* Laboratory of Experimental Pathology, Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709;
Pathology AssociatesA Charles River Company, Durham, North Carolina 27713;
Experimental Pathology Laboratories, Research Triangle Park, North Carolina 27709; ¶ Battelle Columbus Laboratories, Columbus, Ohio 43201; and || Toxicology Operations Branch, ||| Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
1 To whom correspondence should be addressed at NIEHS, P.O. Box 12233, Mail Drop B3-06, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709. Fax: (919) 541-7666. E-mail: nyska{at}niehs.nih.gov
Received September 15, 2004; accepted October 20, 2004
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ABSTRACT |
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Key Words: gingival squamous hyperplasia; squamous cell carcinoma; rat; dioxin; dioxin-like compounds.
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INTRODUCTION |
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The incidences of cancer have been evaluated in several human populations that received elevated exposures to TCDD and DLCs (ATSDR, 1998, 2000
). A study in Seveso, Italy, indicated that exposure apparently induced an increase in all cancers combined and several specific cancers, such as lung cancer, Hodgkin's disease, non-Hodgkin's lymphoma, and myeloid leukemia (Bertazzi et al., 2001
). More than 2000 people each in Japan (1968) and Taiwan (1979) were reported to ingest accidentally PCBs and PCDFs in rice bran oil (Asahi, 1993
; Guo et al., 1999
; Miller, 1985
; Wang et al., 2003
); follow-up studies indicated increased mortality chiefly from liver cancer and other liver disease (McGregor et al., 1998
). Several reports discuss whether exposure to PCBs causes an increased incidence of human cancer (Kimbrough, 1985
; McGregor et al., 1998
), and experimental studies provide meaningful evidence that they exert probable carcinogenic effects in humans (ATSDR, 2000
; United States Environmental Protection Agency, 1996
). Although much evidence exists of induction of cancer in humans by DLCs, a conclusive link between these compounds and increased incidences of oral tumors has not been established.
Recently, the NTP conducted two-year bioassays in female rats to evaluate the chronic pathology and carcinogenicity induced by dioxin and DLCs, structurally-related PCBs, and mixtures of these compounds, such as TCDD; 3,3',4,4',5-pentachlorobiphenyl (PCB126); 2,3,4,7,8-pentachloro-dibenzofuran (PeCDF); 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153); the Toxic Equivalency Factor (TEF) tertiary mixture of TCDD, PCB126, and PeCDF; and the binary mixtures of PCB126 and 153 and PCB126 and 2,3',4,4',5-pentachlorobiphenyl (PCB118) (National Toxicology Program, 2004a,b
,c
,d
,e
,f
,g
). In these studies, in several tissues, a significant increase occurred in the incidence of neoplastic and nonneoplastic effects, such as cholangiocarcinoma and/or hepatocellular adenoma of the liver and cystic keratinizing epithelioma of the lung (Brix et al., 2004
; Jokinen et al., 2003
; National Toxicology Program, 2004a
,b
,c
,d
,e
,f
,g
; Nyska et al., 2004
; Tani et al., 2004
; Walker et al., submitted manuscript). Additionally, the incidences of gingival squamous hyperplasia (GSH) and/or squamous cell carcinoma (SCC) were increased in all studies except PCB 153. Ten chemicals that induce oral tumors in rats have been reported by the National Toxicology Program (NTP) (Table 1, NTP Web Site: http://ntp-server.niehs.nih.gov/htdocs/pub.html).
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MATERIALS AND METHODS |
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Animals. All experiments, for the duration of these studies, were conducted in the AAALAC-accredited facility of Battelle-Columbus Laboratories (Columbus, OH). Animal handling and husbandry met all NIH guidelines (Grossblatt, 1996). Female Harlan Sprague-Dawley rats were approximately eight weeks of age at the start of the study. Animals were randomly assigned to control or treated groups and housed five to a cage in solid-bottom polycarbonate cages (Lab Products, Inc., Maywood, NJ). The animal rooms were maintained at 6975°F with 3565% relative humidity and 12 h each of light and darkness. Irradiated NTP-2000 pelleted feed (Zeigler Bros., Inc., Gardner, PA) and water were available ad libitum.
Pathology. Moribund and all scheduled-to-be-sacrificed animals were euthanized by carbon dioxide. Complete necropsies were performed on all animals using standardized methodology. At necropsy, all tissues, including masses and macroscopic abnormalities, were removed and fixed in 10% neutral buffered formalin. The maxillae, including the nose, were decalcified in a 5% Nitric Acid Decal Solution (Poly Scientific, Inc., Bay Shore, NY) for three days. Three nasal sections that included oral tissues were examined. The maxilla was trimmed just posterior to the upper incisors (Section I), midway between the incisors and first molar at the anterior surface of the incisive papilla (Section II), and at the middle of the first molar (Section III). After fixation and/or decalcification, all of the tissues were trimmed, dehydrated, cleared, embedded in paraffin, sectioned into 5-µm-thick sections, stained with hematoxylin and eosin (H&E), and examined microscopically. The severity of lesions was graded on a four-point scale of 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked. The pathology results underwent comprehensive NTP peer review by Pathology-Working-Group pathologists (Boorman et al., 2002). The tongue and mandible were not routinely examined histopathologically, and no gross abnormality was observed in these organs.
Statistical analysis. The probability of survival was estimated by the product-limit procedure of Kaplan-Meier (Kaplan and Meier, 1958). The incidences of lesions were evaluated statistically by the poly-3 test (Bailer and Portier, 1988
; Portier and Bailer, 1989
), which makes adjustments for survival differences among groups. For animals in the two-year studies, the total-lesion incidences, including findings from animals that survived until study termination and early-death animals, were included in the analysis.
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RESULTS |
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Doses of 3 ng/kg or greater of TCDD induced GSH, and the average severities increased at higher dosing levels. In the groups receiving 46 ng/kg or greater of TCDD, the incidence of oral SCC increased, and a statistically significant difference occurred in the highest dosed group (incidence rate: 19%), compared to the control group (2%). In the 100 ng/kg stop group, the incidence of oral GSH was still increased significantly, and the tendency toward an increased occurrence rate of SCC could be seen (incidence rate: 10%), compared to the control group (2%).
Although an increased incidence of GSH in PCB126-treated rats in the two-year study could not be detected, 1000 ng/kg of PCB126 induced oral SCC significantly (incidence rate: 13%), compared to controls (0%). In the 550 ng/kg and 1000 ng/kg stop groups, the incidences of oral GSH and SCC were slightly higher than those of the control group, but without a statistically significant difference.
In the TEF study of TCDD, PCB126, and PeCDF, all doses in the study induced GSH significantly with no differences in severities. The incidence of oral SCC, however, did not increase with any statistical significance.
In the mixture study of PCB126 and 153, the levels greater than 100 ng/100 µg/kg induced GSH significantly; however, the average severities did not increase at higher dosing levels. In groups administered 300 ng/300 µg/kg or greater, the incidences of oral SCC increased significantly compared to those of control groups.
Dosages of 22 ngTEQ/kg or higher of the mixture of PCB126 and 118 induced GSH significantly. The incidence of oral SCC did not, however, increase with any statistical significance. In the 360 ngTEQ/kg stop group, the incidence of oral GSH was increased significantly, similar to that of the 360 ngTEQ/kg continuous treatment group.
In contrast to the above-mentioned studies, no significant differences occurred in the incidence and severity of oral GSH and SCC between controls and any dosed groups in the PeCDF and PCB153 two-year studies.
Histopathological Characteristics of Oral GSH and SCC
Cases showing the presence of hair shafts with or without inflammation in the periodontal tissue adjacent the molar tooth in nasal Section III were noted sporadically in control and dosed animals in all studies (Figs. 1a and 1b). The inflammation manifested as gingivitis may have contributed to the grade of hyperplasia. No significant statistical differences in the incidences of gingivitis occurred between control and dosed groups in all studies (data not shown).
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Squamous cell carcinoma induced by treatment with TCDD and DLCs occurred within the oral mucosa of the palate, located mainly lateral to the molar tooth (Fig. 2a), and was characterized by irregular cords and clusters of stratified SE that invaded deeply into the underlying connective tissue, as well as cellular atypia (Fig. 2b). Both cauliflower-like exophytic projections into the oral cavity and endophytic invasion into the maxillary bone occurred, with the formation of keratin pearls composed of concentric layers of squamous cells around central layers of keratin. Cells with SCC exhibited frequent mitotic figures, formed buds and nets, and often infiltrated into the nasal cavities and destroyed nasal structure (Fig. 2c). No evidence for metastasis of SCC was noted in any other organ.
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DISCUSSION |
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It is not clear what the association is between GSH and gingival SCC. In this examination of the H&E slides from the NTP studies, dystrophic changes manifested themselves as large nuclei with clear nucleoli and eosinophilic cytoplasm. Cells contained bizarre mitotic figures and cellular atypia that added complexity to the GSH. Nauta et al. (1996) described oral epithelial dysplasia with distinctive histological features in the Wistar rats: drop-shaped rete ridges, irregular epithelial stratification, basal cell hyperplasia, loss of intercellular adherence, loss of polarity, anisocytosis and anisonucleosis, pleomorphic cells and nuclei, mitotic activity, and/or bizarre mitoses. Squamous epithelium displaying cellular atypia has been diagnosed as epithelial dysplasia characterized by abnormally differentiated squamous layers usually accompanied by thickening of the epithelium. This lesion possesses the potential to progress to squamous cell tumors in oral cavities (Nauta et al., 1996
; Okazaki et al., 2002
; Umeda et al., 2004
). Our findings of a histopathological similarity between SCC and dysplastic change accompanied by cellular atypia could indicate that GSH associated with dysplasia may develop into SCC in TCDD- and DLC-treated animals.
Responses to TCDD and DLCs are mediated by the AhR, a ligand-activated transcription factor, which acts in concert with the AhR nuclear translocator protein (Denison and Nagy, 2003; Peters et al., 1999
; Schmidt and Bradfield, 1996
). Planar PCBs (e.g., PCB126) interact predominantly with the AhR (Hestermann et al., 2000
; Poland and Knutson, 1982
); however, unlike planar compounds, nonplanar PCBs (PCB153) do not have dioxin-like activity. For the PCB 126 and 118 mixture, the predominant dioxin-like activity is mostly due to the PCB126 component. In oral tissues, AhR can be detected in molar teeth buds and palatal epithelial cells, in particular from the late embryonic stage in rodents and humans (Abbott et al., 1994a
,b
; Gao et al., 2004
; Sahlberg et al., 2002
). In in vivo and/or in vitro studies of rats, mice, and/or humans exposed to TCDD during morphogenesis of the palate (Abbott and Birnbaum, 1989
, 1990
, 1991
), TCDD becomes distributed rapidly to the secondary palate (Abbott et al., 1996
), downregulates the AhR throughout the palate (Abbott et al., 1994b
), and alters the differentiation and proliferation of palatal epithelial cells, followed by abnormal production of a stratified SE (Abbott et al., 1999
). Ligand-dependent activation of AhR enhances terminal differentiation in skin cells and the palatal epithelium (Greenlee et al., 2001
), and TCDD accelerates differentiation and proliferation in human keratinocytic and/or oral SCC cell lines (Hëbert et al., 1990
; Ray and Swanson, 2003
).
Table 4 presents a comparison of oral lesions in animals and humans exposed to TCDD and DLCs. Previous researchers have shown several effects on oral cavities induced by TCDD in animals, and developmental dental aberrations, such as enamel defect and hypodentia, were reported recently in humans (Alaluusua et al., 2004). TCDD induced developmental dental defects, particularly prevention of molar development, in young rats by in utero and/or lactational exposure (Kattainen et al., 2001
; Lukinmaa et al., 2001
). In contrast, exposure to a large amount of TCDD caused abnormal incisor development in adult rats (Alaluusua et al., 1993
; Gao et al., 2004
). Many studies of TCDD administered for longer times of exposure utilized several kinds of animals (ATSDR, 1998
), such as rats (Kociba et al., 1978
; National Toxicology Program, 1982a
), mice (Della Porta et al., 1987
; National Toxicology Program, 1982a
,b
; Toth et al., 1979
), monkeys (McNulty, 1985
), hamster (Rao et al., 1988
), and mink (Render et al., 2000b
, 2001
). Only three of these reports describe TCDD-induced oral proliferative lesions. In a TCDD feed study by Kociba and colleagues (1978)
, increases occurred in the incidences of SCC of the hard palate/nasal turbinate in Spartan Sprague-Dawley rats. Gingival hyperplasia characterized by cystic nests and infiltrative SE in periodontal ligament appeared in mink during TCDD exposure (Render et al., 2000b
, 2001
). These gingival lesions occurred in locations adjacent the molars. Oral lesions from our studies appear similar to those reported in the studies of Kociba et al. (1978)
and Render et al. (2000b
, 2001
).
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The location of the appearances of these oral lesions merits discussion. In our studies, we detected them lesions within the area of the molar-tooth ligament (tooth pocket, gingival sulcus). In the rat, the gingiva consists of a keratinized stratified squamous epithelium, connective tissue with fibroblasts, and the extracellular matrix composed chiefly of collagen fibers and ground substance containing sulfated glycosaminoglycans (Brunet et al., 1996; Haschek and Rousseaux, 1998
; Tintari, 1983
). The gingival epithelium in the molar-tooth area is classified as gingival oral epithelium, sulcular epithelium, and junctional epithelium, which appears nonkeratinized and forms the floor of the gingival sulcus. Gingival epithelium manifests a higher proliferative capacity and higher rate of absorption of drugs and chemicals than the skin (Haschek and Rousseaux, 1998
; Shojaei, 1998
). Mitotic activity appears greatest at the dento-gingival junction of molars, especially within the junctional epithelium (Löe et al., 1972
; Shimono et al., 2003
; Watanabe et al., 2004
). Absorption of chemicals and the conversion by cytochrome P450 proteins to xenobiotic metabolites can occur in gingival epithelia (Vondracek et al., 2001
). Our literature search revealed that, in animals, the molar teeth and their gingivae seem to be most sensitive to dioxin-induced toxicity. The junctional epithelium of molars, with high proliferative and metabolic activity, may change pathologically and constitute the earliest gingival change induced by TCDD and some kinds of DLCs.
Reports implicate several underlying mechanisms of chemical induction of GH. Three classifications of drugs administered to humanscalcium channel blockers (e.g., nifedipine), immunosuppressants (e.g., cyclosporine), and anticonvulsants (e.g., phenytoin)comprise the main causative agents of drug-induced gingival hyperplasia (GH) (Abdollahi and Radfar, 2003; Brunet et al., 1996
; Butler et al., 1987
; Guggenheimer, 2002
). In association with lesions induced by phenytoin and cyclosporine, the occurrence of oral SCC has also been reported (McLoughlin et al., 1995
; Varga and Tyldesley, 1991
). Bacteria-associated inflammation manifested as gingivitis and the appearance of sulcular epithelium of the teeth have played essential roles in some cases of drug-induced GH (Brown et al., 1991
). Although gingivitis appeared in all dosed groups in our rat studies, we observed no significant differences in its occurrence between control and dosed groups. Gingivitis with hair impaction has been occasionally observed in rat toxicity studies (Brown and Hardisty, 1990
). A direct action upon the gingival epithelium, rather than the development of gingivitis, appears therefore to have played a key role in the induction of GSH in our rat studies. Indirect alterations in retinoid homeostasis in the liver may constitute another possible mechanism for the action of DLCs in the oral cavity. In rodents, mobilization of retinoid stores by TCDD and DLCs leads to a disruption in retinoid homeostasis, as well as vitamin A deficiency (Fattore et al., 2000
; Fiorella et al., 1995
; Schmidt et al., 2003
; Van Birgelen et al., 1994
, 1995
). Abnormal epithelial differentiation creating a keratinized squamous phenotype characterizes retinoid deficiency (Lancillotti et al., 1992
; Lotan, 1994
). The action of DLCs may therefore involve a disruption of retinoid action leading to altered growth and differentiation of the oral gingival epithelium that result in development of GSH and, ultimately, neoplasia. Since the mechanisms of dioxin- and DLC-induced GSH and SCC remain to be elucidated, concentration on gene- and protein-related functions could enhance understanding of the pathogenesis of oral lesions. Additional research is needed to analyze the mechanism(s) of this induction and provide understanding of the potential extrapolations to humans of dioxin-induced oral lesions.
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ACKNOWLEDGMENTS |
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REFERENCES |
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Abbott, B. D., and Birnbaum, L. S. (1990). Rat embryonic palatal shelves respond to TCDD in organ culture. Toxicol. Appl. Pharmacol. 103, 441451.[CrossRef][ISI][Medline]
Abbott, B. D., and Birnbaum, L. S. (1991). TCDD exposure of human embryonic palatal shelves in organ culture alters the differentiation of medial epithelial cells. Teratology 43, 119132.[ISI][Medline]
Abbott, B. D., Birnbaum, L. S., and Diliberto, J. J. (1996). Rapid distribution of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) to embryonic tissues in C57BL/6N mice and correlation with palatal uptake in vitro. Toxicol. Appl. Pharmacol. 141, 256263.[CrossRef][ISI][Medline]
Abbott, B. D., Held, G. A., Wood, C. R., Buckalew, A. R., Brown, J. G., and Schmid, J. (1999). AhR, ARNT, and CYP1A1 mRNA quantitation in cultured human embryonic palates exposed to TCDD and comparison with mouse palate in vivo and in culture. Toxicol. Sci. 47, 6275.[Abstract]
Abbott, B. D., Perdew, G. H., and Birnbaum, L. S. (1994a). Ah receptor in embryonic mouse palate and effects of TCDD on receptor expression. Toxicol. Appl. Pharmacol. 126, 1625.[CrossRef][ISI][Medline]
Abbott, B. D., Probst, M. R., and Perdew, G. H. (1994b). Immunohistochemical double-staining for Ah receptor and ARNT in human embryonic palatal shelves. Teratology 50, 361366.[ISI][Medline]
Abdollahi, M., and Radfar, M. (2003). A review of drug-induced oral reactions. J. Contemp. Dent. Pract. 3, 1031.
Agency for Toxic Substances and Disease Registry (ATSDR). (1998). Toxicological profile for chlorinated dibenzo-p-dioxins. Atlanta, GA.
Agency for Toxic Substances and Disease Registry (ATSDR). (2000). Toxicological profile for polychlorinated biphenyls (PCBs). Atlanta, GA.
Alaluusua, S., Lukinmaa, P. L., Pohjanvirta, R., Unkila, M., and Tuomisto, J. (1993). Exposure to 2,3,7,8-tetrachlorodibenzo-para-dioxin leads to defective dentin formation and pulpal perforation in rat incisor tooth. Toxicology 81, 113.[CrossRef][ISI][Medline]
Alaluusua, S., Calderara, P., Gerthoux, P. M., Lukinmaa, P. L., Kovero, O., Needham, L., Patterson, D. G., Tuomisto, J., and Mocarelli, P. (2004). Developmental dental aberrations after the dioxin accident in Seveso. Environ. Health Perspect. 112, 13131318.[ISI][Medline]
Arnold, D. L., Bryce, F., Mes, J., Tryphonas, H., Hayward, S., and Malcolm, S. (1999). Toxicological consequences of feeding PCB congeners to infant rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys. Food Chem. Toxicol. 37, 153167.[CrossRef][ISI][Medline]
Asahi, M. (1993). Clinical features and pathogenesis of Yusho (PCB poisoning). J. UOEH 15, 111 (abstract in English, text in Japanese).[Medline]
Bailer, A. J., and Portier, C. J. (1988). Effect of treatment-induced mortality and tumor-induced mortality in tests for carcinogenicity in small samples. Biometrics 44, 417431.[ISI][Medline]
Bertazzi, P. A., Consonni, D., Bachetti, S., Rubagotti, M., Baccarelli, A., Zocchetti, C., and Pesatori, A. C. (2001). Health effects of dioxin exposure: A 20-year mortality study. Am. J. Epidemiol. 153, 10311044.
Boorman, G. A., Haseman, J. K., Waters, M. D., Hardisty, J. F., and Sills, R. C. (2002). Quality review procedures necessary for rodent pathology databases and toxicogenomic studies: The National Toxicology Program experience. Toxicol. Pathol. 30, 8892.[CrossRef][ISI][Medline]
Bosetti, C., Negri, E., Fattore, E., and La Vecchia, C. (2003). Occupational exposure to polychlorinated biphenyls and cancer risk. Eur. J. Cancer Prev. 12, 251252.[CrossRef][ISI][Medline]
Brambilla, G., Cherubini, G., De Filippis, S., Magliuolo, M., and Domenico, A. D. (2004). Review of aspects pertaining to food contamination by polychlorinated dibenzodioxins, dibenzofurans, and biphenyl at the farm level. Analytica Chimica Acta 514, 17.[CrossRef][ISI]
Brix, A. E., Jokinen, M. P., Walker, N. J., Sells, D. M., and Nyska, A. (2004). Characterization of bronchiolar metaplasia of the alveolar epithelium in female Sprague-Dawley rats exposed to 3,3',4,4'5-pentachlorobiphenyl (PCB126). Toxicol. Pathol. 32, 333337.[CrossRef][ISI][Medline]
Brouwer, A., Ahlborg, U. G., van Leeuwen, F. X. R., and Feeley, M. M. (1998). Report of the WHO working group on the assessment of health risks for human infants from exposure to PCDDS, PCDFS and PCBS. Chemosphere 37, 16271643.[CrossRef][ISI][Medline]
Brown, H. R., and Hardisty, J. F. (1990). Oral cavity, esophagus, and stomach. In Pathology of the Fischer Rat, Reference and Atlas (G. A. Boorman, C. A. Montgomery, and W. F. MacKenzie, Eds.), pp. 930. Academic Press, San Diego.
Brown, R. S., Beaver, W. T., and Bottomley, W. K. (1991). On the mechanism of drug-induced gingival hyperplasia. J. Oral Pathol. Med. 20, 201209.[ISI][Medline]
Brunet, L., Miranda, J., Farre, M., Berini, L., and Mendieta, C. (1996). Gingival enlargement induced by drugs. Drug Saf. 15, 219231.[ISI][Medline]
Butler, R. T., Kalkwarf, K. L., and Kaldahl, W. B. (1987). Drug-induced gingival hyperplasia: Phenytoin, cyclosporine, and nifedipine. J. Am. Dent. Assoc. 114, 5660.[ISI][Medline]
Chu, I., Villeneuve, D. C., Yagminas, A., LeCavalier, P., Hakansson, H., Ahlborg, U. G., Valli, V. E., Kennedy, S. W., Bergman, A., Seegal, R. F., and Feeley, M. (1995). Toxicity of PCB77 (3,3',4,4'-tetrachlorobiphenyl) and PCB118 (2,3',4,4',5-pentachlorobiphenyl) in the rat following subchronic dietary exposure. Fundam. Appl. Toxicol. 26, 282292.[CrossRef][ISI][Medline]
Chu, I., Villeneuve, D. C., Yagminas, A., LeCavalier, P., Poon, R., Feeley, M., Kennedy, S. W., Seegal, R. F., Häkansson, H., Ahlborg, U. G., and Valli, V. E. (1994). Subchronic toxicity of 3,3',4,4',5-pentachlorobiphenyl in the rat. Fundam. Appl. Toxicol. 22, 457468.[CrossRef][ISI][Medline]
Della Porta, G., Dragani, T. A., and Sozzi, G. (1987). Carcinogenic effects of infantile and long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment in the mouse. Tumori 73, 99107.[ISI][Medline]
Denison, M. S., and Nagy, S. R. (2003). Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemical. Annu. Rev. Pharmacol. Toxicol. 43, 309334.[CrossRef][ISI][Medline]
Fattore, E., Trossvik, C., and Hakansson, H. (2000). Relative potency values derived from hepatic vitamin A reduction in male and female Sprague-Dawley rats following subchronic dietary exposure to individual polychlorinated dibenzo-p-dioxin and dibenzofuran congeners and a mixture thereof. Toxicol. Appl. Pharmacol. 165, 184194.[CrossRef][ISI][Medline]
Fiorella, P. D., Olson, J. R., and Napoli, J. L. (1995). 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces diverse retinoic acid metabolites in multiple tissues of the Sprague-Dawley rat. Toxicol. Appl. Pharmacol. 134, 222228.[CrossRef][ISI][Medline]
Gao, Y., Sahlberg, C., Kiukkonen, A., Alauusua, S., Pohjavirta, R., Tuomisto, J., and Lukinmaa, P. L. (2004). Lactational exposure of Han/Wistar rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin interferes with enamel maturation and retards dentin mineralization. J. Dent. Res. 83, 139144.
Garant, P. R., and Cho, M. I. (1979). Histopathogenesis of spontaneous periodontal disease in conventional rats. I. Histometric and histologic study. J. Periodontal Res. 14, 297309.[ISI][Medline]
Greenlee, W. F., Hushka, L. J., and Hushka, D. R. (2001). Molecular basis of dioxin actions: Evidence supporting chemoprotection. Toxicol. Pathol. 29, 67.[CrossRef][ISI][Medline]
Grossblatt, N. (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC.
Guggenheimer, J. (2002). Oral manifestations of drug therapy. Dent. Clin. N. Am. 46, 857868.[Medline]
Guo, Y. L., Yu, M. L., Hsu, C. C., and Rogan, W. J. (1999). Choracne, goiter, arthritis, and anemia after polychlorinated biphenyl poisoning: 14-Year follow-up of the Taiwan Yucheng cohort. Environ. Health Perspect. 107, 715719.[ISI][Medline]
Haschek, W. M., and Rousseaux, C. G. (1998). Oral mucosa. In Fundamentals of Toxicologic Pathology (W. M. Haschek, and C. G. Rousseaux, Eds.), pp. 5456. Academic Press, San Diego.
Hashiguchi, I., Akamine, A., and Fukuyama H. (1983). Ultrastructual changes in the gingival epithelium on the experimental PCB poisoning in the crab eating monkeys. Fukuoka Igaku Zasshi 74, 246254 (abstract in English, text in Japanese).[Medline]
Hashiguchi, I., Akamine, A., Miyatake, S., Hara, Y., Maeda, K., Toriya, Y., Aono, M., Fukuyama, H., and Okumura, H. (1987). Histological study on the gingiva in the patient with Yusho and the PCB poisoned monkey. Fukuoka Igaku Zasshi 78, 259265 (abstract in English, text in Japanese).[Medline]
Hashiguchi, I., Anan, H., Maeda, K., Akamine, A., Fukuyama, H., and Okumura, H. (1997). An epidemiologic examination on the prevalence of the periodontal disease and oral pigmentation in Yusho patients in 1996. Fukuoka Igaku Zasshi 88, 226230 (abstract in English, text in Japanese).[Medline]
Hashiguchi, I., Toriya, Y., Anan, H., Maeda, K., Akamine, A., Aono, M., Fukuyama, H., and Okumura, H. (1995). An epidemiologic examination on the prevalence of the periodontal disease and oral pigmentation in Yusho patients. Fukuoka Igaku Zasshi 86, 256260 (abstract in English, text in Japanese).[Medline]
Hëbert, C. D., Cao, Q. L., and Birnbaum, L. S. (1990). Inhibition of high-density growth arrest in human squamous carcinoma cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Carcinogenesis 11, 13351342.[Abstract]
Hestermann, E. V., Stegeman, J. J., and Hahn, M. E. (2000). Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency. Toxicol. Appl. Pharmacol. 168, 160172.[CrossRef][ISI][Medline]
Hori, S., Obana, H., Kashimoto, T., Otake, T., Nishimura, H., Ikegami, N., Kunita, N., and Uda, H, (1982). Effect of polychlorinated biphenyls and polychlorinated quaterphenyls in cynomolgus monkey (Macaca fascicularis). Toxicology 24, 123139.[CrossRef][ISI][Medline]
Huff, J., Lucier, G., and Tritscher, A. (1994). Carcinogenicity of TCDD: Experimental, mechanistic, and epidemiologic evidence. Annu. Rev. Pharmacol. Toxicol. 34, 343372.[CrossRef][ISI][Medline]
Jokinen, M. P., Walker, N. J., Brix, A. E., Sells, D. M., Haseman, J. K., and Nyska, A. (2003). Increase in cardiovascular pathology in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3,3,'4,4'5-pentachlorobiphenyl. Cardiovasc. Toxicol. 3, 299310.[CrossRef][Medline]
Kaplan, E. L., and Meier, P. (1958). Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457481.[ISI]
Kattainen, H., Tuukkanen, J., Simanainen, U., Tuomisto, J. T., Kovero, O., Lukinmaa, P. L., Alauusua, S., Tuomisto, J., and Viluksela, M. (2001). In utero/lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure impairs molar tooth development in rats. Toxicol. Appl. Pharmacol. 174, 216224.[CrossRef][ISI][Medline]
Kimbrough, R. D. (1985). Laboratory and human studies on polychlorinated biphenyls (PCBs) and related compounds. Environ. Health Perspect. 59, 99106.[ISI][Medline]
Kociba, R. J., Keyes, D. G., Beyer, J. E., Carreon, R. M., Wade, C. E., Dittenber, D. A., Kalnins, R. P., Frauson, L. E., Park, C. N., Barnard, S. D., Hummel, R. A., and Humiston, C. G. (1978). Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol. Appl. Pharmacol. 46, 279303.[ISI][Medline]
Lancillotti, F., Darwiche, N., Celli, G., and De Luca, L. M. (1992). Retinoid status and the control of keratin expression and adhesion during the histogenesis of squamous metaplasia of tracheal epithelium. Cancer Res. 52, 61446152.[Abstract]
Löe, H., Karring, T., and Hara, K. (1972). The site of mitotic activity in rat and human oral epithelium. Scand. J. Dent. Res. 80, 111119.[ISI][Medline]
Lotan, R. (1994). Suppression of squamous cell carcinoma growth and differentiation by retinoids. Cancer Res. 54, 1987s1990s.[Abstract]
Lukinmaa, P. L., Sahlberg, C., Leppaniemi, A., Partanen, A. M., Kovero, O., Pohjanvirta, R., Tuomisto, J., and Alauusua, S. (2001). Arrest of rat molar tooth development by lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 173, 3847.[CrossRef][ISI][Medline]
McGregor, D. B., Partensky, C., Wilbourn, J., and Rice, J. M. (1998). An IARC evaluation of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans as risk factors in human carcinogenesis. Environ. Health Perspect. 106, 755760.[ISI][Medline]
McLoughlin, P., Newman, L., and Brown, A. (1995). Oral squamous cell carcinoma arising in phenytoin-induced hyperplasia. Br. Dent. J. 178, 183184.[CrossRef][ISI][Medline]
McNulty, W. P. (1985). Toxicity and fetotoxicity of TCDD, TCDF and PCB isomers in rhesus macaques (Macaca mulatta). Environ. Health Perspect. 60, 7788.[ISI][Medline]
Miller, R. W. (1985). Congenital PCB poisoning: A reevaluation. Environ. Health Perspect. 60, 211214.[ISI][Medline]
National Toxicology Program (1982a). Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin (CAS No. 1746-01-6) in Osborne-Mendel rats and B6C3F1 mice (gavage study). TR209. Research Triangle Park, NC.
National Toxicology Program (1982b). Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin (CAS No. 1746-01-6) in Swiss-Webster mice (dermal study). TR201. Research Triangle Park, NC.
National Toxicology Program (2004a). Toxicology and carcinogenesis studies of a mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB126) (CAS No. 57465-28-8) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) in female Harlan Sprague-Dawley rats (gavage studies). TR530. Research Triangle Park, NC.
National Toxicology Program (2004b). Toxicology and carcinogenesis studies of a mixture of 3,3',4,4',5-pentachlorobiphenyl (PCB126) (CAS No. 57465-28-8) and 2,3',4,4',5-pentachlorobiphenyl (PCB118) (CAS No. 31508-00-6) in female Harlan Sprague-Dawley rats (gavage studies) TR531. Research Triangle Park, NC.
National Toxicology Program (2004c). Toxicology and carcinogenesis studies of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (CAS No. 1746-01-6), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4), and 3,3',4,4',5-pentachlorobiphenyl (PCB126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (gavage studies). TR526. Research Triangle Park, NC.
National Toxicology Program (2004d). Toxicology and carcinogenesis studies of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) (CAS No. 57065-27-1) in female Harlan Sprague-Dawley rats (gavage studies) TR529. Research Triangle Park, NC.
National Toxicology Program (2004e). Toxicology and carcinogenesis studies of 3,3',4,4',5-pentachlorobiphenyl (PCB126) (CAS No. 57465-28-8) in female Harlan Sprague-Dawley rats (gavage studies). TR520. Research Triangle Park, NC.
National Toxicology Program (2004f). Toxicology and carcinogenesis studies of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) (CAS No. 57117-31-4) in female Harlan Sprague-Dawley rats (gavage studies). TR525. Research Triangle Park, NC.
National Toxicology Program (2004g). Toxicology and carcinogenesis studies of 2,3,7,8-tetrachloribenzo-p-dioxin (TCDD) (CAS No. 1746-01-6) in female Harlan Sprague-Dawley rats (gavage studies). TR521. Research Triangle Park, NC.
Nauta, J. M., Roodenburg, J. L. N., Nikkels, P. G. J., Witjes, M. J. H., and Vermey, A. (1996). Epithelial dysplasia and squamous cell carcinoma of the Wistar rat palatal mucosa: 4NQO model. Head Neck 18, 441449.[ISI][Medline]
Nyska, A., Jokinen, M. P., Brix, A. E., Sells, D. M., Wyde, M. E., Orzech, D., Haseman, J. K., Flake, G., and Walker, N. J. (2004). Exocrine pancreatic pathology in female Harlan Sprague-Dawley rats after chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like compounds. Environ. Health Perspect. 112, 903909.[ISI][Medline]
Ogawa, T., Asai, Y., Yamashita, M., and Takasuga, T. (2003). Detectable dioxins in human saliva and their effects on gingival epithelial cells. J. Dent. Res. 82, 849853.
Okazaki, Y., Tanaka, Y., Tonogi, M., and Yamane G. (2002). Investigation of environmental factors for diagnosing malignant potential in oral epithelial dysplasia. Oral Oncol. 38, 562573.[CrossRef][ISI][Medline]
Peters, J. M., Narotsky, M. G., Elizondo, G., Fernandez-Salguero, P. M., Gonzalez, F. J., and Abott, B. D. (1999). Amelioration of TCDD-induced teratogenesis in aryl hydrocarbon receptor (AhR)-null mice. Toxicol. Sci. 47, 8692.[Abstract]
Poland, A., and Knutson, J. C. (1982). 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity. Annu. Rev. Pharmacol. Toxicol. 22, 517554.[CrossRef][ISI][Medline]
Portier, C. J., and Bailer, A. J. (1989). Testing for increased carcinogenicity using a survival-adjusted quantal response test. Fundam. Appl. Toxicol. 12, 731737.[CrossRef][ISI][Medline]
Rao, M. S., Subbarao, V., Prasad, J. D., and Scarpelli, D. G. (1988). Carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the Syrian golden hamster. Carcinogenesis 9, 16771679.[Abstract]
Ray, S. S., and Swanson, H. I. (2003). Alteration of keratinocyte differentiation and senescence by the tumor promoter dioxin. Toxicol. Appl. Pharmacol. 192, 131145.[CrossRef][ISI][Medline]
Render, J. A., Aulerich, R. J., Bursian, S. J., and Nachreiner, R. F. (2000a). Proliferation of maxillary and mandibular periodontal squamous cells in mink fed 3,3',4,4',5-pentachlorobiphenyl (PCB126). J. Vet. Diagn. Invest. 12, 477479.[ISI][Medline]
Render, J. A., Bursian, S. J., Rosenstein, D. S., and Aulerich, R. J. (2001). Squamous epithelial proliferation in the jaws of mink fed diets containing 3,3',4,4',5-pentachlorobiphenyl (PCB126) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Vet. Human Toxicol. 43, 2226.[ISI][Medline]
Render, J. A., Hochstein, J. R., Aulerich, R. J., Bursian, S. J. (2000b). Proliferation of periodontal squamous epithelium in mink fed 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Vet. Human Toxicol. 42, 8586.[ISI][Medline]
Sahlberg, C., Pohjanvirta, R., Gao, Y., Alauusua, S., Tuomisto, J., and Lukinmaa, P. L. (2002). Expression of the mediators of dioxin toxicity, aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT), is developmentally regulated in mouse teeth. Int. J. Dev. Biol. 46, 295300.[CrossRef][ISI][Medline]
Schaeffer, E., Greim, H., and Goessner, W. (1984). Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats. Toxicol. Appl. Pharmacol. 75, 278288.[CrossRef][ISI][Medline]
Schmidt, J. V., and Bradfield, C. A. (1996). Ah receptor signaling pathway. Annu. Rev. Cell. Dev. Biol. 12, 5589.[CrossRef][ISI][Medline]
Schmidt, C. K., Hoegberg, P., Fletcher, N., Nilsson, C. B., Trossvik, C., Hakansson, H., and Nau, H.. (2003). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the endogenous metabolism of all trans-retinoic acid in the rat. Arch. Toxicol. 77, 371383.[CrossRef][ISI][Medline]
Shimizu, K., Nakata, S., Murakami, T., Tamari, K., Takahama, Y., Akamine, A., and Aomo, M. (1992). Long-term occlusal guidance of a severely intoxicated patients with yusho (PCB poisoning): A case report. Am. J. Orthod. Dentofacial Orthop. 101, 393402.[ISI][Medline]
Shimono, M., Ishikawa, T., Enokiya, Y. M., Muramatsu, T., Matsuzaka, K., Inoue, T., Abiko, Y., Yamaza, T., Kido, M. A., Tanaka, T., and Hashimoto, S. (2003). Biological characteristics of the junctional epithelium. J. Electron Microsc. (Tokyo) 52, 627639.
Shojaei, A. H. (1998). Buccal mucosa as a route for systemic drug delivery: A review. J. Pharm. Pharmaceut. Sci. 1, 1530.[Medline]
Steenland, K., Deddens, J., and Piacitelli, L. (2001). Risk assessment for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on an epidemiologic study. Am. J. Epidemiol. 154, 451458.
Tani, Y., Maronpot, R. R., Foley, J. F., Haseman, J. K., Walker, N. J., and Nyska, A. (2004). Follicular epithelial cell hypertrophy induced by chronic oral administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley rats. Toxicol. Pathol. 32, 4149.[CrossRef][ISI][Medline]
Tintari, C. R. (1983). Junctional epithelium: A literature review. Quintessence Int. 2187, 327334.
Toth, K., Somfai-Relle, S., Sugar, J., and Bence, J. (1979). Carcinogenicity testing of herbicide 2,4,5-trichlorophenoxyethanol containing dioxin and of pure dioxin in Swiss mice. Nature 278, 548549.[ISI][Medline]
Tryphonas, L., Arnold, D. L., Zawidzka, Z., Me, J., Charbonneau, S., and Wong, J. (1986). A pilot study in adult rhesus monkeys (M. mulatta) treated with aroclor 1254 for two years. Toxicol. Pathol. 14, 110.[Medline]
Umeda, Y., Matsumoto, M., Yamazaki, K., Ohnishi, M., Arito, H., Nagano K, Yamamoto, S., and Matsuhima. (2004). Carcinogenicity and chronic toxicity in mice and rats administered vinyl acetate monomer in drinking water. J. Occup. Health 46, 8799.[CrossRef][ISI][Medline]
United States Environmental Protection Agency (1996). PCBs: Cancer dose-response assessment and application to environmental mixtures. EPA/600/P-96/001F. Washington, DC.
Van Birgelen, A. P., Van der Kolk, J., Fase, K. M., Bol, I., Poiger, H., Brouwer, A., and Van den Berg, M. (1994). Toxic potency of 3,3',4,4',5-pentachlorobiphenyl relative and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin in a subchronic feeding study in the rat. Toxicol. Appl. Pharmacol. 127, 209221.[CrossRef][ISI][Medline]
Van Birgelen, A. P., Van der Kolk, I., Fase, K. M., Bol, I., Poiger, H., Brouwer, A., Van den Berg, M. (1995). Subchronic dose-response study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats. Toxicol. Appl. Pharmacol. 132, 113.[ISI][Medline]
Van den Berg, M., Birnbaum, L., Bosveld, A. T. C., Brunstrom, B., Cook, P., Feeley, M., Giesy, J. P., Hanberg, A., Hasegawa, R., Kennedy, S. W., Kubiak, T., Larsen, J. C., van Leeuwen, F. X. R., Liem, A. K. D., Nolt, C., Peterson, R. E., Poellinger, L., Safe, S., Schrenk, D., Tillitt, D., Tysklind, M., Younes, M., Waern, F., and Zacharewski, T. (1998). Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ. Health Perspect. 106, 775792.[ISI][Medline]
Varga, E., and Tyldesley, W. R. (1991). Carcinoma arising in cyclosporin-induced gingival hyperplasia. Br. Dent. J. 171, 2627.[ISI][Medline]
Vondracek, M., Xi, Z., Larsson, P., Baker, V., Mace, K., Pfeifer, A., Tjälve, H., Donato, M. J., Gomez-Lechon, M. J., and Grafstrom, R. C. (2001). Cytochrome P450 expression and related metabolism in human buccal mucosa. Carcinogenesis 22, 481488.
Wang, S. L., Chen, T. T., Hsu, J. F., Hsu, C. C., Chang, L. W., Ryan, J. J., Guo, Y. L., and Lambert, G. H. (2003). Neonatal and childhood teeth in relation to perinatal exposure to polychlorinated biphenyls and dibenzofurans; observations of the Yucheng children in Taiwan. Environ. Res. 93, 131137.[CrossRef][ISI][Medline]
Watanabe, K., Petro, B. J., Sevandal, M., Anshuman, S., Jovanovic, A., and Tyner, A. L. (2004). Histochemical examination of periodontal junctional epithelium in p21/p27 double knockout mice. Eur. J. Oral Sci. 112, 253258.[CrossRef][ISI][Medline]
Yamashita, F., and Hayashi, M. (1985). Fetal PCB syndrome: clinical features, intrauterine growth retardation and possible alteration in calcium metabolism. Environ. Health Perspect. 59, 4145.[ISI][Medline]
Yoshihara, S., Ozawa, N., Yoshimura, H., Masuda, Y., Yamaryo, T., Kuroki, H., Murai, K., Akagi, K., Yamanaka, M., Omae, T., Okumura, M., Fujita, M., Yamamoto, T., Ohnishi, A., Iwashita, H., Kohno, T., Ohnishi, Y., Ishibashi, T., Kikuchi, M., Fukuyama, H., Anan, Y., Akamine, A., and Aono, M. (1979). Preliminary studies on the experimental PCB poisoning in rhesus monkeys (author's transl.). Fukuoka Igaku Zasshi 70, 135171 (abstract in English, text in Japanese).[Medline]
Yoshimura, T., and Hayabuchi, H. (1985). Relationship between the amount of rice oil ingested by patients with Yusho and their subjective symptoms. Environ. Health Perspect. 59, 4751.[ISI][Medline]