days after treatment. Similar symptoms of toxicity were observed in the third animal 58 days after 4PeCDF administration, but this animal appeared to fully recover and was administered 4PeCDF orally and [3H]1,2,3,7,8-pentachloro-dibenzofuran (1PeCDF) dermally 238 days after the initial iv dose. In this animal, approximately 2% of an oral dose of [14C]-4PeCDF was absorbed from the stomach and small intestine in 6 hr and was distributed mainly to the muscle and skin and less than 99% of a dermal dose of 1PeCDF remained at the site of application. Pathological findings in the monkeys that died indicated hyperplastic and metaplastic changes in the gastric mucosa, the Meibomian glands of the eyelid, and the ceruminous glands of the ear. Regression of these lesions was present in the surviving animal. Therefore, 4PeCDF produces dioxin-like toxicity in the monkey similar to that reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in the same dose range.

Topics: Absorption; Animals; Benzofurans; Body Weight; Carbon Radioisotopes; Environmental Pollutants; Gastric Mucosa; Half-Life; Macaca mulatta; Male; Muscles; Polychlorinated Dibenzodioxins; Thyroid Hormones; Tissue Distribution

1. The effect of activated charcoal beads on the faecal excretion of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), a causal agent of yusho, which accumulates in the body, was studied for 12 weeks in rats. 2. Diets supplemented with 1% and 5% activated charcoal beads stimulated faecal excretion of PenCDF about 2- and 4-fold, respectively. The concentration of PenCDF in liver, the major storage site, was decreased significantly and dose-dependently by the treatment. 3. The charcoal bead treatment decreased the extent of fatty liver, thymic atrophy, and induction of hepatic benzo[a]pyrene hydroxylase.

Topics: Animals; Benzofurans; Charcoal; Chromatography, Gas; Dose-Response Relationship, Drug; Enzyme Induction; Feces; Liver; Male; Rats; Rats, Inbred Strains; Time Factors

The disposition of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), a highly toxic environmental contaminant which accumulates in human tissues, was examined in the male Fischer rat after iv and oral exposure. Greater than 70% of an oral dose of 0.1, 0.5, or 1.0 mumol PeCDF/kg body wt was absorbed by the gastrointestinal system. After either oral or iv administration of 0.1 mumol/kg, the dibenzofuran was rapidly removed from the blood and accumulated in the liver and adipose tissue and to a lesser extent in the skin and muscle. Three days after administration, 70% of the iv dose of PeCDF was found in the liver, 7% in the fat, 1% in the skin, and 0.5% in the muscle. Route of exposure had little effect on tissue distribution. TLC analyses indicated that greater than 99% of the [14C]-PeCDF-derived radioactivity which had accumulated in the liver and adipose tissue was unmetabolized PeCDF which was eliminated very slowly (t1/2 = 193 and 69 days, respectively). The whole body half-life calculated from the daily fecal excretion rate was approximately 64 days. Excretion occurred primarily via the feces. No radioactivity was detected in expired air and less than 0.02% was detected in the urine. TLC analysis of fecal extracts indicated greater than 90% of the [14C]PeCDF-derived radioactivity in the feces was polar metabolites of the parent compound. Pretreatment with 500 micrograms PeCDF/kg body wt caused biliary excretion to nearly double. Treatment of bile with beta-glucuronidase or arylsulfatase had little effect on the chromatographic profile. Therefore, PeCDF was readily absorbed from the gastrointestinal tract, concentrated primarily in the liver, and was slowly eliminated from the body as polar metabolites. The long half-life and high body burden of PeCDF suggest that the toxicity of this chemical may be enhanced due to bioaccumulation upon chronic low-level exposure.

Topics: Animals; Benzofurans; Bile; Half-Life; Intestinal Absorption; Male; Rats; Rats, Inbred F344; Tissue Distribution

Topics: Animals; Benzofurans; Liver; Male; Rats; Rats, Inbred Strains; Tissue Distribution

Enhancement of diethylnitrosamine(DENA)-induced hepatic tumor production in rats was observed by sequential exposure to 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) or 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF). This effect was more evident in the group of rats treated with 2,3,4,7,8-PenCDF (80 micrograms/rat), in which approximately 43% of this compound administered was accumulated in the liver at 8 weeks after the last treatment.

Topics: Animals; Benzofurans; Body Weight; Diethylnitrosamine; Liver Neoplasms, Experimental; Male; Polymers; Rats; Rats, Inbred Strains; Thymus Gland

Topics: Animals; Benzofurans; Biological Availability; Carbon; Coal Ash; Cyprinidae; Dioxins; Furans; Goldfish; Mass Spectrometry; Particulate Matter; Polychlorinated Dibenzodioxins; Stereoisomerism; Water Pollutants; Water Pollutants, Chemical

The present paper describes a marked induction of liver microsomal cytochrome P-450 and cytosolic DT-diaphorase to cause possible disorder of steroid homeostasis and promotion of carcinogenicity of 4-nitroquinoline N-oxide (4-NQO) in rats by pretreatment with 3,4,5,3',4'-pentachlorobiphenyl (PenCB) or 2,3,4,7,8-pentachlorodibenzofuran (PenCDF). The animals were sacrificed 5 days after the pretreatment. These induction experiments showed that 7 alpha-hydroxylation of both progesterone and testosterone in liver microsomes was selectively increased to a great extent, but hydroxylations at the 2 alpha-, 6 beta- and 16 alpha-positions were depressed, together with 5 alpha-reduction. From the same microsomes, three of the strongly induced P-450 isozymes, i.e., high- and low-spin P-448s and P-452, were purified. The last isozyme was most responsible for 7 alpha-hydroxylation of testosterone. The pretreatment, also increased activity of DT-diaphorase and reduction of 4-NQO about 10-fold in liver 9000g supernatants. This reduction of 4-NQO was solely catalyzed by DT-diaphorase and the only product was 4-hydroxylaminoquinoline N-oxide, a proximate carcinogen, indicating that the pretreatment strongly increased production of a proximate carcinogen from 4-NQO. Such an enhancement of the metabolic activation of 4-NQO by the pretreatment was also observed to some extent in the lung and the skin. Persistency of PenCB and PenCDF in the liver of rats was also discussed.

Topics: 4-Nitroquinoline-1-oxide; Animals; Benzofurans; Carcinogens; Cytochrome P-450 Enzyme System; Enzyme Induction; In Vitro Techniques; Isoenzymes; Male; Microsomes, Liver; Polychlorinated Biphenyls; Quinone Reductases; Rats; Rats, Inbred Strains; Steroids

Topics: Adipose Tissue; Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Dioxins; Liver; Lung; Male; Mice; Mice, Inbred Strains; Polychlorinated Biphenyls

Topics: Animals; Benzofurans; Enzyme Induction; Male; Microsomes, Liver; Rats; Rats, Inbred Strains

Topics: Animals; Benzofurans; Feces; Liver; Male; Rats; Rats, Inbred Strains; Squalene; Stimulation, Chemical

The tissue and subcellular distributions of 14C-2,3,4,7,8-pentachlorodibenzofuran (PenCDF), one of the most important causal agents of yusho, were studied using rats. More than 60% of the radioactivity given orally was accumulated in the liver after 5 d and this high percentage persisted over a period of 3 weeks. Subcellular fractionation of the liver homogenate showed unusual separation by PenCDF-pretreatment, but the distribution of radioactivity was just parallel to those of cytochrome P-450 content and glucose-6-phosphatase (EC3.1.3.9) activity. Gas chromatographic analysis provided evidence that the extracts from the liver and its subcellular fractionations contained only unchanged PenCDF. Those results strongly suggest that PenCDF has some affinity to endoplasmic reticulum of rat liver.

Topics: Animals; Benzofurans; Chromatography, Gas; Cytochrome P-450 Enzyme System; Endoplasmic Reticulum; Feces; Glucose-6-Phosphatase; Male; Microsomes, Liver; Rats; Rats, Inbred Strains; Subcellular Fractions; Tissue Distribution

Topics: Benzofurans; Carbon Radioisotopes