The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Ursula A. Matulonis - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Toxicity with the VEGF/PDGF receptor TKI AZD-2171 (RecentinTM) in a phase II study of recurrent müllerian tumors
Molecular Cancer Therapeutics, 2007Co-Authors: Richard T. Penson, Suzanne Berlin, Carolyn Krasner, Maria Roche, Karin Tyburski, Sarah Belden, Gilbert Daniels, Rajesh Garg, Percy Ivy, Ursula A. MatulonisAbstract:A16 Background: Vascular endothelial growth factor (VEGF) is the primary promoter of tumor angiogenesis. AZD-2171 (RecentinTM) is a potent oral pan VEGFR, PDGFR and c-kit tyrosine kinase inhibitor. Methods: We are conducting a NCI sponsored (NCI#7102) phase II trial in patients with recurrent epithelial ovarian, fallopian, or primary peritoneal, cancer with elevated CA125 with or without measurable disease, predominantly asymptomatic rising CA-125 recurrence. Patients may have received up to 2 prior lines of therapy, for platinum sensitive or resistant tumors. The first 11 patients commenced 45 mg AZD-2171 PO QD continuously, but because of Toxicity the starting dose was then reduced to 30 mg. Principle endpoints include response, PFS, angiogenic biomarkers, and Toxicity. Results: Since 11/05, 23 patients have been enrolled. Of the 18 evaluable patients, 16 presented with advanced serous ovarian cancer, (1 stage IIC, 11 stage III, and 6 stage IV), and median age was 57 (range 41-72). Grade 3 Toxicity in the first 11 patents included fatigue, hypertension, vomiting and hypoThyroidism. Grade 3 Toxicity all patients: hypertension (n=8), fatigue (n=5), diarrhea (n=4), vomiting (n=2), hemorrhage (n=1), pain (n=1), constipation (n=1), hypothermia (n=1). The second patient on study was admitted hypothermic (94.7), hypertensive with diarrhea, and tendinitis, and a TSH of 15 uU/ml. 9 of the 19 patients (47%) who have been on drug for >1 month have had symptomatic hypoThyroidism (4 grade (gr) 1, 4 gr 2, 1 gr 3), and two hyperThyroidism (both gr 1). In 11 of the 19 (58%), TSH typically rose (range 5.4-26.8) abruptly within two months (Median day 48, range 21-120). Mechanism: AZD-2171 causes decreased endothelial cell fenestrations and follicular epithelial cell atrophy in animal studies. It is highly protein bound and causes a 40-60% reduction in CYP1A activity. Although the mechanism remains unclear altered angiogenesis may influence the immune profile in the microenvironment, act directly, or indirectly with ret suppression through VEGFR2. Conclusion: AZD-2171 is associated with significant symptomatic hypoThyroidism that should be anticipated and treated.
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Thyroid Toxicity with the vegf pdgf receptor tki azd 2171 recentintm in a phase ii study of recurrent mullerian tumors
Molecular Cancer Therapeutics, 2007Co-Authors: Richard T. Penson, Suzanne Berlin, Carolyn Krasner, Maria Roche, Karin Tyburski, Sarah Belden, Gilbert Daniels, Rajesh Garg, Percy Ivy, Ursula A. MatulonisAbstract:A16 Background: Vascular endothelial growth factor (VEGF) is the primary promoter of tumor angiogenesis. AZD-2171 (RecentinTM) is a potent oral pan VEGFR, PDGFR and c-kit tyrosine kinase inhibitor. Methods: We are conducting a NCI sponsored (NCI#7102) phase II trial in patients with recurrent epithelial ovarian, fallopian, or primary peritoneal, cancer with elevated CA125 with or without measurable disease, predominantly asymptomatic rising CA-125 recurrence. Patients may have received up to 2 prior lines of therapy, for platinum sensitive or resistant tumors. The first 11 patients commenced 45 mg AZD-2171 PO QD continuously, but because of Toxicity the starting dose was then reduced to 30 mg. Principle endpoints include response, PFS, angiogenic biomarkers, and Toxicity. Results: Since 11/05, 23 patients have been enrolled. Of the 18 evaluable patients, 16 presented with advanced serous ovarian cancer, (1 stage IIC, 11 stage III, and 6 stage IV), and median age was 57 (range 41-72). Grade 3 Toxicity in the first 11 patents included fatigue, hypertension, vomiting and hypoThyroidism. Grade 3 Toxicity all patients: hypertension (n=8), fatigue (n=5), diarrhea (n=4), vomiting (n=2), hemorrhage (n=1), pain (n=1), constipation (n=1), hypothermia (n=1). The second patient on study was admitted hypothermic (94.7), hypertensive with diarrhea, and tendinitis, and a TSH of 15 uU/ml. 9 of the 19 patients (47%) who have been on drug for >1 month have had symptomatic hypoThyroidism (4 grade (gr) 1, 4 gr 2, 1 gr 3), and two hyperThyroidism (both gr 1). In 11 of the 19 (58%), TSH typically rose (range 5.4-26.8) abruptly within two months (Median day 48, range 21-120). Mechanism: AZD-2171 causes decreased endothelial cell fenestrations and follicular epithelial cell atrophy in animal studies. It is highly protein bound and causes a 40-60% reduction in CYP1A activity. Although the mechanism remains unclear altered angiogenesis may influence the immune profile in the microenvironment, act directly, or indirectly with ret suppression through VEGFR2. Conclusion: AZD-2171 is associated with significant symptomatic hypoThyroidism that should be anticipated and treated.
B. Van Ravenzwaay - One of the best experts on this subject based on the ideXlab platform.
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Standardization of the perchlorate discharge assay for Thyroid Toxicity testing in rats.
Regulatory toxicology and pharmacology : RTP, 2007Co-Authors: G. Coelho-palermo Cunha, B. Van RavenzwaayAbstract:The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect Thyroid Toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and beta-naphthoflavone (indirect toxic mechanism) enhanced Thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on Thyroid: blood (125)I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the Thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T(3)), thyroxine (T(4)) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe Thyroid follicular cell hypertrophy and hyperplasia, reduced serum T(3) and T(4) levels and increased serum TSH levels, and reduced Thyroidal radioiodide accumulation; perchlorate administration significantly reduced Thyroid: blood (125)I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked Thyroidal radioiodide accumulation, without significant effects on serum T(3), T(4), and TSH levels and a microscopic correlate for higher Thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect Thyroid Toxicity mechanisms.
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Evaluation of mechanisms inducing Thyroid Toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes
Archives of Toxicology, 2005Co-Authors: G. Coelho-palermo Cunha, B. Van RavenzwaayAbstract:The OECD has developed an “enhanced Test Guideline 407” (TG 407) protocol for detecting endocrine effects during the course of a 28-day testing scheme. This protocol has gone through a validation process with (anti)estrogenic and (anti)androgenic compounds and substances that affect the Thyroid (thyroxine and propylthiouracil). This review investigates whether a 28-day testing scheme would show up alterations in the Thyroid-related parameters of the “enhanced TG 407” (T3, T4, TSH, Thyroid weight and histopathology), irrespective of the mode of action. For each mode of action, a generally accepted reference chemical was selected and an in-depth literature survey was carried out, and the chemical was evaluated for treatment-related changes of Thyroid-dependent parameters. The following model chemicals were selected: ion perchlorate, blockage of iodine uptake; propylthiouracil, inhibition of Thyroid hormone synthesis; excess of iodine, blockage of Thyroid hormone release; pyrazole, Thyroid cytoToxicity; minocycline, Thyroid pigmentation; amiodarone, inhibition of TSH synthesis; diethylstilbestrol, competition for Thyroid hormone binding globulin; selenium-deficient diet, inhibition of thyroxine deiodination; FD&C Red No. 3, inhibition of peripheral 5′-deiodinase; cadmium, lipid peroxidation; phenobarbital, increase in thyroxine conjugation and biliary excretion; temelastine, thyroxine accumulation. Test data for treatments lasting approximately one month were available for most of these model chemicals, and these demonstrated the expected Thyroid-related changes. Thus, it can be concluded that a 28-day testing scheme allows for the detection of Thyroid-disrupting chemicals. The literature data also were evaluated according to whether preference can be given to any of the Thyroid-related parameters (Thyroid/pituitary hormones, Thyroid weight and histopathology) with regard to dose-related sensitivities. Due to different study designs (such as treatment duration, application mode, dose selection and parameters used), no clear picture emerged. Therefore, consideration should be given to all of these parameters, which should also help to define the mode of action. Overall, this literature review provides support for the contention that the newly developed “enhanced TG 407” test protocol is well suited to the detection of chemicals that affect the Thyroid gland.
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Evaluation of mechanisms inducing Thyroid Toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes.
Archives of toxicology, 2005Co-Authors: G. Coelho-palermo Cunha, B. Van RavenzwaayAbstract:The OECD has developed an “enhanced Test Guideline 407” (TG 407) protocol for detecting endocrine effects during the course of a 28-day testing scheme. This protocol has gone through a validation process with (anti)estrogenic and (anti)androgenic compounds and substances that affect the Thyroid (thyroxine and propylthiouracil). This review investigates whether a 28-day testing scheme would show up alterations in the Thyroid-related parameters of the “enhanced TG 407” (T3, T4, TSH, Thyroid weight and histopathology), irrespective of the mode of action. For each mode of action, a generally accepted reference chemical was selected and an in-depth literature survey was carried out, and the chemical was evaluated for treatment-related changes of Thyroid-dependent parameters. The following model chemicals were selected: ion perchlorate, blockage of iodine uptake; propylthiouracil, inhibition of Thyroid hormone synthesis; excess of iodine, blockage of Thyroid hormone release; pyrazole, Thyroid cytoToxicity; minocycline, Thyroid pigmentation; amiodarone, inhibition of TSH synthesis; diethylstilbestrol, competition for Thyroid hormone binding globulin; selenium-deficient diet, inhibition of thyroxine deiodination; FDC cadmium, lipid peroxidation; phenobarbital, increase in thyroxine conjugation and biliary excretion; temelastine, thyroxine accumulation. Test data for treatments lasting approximately one month were available for most of these model chemicals, and these demonstrated the expected Thyroid-related changes. Thus, it can be concluded that a 28-day testing scheme allows for the detection of Thyroid-disrupting chemicals. The literature data also were evaluated according to whether preference can be given to any of the Thyroid-related parameters (Thyroid/pituitary hormones, Thyroid weight and histopathology) with regard to dose-related sensitivities. Due to different study designs (such as treatment duration, application mode, dose selection and parameters used), no clear picture emerged. Therefore, consideration should be given to all of these parameters, which should also help to define the mode of action. Overall, this literature review provides support for the contention that the newly developed “enhanced TG 407” test protocol is well suited to the detection of chemicals that affect the Thyroid gland.
Richard T. Penson - One of the best experts on this subject based on the ideXlab platform.
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Thyroid Toxicity with the VEGF/PDGF receptor TKI AZD-2171 (RecentinTM) in a phase II study of recurrent müllerian tumors
Molecular Cancer Therapeutics, 2007Co-Authors: Richard T. Penson, Suzanne Berlin, Carolyn Krasner, Maria Roche, Karin Tyburski, Sarah Belden, Gilbert Daniels, Rajesh Garg, Percy Ivy, Ursula A. MatulonisAbstract:A16 Background: Vascular endothelial growth factor (VEGF) is the primary promoter of tumor angiogenesis. AZD-2171 (RecentinTM) is a potent oral pan VEGFR, PDGFR and c-kit tyrosine kinase inhibitor. Methods: We are conducting a NCI sponsored (NCI#7102) phase II trial in patients with recurrent epithelial ovarian, fallopian, or primary peritoneal, cancer with elevated CA125 with or without measurable disease, predominantly asymptomatic rising CA-125 recurrence. Patients may have received up to 2 prior lines of therapy, for platinum sensitive or resistant tumors. The first 11 patients commenced 45 mg AZD-2171 PO QD continuously, but because of Toxicity the starting dose was then reduced to 30 mg. Principle endpoints include response, PFS, angiogenic biomarkers, and Toxicity. Results: Since 11/05, 23 patients have been enrolled. Of the 18 evaluable patients, 16 presented with advanced serous ovarian cancer, (1 stage IIC, 11 stage III, and 6 stage IV), and median age was 57 (range 41-72). Grade 3 Toxicity in the first 11 patents included fatigue, hypertension, vomiting and hypoThyroidism. Grade 3 Toxicity all patients: hypertension (n=8), fatigue (n=5), diarrhea (n=4), vomiting (n=2), hemorrhage (n=1), pain (n=1), constipation (n=1), hypothermia (n=1). The second patient on study was admitted hypothermic (94.7), hypertensive with diarrhea, and tendinitis, and a TSH of 15 uU/ml. 9 of the 19 patients (47%) who have been on drug for >1 month have had symptomatic hypoThyroidism (4 grade (gr) 1, 4 gr 2, 1 gr 3), and two hyperThyroidism (both gr 1). In 11 of the 19 (58%), TSH typically rose (range 5.4-26.8) abruptly within two months (Median day 48, range 21-120). Mechanism: AZD-2171 causes decreased endothelial cell fenestrations and follicular epithelial cell atrophy in animal studies. It is highly protein bound and causes a 40-60% reduction in CYP1A activity. Although the mechanism remains unclear altered angiogenesis may influence the immune profile in the microenvironment, act directly, or indirectly with ret suppression through VEGFR2. Conclusion: AZD-2171 is associated with significant symptomatic hypoThyroidism that should be anticipated and treated.
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Thyroid Toxicity with the vegf pdgf receptor tki azd 2171 recentintm in a phase ii study of recurrent mullerian tumors
Molecular Cancer Therapeutics, 2007Co-Authors: Richard T. Penson, Suzanne Berlin, Carolyn Krasner, Maria Roche, Karin Tyburski, Sarah Belden, Gilbert Daniels, Rajesh Garg, Percy Ivy, Ursula A. MatulonisAbstract:A16 Background: Vascular endothelial growth factor (VEGF) is the primary promoter of tumor angiogenesis. AZD-2171 (RecentinTM) is a potent oral pan VEGFR, PDGFR and c-kit tyrosine kinase inhibitor. Methods: We are conducting a NCI sponsored (NCI#7102) phase II trial in patients with recurrent epithelial ovarian, fallopian, or primary peritoneal, cancer with elevated CA125 with or without measurable disease, predominantly asymptomatic rising CA-125 recurrence. Patients may have received up to 2 prior lines of therapy, for platinum sensitive or resistant tumors. The first 11 patients commenced 45 mg AZD-2171 PO QD continuously, but because of Toxicity the starting dose was then reduced to 30 mg. Principle endpoints include response, PFS, angiogenic biomarkers, and Toxicity. Results: Since 11/05, 23 patients have been enrolled. Of the 18 evaluable patients, 16 presented with advanced serous ovarian cancer, (1 stage IIC, 11 stage III, and 6 stage IV), and median age was 57 (range 41-72). Grade 3 Toxicity in the first 11 patents included fatigue, hypertension, vomiting and hypoThyroidism. Grade 3 Toxicity all patients: hypertension (n=8), fatigue (n=5), diarrhea (n=4), vomiting (n=2), hemorrhage (n=1), pain (n=1), constipation (n=1), hypothermia (n=1). The second patient on study was admitted hypothermic (94.7), hypertensive with diarrhea, and tendinitis, and a TSH of 15 uU/ml. 9 of the 19 patients (47%) who have been on drug for >1 month have had symptomatic hypoThyroidism (4 grade (gr) 1, 4 gr 2, 1 gr 3), and two hyperThyroidism (both gr 1). In 11 of the 19 (58%), TSH typically rose (range 5.4-26.8) abruptly within two months (Median day 48, range 21-120). Mechanism: AZD-2171 causes decreased endothelial cell fenestrations and follicular epithelial cell atrophy in animal studies. It is highly protein bound and causes a 40-60% reduction in CYP1A activity. Although the mechanism remains unclear altered angiogenesis may influence the immune profile in the microenvironment, act directly, or indirectly with ret suppression through VEGFR2. Conclusion: AZD-2171 is associated with significant symptomatic hypoThyroidism that should be anticipated and treated.
Don A. Delker - One of the best experts on this subject based on the ideXlab platform.
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Molecular Characterization of Thyroid Toxicity: Anchoring Gene Expression Profiles to Biochemical and Pathologic End Points
Environmental Health Perspectives, 2005Co-Authors: Christine M. Glatt, John O Connor, Greg Poindexter, Suzanne Snajdr, John W Green, William J. Welsh, Steven R. Frame, Ming Ouyang, Nancy E Everds, Don A. DelkerAbstract:Thyroid cancer, a fairly uncommon form of cancer in the human population, has causal links to environmental radiation exposures (Meirmanov et al. 2003). Although there are multiple epidemiology studies that associate radiation exposure with Thyroid cancer, there have been no studies to associate human Thyroid cancer with environmental chemical exposures (Hard 1998). The human Thyroid responds toxicologically to multiple antiThyroid drugs, including excess iodide, propylthiouracil (PTU), and thionamides, but the progression to cancer after repetitive administration has not been observed (Hard 1998; Hill et al. 1998; Markou et al. 2001). In contrast, multiple antiThyroid drugs administered to the rat have demonstrated an increase in Thyroid tumors, including PTU, thionamides, and the hepatic enzyme inducer phenobarbital (PB) (Capen 1997; Hurley et al. 1998; McClain et al. 1988). Other xenobiotics, including several organic iodides such as amiodarone and erythrosine, have also been associated with Thyroid tumor development in the rat. Many organic iodides alter rat Thyroid homeostasis, causing Thyroid hypertrophy and alterations in colloid that may potentially lead to Thyroid tumors after chronic administration (Capen 1997; Hurley et al. 1998). The mechanisms by which organic iodides induce Thyroid Toxicity are varied and may include excess iodide being released into the blood during xenobiotic metabolism, Toxicity to the liver that alters Thyroid hormone metabolism, and/or direct Thyroid Toxicity that inhibits the release of Thyroid hormones into the circulation (Capen 1997; Hurley et al. 1998). In subchronic toxicology studies it has been difficult to predict whether early changes in Thyroid pathology could lead to Thyroid cancer in the rat after chronic administration of organic iodides. Excess iodide alone can be toxic to Thyroid cells in culture and cause Thyroid hypertrophy and changes in colloid in vivo in the rat model (Capen 1997; Vitale et al. 2000). It has also been reported that administration of excess iodide promotes Thyroid tumor development in rats initiated with N-bis(2-hydroxypropyl)-nitrosamine (Kanno et al. 1992). However, iodide excess alone has not been sufficient in inducing follicular cell hyperplasia and Thyroid tumors in rats but more commonly causes hypoThyroidism (Backer and Hollowell 2000; Kanno et al. 1994). This is believed to be due partly to the escape from the Wolff-Chaikoff effect (acute inhibition of iodine organification) that is seen within days of exposure to excess iodide (Wolff and Chaikoff 1948). This escape phenomenon is associated with the down-regulation of the sodium iodide (NaI) symporter (NIS) thereby reducing the amount of inorganic iodine in the Thyroid so that thyroxine (T4) and Thyroid-stimulating hormone (TSH) secretions are returned to normal physiological levels (Eng et al. 1999). Chronic elevation of TSH levels has been associated with an increased risk of Thyroid tumors in the rat, which may be due, in part, to the high turnover of the circulating Thyroid hormone triiodothyronine (T3) in this species compared with the lower T3 turnover rate in humans (Capen 1997). Many antiThyroid drugs and PB mediate their carcinogenic properties by elevating circulating TSH levels in the rat albeit by different mechanisms (Hood et al. 1999; McClain et al. 1988). Although PTU reduces Thyroid hormone production by inhibiting thyroglobulin organification in the Thyroid and inhibiting the peripheral conversion of T4 to active T3, PB reduces circulating T4 by increasing its hepatic metabolism and excretion via glucoronidation. Reductions in Thyroid hormone (T4 and T3) by either mechanism causes an elevation in TSH that is sufficient in causing Thyroid tumors in rats after prolonged exposure without any evidence of Thyroid DNA damage (McClain 1992). Organic iodides may also increase TSH levels by similar mechanisms; however, it is unknown what contribution iodide excess has in their overall Toxicity to the rat Thyroid. To this end we have implemented biochemical, pathological, and molecular analyses to characterize the rat Thyroid response to three model toxicants: excess iodide by using NaI a noncarcinogen, and the rodent Thyroid carcinogens PB and PTU, in a modified 2-week endocrine battery (O’Connor et al. 2002). The goals of this study were to identify dose-dependent gene expression profiles induced by excess iodide in rats, determine whether gene expression profiles could be obtained that correlate with clinical and pathological end points in rats, and determine whether profiles are predictive of the carcinogenic potential of each chemical in rats.
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Molecular characterization of Thyroid Toxicity: anchoring gene expression profiles to biochemical and pathologic end points.
Environmental health perspectives, 2005Co-Authors: Christine M. Glatt, John O Connor, Greg Poindexter, Suzanne Snajdr, John W Green, William J. Welsh, Steven R. Frame, Ming Ouyang, Nancy E Everds, Don A. DelkerAbstract:Organic iodides have been shown to induce Thyroid hypertrophy and increase alterations in colloid in rats, although the mechanism involved in this Toxicity is unclear. To evaluate the effect that free iodide has on Thyroid Toxicity, we exposed rats for 2 weeks by daily gavage to sodium iodide (NaI). To compare the effects of compounds with alternative mechanisms (increased Thyroid hormone metabolism and decreased Thyroid hormone synthesis, respectively), we also examined phenobarbital (PB) and propylthiouracil (PTU) as model Thyroid toxicants. Follicular cell hypertrophy and pale-staining colloid were present in Thyroid glands from PB-treated rats, and more severe hypertrophy/colloid changes along with diffuse hyperplasia were present in Thyroid glands from PTU-treated rats. In PB- and PTU-treated rats, Thyroid-stimulating hormone (TSH) levels were significantly elevated, and both thyroxine and triiodothyronine hormone levels were significantly decreased. PB induced hepatic uridine diphosphate-glucuronyltransferase (UDPGT) activity almost 2-fold, whereas PTU reduced hepatic 5 -deiodinase I (5 -DI) activity to < 10% of control in support of previous reports regarding the mechanism of action of each chemical. NaI also significantly altered liver weights and UDPGT activity but did not affect Thyroid hormone levels or Thyroid pathology. Thyroid gene expression analyses using Affymetrix U34A GeneChips, a regularized t-test, and Gene Map Annotator and Pathway Profiler demonstrated significant changes in rhodopsin-like G-protein-coupled receptor transcripts from all chemicals tested. NaI demonstrated dose-dependent changes in multiple oxidative stress-related genes, as also determined by principal component and linear regression analyses. Differential transcript profiles, possibly relevant to rodent follicular cell tumor outcomes, were observed in rats exposed to PB and PTU, including genes involved in Wnt signaling and ribosomal protein expression.
G. Coelho-palermo Cunha - One of the best experts on this subject based on the ideXlab platform.
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Standardization of the perchlorate discharge assay for Thyroid Toxicity testing in rats.
Regulatory toxicology and pharmacology : RTP, 2007Co-Authors: G. Coelho-palermo Cunha, B. Van RavenzwaayAbstract:The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect Thyroid Toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and beta-naphthoflavone (indirect toxic mechanism) enhanced Thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on Thyroid: blood (125)I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the Thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T(3)), thyroxine (T(4)) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe Thyroid follicular cell hypertrophy and hyperplasia, reduced serum T(3) and T(4) levels and increased serum TSH levels, and reduced Thyroidal radioiodide accumulation; perchlorate administration significantly reduced Thyroid: blood (125)I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked Thyroidal radioiodide accumulation, without significant effects on serum T(3), T(4), and TSH levels and a microscopic correlate for higher Thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect Thyroid Toxicity mechanisms.
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Evaluation of mechanisms inducing Thyroid Toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes
Archives of Toxicology, 2005Co-Authors: G. Coelho-palermo Cunha, B. Van RavenzwaayAbstract:The OECD has developed an “enhanced Test Guideline 407” (TG 407) protocol for detecting endocrine effects during the course of a 28-day testing scheme. This protocol has gone through a validation process with (anti)estrogenic and (anti)androgenic compounds and substances that affect the Thyroid (thyroxine and propylthiouracil). This review investigates whether a 28-day testing scheme would show up alterations in the Thyroid-related parameters of the “enhanced TG 407” (T3, T4, TSH, Thyroid weight and histopathology), irrespective of the mode of action. For each mode of action, a generally accepted reference chemical was selected and an in-depth literature survey was carried out, and the chemical was evaluated for treatment-related changes of Thyroid-dependent parameters. The following model chemicals were selected: ion perchlorate, blockage of iodine uptake; propylthiouracil, inhibition of Thyroid hormone synthesis; excess of iodine, blockage of Thyroid hormone release; pyrazole, Thyroid cytoToxicity; minocycline, Thyroid pigmentation; amiodarone, inhibition of TSH synthesis; diethylstilbestrol, competition for Thyroid hormone binding globulin; selenium-deficient diet, inhibition of thyroxine deiodination; FD&C Red No. 3, inhibition of peripheral 5′-deiodinase; cadmium, lipid peroxidation; phenobarbital, increase in thyroxine conjugation and biliary excretion; temelastine, thyroxine accumulation. Test data for treatments lasting approximately one month were available for most of these model chemicals, and these demonstrated the expected Thyroid-related changes. Thus, it can be concluded that a 28-day testing scheme allows for the detection of Thyroid-disrupting chemicals. The literature data also were evaluated according to whether preference can be given to any of the Thyroid-related parameters (Thyroid/pituitary hormones, Thyroid weight and histopathology) with regard to dose-related sensitivities. Due to different study designs (such as treatment duration, application mode, dose selection and parameters used), no clear picture emerged. Therefore, consideration should be given to all of these parameters, which should also help to define the mode of action. Overall, this literature review provides support for the contention that the newly developed “enhanced TG 407” test protocol is well suited to the detection of chemicals that affect the Thyroid gland.
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Evaluation of mechanisms inducing Thyroid Toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes.
Archives of toxicology, 2005Co-Authors: G. Coelho-palermo Cunha, B. Van RavenzwaayAbstract:The OECD has developed an “enhanced Test Guideline 407” (TG 407) protocol for detecting endocrine effects during the course of a 28-day testing scheme. This protocol has gone through a validation process with (anti)estrogenic and (anti)androgenic compounds and substances that affect the Thyroid (thyroxine and propylthiouracil). This review investigates whether a 28-day testing scheme would show up alterations in the Thyroid-related parameters of the “enhanced TG 407” (T3, T4, TSH, Thyroid weight and histopathology), irrespective of the mode of action. For each mode of action, a generally accepted reference chemical was selected and an in-depth literature survey was carried out, and the chemical was evaluated for treatment-related changes of Thyroid-dependent parameters. The following model chemicals were selected: ion perchlorate, blockage of iodine uptake; propylthiouracil, inhibition of Thyroid hormone synthesis; excess of iodine, blockage of Thyroid hormone release; pyrazole, Thyroid cytoToxicity; minocycline, Thyroid pigmentation; amiodarone, inhibition of TSH synthesis; diethylstilbestrol, competition for Thyroid hormone binding globulin; selenium-deficient diet, inhibition of thyroxine deiodination; FDC cadmium, lipid peroxidation; phenobarbital, increase in thyroxine conjugation and biliary excretion; temelastine, thyroxine accumulation. Test data for treatments lasting approximately one month were available for most of these model chemicals, and these demonstrated the expected Thyroid-related changes. Thus, it can be concluded that a 28-day testing scheme allows for the detection of Thyroid-disrupting chemicals. The literature data also were evaluated according to whether preference can be given to any of the Thyroid-related parameters (Thyroid/pituitary hormones, Thyroid weight and histopathology) with regard to dose-related sensitivities. Due to different study designs (such as treatment duration, application mode, dose selection and parameters used), no clear picture emerged. Therefore, consideration should be given to all of these parameters, which should also help to define the mode of action. Overall, this literature review provides support for the contention that the newly developed “enhanced TG 407” test protocol is well suited to the detection of chemicals that affect the Thyroid gland.