benzofurans and 3-4-5-3--4--pentachlorobiphenyl

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

Emerging evidence supports that exposure to persistent organic pollutants (POPs) can impact the interaction between the gut microbiota and host. Recent efforts have characterized the relationship between gut microbiota and environment pollutants suggesting additional research is needed to understand potential new avenues for toxicity. Here, we systematically examined the direct effects of POPs including 2,3,7,8-tetrachlorodibenzofuran (TCDF), 2,3,7,8-tetrachlorodibenzo-

Topics: Animals; Bacteria; Benzofurans; Carbon; Cecum; Citric Acid Cycle; Gastrointestinal Microbiome; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Persistent Organic Pollutants; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Protein Transport; Pyruvic Acid

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

The concentrations of POPs (persistent organic pollutants) including 16 compounds of OCPs, 12 dioxin-like PCBs congeners, and 17 PCDDs/Fs congeners were determined in 46 human adipose tissue samples gathered from Jordanian citizens. Thirteen adipose tissue samples of healthy people were collected from Jordan University Hospital and 33 adipose tissue samples of cancer-affected patients were collected from King Hussein Cancer Center. All samples were extracted, cleaned-up, and analyzed using GC/MS. In the healthy person's samples, among the OCP compounds, the highest concentration was found for heptachlor-oxo-epoxide (5696.71 μg/kg), while among the PCB congeners, the non-ortho PCB 126 shows the highest TEQ concentrations (5554.5 μg TEQ/kg) and among the PCDDs/Fs congeners, the highest TEQ value was found for the congener 2,3,4,7,8-PeCDFs (5.93 μg TEQ/kg). For the cancer-affected patient's samples, the highest concentration among the OCP compounds was found for o,p-DDT (638.7 μg/kg), while among the PCBs congeners, the highest TEQ value was found for the non-ortho-PCB 126 (3366.24 μg TEQ/kg) and among the PCDDs/Fs congeners, the highest TEQ value was found for the congener 1,2,3,7,8-PeCDDs (20.64 μg TEQ/kg). OCP concentration level in adipose tissue samples for healthy people was 32 times higher than for cancer patient persons, while the TEQ values for dioxin-like PCB concentrations in adipose tissue samples of healthy people was 2.2 times higher than in the samples of cancer-affected patient and the TEQ values for PCDDs/Fs in adipose tissue samples of cancer-affected patient was 3 times higher than in the samples of healthy people.

Topics: Benzofurans; DDT; Dibenzofurans, Polychlorinated; Dioxins; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Female; Furans; Gas Chromatography-Mass Spectrometry; Humans; Jordan; Male; Neoplasms; Pesticides; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

Products of animal origin represent the main route of human exposure to dioxins and dioxin-like PCBs (DL-compounds). Recently, concerns have been raised about ovine products, particularly the liver, in which relatively high levels of DL-compounds have been reported. We surveyed ovine and bovine livers in areas with no known sources of dioxin or DL-PCB contamination, in order to assess accumulation patterns for both DL-compounds and non-DL (NDL-) PCBs. None of the ovine and bovine samples exceeded the current Maximum Limits (MLs) for DL-compounds. Liver DL-compound TEQ concentrations were up to 5-fold higher in sheep than in cows. No statistically significant differences in total NDL-PCBs levels were found. The main contributors to TEQ levels were the Penta- and Hexa-chlorinated PCDFs and PCB 126. The results confirm the increased bioaccumulation in ovine liver towards specific DL-compounds even in ewes reared in areas with no known sources of PCDD/Fs or DL-PCBs contamination.

Topics: Animals; Benzofurans; Cattle; Dibenzofurans, Polychlorinated; Female; Humans; Italy; Liver; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Sheep; Species Specificity

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), pentachlorobenzene (PeCBz) and hexachlorobenzene (HxCBz), which are listed in the Stockholm Convention, are commonly known as unintentionally produced persistent organic pollutants (UPOPs). As municipal waste incinerators (MWIs) have burgeoned in China, the emission of UPOPs is of great concerns. Compared to the extensive studies of PCDD/Fs emission, not much information of non-dioxin UPOPs (i.e., PCBs, HxCBz, and PeCBz) is available. In the present study, samples from raw gas (RG) after boiler, stack gas (SG) after air pollution control devices (APCDs) and fly ash (FA) samples were collected from typical MWIs in China. The analyses of SG samples indicate that PCDD/Fs are the major contributor to TEQ value, but non-dioxin UPOPs are the dominant compounds in terms of mass concentration. The mean emission factors of dl-PCBs, PeCBz, and HxCBz in SG are 0.372, 144, and 84.7 μg/t, respectively. In contrast with gaseous samples, FA contains higher mass concentration of PCDD/Fs and PCBs than that of PeCBz and HxCBz. In terms of homologues distribution of PCBs, di- to tetra-CBs were the predominant species in both SG and FA samples. PCB-126 is the major contributor to the TEQ concentration. The comparison of UPOPs composition in SG and RG samples shows that activated carbon adsorption process is capable of removing most PCDD/Fs, but less efficient for the removal of non-dioxin UPOPs.

Topics: Air Pollutants; Benzofurans; China; Chlorobenzenes; Coal Ash; Dibenzofurans, Polychlorinated; Environmental Monitoring; Environmental Restoration and Remediation; Gases; Hexachlorobenzene; Incineration; Industrial Waste; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

Caffeic acid derivatives (CADs) are well-known phytochemicals with multiple physiological and pharmacological activities. This study aimed to investigate the combined protective effects of CADs on PCB126-induced liver damages and oxidative stress in mice. Here, we used chemiluminescence and chose chlorogenic acid (CGA), salvianolic acid B (Sal B) as the best antioxidants. Then, mice were intragastrically administered with 60mg/kg/d CGA, Sal B, and CGA plus Sal B (1:1) for 3 weeks before exposing to 0.05mg/kg/d PCB126 for 2 weeks. We found that pretreatment with CGA, Sal B, and CGA plus Sal B effectively attenuated liver injury and cytotoxicity caused by PCB126, but improved the expressions of superoxide dismutase (SOD), glutathione reduced (GSH), heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2), CGA plus Sal B especially, was found to have the best effects that indicated a synergetic protective effect. Taken together, as the Nrf2 regulates the cyto-protective response by up-regulating the expression of antioxidant genes, we suggested that CGA plus Sal B had a combined protection on PCB126-induced tissue damages and that the Nrf2 signaling might be involved.

Topics: Animals; Antioxidants; Benzofurans; Biomarkers; Chlorogenic Acid; DNA Damage; Drug Synergism; Environmental Pollutants; Heme Oxygenase-1; Liver; Male; Membrane Proteins; Mice, Inbred ICR; Molecular Structure; Oxidative Stress; Polychlorinated Biphenyls

This study provides, for the first time, a baseline evaluation of dioxin-like biological activity in sediments and fish sampled in- and adjacent to anchorages along the Mediterranean and Red Sea coasts of Israel. It indicates the effect of past pollution, still present in the sediments of older Israeli harbors, with putative contribution of still existing sources of pollution. A commercial reporter gene bioassay was used to evaluate the biological activity of dioxin-like compounds extracted from the samples. HRGC/HRMS analysis of several samples contributed a profile of dioxin-like compounds in sediments and fish. The results point out 1,2,3,4,6,7,8-HeptaCDD, 2,3,4,6,7,8-HexaCDF, 1,2,3,4,6,7,8-HeptaCDF, РСВ-126 and РСВ-118 as major contributors to the dioxin-like activity in sediments. It indicates polychlorinated biphenyls non-selective absorption in fish livers, in contrary to a biased accumulation of poorly chlorinated and more potent dibenzodioxins and dibenzofurans.

Topics: Animals; Benzofurans; Biological Assay; Dioxins; Environmental Monitoring; Fishes; Genes, Reporter; Geologic Sediments; Indian Ocean; Israel; Liver; Mediterranean Sea; Polychlorinated Biphenyls; Tissue Extracts; Water Pollutants, Chemical

Both dioxins/dioxin-like compounds and polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants and cause multiple adverse health effects on human and wildlife. Cyp1a is the most commonly used biomarker induced by these pollutants through activation of the aryl hydrocarbon receptor (AhR) pathway. Here we generated Tg(cyp1a:gfp) transgenic zebrafish for establishing a convenient in vivo assay for analysing these xenobiotic compounds. The Tg(cyp1a:gfp) larvae at 4 day post-fertilization were tested with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and GFP induction was observed mainly in the kidney, liver and gut. Similar GFP expression was also induced strongly by two dioxin-like chemicals, co-planar polychlorinated biphenyl (PCB126) and polychlorinated dibenzo-p-furan (PeCDF) and relatively weakly by two PAHs, 3-methylcholanthrene (3-MC) and benzo[a]pyrene (BAP). The lowest observed effective concentration (LOEC) of TCDD was estimated to be ∼1 pM and the EC50 (effective concentration to induce GFP in 50 % of Tg(cyp1a:gfp) larvae) was ∼10 pM. PCB126 and PeCDF had ∼10× lower potencies in GFP induction than TCDD, while the potencies for 3-MC and BAP were at least 1000× lower. The sensitivity of Tg(cyp1a:gfp) larvae to respond TCDD was also favourable compared to that of ethoxyresorufin-O-deethylase (EROD) assay in both zebrafish larvae and adult livers. As GFP-based assay in transgenic zebrafish can be easily accommodated in multi-well dishes, the Tg(cyp1a:gfp) zebrafish should provide not only a valuable biomonitoring tool for aquatic contaminants but also a potential high-throughput chemical screening platform for identification of new AhR agonists.

Topics: Animals; Animals, Genetically Modified; Benzofurans; Biological Assay; Cytochrome P-450 CYP1A1; Female; Liver; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polymers; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Zebrafish

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

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 toxic equivalency factor (TEF) approach recommended by the World Health Organization is used to quantify dioxin-like exposure concentrations for mixtures of polychlorinated dibenzo-dioxins, -furans, and polychlorinated biphenyls (PCBs), including 2,3,7,8-tetrachlorodibenzofuran (TCDF) and 3,3',4,4',5-pentachlorobiphenyl (PCB126) relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Whole-genome microarrays were used to evaluate the hepatic gene expression potency of TCDF and PCB126 relative to TCDD with complementary histopathology, tissue level analysis, and ethoxyresorufin-O-deethylase (EROD) assay results. Immature ovariectomized C57BL/6 mice were gavaged with 0.001, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, and 300 μg/kg TCDD and TEF-adjusted doses (TEF for TCDF and PCB126 is 0.1) of TCDF or PCB126 (1, 3, 10, 30, 100, 300, 1000, and 3000 μg/kg of TCDF or PCB126) or sesame oil vehicle and sacrificed 24 h post dose. In general, TCDD, TCDF, and PCB126 tissue levels, as well as histopathological effects, were comparable when comparing TEF-adjusted doses. Automated dose-response modeling (ToxResponse Modeler) of the microarray data identified 210 TCDF and 40 PCB126 genes that exhibited sigmoidal dose-response curves with comparable slopes when compared with TCDD. These similar responses were used to calculate a median TCDF gene expression relative potency (REP) of 0.06 and a median PCB126 gene expression REP of 0.02. REPs of 0.02 were also calculated for EROD induction for both compounds. Collectively, these data suggest that differences in the ability of the liganded aryl hydrocarbon receptor:AhR nuclear translocator complex to elicit differential hepatic gene expression, in addition to pharmacokinetic differences between ligands, influence their potency in immature ovariectomized C57BL/6 mice.

Topics: Animals; Benzofurans; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Environmental Pollutants; Female; Gene Expression; Ligands; Liver; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Organ Size; Ovariectomy; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; RNA, Messenger; Toxicogenetics

Reports indicate that toxic equivalency factors (TEFs) based primarily on rodent data do not accurately predict in vitro human responsiveness to certain dioxin-like chemicals (DLCs). To investigate this in cells responsive to dioxins and relevant to chloracne, normal human epidermal keratinocytes were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and several DLCs, each with a TEF value of 0.1, representing three classes of congeners. We estimated half maximal effective concentration (EC50)-based donor-specific relative potency (REP) values for cytochrome P450 1A1 (CYP1A1) messenger RNA (mRNA) induction for TCDD, 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,6,7,8-hexachlorodibenzofuran (HxCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126). We also determined EC50-based population-level REP values (n = 4) for CYP1A1 mRNA induction for TCDD, HxCDF, and PCB 126. Furthermore, an alternative factor, the relative threshold factor (RTF) based on the low end (threshold) of the dose-response curve, was calculated. Our results demonstrated that HxCDF had a population-based REP value of 0.98, 9.8-fold higher than its assigned TEF value of 0.1. Conversely, PCB 126 had an REP value of 0.0027 and an RTF of 0.0022, 37-fold and 45-fold less than its assigned TEF of 0.1, respectively. The REP values for HxCDD and TCDF were 0.24 and 0.10, respectively, similar to their assigned value of 0.1. Therefore, although the DLCs tested in the current study all possessed the same assigned TEF value of 0.1, congener-specific differences in REPs and RTFs were observed for human keratinocytes. These congener-specific discrepancies are likely because of differences in interspecies factors that have yet to be defined.

Topics: Animals; Benzofurans; Cell Line, Tumor; Cell Survival; Cytochrome P-450 CYP1A1; Dioxins; Dose-Response Relationship, Drug; Environmental Pollutants; Gene Expression Regulation, Enzymologic; Humans; Keratinocytes; Polychlorinated Biphenyls; Rats; Risk Assessment; RNA, Messenger; Species Specificity

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

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

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 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

The Biobio River basin, located in central Chile, is one of the most important freshwater resources for a population of 1 million inhabitants. The river receives discharges of pulp mills, sewage treatment plants and there is a diffuse input of materials coming from the drainage basin. Previous studies reported high levels of etoxyresorufin-O-deethylase (EROD) induction in fish from the lower stretch of the river, mainly due to polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) exposure. The present study investigates polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzo-furans (PCDFs) levels as well as EROD induction in fish livers from Central Chile's Biobio River. Dioxin and furan levels in fish livers are reported for the first time in three areas of the Basin. In all samples the highest concentrations were found for the octachlorodibenzo-p-dioxin (OCDD) and PCDD/F TEQ concentrations ranged from 2.83 to 6.33 ppt (wet weight). The results indicate a clear induction of EROD activity in different fish species as the river mouth is approached, although this induction is not clearly related with dioxin and furan levels found in the fish livers. Our results clearly show that other pollutants might be acting as EROD inductors in the Biobio Basin.

Topics: Animals; Benzofurans; Chile; Cytochrome P-450 CYP1A1; Dibenzofurans, Polychlorinated; Environmental Monitoring; Fishes; Liver; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Rivers; 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

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

In vitro induction of ethoxyresorufin O-deethylase (EROD) activity in cell cultures is an extensively validated tool for measuring overall potencies of mixtures of halogenated aromatic hydrocarbons (HAHs) in samples from the abiotic or biotic environment. For risk assessment with special attention to effects in wild birds, an assay was developed that makes use of chicken embryo hepatocytes. However, it was questioned whether compound-specific responses are consistent at the various developmental stages. The results of our present study show that there are considerable differences between early and late embryonal and post-hatching stages. The induction of EROD was measured in primary chicken hepatocyte cultures. The cells were isolated at day 14 and day 19 of embryonal development and at day 1 post hatching. Hepatocytes were exposed in vitro to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126, IUPAC nomenclature) and 2,3',4,4',5-pentachlorobiphenyl (PCB 118). The respective compounds were chosen as representatives for dioxins, furans, non-ortho PCBs, and mono-ortho PCBs. These groups of chemicals have been identified as environmental contaminants with major dioxin-like effects that are mediated by a common receptor, the arylhydrocarbon (Ah) receptor. At all developmental stages, TCDF was more potent than TCDD. Relative potencies (RP = EC50TCDD/EC50HAH) decreased in the order TCDF < TCDD < PCB 126 < PCB 118. Depending on the developmental stage, TCDF was 1.2 to 3.4 times more potent than TCDD. PCB 126 was equipotent or less potent by a factor of 3 than TCDD. PCB 118 was 100 to 300 times less potent than TCDD. Both the mean effective concentration (EC50) and the maximum EROD activity (Ymax) of all compounds were lower in hepatocyte cultures from 14-day-old embryos than those from 19-day-old embryos or 1-day-old hatchlings. RPs were comparable in 19-day-old embryos and in hatchlings, but significantly different in 14-day-old embryos.

Topics: Animals; Animals, Newborn; Benzofurans; Cells, Cultured; Chick Embryo; Chickens; Cytochrome P-450 CYP1A1; Enzyme Induction; Liver; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

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

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