3,3',4,4',5-五氯联苯(PCB 126) (Cas No. 57465-28-8)和2,2',4,4',5,5'-六氯联苯(PCB 153) (Cas No. 35065-27-1)对雌性Harlan Sprague-Dawley大鼠的毒理学和致癌作用研究(灌食研究)。

Q4 Medicine National Toxicology Program technical report series Pub Date : 2006-08-01
{"title":"3,3',4,4',5-五氯联苯(PCB 126) (Cas No. 57465-28-8)和2,2',4,4',5,5'-六氯联苯(PCB 153) (Cas No. 35065-27-1)对雌性Harlan Sprague-Dawley大鼠的毒理学和致癌作用研究(灌食研究)。","authors":"","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>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 bio-concentrate 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 occurs as 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, 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-YEAR STUDY: The 2-year study of a binary mixture of PCB 126 and PCB 153 was designed to assess the carcinogenicity of a constant ratio mixture of PCB 126 and PCB 153. In addition, varying ratio mixture groups were used to assess the impact of increasing PCB 153 on the carcinogenicity of PCB 126. Dose groups were divided into two study arms (Figure 1). TCDD equivalent (TEQ) doses are based on the PCB 126 doses after adjustment for the PCB 126 TEF of 0.1. Groups of 81 (Groups 2, 3, 5, and 7) or 80 (Groups 4 and 6) female rats received a mixture of PCB 126 and PCB 153 in corn oil:acetone (99:1) by gavage 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle only and served as the vehicle control (Group 1). Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of Groups 4 and 5 were generally less than those of the vehicle controls after week 25. The mean body weights of Group 6 were less after week 12, and those of Group 7 were less after week 8. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. In the constant ratio groups, serum total thyroxine (T(4)) and free T(4) generally showed a treatment-related decrease relative to controls. Serum total triiodothyronine (T(3)) exhibited a treatment-related increase at the 14-, 31-, and 53-week interim evaluations, but serum thyroid stimulating hormone (TSH) levels were increased at the 14-week time point only. In the varying ratio groups, the decrease in total and free T(4) was more pronounced in those groups dosed with the increasing proportion of PCB 153 at the 31- and 53-week time points. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. At 31 and 53 weeks, a significant increase in the hepatocellular labeling index occurred in Group 7. In the varying ratio groups, the labeling index at the 53-week interim time point was significantly higher in Group 6, which had the highest proportion of PCB 153 compared to the other varying ratio groups. Cytochrome P450 Enzyme Activities: To evaluate the expression of known PCB 126-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, PCB 153-inducible CYP2B-associated 7-pent-oxyresorufin-O-dealkylase (PROD) activity was analyzed. In the constant ratio Groups 2, 3, 5, and 7, hepatic and pulmonary EROD (CYP1A1) activities, hepatic A4H (CYP1A2) activities, and hepatic PROD (CYP2B) activities were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. In the varying ratio groups, hepatic EROD, A4H, and PROD activities at 14 weeks were higher in groups receiving a greater proportion of PCB 153 in the PCB mixture. At 31 and 53 weeks, hepatic CYP1A1 and CYP1A2 enzyme activities in Group 6 were generally lower than in Groups 4 and 5. Determinations of PCB 126 and PCB 153 Concentrations in Tissues: Concentrations of PCB 126 and PCB 153 were determined in fat, liver, lung, and blood at the 14-, 31-, and 53-week interim evaluations and at the end of the 2-year study (105 weeks). PCB 126 was not detectable in vehicle control animals, but increased with increasing dose of PCB 126 and duration of exposure; the highest concentrations were found in liver and fat, and lower levels were seen in lung and blood. Increasing the proportion of PCB 153 in the mixture relative to PCB 126 led to a general decrease in the amount of PCB 126 in liver and lung at the later time points, whereas in fat and blood, there was generally either no effect of PCB 153 on the disposition of PCB 126, or there was an increase in the amount of PCB 126 in the tissue. In vehicle control animals, PCB 153 was detectable in the fat at all time points, in the lung at all time points except 53 weeks, and in the liver and blood at 2 years. PCB 153 was measurable in all examined tissues of treated animals, with the highest concentrations found in fat at the end of the 2-year study in groups administered the highest doses of PCB 153. Pathology and Statistical Analyses -- Constant Ratio Mixture of PCB 126 and PCB 153: At 14, 31, and 53 weeks, the absolute and relative liver weights of all dosed groups were generally greater than those of the vehicle controls. Exposure to the PCB mixture led to significant toxicity in the liver. At 14 weeks, the incidences of several nonneoplastic liver lesions were increased compared to the vehicle controls including hepatocyte hypertrophy, pigmentation, multinucleated hepatocytes, and diffuse fatty change. The spectrum and severity of effects increased with dose and duration of exposure. At the end of the 2-year study, there were significantly increased incidences and severities of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, diffuse and focal fatty change, eosinophilic focus, nodular hyperplasia, cholangiofibrosis, oval cell hyperplasia, bile duct cysts, bile duct hyperplasia, necrosis, and portal fibrosis. Significantly increased incidences of hepatocellular adenoma, cholangiocarcinoma, and hepatocholangioma were observed in the study. In addition, two animals in the highest dose group had hepatocellular carcinoma. The incidences of these lesions generally exceeded the historical vehicle control ranges. At 2 years, a significantly increased incidence of cystic keratinizing epithelioma of the lung was observed in Group 7. In addition, single occurrences of squamous cell carcinoma were seen in the top two dose groups. Nonneoplastic effects whose incidences were increased in the lung included bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia. Significantly increased incidences of squamous cell carcinoma (gingival) of the oral mucosa were seen at the end of the 2-year study and were accompanied by increased incidences of gingival squamous hyperplasia. In the pancreas at 53 weeks, the incidence of acinar cytoplasmic vacuolization was significantly increased in the highest dose group. At 2 years, increased incidences of acinar atrophy and acinar cytoplasmic vacuolization were seen in addition to pancreatic acinar neoplasms in dosed groups. In Groups 5 and 7, these incidences exceeded the historical vehicle control ranges. In the uterus at 2 years, there was a marginal increase in the incidence of squamous cell carcinoma in Group 5. Numerous nonneoplastic effects were seen in other organs at the interim time points including atrophy of the thymus and follicular cell hypertrophy of the thyroid gland. These responses were also affected by administration of the mixture of PCB 126 and PCB 153 at the end of the 2-year study and were accompanied by additional nonneoplastic responses in numerous organs including atrophy of the adrenal cortex and cortical hyperplasia, severity of nephropathy, and incidences of pigmentation of the kidney. Other nonneoplastic lesions that were treatment related were forestomach hyperplasia, hyperplasia of the nasal respiratory epithelium, metaplasia of the olfactory epithelium, and ectasia of the mandibular lymph node. Varying Ratio Mixture of PCB 126 and PCB 153: An effect of increasing the proportion of PCB 153 in the PCB mixture was seen in several tissues, most notably in the liver. Treatment-related nonneoplastic effects seen across the varying ratio groups were generally the same as those seen in the constant ratio groups. In general there was a positive effect of PCB 153 in the mixture on the incidences and severities of these lesions with higher incidences and higher severities being seen in Group 6, which had the highest proportion of PCB 153. (ABSTRACT TRUNCATED).</p>","PeriodicalId":19036,"journal":{"name":"National Toxicology Program technical report series","volume":" 530","pages":"1-258"},"PeriodicalIF":0.0000,"publicationDate":"2006-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Toxicology and carcinogenesis studies of a binary mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (gavage studies).\",\"authors\":\"\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 bio-concentrate 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 occurs as 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, 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-YEAR STUDY: The 2-year study of a binary mixture of PCB 126 and PCB 153 was designed to assess the carcinogenicity of a constant ratio mixture of PCB 126 and PCB 153. In addition, varying ratio mixture groups were used to assess the impact of increasing PCB 153 on the carcinogenicity of PCB 126. Dose groups were divided into two study arms (Figure 1). TCDD equivalent (TEQ) doses are based on the PCB 126 doses after adjustment for the PCB 126 TEF of 0.1. Groups of 81 (Groups 2, 3, 5, and 7) or 80 (Groups 4 and 6) female rats received a mixture of PCB 126 and PCB 153 in corn oil:acetone (99:1) by gavage 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle only and served as the vehicle control (Group 1). Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of Groups 4 and 5 were generally less than those of the vehicle controls after week 25. The mean body weights of Group 6 were less after week 12, and those of Group 7 were less after week 8. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. In the constant ratio groups, serum total thyroxine (T(4)) and free T(4) generally showed a treatment-related decrease relative to controls. Serum total triiodothyronine (T(3)) exhibited a treatment-related increase at the 14-, 31-, and 53-week interim evaluations, but serum thyroid stimulating hormone (TSH) levels were increased at the 14-week time point only. In the varying ratio groups, the decrease in total and free T(4) was more pronounced in those groups dosed with the increasing proportion of PCB 153 at the 31- and 53-week time points. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. At 31 and 53 weeks, a significant increase in the hepatocellular labeling index occurred in Group 7. In the varying ratio groups, the labeling index at the 53-week interim time point was significantly higher in Group 6, which had the highest proportion of PCB 153 compared to the other varying ratio groups. Cytochrome P450 Enzyme Activities: To evaluate the expression of known PCB 126-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, PCB 153-inducible CYP2B-associated 7-pent-oxyresorufin-O-dealkylase (PROD) activity was analyzed. In the constant ratio Groups 2, 3, 5, and 7, hepatic and pulmonary EROD (CYP1A1) activities, hepatic A4H (CYP1A2) activities, and hepatic PROD (CYP2B) activities were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. In the varying ratio groups, hepatic EROD, A4H, and PROD activities at 14 weeks were higher in groups receiving a greater proportion of PCB 153 in the PCB mixture. At 31 and 53 weeks, hepatic CYP1A1 and CYP1A2 enzyme activities in Group 6 were generally lower than in Groups 4 and 5. Determinations of PCB 126 and PCB 153 Concentrations in Tissues: Concentrations of PCB 126 and PCB 153 were determined in fat, liver, lung, and blood at the 14-, 31-, and 53-week interim evaluations and at the end of the 2-year study (105 weeks). PCB 126 was not detectable in vehicle control animals, but increased with increasing dose of PCB 126 and duration of exposure; the highest concentrations were found in liver and fat, and lower levels were seen in lung and blood. Increasing the proportion of PCB 153 in the mixture relative to PCB 126 led to a general decrease in the amount of PCB 126 in liver and lung at the later time points, whereas in fat and blood, there was generally either no effect of PCB 153 on the disposition of PCB 126, or there was an increase in the amount of PCB 126 in the tissue. In vehicle control animals, PCB 153 was detectable in the fat at all time points, in the lung at all time points except 53 weeks, and in the liver and blood at 2 years. PCB 153 was measurable in all examined tissues of treated animals, with the highest concentrations found in fat at the end of the 2-year study in groups administered the highest doses of PCB 153. Pathology and Statistical Analyses -- Constant Ratio Mixture of PCB 126 and PCB 153: At 14, 31, and 53 weeks, the absolute and relative liver weights of all dosed groups were generally greater than those of the vehicle controls. Exposure to the PCB mixture led to significant toxicity in the liver. At 14 weeks, the incidences of several nonneoplastic liver lesions were increased compared to the vehicle controls including hepatocyte hypertrophy, pigmentation, multinucleated hepatocytes, and diffuse fatty change. The spectrum and severity of effects increased with dose and duration of exposure. At the end of the 2-year study, there were significantly increased incidences and severities of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, diffuse and focal fatty change, eosinophilic focus, nodular hyperplasia, cholangiofibrosis, oval cell hyperplasia, bile duct cysts, bile duct hyperplasia, necrosis, and portal fibrosis. Significantly increased incidences of hepatocellular adenoma, cholangiocarcinoma, and hepatocholangioma were observed in the study. In addition, two animals in the highest dose group had hepatocellular carcinoma. The incidences of these lesions generally exceeded the historical vehicle control ranges. At 2 years, a significantly increased incidence of cystic keratinizing epithelioma of the lung was observed in Group 7. In addition, single occurrences of squamous cell carcinoma were seen in the top two dose groups. Nonneoplastic effects whose incidences were increased in the lung included bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia. Significantly increased incidences of squamous cell carcinoma (gingival) of the oral mucosa were seen at the end of the 2-year study and were accompanied by increased incidences of gingival squamous hyperplasia. In the pancreas at 53 weeks, the incidence of acinar cytoplasmic vacuolization was significantly increased in the highest dose group. At 2 years, increased incidences of acinar atrophy and acinar cytoplasmic vacuolization were seen in addition to pancreatic acinar neoplasms in dosed groups. In Groups 5 and 7, these incidences exceeded the historical vehicle control ranges. In the uterus at 2 years, there was a marginal increase in the incidence of squamous cell carcinoma in Group 5. Numerous nonneoplastic effects were seen in other organs at the interim time points including atrophy of the thymus and follicular cell hypertrophy of the thyroid gland. These responses were also affected by administration of the mixture of PCB 126 and PCB 153 at the end of the 2-year study and were accompanied by additional nonneoplastic responses in numerous organs including atrophy of the adrenal cortex and cortical hyperplasia, severity of nephropathy, and incidences of pigmentation of the kidney. Other nonneoplastic lesions that were treatment related were forestomach hyperplasia, hyperplasia of the nasal respiratory epithelium, metaplasia of the olfactory epithelium, and ectasia of the mandibular lymph node. Varying Ratio Mixture of PCB 126 and PCB 153: An effect of increasing the proportion of PCB 153 in the PCB mixture was seen in several tissues, most notably in the liver. Treatment-related nonneoplastic effects seen across the varying ratio groups were generally the same as those seen in the constant ratio groups. In general there was a positive effect of PCB 153 in the mixture on the incidences and severities of these lesions with higher incidences and higher severities being seen in Group 6, which had the highest proportion of PCB 153. (ABSTRACT TRUNCATED).</p>\",\"PeriodicalId\":19036,\"journal\":{\"name\":\"National Toxicology Program technical report series\",\"volume\":\" 530\",\"pages\":\"1-258\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2006-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"National Toxicology Program technical report series\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"National Toxicology Program technical report series","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Medicine","Score":null,"Total":0}
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摘要

二恶英毒性等效因子评价综述:2,3,7,8-四氯二苯并-对二恶英(TCDD)等多卤代芳烃具有结合并激活配体激活转录因子芳烃受体(AhR)的能力。与AhR结合并表现出与TCDD相似的生物作用的结构相关化合物通常被称为“类二恶英化合物”(dlc)。人类在环境中接触dlc是通过摄入含有dlc残留物的食物而发生的,dlc残留物通过食物链进行生物浓缩。由于它们的亲脂性和持久性,一旦内化,它们就会积累在身体组织中,主要是脂肪,导致慢性终身暴露在人体中。由于人类接触dlc总是以复杂混合物的形式发生,因此已开发出毒性等效系数(TEF)方法,作为评估这些化合物复杂混合物构成的健康风险的数学工具。TEF方法是一种相对效价方案,将一种化合物的类二恶英活性相对于最有效的同系物TCDD进行排序。这样就可以根据一种涉及dlc与AhR初始结合的共同作用机制,对化学混合物的潜在二恶英样活性进行估计。dlc的毒性当量被提名进行评估,因为人类广泛接触dlc,并且缺乏TEF方法预测癌症风险相对效力的充分性的数据。为了解决这个问题,国家毒理学计划对雌性哈伦斯普拉格-道利大鼠进行了一系列为期两年的生物测定,以评估dlc和结构相关的多氯联苯(PCBs)及其混合物的慢性毒性和致癌性。为期2年的研究:为期2年的多氯联苯126和多氯联苯153的二元混合物研究旨在评估多氯联苯126和多氯联苯153的恒定比例混合物的致癌性。此外,采用变比例混合组来评估增加PCB 153对PCB 126致癌性的影响。剂量组分为两个研究组(图1)。TCDD当量(TEQ)剂量基于PCB 126 TEF为0.1调整后的PCB 126剂量。每组81只(2、3、5、7组)或80只(4、6组)雌性大鼠以玉米油:丙酮(99:1)混合的多氯联苯126和多氯联苯153灌胃,每周5天,连续灌胃105周;雌性大鼠81只给予玉米油:丙酮(99:1)对照,作为对照(1组)。在14、31和53周时,每组最多10只大鼠进行评估。所有给药组的生存率与载体对照组相似。第25周后,第4组和第5组的平均体重普遍低于载药对照组。第6组的平均体重在第12周后下降,第7组的平均体重在第8周后下降。甲状腺激素浓度:在14周、31周和53周的中期评估中评估血清甲状腺激素水平的变化。在恒比组中,血清总甲状腺素(T(4))和游离T(4)与对照组相比,普遍出现治疗相关的下降。血清总三碘甲状腺原氨酸(T(3))在第14周、31周和53周的中期评估中显示出与治疗相关的升高,但血清促甲状腺激素(TSH)水平仅在第14周时升高。在不同比例的组中,总T和游离T(4)的下降在31周和53周时间点以PCB 153比例增加的组中更为明显。肝细胞增殖数据:为了评估肝细胞的复制,在14周、31周和53周的中期评估中,用5-溴-2'-脱氧尿苷对复制的肝细胞进行了标记分析。在31周和53周时,第7组肝细胞标记指数显著升高。在变比组中,第6组在53周的中间时间点的标记指数明显更高,与其他变比组相比,第6组PCB 153的比例最高。细胞色素P450酶活性:为了评估已知PCB 126应答基因的表达,cyp1a1相关的7-乙氧基间苯二酚- o -去乙基化酶(EROD)和cyp1a2相关的乙酰苯胺-4-羟化酶(A4H)活性在14周、31周和53周的中期评估中进行了评估。此外,还分析了PCB 153诱导的cyp2b相关的7- p5 -氧间苯二酚-o -脱烷基酶(PROD)活性。在恒定比例的第2、3、5和7组中,在第14、31和53周,所有给药组的肝脏和肺部EROD (CYP1A1)活性、肝脏A4H (CYP1A2)活性和肝脏PROD (CYP2B)活性均显著高于对照。在不同比例的组中,14周时肝脏EROD, A4H和PROD活性在PCB混合物中接受较大比例PCB 153的组中较高。 在31和53周时,第6组肝脏CYP1A1和CYP1A2酶活性普遍低于第4和第5组。组织中PCB 126和PCB 153浓度的测定:在14周、31周和53周的中期评估和2年研究结束时(105周),测定脂肪、肝脏、肺和血液中PCB 126和PCB 153的浓度。在对照动物中检测不到PCB 126,但随着PCB 126剂量的增加和暴露时间的延长而增加;肝脏和脂肪中的浓度最高,肺和血液中的浓度较低。增加混合物中PCB 153相对于PCB 126的比例,导致肝脏和肺中PCB 126的含量在较晚的时间点普遍下降,而在脂肪和血液中,PCB 153通常对PCB 126的处置没有影响,或者组织中PCB 126的含量增加。在对照动物中,各时间点脂肪中均检测到PCB 153,除53周外各时间点肺中均检测到PCB 153, 2岁时肝脏和血液中均检测到PCB 153。在治疗动物的所有检查组织中均可测量到PCB 153,在给予最高剂量PCB 153的2年研究结束时,在脂肪中发现的浓度最高。病理和统计分析——PCB 126和PCB 153的恒比混合物:在14、31和53周时,所有给药组的绝对和相对肝脏重量普遍大于载体对照组。接触多氯联苯混合物会导致肝脏出现严重毒性。14周时,与对照组相比,几种非肿瘤性肝脏病变的发生率增加,包括肝细胞肥大、色素沉着、多核肝细胞和弥漫性脂肪改变。影响的范围和严重程度随着剂量和暴露时间的延长而增加。在2年的研究结束时,以肝细胞肥大、多核肝细胞、色素沉着、弥漫性和局灶性脂肪改变、嗜酸性病灶、结节性增生、胆管纤维化、卵形细胞增生、胆管囊肿、胆管增生、坏死和门脉纤维化为特征的中毒性肝病的发生率和严重程度显著增加。研究中观察到肝细胞腺瘤、胆管癌和肝胆管瘤的发生率显著增加。此外,最高剂量组有2只动物发生肝细胞癌。这些病变的发生率一般超过历史车辆控制范围。2年后,观察到第7组肺囊性角化上皮瘤的发生率显著增加。此外,单例鳞状细胞癌在前两个剂量组可见。在肺中发病率增加的非肿瘤性影响包括肺泡上皮细支气管化生和鳞状化生。在为期2年的研究结束时,口腔黏膜的鳞状细胞癌(牙龈)的发病率显著增加,并伴有牙龈鳞状增生的发病率增加。在53周的胰腺中,最高剂量组的腺泡细胞质空泡发生率显著增加。2年后,在给药组中,除了胰腺腺泡肿瘤外,还观察到腺泡萎缩和腺泡细胞质空泡化的发生率增加。在第5组和第7组,这些发生率超过了历史车辆控制范围。在子宫2年时,第5组鳞状细胞癌的发生率略有增加。在中间时间点,其他器官出现了许多非肿瘤性影响,包括胸腺萎缩和甲状腺滤泡细胞肥大。在为期2年的研究结束时,这些反应也受到PCB 126和PCB 153混合物的影响,并且在许多器官中伴有额外的非肿瘤性反应,包括肾上腺皮质萎缩和皮质增生,肾病的严重程度和肾脏色素沉积的发生率。其他与治疗相关的非肿瘤性病变包括前胃增生、鼻呼吸上皮增生、嗅觉上皮化生和下颌淋巴结扩张。多氯联苯126和多氯联苯153的不同比例混合物:多氯联苯混合物中多氯联苯153的比例增加对几个组织的影响,尤其是在肝脏中。在不同比例组中观察到的与治疗相关的非肿瘤效应通常与在恒定比例组中观察到的相同。总体而言,混合物中的PCB 153对这些病变的发病率和严重程度有积极影响,其中PCB 153比例最高的第6组发病率和严重程度较高。(抽象截断)。
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Toxicology and carcinogenesis studies of a binary mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) (Cas No. 57465-28-8) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) (CAS No. 35065-27-1) in female Harlan Sprague-Dawley rats (gavage studies).

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 bio-concentrate 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 occurs as 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, 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-YEAR STUDY: The 2-year study of a binary mixture of PCB 126 and PCB 153 was designed to assess the carcinogenicity of a constant ratio mixture of PCB 126 and PCB 153. In addition, varying ratio mixture groups were used to assess the impact of increasing PCB 153 on the carcinogenicity of PCB 126. Dose groups were divided into two study arms (Figure 1). TCDD equivalent (TEQ) doses are based on the PCB 126 doses after adjustment for the PCB 126 TEF of 0.1. Groups of 81 (Groups 2, 3, 5, and 7) or 80 (Groups 4 and 6) female rats received a mixture of PCB 126 and PCB 153 in corn oil:acetone (99:1) by gavage 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle only and served as the vehicle control (Group 1). Up to 10 rats per group were evaluated at 14, 31, and 53 weeks. Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of Groups 4 and 5 were generally less than those of the vehicle controls after week 25. The mean body weights of Group 6 were less after week 12, and those of Group 7 were less after week 8. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31-, and 53-week interim evaluations. In the constant ratio groups, serum total thyroxine (T(4)) and free T(4) generally showed a treatment-related decrease relative to controls. Serum total triiodothyronine (T(3)) exhibited a treatment-related increase at the 14-, 31-, and 53-week interim evaluations, but serum thyroid stimulating hormone (TSH) levels were increased at the 14-week time point only. In the varying ratio groups, the decrease in total and free T(4) was more pronounced in those groups dosed with the increasing proportion of PCB 153 at the 31- and 53-week time points. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. At 31 and 53 weeks, a significant increase in the hepatocellular labeling index occurred in Group 7. In the varying ratio groups, the labeling index at the 53-week interim time point was significantly higher in Group 6, which had the highest proportion of PCB 153 compared to the other varying ratio groups. Cytochrome P450 Enzyme Activities: To evaluate the expression of known PCB 126-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activities were evaluated at the 14-, 31-, and 53-week interim evaluations. In addition, PCB 153-inducible CYP2B-associated 7-pent-oxyresorufin-O-dealkylase (PROD) activity was analyzed. In the constant ratio Groups 2, 3, 5, and 7, hepatic and pulmonary EROD (CYP1A1) activities, hepatic A4H (CYP1A2) activities, and hepatic PROD (CYP2B) activities were significantly greater in all dosed groups compared to the vehicle controls at weeks 14, 31, and 53. In the varying ratio groups, hepatic EROD, A4H, and PROD activities at 14 weeks were higher in groups receiving a greater proportion of PCB 153 in the PCB mixture. At 31 and 53 weeks, hepatic CYP1A1 and CYP1A2 enzyme activities in Group 6 were generally lower than in Groups 4 and 5. Determinations of PCB 126 and PCB 153 Concentrations in Tissues: Concentrations of PCB 126 and PCB 153 were determined in fat, liver, lung, and blood at the 14-, 31-, and 53-week interim evaluations and at the end of the 2-year study (105 weeks). PCB 126 was not detectable in vehicle control animals, but increased with increasing dose of PCB 126 and duration of exposure; the highest concentrations were found in liver and fat, and lower levels were seen in lung and blood. Increasing the proportion of PCB 153 in the mixture relative to PCB 126 led to a general decrease in the amount of PCB 126 in liver and lung at the later time points, whereas in fat and blood, there was generally either no effect of PCB 153 on the disposition of PCB 126, or there was an increase in the amount of PCB 126 in the tissue. In vehicle control animals, PCB 153 was detectable in the fat at all time points, in the lung at all time points except 53 weeks, and in the liver and blood at 2 years. PCB 153 was measurable in all examined tissues of treated animals, with the highest concentrations found in fat at the end of the 2-year study in groups administered the highest doses of PCB 153. Pathology and Statistical Analyses -- Constant Ratio Mixture of PCB 126 and PCB 153: At 14, 31, and 53 weeks, the absolute and relative liver weights of all dosed groups were generally greater than those of the vehicle controls. Exposure to the PCB mixture led to significant toxicity in the liver. At 14 weeks, the incidences of several nonneoplastic liver lesions were increased compared to the vehicle controls including hepatocyte hypertrophy, pigmentation, multinucleated hepatocytes, and diffuse fatty change. The spectrum and severity of effects increased with dose and duration of exposure. At the end of the 2-year study, there were significantly increased incidences and severities of toxic hepatopathy characterized by hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, diffuse and focal fatty change, eosinophilic focus, nodular hyperplasia, cholangiofibrosis, oval cell hyperplasia, bile duct cysts, bile duct hyperplasia, necrosis, and portal fibrosis. Significantly increased incidences of hepatocellular adenoma, cholangiocarcinoma, and hepatocholangioma were observed in the study. In addition, two animals in the highest dose group had hepatocellular carcinoma. The incidences of these lesions generally exceeded the historical vehicle control ranges. At 2 years, a significantly increased incidence of cystic keratinizing epithelioma of the lung was observed in Group 7. In addition, single occurrences of squamous cell carcinoma were seen in the top two dose groups. Nonneoplastic effects whose incidences were increased in the lung included bronchiolar metaplasia of the alveolar epithelium and squamous metaplasia. Significantly increased incidences of squamous cell carcinoma (gingival) of the oral mucosa were seen at the end of the 2-year study and were accompanied by increased incidences of gingival squamous hyperplasia. In the pancreas at 53 weeks, the incidence of acinar cytoplasmic vacuolization was significantly increased in the highest dose group. At 2 years, increased incidences of acinar atrophy and acinar cytoplasmic vacuolization were seen in addition to pancreatic acinar neoplasms in dosed groups. In Groups 5 and 7, these incidences exceeded the historical vehicle control ranges. In the uterus at 2 years, there was a marginal increase in the incidence of squamous cell carcinoma in Group 5. Numerous nonneoplastic effects were seen in other organs at the interim time points including atrophy of the thymus and follicular cell hypertrophy of the thyroid gland. These responses were also affected by administration of the mixture of PCB 126 and PCB 153 at the end of the 2-year study and were accompanied by additional nonneoplastic responses in numerous organs including atrophy of the adrenal cortex and cortical hyperplasia, severity of nephropathy, and incidences of pigmentation of the kidney. Other nonneoplastic lesions that were treatment related were forestomach hyperplasia, hyperplasia of the nasal respiratory epithelium, metaplasia of the olfactory epithelium, and ectasia of the mandibular lymph node. Varying Ratio Mixture of PCB 126 and PCB 153: An effect of increasing the proportion of PCB 153 in the PCB mixture was seen in several tissues, most notably in the liver. Treatment-related nonneoplastic effects seen across the varying ratio groups were generally the same as those seen in the constant ratio groups. In general there was a positive effect of PCB 153 in the mixture on the incidences and severities of these lesions with higher incidences and higher severities being seen in Group 6, which had the highest proportion of PCB 153. (ABSTRACT TRUNCATED).

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