ABSTRACT
The National Toxicology Program tested two common radiofrequency radiation (RFR) modulations emitted by cellular telephones in a 2-year rodent cancer bioassay that included interim assessments of additional animals for genotoxicity endpoints. Male and female Hsd:Sprague Dawley SD rats and B6C3F1/N mice were exposed from Gestation day 5 or Postnatal day 35, respectively, to code division multiple access (CDMA) or global system for mobile modulations over 18 hr/day, at 10-min intervals, in reverberation chambers at specific absorption rates of 1.5, 3, or 6 W/kg (rats, 900 MHz) or 2.5, 5, or 10 W/kg (mice, 1,900 MHz). After 19 (rats) or 14 (mice) weeks of exposure, animals were examined for evidence of RFR-associated genotoxicity using two different measures. Using the alkaline (pH > 13) comet assay, DNA damage was assessed in cells from three brain regions, liver cells, and peripheral blood leukocytes; using the micronucleus assay, chromosomal damage was assessed in immature and mature peripheral blood erythrocytes. Results of the comet assay showed significant increases in DNA damage in the frontal cortex of male mice (both modulations), leukocytes of female mice (CDMA only), and hippocampus of male rats (CDMA only). Increases in DNA damage judged to be equivocal were observed in several other tissues of rats and mice. No significant increases in micronucleated red blood cells were observed in rats or mice. In conclusion, these results suggest that exposure to RFR is associated with an increase in DNA damage. Environ. Mol. Mutagen. 61:276-290, 2020. © 2019 Wiley Periodicals, Inc.
Subject(s)
Cell Phone , DNA Damage , Radio Waves/adverse effects , Animals , Comet Assay , Female , Male , Mice , Micronucleus Tests , Rats , Rats, Sprague-DawleyABSTRACT
Early deaths of young or juvenile animals (before sexual maturation is achieved) in routine regulatory safety studies present pathologists and toxicologists with the challenge of interpreting findings in the male reproductive tract. Additionally, the advent of toxicity testing regulations has resulted in a growing need for the use of juvenile animals in toxicology studies. Here, we present the reproductive toxicity findings from a 13-week inhalation toxicity study with ortho-phthalaldehyde (OPA) in male rats and mice as a case example for working through this challenging task. In this study with OPA, survival was significantly reduced in the two highest exposure concentrations of OPA tested. Early deaths and histopathological lesions in the testes and epididymides were generally also limited to these two highest exposure groups. Therefore, there was concern that peripubertal morphological features could be a confounding factor for the histopathological evaluation of exposure-related testicular and epididymal findings. Although it can be difficult to differentiate exposure-related effects from the normal morphological features defining peripubertal changes in the testes and epididymides in animals that die early in a toxicity study, the use of age-matched controls in this case study with OPA provided a reference and aided in the differentiation of these effects.
Subject(s)
Aging/drug effects , Inhalation Exposure/adverse effects , Sexual Maturation/drug effects , Testis/drug effects , o-Phthalaldehyde/toxicity , Aging/pathology , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Male , Mice, Inbred Strains , Organ Size/drug effects , Rats, Sprague-Dawley , Species Specificity , Sperm Count , Testis/growth & development , Testis/pathologyABSTRACT
Radiofrequency radiation (RFR) causes heating, which can lead to detrimental biological effects. To characterize the effects of RFR exposure on body temperature in relation to animal size and pregnancy, a series of short-term toxicity studies was conducted in a unique RFR exposure system. Young and old B6C3F1 mice and young, old, and pregnant Harlan Sprague-Dawley rats were exposed to Global System for Mobile Communication (GSM) or Code Division Multiple Access (CDMA) RFR (rats = 900 MHz, mice = 1,900 MHz) at specific absorption rates (SARs) up to 12 W/kg for approximately 9 h a day for 5 days. In general, fewer and less severe increases in body temperature were observed in young than in older rats. SAR-dependent increases in subcutaneous body temperatures were observed at exposures ≥6 W/kg in both modulations. Exposures of ≥10 W/kg GSM or CDMA RFR induced excessive increases in body temperature, leading to mortality. There was also a significant increase in the number of resorptions in pregnant rats at 12 W/kg GSM RFR. In mice, only sporadic increases in body temperature were observed regardless of sex or age when exposed to GSM or CDMA RFR up to 12 W/kg. These results identified SARs at which measurable RFR-mediated thermal effects occur, and were used in the selection of exposures for subsequent toxicology and carcinogenicity studies. Bioelectromagnetics. 39:190-199, 2018. © 2018 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc.
Subject(s)
Body Temperature/radiation effects , Cell Phone , Radiation Exposure/adverse effects , Radio Waves/adverse effects , Aging/physiology , Animals , Female , Mice , Pilot Projects , Pregnancy , Rats , Rats, Sprague-DawleyABSTRACT
ortho-Phthalaldehyde (OPA) is a high-level chemical disinfectant that is commonly used for chemical sterilization of dental and medical instruments as an alternative to glutaraldehyde, a known skin and respiratory sensitizer. Concern for safe levels of human exposure remains due to a lack of toxicity data as well as human case reports of skin and respiratory sensitization following OPA exposure. The present study evaluated the inhalational toxicity of OPA in Harlan Sprague-Dawley rats and B6C3F1/N mice. Groups of 10 male and female rats and mice were exposed to OPA by whole-body inhalation for 3 months at concentrations of 0 (control), 0.44, 0.88, 1.75, 3.5, or 7.0 ppm. Rats and mice developed a spectrum of lesions at sites of contact throughout the respiratory tract (nose, larynx, trachea, lung), as well as in the skin and eye, consistent with a severe irritant response. In general, histologic lesions (necrosis, inflammation, regeneration, hyperplasia and metaplasia) occurred at deeper sites within the respiratory tract with increasing exposure concentration. As a first site of contact, the nose exhibited the greatest response to OPA exposure and resulted in an increased incidence, severity and variety of lesions compared to a previous study of glutaraldehyde exposure at similar exposure concentrations. This increased response in the nasal cavity, combined with extensive lesions throughout the respiratory tract, provides concern for use of OPA as a replacement for glutaraldehyde as a high-level disinfectant.
Subject(s)
Disinfectants/toxicity , Glutaral/toxicity , Respiratory System/drug effects , o-Phthalaldehyde/toxicity , Administration, Inhalation , Animals , Female , Male , Mice , Rats, Sprague-Dawley , Respiratory System/pathologyABSTRACT
Zinc deficiency and excess can result in adverse health outcomes. There is conflicting evidence regarding whether excess or deficient zinc in the diet can contribute to carcinogenicity. The objective of this study was to characterize zinc carbonate basic for use as a source of dietary zinc in a rodent toxicity and carcinogenicity study investigating the effects of zinc deficiency and excess. Because of the complex chemistries of zinc carbonate basic compounds, inconsistent nomenclature, and literature and reference spectra gaps, it was necessary to employ multiple analytical techniques, including Karl Fischer titration, combustion analysis, inductively coupled plasma-optical emission spectrometry, X-ray diffraction, infrared spectroscopy, X-ray fluorescence spectrometry, and thermogravimetric analysis to characterize the test article. Based on the collective evidence and through the process of elimination, the test article was found to be composed mainly of zinc carbonate basic with zinc oxide as a minor component. The zinc content was determined to be 56.6% (w/w) with heavy metals such as arsenic, cadmium, mercury and lead below the limit of quantitation of less than or equal to 0.01%. The test material was stable at ambient temperature. Based on the work described in this manuscript, the test article was suitable for use as a source of zinc in studies of deficiency and excess in the diet.
ABSTRACT
Vinylidene chloride (VDC) has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 mice to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increases in renal cell hyperplasia, renal cell adenoma, and renal cell carcinomas (RCCs). Among those differentially expressed genes from controls and RCC of VDC-exposed mice, there was an overrepresentation of genes from pathways associated with chronic xenobiotic and oxidative stress as well as c-Myc overexpression and dysregulation of TP53 cell cycle checkpoint and DNA damage repair pathways in RCC. Trend analysis comparing RCC, VDC-exposed kidney, and chamber control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the pathogenesis of RCC in VDC-exposed mice.
Subject(s)
Carcinoma, Renal Cell , Dichloroethylenes/toxicity , Kidney Neoplasms , Oxidative Stress/drug effects , Signal Transduction/drug effects , Tumor Suppressor Protein p53/genetics , Animals , Carcinoma, Renal Cell/chemically induced , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/physiopathology , Dose-Response Relationship, Drug , Female , Gene Expression Profiling , Kidney/drug effects , Kidney/pathology , Kidney Neoplasms/chemically induced , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Kidney Neoplasms/physiopathology , Male , Mice , Mutation , Toxicity Tests, Chronic , Tumor Suppressor Protein p53/metabolismABSTRACT
A majority (â¼80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, and genetic factors) account for up to 30% of cases. A recent 2-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and VDC-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from VDC-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, interleukin (IL)-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and natural killer and dendritic cells signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, pro-inflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor, and cell cycle regulation, resulting in an increased incidence of mesothelioma.
Subject(s)
Dichloroethylenes/toxicity , Gene Expression Regulation, Neoplastic/drug effects , Immune System Diseases/chemically induced , Inflammation/chemically induced , Lung Neoplasms/chemically induced , Lung Neoplasms/genetics , Mesothelioma/chemically induced , Mesothelioma/genetics , Animals , Cell Line, Tumor , DNA Damage , Female , Genes, cdc/drug effects , Immune System Diseases/immunology , Inflammation/physiopathology , Male , Mesothelioma, Malignant , Microarray Analysis , Peritoneal Neoplasms/chemically induced , Peritoneal Neoplasms/pathology , RNA, Neoplasm/biosynthesis , Rats , Rats, Inbred F344 , Signal Transduction/drug effects , Testicular Neoplasms/chemically induced , Testicular Neoplasms/pathologyABSTRACT
Pyrogallol (CAS No. 87-66-1), a benzenetriol used historically as a hair dye and currently in a number of industrial applications, was nominated to the National Toxicology Program (NTP) for testing based on the lack of toxicity and carcinogenicity data. Three-month and two-year toxicity studies to determine the toxicity and carcinogenicity of pyrogallol when applied to naïve skin (i.e. dermal administration) were conducted in both sexes of F344/N rats and B6C3F1/N mice. In the three-month studies, adult rodents were administered pyrogallol in 95% ethanol five days per week for 3 months at doses of up to 150 mg/kg body weight (rats) or 600 mg/kg (mice). Based on the subchronic studies, the doses for the two-year studies in rats and mice were 5, 20 and 75 mg/kg of pyrogallol. All mice and most rats survived until the end of the three-month study and body weights were comparable to controls. During the two-year study, survival of dosed rats and male mice was comparable to controls; however survival of 75 mg/kg female mice significantly decreased compared to controls. The incidences of microscopic non-neoplastic lesions at the site of application were significantly higher in all dosed groups of rats and mice and in both the 3-months and two-year studies. In the two-year study, hyperplasia, hyperkeratosis and inflammation tended to be more severe in mice than in rats, and in the mice they tended to be more severe in females than in males. The incidence of squamous cell carcinoma at the site of application (SOA) in 75 mg/kg female mice and SOA squamous cell papillomas in 75 mg/kg male mice were greater than controls. Pyrogallol was carcinogenic in female mice and may have caused tumors in male mice.
Subject(s)
Carcinogens/toxicity , Carcinoma, Squamous Cell/chemically induced , Papilloma/chemically induced , Pyrogallol/toxicity , Skin Neoplasms/chemically induced , Skin/drug effects , Administration, Cutaneous , Animals , Carcinoma, Squamous Cell/pathology , Female , Fibrosis/chemically induced , Fibrosis/pathology , Hair Dyes , Hyperplasia/chemically induced , Hyperplasia/pathology , Keratosis/chemically induced , Keratosis/pathology , Male , Mice , Papilloma/pathology , Rats , Rats, Inbred F344 , Skin/pathology , Skin Neoplasms/pathology , Toxicity Tests, Chronic , Toxicity Tests, SubchronicABSTRACT
To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present.
Subject(s)
Indoles/toxicity , Lipidoses/chemically induced , Lymphangiectasis, Intestinal/chemically induced , Administration, Oral , Animals , Body Weight/drug effects , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP1A2/metabolism , Female , Histocytochemistry , Indoles/administration & dosage , Intestine, Small/drug effects , Intestine, Small/metabolism , Intestine, Small/pathology , Lipidoses/metabolism , Lipidoses/pathology , Liver/drug effects , Liver/enzymology , Liver/metabolism , Lung/drug effects , Lung/enzymology , Lung/metabolism , Lymph Nodes/drug effects , Lymph Nodes/metabolism , Lymph Nodes/pathology , Lymphangiectasis, Intestinal/metabolism , Lymphangiectasis, Intestinal/pathology , Male , Mice , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Toxicity Tests, Chronic , Toxicity Tests, SubchronicABSTRACT
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and structurally-similar dioxin-like compounds affect thyroid function and morphology and thyroid hormone metabolism in animals and humans. The National Toxicology Program conducted eight 2-year gavage studies in female Harlan Sprague-Dawley rats to determine the relative potency of chronic toxicity and carcinogenicity of TCDD, 3,3',4,4',5-pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), 2,3',4,4',5-pentachlorobiphenyl (PCB118), 2,2',4,4',5,5'-hexachloro-biphenyl (PCB153), a tertiary mixture of TCDD/PCB126/PeCDF, and two binary mixtures (PCB126/PCB153 and PCB126/PCB118). Administration of these compounds was associated with increased incidences of thyroid follicular cell hypertrophy, variably observed in the 14-, 31-, and 53-week interim and 2-year sacrifice groups. In all studies, the incidences of follicular cell adenoma and carcinoma were not increased. Decreased levels of serum thyroxine were primarily noted in the 14-or-later -week interim groups of all chemicals. Serum triiodothyronine (T3) levels were increased in the TCDD, PCB126, PeCDF, TCDD/PCB126/PeCDF, and PCB126/PCB153 studies, while decreased levels were noted in the PCB153 and PCB126/PCB118 studies. TCDD, PCB126, PCB126/PCB153, and PCB126/PCB118 increased levels of serum thyroid-stimulating hormone almost in a dose-dependent manner in the 14-week groups. These data suggest that although dioxin-like compounds alter thyroid hormones and increase follicular cell hyperplasia, there is not an increase in thyroid adenoma or carcinoma in female Sprague-Dawley rats.
Subject(s)
Environmental Pollutants/toxicity , Polychlorinated Dibenzodioxins/toxicity , Thyroid Diseases/chemically induced , Thyroid Gland/drug effects , Animals , Carcinogenicity Tests , Cell Enlargement/drug effects , Dose-Response Relationship, Drug , Female , Hypertrophy/chemically induced , Hypertrophy/pathology , Polychlorinated Dibenzodioxins/analogs & derivatives , Rats , Rats, Sprague-Dawley , Thyroid Diseases/blood , Thyroid Diseases/pathology , Thyroid Gland/pathology , Thyrotropin/blood , Thyroxine/blood , Toxicity Tests, Chronic , Triiodothyronine/bloodABSTRACT
Results from previously published animal studies suggest that prenatal and postnatal exposure to dioxin and dioxin-like compounds (DLCs) may profoundly affect the reproductive system of both sexes via endocrine disruption. In the present work, we evaluate the toxicity and carcinogenicity of various DLCs, with an emphasis on their effect on the reproductive organs, induced by chronic exposure of female adult Harlan Sprague-Dawley rats. This investigation represents part of an initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For fourteen, thirty-one, or fifty-three weeks or for two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); 2,3',4,4',5-pentachlorobiphenyl (PCB118); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and PCB118. The ranges of treatment-related changes in the reproductive system included chronic active inflammation in the ovary that occurred in the 1,000 and 3,000 microg/kg core groups (two-year exposure) of PCB153 and in the 300 ng/3,000 microg/kg core group of binary mixture of PCB126 and PCB153. Increases in the incidence of acute and/or chronic active inflammation of the uterus were observed in all dosed groups, including the stop-exposure group (withdrawal after thirty-week exposure) of PeCDF and the 1,000 microg/kg and/or higher group dosed with PCB153. The incidence of cystic endometrial hyperplasia was marginally increased in the 92 PeCDF ng/kg group at two years. The incidence of squamous metaplasia was significantly increased in the 44 ng/kg and higher dose group, including the stop-exposure group. The incidence of uterine squamous cell carcinoma was significantly or marginally increased in the 6 ng/kg core and 100 ng/kg stop-exposure groups of TCDD and in the 300 ng/300 microg/kg core group that received the binary mixture of PCB126 and 153. The incidence of uterine carcinoma was marginally increased in the 92 ng/kg PeCDF group at two years and clearly increased in the 1,000 and 4,600 microg/kg PCB118 core group and the 4,600 microg/kg stop group. In the studies of PCB 126, the tertiary mixture, and the binary mixture of PCB126 and PCB118, no increased incidence of any change occurred in the reproductive systems. The range of changes seen with the different compounds suggests that more than one mechanism may have been involved in promoting the female reproductive pathology.
Subject(s)
Carcinogens/toxicity , Dioxins/toxicity , Ovary/drug effects , Polychlorinated Biphenyls/toxicity , Uterus/drug effects , Administration, Oral , Animals , Benzofurans/toxicity , Carcinoma, Squamous Cell/chemically induced , Carcinoma, Squamous Cell/pathology , Endometrial Hyperplasia/chemically induced , Endometrial Hyperplasia/pathology , Female , Metaplasia/chemically induced , Metaplasia/pathology , Ovary/pathology , Polychlorinated Dibenzodioxins/toxicity , Rats , Rats, Sprague-Dawley , Reproduction/drug effects , Toxicity Tests , Uterine Neoplasms/chemically induced , Uterine Neoplasms/pathology , Uterus/pathologyABSTRACT
Dioxin and dioxin-related compounds have been associated with high incidences of pulmonary dysfunctions and/or cancers in humans. To evaluate the relative potencies of effects of these compounds, the National Toxicology Program completed a series of two-year bioassays which were conducted using female Harlan Sprague-Dawley rats. The rats were treated orally for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and a ternary mixture of TCDD, PCB126 and PeCDF. In addition to treatment-related effects reported in other organs, a variety of pulmonary lesions were observed that were related to exposure. Pulmonary CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was increased in all dosed groups. The most common non-neoplastic lesions, which occurred in all studies, were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm which occurred in all studies. A low incidence of squamous cell carcinoma was associated only with PCB126 treatment. Potential mechanisms leading to altered differentiation and/or proliferation of bronchiolar and alveolar epithelia may be through CYP1A1 induction or disruption of retinoid metabolism.
Subject(s)
Benzofurans/toxicity , Lung/drug effects , Polychlorinated Biphenyls/toxicity , Polychlorinated Dibenzodioxins/toxicity , Administration, Oral , Animals , Cytochrome P-450 CYP1A1/physiology , Female , Lung/pathology , Metaplasia , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
The cancer bioassay for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) conducted by the Dow Chemical company in the mid 70s has been used extensively for conducting quantitative cancer risk assessments for human exposure to TCDD. More recently the National Toxicology Program (NTP) conducted a cancer bioassay of similar design as part of its evaluation of the dioxin toxic equivalency factor methodology. This report compares the design and the results of these two cancer bioassays. This comparison confirms, in most cases, previously published and widely used carcinogenic response characteristics with respect to dose, time course, organ selectivity, tumor type and maximum intensity of TCDD-induced carcinogenicity and toxicity in the Sprague-Dawley rat. Specifically, increases in the incidences of neoplasms were seen in both studies in the liver, lung and oral mucosa. The most notable difference was the significant increase in the incidence of cholangiocarcinoma of the liver seen in the NTP study but not in the Dow study. The experimental designs for the two studies are similar but some protocol parameters differed, such as vehicle, dosing schedule, diet and rat sub-strain utilized. Differences in the shapes of the dose response curves for several neoplasms were noted between the studies, with the NTP study showing non-linearity for all neoplasms. This may result from differences in the experimental protocols as well as divergence in the biological behavior of the different stocks of Sprague-Dawley rat strains used.
Subject(s)
Carcinogenicity Tests , Neoplasms/chemically induced , Polychlorinated Dibenzodioxins/toxicity , Toxicity Tests , Animals , Bile Ducts/pathology , Cholangiocarcinoma/chemically induced , Dose-Response Relationship, Drug , Female , Hyperplasia , Kinetics , Liver Neoplasms/chemically induced , Lung Neoplasms/chemically induced , Mouth Neoplasms/chemically induced , Polychlorinated Dibenzodioxins/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
The plasticizer di-n-butyl phthalate (DBP) is a reproductive toxicant in rodents. Exposure to DBP in utero at high doses alters early reproductive development in male rats. Di-n-butyl phthalate also affects hepatic and extrahepatic enzymes. The objectives of this study were to determine the responsiveness of steroid-metabolizing enzymes in fetal liver to DBP and to investigate the potential of DBP to activate nuclear receptors that regulate the expression of liver enzymes. Pregnant Sprague-Dawley rats were orally dosed with DBP at levels of 10, 50, or 500 mg/kg/day from gestation days 12 to 19; maternal and fetal liver samples were collected on day 19 for analyses. Increased protein and mRNA levels of CYP 2B1, CYP 3A1, and CYP 4A1 were found in both maternal and fetal liver in the 500-mg dose group. Di-n-butyl phthalate at high doses also caused an increase in the mRNA of hepatic estrogen sulfotransferase and UDP-glucuronosyltransferase 2B1 in the dams but not in the fetuses. Xenobiotic induction of CYP3A1 and 2B1 is known to be mediated by the nuclear hormone receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). In vitro transcriptional activation assays showed that DBP activates both PXR and CAR. The main DBP metabolite, mono-butyl-phthalate (MBP) did not interact strongly with either CAR or PXR. These data indicate that hepatic steroid- and xenobiotic-metabolizing enzymes are susceptible to DBP induction at the fetal stage; such effects on enzyme expression are likely mediated by xenobiotic-responsive transcriptional factors, including CAR and PXR. Our study shows that DBP is broadly reactive with multiple pathways involved in maintaining steroid and lipid homeostasis.
Subject(s)
Dibutyl Phthalate/toxicity , Fetus/drug effects , Liver/drug effects , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Transcription Factors/metabolism , Animals , Cell Line, Tumor , Constitutive Androstane Receptor , Cytochrome P-450 Enzyme System/metabolism , Female , Fetus/enzymology , Fetus/metabolism , Humans , Liver/embryology , Liver/enzymology , No-Observed-Adverse-Effect Level , PPAR alpha/metabolism , Pregnancy , Pregnane X Receptor , Rats , Rats, Sprague-DawleyABSTRACT
The National Toxicology Program recently completed a series of studies to evaluate the relative potency for toxicity and carcinogenicity of several polyhalogenated aromatic hydrocarbons including dioxin-like compounds (DLCs) and polychlorinated biphenyls. Female Sprague-Dawley rats were administered by gavage for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and 2,3',4,4',5-pentachlorobiphenyl (PCB118); control animals received corn oil-acetone vehicle (99:1) alone. Nasal epithelial changes were observed only in animals exposed for 2 years to the higher doses of the binary mixtures of PCB126 + PCB153 (1000 ng/kg and 1000 microg/kg) and PCB126 + PCB118 (216 and 360 ng TCDD equivalents/kg). In both studies, the changes were of the same nonneoplastic nature, localized to nasal sections II and III located, respectively, at the level of the incisive papilla anterior to the first palatial ridge (section II) and through the middle of the second molar teeth (section III). The changes consisted of hyperplasia of the respiratory epithelium (level II) and metaplasia of olfactory epithelium to respiratory epithelium with further hyperplasia of the metaplastic respiratory epithelium (levels II and III). Variable amounts of acute inflammatory exudate appeared within the lumen of the nasal cavity, overlying the affected epithelium. Occasionally, the inflammation eroded through the skull and into the adjacent olfactory bulbs.
Subject(s)
Hyperplasia/pathology , Metaplasia/pathology , Olfactory Mucosa/pathology , Polychlorinated Biphenyls/toxicity , Toxicity Tests, Chronic , Administration, Oral , Animals , Dose-Response Relationship, Drug , Female , Hyperplasia/chemically induced , Metaplasia/chemically induced , Molecular Structure , Olfactory Mucosa/drug effects , Polychlorinated Biphenyls/administration & dosage , Polychlorinated Biphenyls/chemistry , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Carcinogens/adverse effects , Dioxins/poisoning , Liver Neoplasms/chemically induced , Lung Neoplasms/chemically induced , Mouth Neoplasms/chemically induced , Animals , Biological Assay , Carcinogens/administration & dosage , Dioxins/administration & dosage , Dose-Response Relationship, Drug , Environmental Pollutants/administration & dosage , Environmental Pollutants/poisoning , Female , Humans , Liver Neoplasms/veterinary , Lung Neoplasms/veterinary , Mouth Neoplasms/veterinary , Polychlorinated Dibenzodioxins/administration & dosage , Polychlorinated Dibenzodioxins/poisoning , Rats , Rats, Sprague-Dawley , Reference Values , Risk AssessmentABSTRACT
We evaluated gingival toxicities induced by chronic exposure of female Harlan Sprague-Dawley rats to dioxin and dioxin-like compounds (DLCs) and compared them to similarly induced oral lesions reported in the literature. This investigation represents part of an ongoing initiative of the National Toxicology Program to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. For two years, animals were administered by gavage 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachlorodibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); a tertiary mixture of TCDD, PCB126, and PeCDF; a binary mixture of PCB126 and 153; or a binary mixture of PCB126 and 2,3',4,4',5-pentachlorobiphenyl (PCB118); control animals received corn oil-acetone vehicle (99:1) alone. A full complement of tissues, including the palate with teeth, was examined microscopically. In the groups treated with TCDD and the mixtures of TCDD, PCB126, and PeCDF; PCB126 and 153; and PCB126 and 118, the incidences of gingival squamous hyperplasia increased significantly. Moreover, in the groups treated with TCDD, PCB126, and the mixture of PCB126 and 153, squamous cell carcinoma (SCC) in the oral cavity increased significantly. This investigation constitutes the first report documenting that chronic administration of dioxin-like PCBs can induce gingival SCC in rats. These results indicate that dioxin and DLCs target the gingiva of the oral cavity, in particular the junctional epithelium of molars.
Subject(s)
Benzofurans/toxicity , Carcinoma, Squamous Cell/chemically induced , Gingiva/pathology , Gingival Neoplasms/chemically induced , Polychlorinated Biphenyls/toxicity , Polychlorinated Dibenzodioxins/toxicity , Administration, Oral , Animals , Carcinogenicity Tests , Carcinoma, Squamous Cell/pathology , Dioxins/toxicity , Dose-Response Relationship, Drug , Drug Synergism , Female , Gingiva/drug effects , Gingival Neoplasms/pathology , Hyperplasia , Rats , Rats, Sprague-Dawley , Time FactorsABSTRACT
Tg.AC mice develop epidermal papillomas in response to treatment with dermally applied nongenotoxic and complete carcinogens. The persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a multi-site rodent carcinogen and tumor promoter that induces the formation of papillomas in Tg.AC mice. To examine the dose-response relationship and compare dermal and oral routes of exposure for TCDD-induced skin papillomas, female Tg.AC mice were exposed dermally to average daily doses of 0, 2.1, 7.3, 15, 33, 52, 71, 152, and 326 ng TCDD/kg/day or 0, 75, 321, and 893 ng TCDD/kg body weight by gavage for 26 weeks. The incidence of cutaneous papillomas was increased in a dose-dependent manner, and tumors developed earlier with higher exposure to TCDD regardless of route of administration. Increased incidences of cutaneous squamous cell carcinomas were observed in mice exposed to dermal (> or =52 ng/kg) and oral (893 ng/kg) TCDD. Higher gavage doses than dermal exposure doses were required to induce papillomas and squamous cell carcinomas. Despite a linear correlation between administered dose and terminal skin concentrations, the incidence of tumor formation was lower in the gavage study than in the dermal study with respect to mean terminal skin TCDD concentrations. These studies demonstrate that, although Tg.AC mice are less responsive to TCDD by gavage than by dermal exposure, the induction of skin neoplasms is a response to systemic exposure and not solely a local response at the site of dermal application. Differences in response between the routes of exposure may reflect pharmacokinetic differences in the delivery of TCDD to the skin over the duration of the study.
Subject(s)
Carcinogenicity Tests/methods , Carcinogens/toxicity , Carcinoma, Squamous Cell/chemically induced , Environmental Pollutants/toxicity , Papilloma/chemically induced , Polychlorinated Dibenzodioxins/toxicity , Skin Neoplasms/chemically induced , Administration, Cutaneous , Administration, Oral , Animals , Carcinogens/administration & dosage , Carcinogens/pharmacokinetics , Carcinoma, Squamous Cell/pathology , Disease Models, Animal , Dose-Response Relationship, Drug , Environmental Pollutants/administration & dosage , Environmental Pollutants/pharmacokinetics , Female , Heterozygote , Mice , Mice, Transgenic , Papilloma/pathology , Polychlorinated Dibenzodioxins/administration & dosage , Polychlorinated Dibenzodioxins/pharmacokinetics , Skin/drug effects , Skin/metabolism , Skin/pathology , Skin Neoplasms/pathology , Tissue DistributionABSTRACT
We evaluated the effect of chronic exposure to dioxin and dioxin-like compounds on the pancreas in female Harlan Sprague-Dawley rats. This investigation represents part of an ongoing National Toxicology Program initiative to determine the relative potency of chronic toxicity and carcinogenicity of polychlorinated dioxins, furans, and biphenyls. Animals were treated by gavage for up to 2 years with 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 toxic-equivalency-factor (TEF) mixture of these agents; control animals received corn oil-acetone vehicle alone. A complete necropsy was performed on all animals, and a full complement of tissues was collected and examined microscopically. Administration of each of the four compounds was associated with increased incidences of several nonneoplastic changes in the exocrine pancreas, including cytoplasmic vacuolation, chronic active inflammation, atrophy, and arteritis. Low incidences, but higher than those in the historical database, of pancreatic acinar adenoma and carcinoma were seen in the TCDD, PeCDF, and TEF-mixture groups. These results indicate that the pancreatic acini are target tissues for dioxin and certain dioxin-like compounds. Key words: carcinogenesis, dioxin, furans, inflammation, pancreas, polychlorinated biphenyls.
Subject(s)
Dioxins/toxicity , Environmental Pollutants/toxicity , Furans/toxicity , Pancreas/drug effects , Pancreas/pathology , Polychlorinated Biphenyls/toxicity , Polychlorinated Dibenzodioxins/toxicity , Administration, Oral , Animals , Dioxins/administration & dosage , Environmental Pollutants/administration & dosage , Female , Furans/administration & dosage , Inflammation , Polychlorinated Biphenyls/administration & dosage , Polychlorinated Dibenzodioxins/administration & dosage , Rats , Rats, Sprague-DawleyABSTRACT
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a persistent environmental contaminant, is a metabolite of the pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT). DDE is similar to phenobarbital (PB) in that both compounds are inducers of rat hepatic cytochrome P450 2B and 3A (CYP 2B and 3A). The induction of CYP 2B and 3A by PB is known to be regulated through the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR), respectively. In the current study, the induction of hepatic CYP 3A1 and 2B1 by DDE was correlated with CAR and PXR activity. Induction of 3A1 and 2B1 was observed in the livers of adult and developing male Sprague-Dawley rats following exposure to DDE. Increased hepatic expression of 3A1, but not 2B1, in developing rats exposed during gestation and lactation persisted into adulthood. In receptor transactivation assays, both CAR and PXR transcriptional activities were significantly enhanced by DDE. Nuclear accumulation of CAR, but not PXR, was observed in the liver tissue following DDE and PB treatment. These data support the idea that induction of hepatic 3A1 and 2B1 by DDE is mediated through the activation of CAR and PXR. This study suggests that regulation by environmental compounds of hepatic enzymes via CAR and PXR may have impact on the metabolism of endogenous and exogenous substrates.