Long-term effects of chemotherapy and radiation received during early childhood on the developing dentition of pediatric cancer patients.

INTRODUCTION: The short-term effects of chemotherapy and irradiation are well documented; however, there is paucity regarding their long-term effects, especially in children and adolescents. CASE DESCRIPTION: This paper discusses the long-term effects of chemotherapy and/or radiation received by the patients during their early childhood on the developing dentition. It comprises the compilation of 11 cases with alteration in the dental development screened from 138 cases of the childhood cancer patients who received the chemotherapy and/or radiation as a part of anticancer therapy. RESULTS AND CONCLUSION: The findings revealed that the age of initiation of anticancer therapy along with the synergistic effect of chemo-irradiation, and the dose of radiation used were the principal determinants for the dental abnormalities. The root-related abnormalities were found to be varied and more common as compared to the missing teeth and defects related to the tooth crown.

Duration and dose of chemotherapy and dental development.

BACKGROUND: Given the susceptibility of developing tissues to drugs, even small doses of anticancer drugs may affect odontogenesis. Although any toxic effect is transient, the treatment regimens are based on repeated drug administration. OBJECTIVES: The study aimed to establish the impact of antineoplastic therapy on the occurrence of longterm adverse dental effects in a dose-dependent manner in young survivors treated for cancer before 10 years of age. MATERIAL AND METHODS: In total, 37 cancer survivors treated with antineoplastic therapy before 10 years of age underwent a dental examination with a thorough analysis of panoramic radiographs. A total of 236 teeth with 243 different developmental abnormalities were revealed in 28 survivors. Agenesis, tooth size reduction, taurodontia, and enamel and root abnormalities were diagnosed. All survivors received multi-agent chemotherapy, with the most frequently used drugs being vincristine (VCR), doxorubicin (DXR), cyclophosphamide (CP), ifosfamide (IF), etoposide (VP-16), carboplatin (CBDCA), cisplatin (CDDP), and actinomycin-D (ActD). A detailed analysis of medical records was also performed to assess the relationship between the treatment duration as well as the cumulative drug dose administered and the occurrence of particular disturbances. RESULTS: When analyzing the treatment duration and the drug doses in the affected and non-affected participants, there were no statistically significant differences between the survivors with different disturbances within most of the specific drug groups. In some groups, the mean cumulative treatment dose was significantly higher in the non-affected patients. According to Spearman's rho, no significant relationships were observed. CONCLUSIONS: In the present study, no significant differences in terms of treatment duration or drug doses were observed between the patients with particular abnormalities. The developmental stage of tooth formation during chemotherapy is likely the most important factor influencing dental changes. For future research with respect to different treatment protocols, an analysis of a more homogenous group of survivors is warranted.

Co-expression of the aryl hydrocarbon receptor and estrogen receptor in the developing teeth of rat offspring after rat mothers' exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and the protective action of α-tocopherol and acetylsalicylic acid.

BACKGROUND: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause adverse effects in many organs. Toxic effects are caused due to the formation of a TCDD complex with the cytoplasmatic aryl hydrocarbon receptor (AhR), whose mechanism of action is similar to that of the estrogen receptor (ER). Some substances, including α-tocopherol (E) and acetylsalicylic acid (ASA), can reduce the toxic effects of TCDD in offspring. OBJECTIVES: The objective of this study was to evaluate the co-expression of AhR and ER in the incisors of rat offspring whose mothers were exposed to TCDD, using immunohistochemical and histological techniques. Moreover, the possible protective role of E and ASA was investigated. MATERIAL AND METHODS: Four groups of 2-day-old rat offspring, whose mothers were intoxicated by TCDD before mating, were established: control group (C), TCDD group, TCDD+E group and TCDD+ASA group. RESULTS: In the TCDD group, there was an increase in ER expression and a decrease in AhR expression in comparison with the C group. In the TCDD+E and TCDD+ASA groups, there was a weak or negative ER expression and slightly stronger expression of AhR than in the TCDD group. CONCLUSIONS: The co-expression of AhR and ER during tooth development suggests the role of AhR and ER in the control of this process. Both receptors are also involved in the process of detoxification of TCDD. The increase in AhR in TCDD+E and TCDD+ASA groups indicate a preventive action of antioxidant and antiinflammatory pharmaceutics, which may limit negative effects of TCDD.

Microdontia after chemotherapy in a patient treated for neuroblastoma: Histopathological findings.

Microdontia is one of the late effects of antineoplastic therapy in children. This study is based on the comparative histological examination of abnormal, peg-shaped premolars, erupted in a patient treated for neuroblastoma, and of non-affected teeth, extracted in a healthy child. Apart from the size, the teeth vary in tissue morphology. The number of dentinal tubules, dependent on the number of odontoblasts, is smaller in the microdontal sample when observation in the same-sized field of view is conducted. Moreover, the youngest, more than 100-micrometer-thick layer of the microdontal dentin seems to be the secondary dentin, with crispy-shaped tubules and empty spaces between them. No irregular dentin is deposited in the samples of physiologically developed teeth. The structure of cementum is different as well. Unlike regularly shaped premolars, in which typical 2-layer tissue is seen, in sections of microdontal teeth, only acellular tissue with cementoblasts overlying its surface is present. Thorough analysis of drug administration effects, which are visible in microscopic sections, and of time of anticancer treatment could provide insight into the developmental mechanisms of tooth germ formation.

Congenital malformation and autism spectrum disorder: Insight from a rat model of autism spectrum disorder.

AIMS AND OBJECTIVES: The primary aim was an evaluation of the pattern of gross congenital malformations in a rat model of autism spectrum disorder (ASD) and the secondary aim was characterization of the most common gross malformation observed. MATERIALS AND METHODS: In females, the late pro-oestrous phase was identified by vaginal smear cytology, and then, they were allowed to mate at 1:3 ratio (male: female). Pregnancy was confirmed by the presence of sperm plug in the vagina and presence of sperm in the vaginal smear. In the ASD group, ASD was induced by injecting valproic acid 600 mg/kg (i.p.) to pregnant female rats (n = 18) on day 12.5 (single injection). Only vehicle (normal saline) was given in the control group (n = 12). After delivery, pups were grossly observed for congenital malformations until the time of sacrifice (3 months) and different types of malformations and their frequency were noted and characterized. RESULTS: In the ASD group, congenital malformation was present in 69.9% of the pups, whereas in the control group, it was 0%. Male pups were most commonly affected (90% in males vs. only 39.72% in female pups). The tail deformity was the most common malformation found affecting 61.2% pups in the ASD group. Other malformations observed were dental malformation (3.82%), genital malformation (3.28%) and paw malformation (1.1%). Hind limb paralysis was observed in one pup. The tail anomalies were characterized as per gross appearance and location of the malformation. CONCLUSION: In this well-validated rat model of ASD, congenital malformation was quite common. It seems screening of congenital malformations should be an integral part of the management of ASD, or the case may be vice versa, i.e., in the case of a baby born with a congenital deformity, they should be screened for ASD.

Increasing Risk of Disturbed Root Development in Permanent Teeth in Childhood Cancer Survivors Undergoing Cancer Treatment at Older Age.

BACKGROUND: Structural anomalies of teeth are observed at high rates in childhood cancer survivors (CCS). Several therapeutic exposures have been shown to be associated with dental developmental disturbances. This study was conducted to analyze the risk factors for dental developmental abnormality (DDA) and investigate the association between age at the time of cancer treatment and DDA in CCS. PATIENTS AND METHODS: Fifty-six CCS were enrolled. Orthopantomography and dental examination were performed in all the patients. We evaluated the prevalence of DDA and analyzed the risk factors for each type of DDA. RESULTS: DDAs were observed in 46.4% of CCS, including hypodontia in 9 (16.1%), abnormal roots in nine (16.1%), enamel defects/hypoplasia in 6 (10.7%), and microdontia in 12 (21.4%) patients. The number of patients with abnormal roots was significantly higher in the group treated with stem cell transplantation or at an age older than 4 years. We observed that the formation period of abnormal teeth coincided with the treatment period in the majority of CCS with DDA. CONCLUSIONS: Particularly regarding the root abnormality, treatment at elder age may be a risk factor for root developmental disturbances. Risk evaluation, appropriate follow-up, and early detection of dental issues are required for all CCS.

Tooth development disorders in infants of rat dams exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and protective role of tocopherol and acetylsalicylic acid.

Aryl hybrocardon receptor (AhR) activation plays a key role in the pathomechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced defective spatial structure of teeth caused by disordered collagen synthesis. The aim of this study was to identify the influence of dioxins present in female Buffalo rats on the dental structure of their offspring's in the neonatal period and the potential of α-tocopherol and acetylsalicylic acid in curbing post-dioxin hard tissue defects. Research material consisted of molar teeth (n=40) of rat pups which had been given a single dose of TCDD and were then treated with tocopherol or acetylsalicylic acid for 3 weeks. In the offspring of rat dams exposed to TCDD, ameloblasts and odontoblasts were less developed in comparison with the control group and less dynamic angiogenesis in the area of dental papilla was observed. In the pups of TCDD-exposed mothers, a smaller number of AhR was found in amelogenic and odontoblastic cells, whereas in the pups of mothers exposed to TCDD followed by tocopherol and acetylsalicylic acid treatment, the expression of AhR in ameloblasts and odontoblasts increased. We conclude that tocopherol and acetylsalicylic acid treatment exerts a protective effect on the TCDD-induced structural defects of tooth tissue.

The global burden of oral diseases in pediatric HIV-infected populations: a workshop report.

OBJECTIVES: To achieve a comprehensive understanding about the global burden of oral diseases in HIV-infected children and to identify research needs. MATERIALS AND METHODS: A literature search was conducted in PubMed (2009-2014) to address five questions: (i) prevalence of oral diseases in HIV-infected compared with uninfected children, (ii) impact of oral diseases on quality of life, (iii) effect of antiretroviral exposure in utero on craniofacial and dental development, (iv) important co-infections and antiretroviral complications, and (v) value of atraumatic restorative treatment. RESULTS: Studies showed a high prevalence of dental caries in HIV-infected children but the relationship between HIV infection and dental caries remains unclear. Also quality of life needs further investigation supported by better study designs and improvement of the instruments used. Up-to-date evidence suggested long-term harms associated with in utero antiretroviral exposure were minor but would require long-term follow-up through National Registries. The reviews also revealed the wide spectrum of metabolic disease due to antiretroviral therapy and co-infections such as tuberculosis. Finally, atraumatic restorative technique appears to be a simple and safe technique to treat dental caries but outcomes need further evaluation. CONCLUSIONS: The impact of antiretroviral therapy in HIV-infected children has raised novel challenging questions in the field of oral health warranting future research.

[Late morphological teeth changes in children after chemotherapy].

BACKGROUND: Teeth changes after chemotherapy are of clinical importance, but no morphological studies were conducted on microscopic level. AIM: To assess morphological changes in teeth developing under chemotherapy. MATERIALS AND METHODS: Twenty-nine adolescents aged 13-16 years that received chemotherapy at the age of 2-13 were included in the study. Teeth morphology was evaluated by means of clinical and radiological data as well as microscopy of extracted teeth (n=13). Thirty healthy children aged 13-16 and 8 teeth extracted for orthodontic reasons served as a control. RESULTS: Chemotherapy has arresting impact on teeth development confirmed by aplasia of germs when influenced on stages I-II (p=0.0001), preliminary apexogenesis resulting in shortened roots in teeth at the later stages of growth and development (p=0.01). Enamel and dentine defects usually located in cervical area are also a specific feature, while caries incidence was not higher when compared to control group. CONCLUSION: Children receiving chemotherapy have high risk of secondary teeth loss because of germs aplasia and extraction of severely decayed teeth. Early diagnostics helps to prevent secondary deformations of dental arches by prompt prosthetic rehabilitation. Root morphology changes should be considered by root canal treatment.

Anestesia local odontológica y su influencia en anomalías del desarrollo dental: revisión sistemática de la literatura / Dental local anesthesia and its influence on dental developmental abnormalities: systematic review of the literature

La anestesia local odontológica es un procedimiento de rutina en la práctica odontológica pediátrica que, tal como otros sucesos, podría generar anomalías en el desarrollo dental, considerando la susceptibilidad de los gérmenes dentales en desarrollo; por lo anterior consideramos necesario determinar la existencia de asociación entre anomalías del desarrollo dental y el uso de técnicas anestésicas. Para esto se diseñó un estudio descriptivo basado en búsqueda sistemática de literatura en las bases de datos: Scopus, MEDLINE, Web of Science Core Collection, ProQuest Central, Korean Journal Database y SciELO, utilizando combinación de términos MeSH: ("odontoblasts" OR "ameloblasts" OR "odontogenesis" OR "amelogenesis" OR "dentinogenesis" OR "odontodysplasia" OR "dental enamel hypoplasia" OR "dental sac" OR "dental papilla" OR "enamel organ") AND ("anesthesia" OR "local anesthesia" OR "nerve block" OR "dental anesthesia"). De un total de 96 artículos, se incluyeron para revisión 5 artículos relacionados con los objetivos de esta revisión, excluyéndose las coincidencias. La evidencia presente en la literatura es contradictoria. Existen múltiples diferencias entre los estudios analizados, las que podrían deberse a las técnicas anestésicas involucradas, tipo de anestésico, la no consideración de otros posibles agentes causales (síndromes) o la terapia odontológica. No puede ser determinado una relación entre estos dos aspectos.

The dental local anesthesia is a routine procedure in pediatric dental practice that, as other events could generate abnormalities in dental development, considering the susceptibility of developing tooth germs. From the foregoing it necessary to determine the existence of association between disorders of tooth development and use of anesthetic techniques. A descriptive study based on systematic literature review in databases: Scopus, MEDLINE, Web of Science Core Collection, ProQuest Central, Korean Journal Database and SciELO data was designed, using the following combination of MeSH terms ("odontoblasts" OR "ameloblasts" OR "odontogenesis" OR "amelogenesis" OR "dentinogenesis" OR "odontodysplasia" OR "dental enamel hypoplasia" OR "dental sac" OR "dental papilla" OR "enamel organ") AND ("anesthesia" OR "local anesthesia "OR" nerve block "OR" dental anesthesia"). A total of 96 articles, were included for review a total of 5 articles related to the objectives of this review, excluding the matches. The present evidence in the literature is contradictory. There are many differences between the studies analyzed, which could be due to the anesthetic techniques involved, type of anesthetic, other possible causative agents (syndromes) or dental treatment are not included. It can not be determined a relationship between these two aspects.

Importance of a multidisciplinary approach and monitoring in fetal warfarin syndrome.

Warfarin is a synthetic oral anticoagulant that crosses the placenta and can lead to a number of congenital abnormalities known as fetal warfarin syndrome. Our aim is to report on the follow-up from birth to age 8 years of a patient with fetal warfarin syndrome. He presented significant respiratory dysfunction, as well as dental and speech and language complications. The patient was the second child of a mother who took warfarin during pregnancy due to a metallic heart valve. The patient had respiratory dysfunction at birth. On physical examination, he had a hypoplastic nose, pectus excavatum, and clubbing of the fingers. Nasal fibrobronchoscopy showed upper airway obstruction due to narrowing of the nasal cavities. He underwent surgical correction with Max Pereira graft, zetaplasty, and osteotomies for the piriform aperture. At dental evaluation, he had caries and delayed eruption of the upper incisors. Speech and language assessment revealed high palate, mouth breathing, little nasal patency, and shortened upper lip. Auditory long latency and cognitive-related potential to auditory stimuli demonstrated functional changes in the cortical auditory pathways. We believe that the frequency of certain findings observed in our patient may be higher in fetal warfarin syndrome than is appreciated, since a significant number result in abortions, stillbirths, or children evaluated in the first year of life without a follow-up. Thus, a multidisciplinary approach and long-term monitoring of these patients may be necessary.

Dental anomalies in children submitted to antineoplastic therapy.

Cancer is the third most frequent cause of death in children in Brazil. Early diagnosis and medical advances have significantly improved treatment outcomes, which has resulted in higher survival rates and the management of late side effects has become increasingly important in caring for these patients. Dental abnormalities are commonly observed as late effects of antineoplastic therapy in the oral cavity. The incidence and severity of the dental abnormalities depend on the child's age at diagnosis and the type of chemotherapeutic agent used, as well as the irradiation dose and area. The treatment duration and aggressivity should also be considered. Disturbances in dental development are characterized by changes in shape, number and root development. Enamel anomalies, such as discoloration, opacities and hypoplasia are also observed in these patients. When severe, these abnormalities can cause functional and esthetic sequelae that have an impact on the children's and adolescents' quality of life. General dentists and pediatric dentists should understand these dental abnormalities and how to identify them aiming for early diagnosis and appropriate treatment.

Dental anomalies in children submitted to antineoplastic therapy

Cancer is the third most frequent cause of death in children in Brazil. Early diagnosis and medical advances have significantly improved treatment outcomes, which has resulted in higher survival rates and the management of late side effects has become increasingly important in caring for these patients. Dental abnormalities are commonly observed as late effects of antineoplastic therapy in the oral cavity. The incidence and severity of the dental abnormalities depend on the child's age at diagnosis and the type of chemotherapeutic agent used, as well as the irradiation dose and area. The treatment duration and aggressivity should also be considered. Disturbances in dental development are characterized by changes in shape, number and root development. Enamel anomalies, such as discoloration, opacities and hypoplasia are also observed in these patients. When severe, these abnormalities can cause functional and esthetic sequelae that have an impact on the children's and adolescents' quality of life. General dentists and pediatric dentists should understand these dental abnormalities and how to identify them aiming for early diagnosis and appropriate treatment.

Long-term effects of chemotherapy on dental status of children cancer survivors.

BACKGROUND: The aim of this study was to investigate the long-term effects of chemotherapy on the dental and gingival health and dental disturbance parameters of children cancer survivors. PROCEDURE: Thirty-eight children (mean age 12.2 ± 0.5 years) who underwent chemotherapy at 4.29 ± 1.71 years of age formed the study group. Forty age- and gender-matched healthy children with a similar socioeconomic background served as controls. Subjects' caries status (number of decayed, missing, or filled permanent teeth [DMF-T]) was recorded according to World Health Organization criteria. Subjects' periodontal status was recorded according to the community periodontal index system. Radiographic dental examination was used to analyze dental malformations. RESULTS: DMF-T, D-T (number of decayed permanent teeth), and F-T (number of filled permanent teeth) were significantly higher in the study group compared to the controls (4.61 ± 3.71, 3.97 ± 4.45, respectively, and 0.58 ± 0.14 vs. 2.21 ± 1.01, 0.84 ± 1.82, and 1.18 ±1.07, respectively. The most frequent dental disturbances were root malformation (52.6%) and agenesis (47.4%). CONCLUSIONS: According to our examination dental status of long-term survivors is worse than in controls. Hence proper oral hygiene for children cancer survivors (CCS) is critical. In order to meet the need for dental care in CCS health authorities are encouraged to revitalize the dental services Long-term follow-up of CCS is necessary to monitor their dental growth and oral health.

Risk factors to cause tooth formation anomalies in chemotherapy of paediatric cancers.

This study aimed to investigate the risk factors of tooth formation anomalies in anti-cancer chemotherapies. Long-term survivors treated by conventional chemotherapy (n = 26), conventional chemotherapy with high-dose chemotherapy (HDC) (n = 14), and HDC with total body irradiation (TBI) (n = 6) were analysed for the incidence of tooth agenesis, microdonts, and short-rooted teeth. The tooth agenesis and/or microdonts were found in second premolars and second molars, but not in first molars or central incisors. The ratio of subjects with tooth agenesis and/or microdonts was 66.7% and 18.2% in subjects administered conventional chemotherapy at <4 years and ≥ 4 years of age, respectively, while it was 100% and 25% in subjects administered HDC at <4 years and ≥ 4 years of age. The incidence of tooth formation anomalies did not related with the duration of conventional chemotherapy but increased by HDC. The incidence of tooth formation anomalies did not show significantly differences between the HDC with and without TBI groups, and was higher in busulfan-administered subjects than in subjects given cyclophosphamide. It may be concluded that the high-risk group of tooth agenesis is the subjects with HDC under 4 years of age. However, protocols of conventional chemotherapy are not an important risk factor to cause the tooth formation anomalies.

Impact of a high-phosphorus diet on the sonographic and CT appearance of kidneys in degus, and possible concurrence with dental problems.

The main aim of this study was to investigate the impact of pelleted diet of different mineral composition on the sonographic and CT appearance of kidneys in degus (Octodon degus). A total of 35 animals were randomly divided into five groups, fed diets containing different calcium and phosphorus contents (13.5 g/kg calcium and 6.3 g/kg phosphorus, or 9.1 g/kg calcium and 9.5 g/kg phosphorus) and given different amounts of exposure to UV light. Endoscopic examination of the oral cavity as well as renal ultrasonography and CT was performed four times at four-month intervals throughout the study. After 14 months of feeding an experimental diet, all degus were euthanased and subsequently all kidneys were collected for histopathological examination. Animals fed a diet with high dietary phosphate and improper calcium to phosphorus ratio showed severe nephrocalcinosis. Ultrasonographic and CT kidney abnormalities presented as hyperechogenicity and hyperdensity (interpreted as nephrocalcinosis), respectively. The most striking changes were seen at the corticomedullary zone. Ultrasonography and CT correlated in all cases with histopathological findings. Dental disease developed quickly in groups fed diets with an improper calcium and phosphorus content, with obvious apical and coronal elongation of all the teeth. A possible influence of UV light access could not be proved in this study.

Developmental dental defects linked with chemoradiotherapy: a case report.

Developmental orofacial dentoalveolar complications associated with chemoradiotherapy in an 8 year old child with a history of rhabdomyosarcoma are reported. This report details, clinically and radiographically, these effects in a child diagnosed at 3 years of age with a lesion primary to the left buccinator. Early evaluation is vital to determine potential dentoalveolar complications and long-term consequences.

Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors.

Rodent incisors regenerate throughout the lifetime of the animal owing to the presence of epithelial and mesenchymal stem cells in the proximal region of the tooth. Enamel, the hardest component of the tooth, is continuously deposited by stem cell-derived ameloblasts exclusively on the labial, or outer, surface of the tooth. The epithelial stem cells that are the ameloblast progenitors reside in structures called cervical loops at the base of the incisors. Previous studies have suggested that FGF10, acting mainly through fibroblast growth factor receptor 2b (FGFR2b), is crucial for development of the epithelial stem cell population in mouse incisors. To explore the role of FGFR2b signaling during development and adult life, we used an rtTA transactivator/tetracycline promoter approach that allows inducible and reversible attenuation of FGFR2b signaling. Downregulation of FGFR2b signaling during embryonic stages led to abnormal development of the labial cervical loop and of the inner enamel epithelial layer. In addition, postnatal attenuation of signaling resulted in impaired incisor growth, characterized by failure of enamel formation and degradation of the incisors. At a cellular level, these changes were accompanied by decreased proliferation of the transit-amplifying cells that are progenitors of the ameloblasts. Upon release of the signaling blockade, the incisors resumed growth and reformed an enamel layer, demonstrating that survival of the stem cells was not compromised by transient postnatal attenuation of FGFR2b signaling. Taken together, our results demonstrate that FGFR2b signaling regulates both the establishment of the incisor stem cell niches in the embryo and the regenerative capacity of incisors in the adult.

Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The current study was performed to describe frequencies and risk factors of altered oral health and odontogenesis in childhood cancer survivors. METHODS: In total, 9308 survivors who were diagnosed between 1970 and 1986 and 2951 siblings from the Childhood Cancer Survivor Study completed a survey that contained oral-dental health information. The authors analyzed treatment impact, socioeconomic data, and patient demographics on dental outcomes using univariate and multivariate logistic regression models to estimate odds ratios (ORs). RESULTS: In multivariate analysis, survivors were more likely to report microdontia (OR, 3.0; 95% confidence interval [95% CI], 2.4-3.8), hypodontia (OR, 1.7; 95% CI, 1.4-2.0), root abnormalities (OR, 3.0; 95% CI, 2.2-4.0), abnormal enamel (OR, 2.4; 95% CI, 2.0-2.9), teeth loss>or=6 (OR, 2.6; 95% CI, 1.9-3.6), severe gingivitis (OR, 1.2; 95% CI, 1.0-1.5), and xerostomia (OR, 9.7; 95% CI, 4.8-19.7). Controlling for chemotherapy and socioeconomic factors, radiation exposure of >or=20 Gray to dentition was associated significantly with an increased risk of >or=1 dental abnormality. Dose-dependent alkylating agent therapy significantly increased the risk of >or=1 anatomic/developmental dental abnormalities in survivors who were diagnosed at age<5 years (OR, 1.7, 2.7, and 3.3 for alkylating agent scores of 1, 2, and 3, respectively). CONCLUSIONS: Radiation and chemotherapy were independent risk factors for adverse oral-dental sequelae among childhood cancer survivors. The authors concluded that patients who received receiving alkylating agents at age<5 years should be closely monitored.

A margin-of-exposure approach to assessment of noncancer risks of dioxins based on human exposure and response data.

BACKGROUND: Risk assessment of human environmental exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDFs) and other dioxin-like compounds is complicated by several factors, including limitations in measuring intakes because of the low concentrations of these compounds in foods and the environment and interspecies differences in pharmacokinetics and responses. OBJECTIVES: We examined the feasibility of relying directly on human studies of exposure and potential responses to PCDD/PCDFs and related compounds in terms of measured lipid-adjusted concentrations to assess margin of exposure (MOE) in a quantitative, benchmark dose (BMD)-based framework using representative exposure and selected response data sets. METHODS: We characterize estimated central tendency and upper-bound general U.S. population lipid-adjusted concentrations of PCDD/PCDFs from the 1970s and early 2000s based on available data sets. Estimates of benchmark concentrations for three example responses of interest (induction of cytochrome P4501A2 activity, dental anomalies, and neonatal thyroid hormone alterations) were derived based on selected human studies. RESULTS: The exposure data sets indicate that current serum lipid concentrations in young adults are approximately 6- to 7-fold lower than 1970s-era concentrations. Estimated MOEs for each end point based on current serum lipid concentrations range from < 10 for neonatal thyroid hormone concentrations to > 100 for dental anomalies-approximately 6-fold greater than would have existed during the 1970s. CONCLUSIONS: Human studies of dioxin exposure and outcomes can be used in a BMD framework for quantitative assessments of MOE. Incomplete exposure characterization can complicate the use of such studies in a BMD framework.