The Experts below are selected from a list of 135 Experts worldwide ranked by ideXlab platform
Nigel J. Walker - One of the best experts on this subject based on the ideXlab platform.
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repeated dose Toxicity and relative potency of 1 2 3 4 6 7 hexachloronaphthalene pcn 66 1 2 3 5 6 7 hexachloronaphthalene pcn 67 compared to 2 3 7 8 tetrachlorodibenzo p dioxin tcdd for induction of cyp1a1 cyp1a2 and thymic atrophy in female harlan s
Toxicology, 2012Co-Authors: Michelle J Hooth, Abraham Nyska, Laurene M Fomby, Daphne Vasconcelos, Molly Vallant, Michael J Devito, Nigel J. WalkerAbstract:Abstract In this study we assessed the relative Toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague–Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50,000 and 500,000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose response modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015–0.0072, for PCN 66 and 0.00029–0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO Toxic Equivalency Factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity.
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dose additive carcinogenicity of a defined mixture of dioxin like compounds
Environmental Health Perspectives, 2004Co-Authors: Nigel J. Walker, Donald M. Sells, Amy E. Brix, Abraham Nyska, Patrick W Crockett, Michael P Jokinen, James R Hailey, Micheal Easterling, Joseph K Haseman, Ming YinAbstract:Use of the dioxin Toxic Equivalency Factor (TEF) approach in human risk assessments assumes that the combined effects of dioxin-like compounds in a mixture can be predicted based on a potency-adjusted dose-additive combination of constituents of the mixture. In this study, we evaluated the TEF approach in experimental 2-year rodent cancer bioassays with female Harlan Sprague-Dawley rats receiving 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a mixture of the three compounds. Statistically based dose–response modeling indicated that the shape of the dose–response curves for hepatic, lung, and oral mucosal neoplasms was the same in studies of the three individual chemicals and the mixture. In addition, the dose response for the mixture could be predicted from a combination of the potency-adjusted doses of the individual compounds. Finally, we showed that use of the current World Health Organization dioxin TEF values adequately predicted the increased incidence of liver tumors (hepatocellular adenoma and cholangiocarcinoma) induced by exposure to the mixture. These data support the use of the TEF approach for dioxin cancer risk assessments.
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characterization of bronchiolar metaplasia of the alveolar epithelium in female sprague dawley rats exposed to 3 3 4 4 5 pentachlorobiphenyl pcb126
Toxicologic Pathology, 2004Co-Authors: Amy E. Brix, Donald M. Sells, Micheal P. Jokinen, Nigel J. Walker, Abraham NyskaAbstract:To test the dioxin Toxic Equivalency Factor methodology, the National Toxicology Program conducted a series of 2-year rat bioassays of dioxin-like compounds. Following gavage exposure of female Harlan Sprague‐Dawley rats to 2,3 � ,4,4 � ,5-pentachlorobiphenyl (PCB126), pulmonary alveolar epithelium at the junction of terminal bronchioles and along alveolar ducts was replaced by cuboidal to columnar ciliated cells. Scattered among these were cells exhibiting characteristics consistent with those of Clara cells; they lacked cilia and had a smooth apical surface that protruded into the alveolar space. This lesion was not typical of alveolar epithelial hyperplasia seen in rodent lungs; therefore, studies were done to characterize the lesion. Results of periodic acid-Schiff (PAS) staining, alcian blue (AB) staining, and GSTPi immunohistochemical staining of the lesions seen in treated rats were more similar to normal bronchiolar epithelium than normal alveolar epithelium or alveolar epithelial hyperplasia. These findings, along with the morphology of the cells, provide evidence that this lesion is closer in character to bronchiolar epithelium than alveolar type I or alveolar type II epithelium, and as a result, was called bronchiolar metaplasia.
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evaluation of Toxic Equivalency Factors for induction of cytochromes p450 cyp1a1 and cyp1a2 enzyme activity by dioxin like compounds
Toxicology and Applied Pharmacology, 2004Co-Authors: Hiroyoshi Toyoshiba, Nigel J. Walker, John A Bailer, Christopher J PortierAbstract:The Toxic Equivalency Factor (TEF) method has been used to characterize the Toxicity of human mixtures of dioxin-like compounds and is being considered for use with other classes of potentially Toxic agents. TEFs are estimated by examining the relative potencies of the various congeners for a series of biological and Toxicological effects. In this paper, we consider changes in activity for two enzymes, cytochrome P450 1A1 (CYP1A1)-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity, resulting from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) or a mixture of these agents. The ratio of median effective dose (ED50) is one way to estimate the relative potencies, especially for gene expression and protein endpoints. ED50's were estimated with a nonlinear regression model in which dose-related changes in mean responses are described by a Hill function. ED50's along with other model parameters were estimated by fitting this model to a given data set. Significant differences in estimated model parameters were tested by likelihood ratio methods. The estimated parameters indicated that congener-specific dose-response shapes were significantly different, that additivity failed for these congeners, and that the ratios of ED50's did not predict the response seen for the mixture. These results indicate that for some biological responses, the use of a single relative potency Factor (RPF) is not appropriate for the comparison of the dose response behavior of different dioxin-like congeners.
Stephen Safe - One of the best experts on this subject based on the ideXlab platform.
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hazard and risk assessment of chemical mixtures using the Toxic Equivalency Factor approach
Environmental Health Perspectives, 1998Co-Authors: Stephen SafeAbstract:There is considerable public, regulatory, and scientific concern regarding human exposure to endocrine-disrupting chemicals, which include compounds that directly modulate steroid hormone receptor pathways (estrogens, antiestrogens, androgens, antiandrogens) and aryl hydrocarbon receptor (AhR) agonists, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. Based on quantitative structure-activity relationships for both AhR and estrogen receptor (ER) agonists, the relative potency (RP) of individual compounds relative to a standard (e.g. TCDD and 17-beta-estradiol) have been determined for several receptor-mediated responses. Therefore, the TCDD or estrogenic equivalent (TEQ or EQ, respectively) of a mixture is defined as TEQ = sigma[T(i)]xRP(i)or EQ=sigma[E(i)]xRP(i), where T(i) and E(i) are concentrations of individual AhR or ER agonists in any mixture. This approach for risk assessment of endocrine-disrupting mixtures assumes that for each endocrine response pathway, the effects of individual compounds are essentially additive. This paper will critically examine the utility of the TEQ/EQ approach for risk assessment, the validity of the assumptions used for this approach, and the problems associated with comparing low dose exposures to xeno and natural (dietary) endocrine disruptors.
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development validation and problems with the Toxic Equivalency Factor approach for risk assessment of dioxins and related compounds
Journal of Animal Science, 1998Co-Authors: Stephen SafeAbstract:Polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF), and biphenyls (PCB) are industrial compounds or by-products that have been widely identified as environmental contaminants, and residues have been detected in fish, wildlife, and humans. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) is the most Toxic member of this class of halogenated aromatic hydrocarbons (HAH); mechanistic studies indicate that the Toxic and biochemical effects associated with exposure to TCDD are mediated via initial binding to the cytosolic aryl hydrocarbon (Ah) receptor protein present in target tissues and organs. Several other 2,3,7, 8-substituted PCDD and PCDF and non-ortho substituted PCB also bind to the Ah receptor and induce Toxic responses similar to those for TCDD. Moreover, for these HAH there is a rank order correlation between their structure-Ah receptor binding and structure-Toxicity relationships, and this supports a role for the Ah receptor in mediating these responses. Thus, the Toxic Equivalency Factor (TEF) approach for HAH is based on the common mechanism of action for TCDD and related compounds in which a TEF value for a "dioxin-like" congener is defined as the potency of the individual (i) congener relative to TCDD ([EC50 [TCDD]/EC50 [test compound]). The Toxic or dioxin equivalent (TEQ) for a mixture of HAH is defined by the following equation: TEQ = sigma [PCDDi] x TEFi + sigma [PCDFi] x TEFi. Industrial emissions and environmental and food residues contain complex mixtures of HAH (exodioxins) and the TEF/TEQ approach is used to regulate emissions and estimate the potential exposure and possible adverse health effects of exodioxins. The TEF approach for risk assessment of exodioxins makes a number of assumptions, including response additivity for individual compounds in a mixture of HAH. This review documents some of the following problems and limitations of the TEF approach: 1) environmental and food residues of HAH contain "non-dioxin-like" PCB that exhibit "antidioxin" activity for some responses; 2) the human diet contains endogenous Ah receptor ligands (endodioxins) such as polynuclear aromatic hydrocarbons (PAH), aromatic amines in cooked foods, indole-3-carbinol (I3C), and related hetero-PAH in cruciferous vegetables. Mass balance and mass potency estimates for human dietary intakes suggest that for some responses the effects of natural or endodioxins may be greater than those of exodioxins; and 3) I3C, a weak Ah receptor agonist, also exhibits Ah receptor antagonist activity, and interactions between I3C and endodioxins may inhibit or inactivate some Toxic responses and decrease TEQ(Exodioxin).
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limitations of the Toxic Equivalency Factor approach for risk assessment of tcdd and related compounds
Teratogenesis Carcinogenesis and Mutagenesis, 1997Co-Authors: Stephen SafeAbstract:Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated biphenyls (PCBs), dibenzo-ρ-dioxins (PCDDs), and dibenzofurans (PCDFs), are industrial compounds or by-products that have been widely identified as environmental contaminants. Hazard and risk assessment of complex HAH mixtures have utilized a Toxic Equivalency Factor (TEF) approach, where the Toxic equivalents (TEQs) of any mixture are equal to the sum of the concentration of individual (i) congeners times their potencies (TEFi) relative to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD, TEF = 1.0). TEQ = Σ [PCDDi] · TEFi + Σ [PCDFi] · TEFi + Σ [PCBi] · TEFi The TEQ (or TCDD equivalents) can be readily calculated from analytical data and provides an estimate of the Toxicity of any mixture containing HAHs. Several in vivo and in vitro studies with some PCDD/PCDF and PCB mixtures have demonstrated correlations between experimentally determined and calculated TEQs. However, results of several studies have also shown that for specific responses, the TEQ for some HAH mixtures are non-additive. For example, PCB mixtures and individual PCB congeners such as 2,2′,4,4′,5,5′-hexachlorobiphenyl inhibit Toxic and biochemical responses induced by TCDD and related compounds. Another problem associated with hazard and risk assessment of background exposure to HAHs is the relative contribution of trace levels of HAHs (exodioxins) compared to relatively high exposure to naturally occurring aryl hydrocarbon receptor (AhR) agonists, which act through the same mechanistic pathway. Teratogenesis Carcinog. Mutagen. 17:285–304, 1997/98. © 1998 Wiley-Liss, Inc.
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Toxic Equivalency Factor approach for risk assessment of combustion by products
Toxicological & Environmental Chemistry, 1995Co-Authors: Stephen Safe, Lewis V Rodriguez, Lawrence S B GoldsteinAbstract:Hazard and risk assessment of individual Toxic chemicals utilizes data obtained from chronic Toxicity and carcinogenicity studies in laboratory animals for regulating emission, cleanup or intake levels for individual chemicals. This approach can be utilized for problems associated with a single chemical emitted from a point source; however, in most situations, Toxic chemicals are formed and emitted into the environment as complex mixtures of different structural classes of Toxic/carcinogenic chemicals. Methodologies for risk assessment of complex mixtures have been developed for polychlorinated dibenzo‐p‐dioxins (PCDDs) and dibenzofurans (PCDFs) which are found as industrial and combustion by‐products. This methodology is based on the common mechanism of action for these chemicals and utilizes the most Toxic PCDD/PCDF congener, 2, 3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), as a reference compound. The relative potencies or Toxic Equivalency Factors (TEFs) are assigned to the other relevant PCDD/PCDF congen...
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comparative potencies of aroclors 1232 1242 1248 1254 and 1260 in male wistar rats assessment of the Toxic Equivalency Factor tef approach for polychlorinated biphenyls pcbs
Toxicological Sciences, 1993Co-Authors: Mark A Harris, T Zacharewski, Stephen SafeAbstract:Comparative Potencies of Aroclors 1232, 1242, 1248, 1254, and 1260 in Male Wistar Rats—Assessment of the Toxic Equivalency Factor (TEF) Approach for Polychlorinated Biphenyls (PCBs). Harris, M., Zacharewski, T., and Safe, S. (1993). Fundam. Appl. Toxicol. 20, 456-463. Immature male Wistar rats were treated with several different doses of the commercial polychlorinated biphenyls (PCBs) Aroclors 1232, 1242, 1248, 1254, and 1260 (10, 40, 160, 480, and 2000 mg/kg) and the effects on body weight gain, thymic atrophy, and the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH), ethoxyresorufin O-deethylase (EROD), and pentoxyresorufin O-deethylase (PROD) activities were measured 14 days after treatment. A significant inhibition in body weight gain was observed only in rats treated with high doses of Aroclors 1232 and 1248 and thymic atrophy was not observed for any of the Aroclors. All the Aroclors caused a dose-dependent increase in hepatic microsomal AHH, EROD, and PROD activities. The corresponding ED50 values for the induction of AHH-EROD activities varied from 51 to 678 mg/kg. Aroclor 1260 was the least active inducer of the P4501A1-mediated enzyme activities. In contrast, Aroclor 1260 was a potent inducer of PROD activity (ED50 37 mg/kg), but Aroclors 1232, 1242, 1248, and 1254 did not induce 50% of the maximal response at the highest dose used in this experiment 2000 mg/kg). Previous studies have quantitated the levels of those PCB congeners which induce AHH EROD activities in Aroclors 1232, 1242, 1254, and 1260 and their potencies or Toxic Equivalency Factors (TEFs) relative to that of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) have also been estimated or experimentally determined. Using highly conservative TEF values it was demonstrated that the calculated ED50s for the Aroclors as inducers of AHH and EROD activity were significantly lower than the observed ED50 values. However, if the TEFs were derived directly from the relative potencies of the PCBs (compared to 2,3,7,8-TCDD) as inducers of AHH and EROD activity, then there was a good correspondence between the observed and calculated ED50 values.
Abraham Nyska - One of the best experts on this subject based on the ideXlab platform.
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repeated dose Toxicity and relative potency of 1 2 3 4 6 7 hexachloronaphthalene pcn 66 1 2 3 5 6 7 hexachloronaphthalene pcn 67 compared to 2 3 7 8 tetrachlorodibenzo p dioxin tcdd for induction of cyp1a1 cyp1a2 and thymic atrophy in female harlan s
Toxicology, 2012Co-Authors: Michelle J Hooth, Abraham Nyska, Laurene M Fomby, Daphne Vasconcelos, Molly Vallant, Michael J Devito, Nigel J. WalkerAbstract:Abstract In this study we assessed the relative Toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague–Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50,000 and 500,000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose response modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015–0.0072, for PCN 66 and 0.00029–0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO Toxic Equivalency Factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity.
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dose additive carcinogenicity of a defined mixture of dioxin like compounds
Environmental Health Perspectives, 2004Co-Authors: Nigel J. Walker, Donald M. Sells, Amy E. Brix, Abraham Nyska, Patrick W Crockett, Michael P Jokinen, James R Hailey, Micheal Easterling, Joseph K Haseman, Ming YinAbstract:Use of the dioxin Toxic Equivalency Factor (TEF) approach in human risk assessments assumes that the combined effects of dioxin-like compounds in a mixture can be predicted based on a potency-adjusted dose-additive combination of constituents of the mixture. In this study, we evaluated the TEF approach in experimental 2-year rodent cancer bioassays with female Harlan Sprague-Dawley rats receiving 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or a mixture of the three compounds. Statistically based dose–response modeling indicated that the shape of the dose–response curves for hepatic, lung, and oral mucosal neoplasms was the same in studies of the three individual chemicals and the mixture. In addition, the dose response for the mixture could be predicted from a combination of the potency-adjusted doses of the individual compounds. Finally, we showed that use of the current World Health Organization dioxin TEF values adequately predicted the increased incidence of liver tumors (hepatocellular adenoma and cholangiocarcinoma) induced by exposure to the mixture. These data support the use of the TEF approach for dioxin cancer risk assessments.
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characterization of bronchiolar metaplasia of the alveolar epithelium in female sprague dawley rats exposed to 3 3 4 4 5 pentachlorobiphenyl pcb126
Toxicologic Pathology, 2004Co-Authors: Amy E. Brix, Donald M. Sells, Micheal P. Jokinen, Nigel J. Walker, Abraham NyskaAbstract:To test the dioxin Toxic Equivalency Factor methodology, the National Toxicology Program conducted a series of 2-year rat bioassays of dioxin-like compounds. Following gavage exposure of female Harlan Sprague‐Dawley rats to 2,3 � ,4,4 � ,5-pentachlorobiphenyl (PCB126), pulmonary alveolar epithelium at the junction of terminal bronchioles and along alveolar ducts was replaced by cuboidal to columnar ciliated cells. Scattered among these were cells exhibiting characteristics consistent with those of Clara cells; they lacked cilia and had a smooth apical surface that protruded into the alveolar space. This lesion was not typical of alveolar epithelial hyperplasia seen in rodent lungs; therefore, studies were done to characterize the lesion. Results of periodic acid-Schiff (PAS) staining, alcian blue (AB) staining, and GSTPi immunohistochemical staining of the lesions seen in treated rats were more similar to normal bronchiolar epithelium than normal alveolar epithelium or alveolar epithelial hyperplasia. These findings, along with the morphology of the cells, provide evidence that this lesion is closer in character to bronchiolar epithelium than alveolar type I or alveolar type II epithelium, and as a result, was called bronchiolar metaplasia.
A Brouwer - One of the best experts on this subject based on the ideXlab platform.
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contribution of planar 0 1 ortho and nonplanar 2 4 ortho fractions of aroclor 1260 to the induction of altered hepatic foci in female sprague dawley rats
Toxicology and Applied Pharmacology, 2000Co-Authors: Simone A. Van Der Plas, H Sundberg, Gunilla Scheu, Peter G Wester, J L De Boer, S Jensen, Jan H. Koeman, H. Berg, Ake Bergman, A BrouwerAbstract:Abstract The hepatic tumor promoting activity of the planar 0–1 ortho (∼9.7% w/w) and the nonplanar 2–4 ortho (∼90.3% w/w) fraction of the commercial PCB mixture Aroclor 1260 was studied using a medium-term two-stage initiation/promotion bioassay in female Sprague–Dawley rats. Fractionation was carried out on an activated charcoal column. The composition of the effluent from the column was tested by GC–ECD. The absence of planar compounds in the 2–4 ortho fraction was confirmed by GC–MS analysis. The dioxin-like Toxic potency of the fractions was determined with the DR-CALUX assay. The animal experiment was started with the initiation procedure (diethylnitrosamine injection, 30 mg/kg body wt ip, 24 h after 2 / 3 hepatectomy), followed 6 weeks later by the promotion treatment, which consisted of a weekly subcutaneous injection during 20 weeks. Exposure groups ( n = 10) received the following treatments (dose/kg body wt/week): Aroclor 1260 (10 mg), 0–1 ortho fraction (0.97 mg), 2–4 ortho fraction (1, 3, or 9 mg), a reconstituted 0–4 ortho fraction (9.97 mg), 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB 153; 1 or 9 mg), 2,3,7,8-TCDD (1 μg; positive control) or corn oil (1 ml; vehicle control). One group did not receive a promotion treatment. All exposure groups exhibited a significantly increased volume fraction of the liver occupied by hepatic foci positive for the placental form of glutathione- S -transferase- p compared to the corn oil control, except for the groups treated with 0–1 ortho fraction and 1 mg PCB 153/kg body wt/week. Approximately 80% of the total tumor promoting capacity of the reconstituted 0–4 ortho fraction could be explained by the 2–4 ortho PCB fraction while the 0–1 ortho fraction had only a negligible contribution. These results suggest that the majority of the tumor promotion potential of PCB mixtures resides in the non-dioxin-like fraction, which is not taken into account in the Toxic Equivalency Factor (TEF) approach for risk assessment of PCBs. This may result in an underestimation of the tumor promotion potential of environmental PCB mixtures.
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the calux chemical activated luciferase expression assay adapted and validated for measuring tcdd equivalents in blood plasma
Environmental Toxicology and Chemistry, 1997Co-Authors: Albertinka J. Murk, Pim E.g. Leonards, Astrid S Bulder, A Jonas, Marcel J C Rozemeijer, Michael S Denison, Jan H. Koeman, A BrouwerAbstract:A method was developed to isolate lipophilic compounds efficiently from small aliquots of blood plasma and test these for total dioxin-like Toxic potency using recombinant rat (H4IIE) and mouse (Hepa1c1c7) hepatoma cell lines, containing the firefly (Photinus pyralis) luciferase gene under trans-activational control of the aryl hydrocarbon receptor (AhR). For this experiment, blood plasma was used originating from eider ducks (Somateria mollissima) that had been dosed with 3,39,4,49-tetrachlorobiphenyl (PCB-77) or with the technical PCB-mixture Clophen A50. For each sample the CALUX (chemical-activated luciferase expression) response of both the fat-containing organic extract and the fat-free, cleaned extract were compared with data from chemical analyses of these samples. The CALUX responses for the extracts were converted into so-called CALUX TEQs (TCDD equivalents), using a 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) standard curve. The CALUX TEQs in both fatty and cleaned extracts correlated significantly with PCB-77 or PCB-153 levels (depending on the dosage group) determined in blood plasma using gas chroma- tography-mass spectrometry (GC-MS). For PCB-77 a Toxic Equivalency Factor (TEF) of 1.5 3 10 23 was calculated based on these correlations. In addition, PCB-118 and PCB-156 levels in abdominal fat (assessed with GC with electron capture detection) and hepatic ethoxyresorufin O-deethylase activities correlated well with the CALUX TEQs in both fatty and cleaned blood plasma extracts, suggesting the TEQ levels in blood offer a good measure for internal dose. Plasma cholesterol and triglyceride levels were determined as a measure of lipid content, in 10-ml aliquots of blood plasma using enzymatic spectrophotometric determination. In conclusion, we have demonstrated that the CALUX assay is a rapid, sensitive assay for assessing the Toxic potency of (mixtures of) AhR-active compounds in small aliquots of blood plasma. The limit of detection for the CALUX assay is currently less than 0.1 fmol (32 fg) TEQ, which corresponds with the amount of TEQs present in 0.1 to 1 ml of blood plasma in environmentally exposed species or man.
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impact of polychlorinated dibenzo p dioxins dibenzofurans and biphenyls on human and environmental health with special emphasis on application of the Toxic Equivalency Factor concept
European Journal of Pharmacology: Environmental Toxicology and Pharmacology, 1992Co-Authors: Ulf G Ahlborg, A Brouwer, Marilyn Fingerhut, Joseph L Jacobson, Sandra W Jacobson, Sean W Kennedy, Antonius A F Kettrup, J H Koeman, H Poiger, Christoffer RappeAbstract:A scientific evaluation was made of the mechanisms of action of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls. Distinction is made between the aryl-hydrocarbon (Ah) receptor-mediated and non-Ah receptor-mediated Toxic responses. Special attention is paid to the applicability of the Toxic Equivalency Factor (TEF) concept.
Kurunthachalam Kannan - One of the best experts on this subject based on the ideXlab platform.
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dioxin like and non dioxin like Toxic effects of polychlorinated biphenyls pcbs implications for risk assessment
Critical Reviews in Toxicology, 1998Co-Authors: John P Giesy, Kurunthachalam KannanAbstract:Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, and Toxic contaminants in the environment. Individual PCB congeners exhibit different physicochemical properties and biological activities that result in different environmental distributions and Toxicity profiles. The variable composition of PCB residues in environmental matrices and their different mechanisms of Toxicity complicate the development of scientifically based regulations for the risk assessment. In this article various approaches for the assessment of risks of PCBs have been critically examined. Recent developments in the Toxic Equivalency Factor (TEF) approach for the assessment of Toxic effects due to dioxin-like PCBs have been examined. PCB exposure studies that describe non-dioxin-like Toxic effects, particularly neurobehavioral effects and their effective doses in animals were compiled. A comparative assessment of effective doses for dioxin-like and non-dioxin-like effects by PCBs has been made to evaluate the relative significance of non-ortho-and ortho-substituted PCBs in risk assessment. Using mink as an example, relative merits and implications of using TEF and total PCB approaches for assessing the potential for Toxic effects in wildlife was examined. There are several advantages and limitations associated with each method used for PCB risk assessment. Toxic effects due to coplanar PCBs occur at relatively smaller concentrations than those due to non-dioxin-like PCBs and therefore the TEF approach derives the risk assessment of PCBs, in the environment. The need for the refinement of TEF approach for more accurate assessment of risks is discussed.