Risk Assessment of Coumarin Intake in the Norwegian Population

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has at the request of the Norwegian Food Safety Authority (Mattilsynet) conducted a risk assessment of the coumarin intake in the Norwegian population. VKM was asked to assess if any part of the population has a total intake of coumarin that will exceed the tolerable daily intake (TDI). It should further be considered whether an intake of coumarin exceeding TDI 1-2 times a week for several years would represent a risk to the health of the consumer. The assessment has been performed by the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panel 4). Coumarin is a naturally flavouring substance in cinnamon and occurs in many plants. The substance can be found in different types of cinnamon to a varying degree. The two main types are Ceylon (Cinnamomum zeylandicum) and Cassia cinnamon (Cinnamomum aromaticum). Cassia cinnamon, which currently is most frequently used in food products on the Norwegian market, contains more coumarin than the lesser used Ceylon cinnamon. Oral intake of coumarin is mostly related to consumption of cinnamon-containing foods or cinnamon as a spice. This includes both direct addition of cinnamon to foods as well as the use of cinnamon oils and other cinnamon extracts by the food industry. Other important sources of exposure could be food supplements based on cinnamon or the use of cosmetic products through dermal exposure, as synthetic coumarin is added as a fragrance ingredient to perfumes, skin gels, lotions and deodorants. It is known from animal experiments that coumarin can cause liver toxicity. It is considered as a non-genotoxic carcinogen in mice and rats. In 2004, the European Food Safety Authority (EFSA) established a TDI of 0.1 mg coumarin/kg body weight (bw), based on a no observed adverse effect level (NOAEL) for liver toxicity in a 2-year dog study. This TDI was maintained when the substance was re-evaluated in 2008. EFSA further concluded that exposure to coumarin resulting in an intake 3 times higher than the TDI for 1-2 weeks was not of safety concern. In order to answer the second question as stated in the terms of reference, the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics found it necessary to further examine the data on toxicity of coumarin, which were the basis for the TDI established by EFSA. The most significant hazards of coumarin appears to be liver toxicity, which is well documented, and demonstrated in mice, rats, dogs, baboons and humans, and kidney adenomas in male rats. In a review of human case reports, a small subgroup of the human population appears for unknown reasons to be more susceptible to medical treatment with coumarin. The lowest reported dose of coumarin associated with liver toxicity in humans is around 0.4 mg/kg bw/day. It should be noted that the liver toxicity of coumarin in humans usually is reversible. Since there were no dose-response data for humans, animal data were used in the hazard characterisation. The VKM Panel decided to use the benchmark dose (BMD) approach to determine a point of departure for adverse effects of coumarin. The 2-year chronic toxicity/carcinogenicity study in rats by the US National Toxicology Program (NTP) was chosen for model simulation and BMD/BMDL (benchmark dose lower confidence limit) calculations. The best model fit of the dose-response data combined with the lowest BMDL05 (dose where the response is likely to be smaller than 5%) was seen for increased relative liver weight in female rats, which gave a BMDL05 of 7 mg/kg bw/day (converted from 10 mg/kg bw, 5 times per week). The VKM Panel used the BMDL05 for relative increase in liver weight in female rats to establish a TDI of 0.07 mg/kg bw/day using an uncertainty factor of 100 to account for interand intraspecies variation. The intake calculations for coumarin from food and drinks in this opinion are based on both data from the nationally representative food consumption surveys Norkost, Ungkost, Småbarnskost and Spedkost, as well as on assumed worst intake scenarios of different cinnamon-containing food products. The average coumarin levels found in cinnamoncontaining food categories such as ginger bread, cinnamon buns and similar bakery products, cinnamon-containing cakes, thin pastry with cinnamon and cinnamon-based tea sold on the Norwegian market, were used to calculate the total coumarin intake in different age groups in the population. For the calculation of the coumarin intake from cinnamon powder sprinkled on oatmeal porridge and rice porridge, a coumarin level of 3000 mg/kg in cinnamon powder was used. The frequency of consumption and the amount of cinnamon powder (from ¼ - 1 teaspoon) sprinkled on the porridge were taken into account in the calculations. To assess if any part of the Norwegian population has an intake of coumarin that will exceed the TDI, the different intake scenarios presented in the opinion have been compared with the TDI of 0.07 mg/kg bw/day established by VKM. The main conclusions from the VKM Panel were: The total estimated intake of coumarin for mean and high consumers of cinnamon-containing foods are below the TDI for all age groups when consumption of cinnamon-based tea and porridge with cinnamon was excluded. Children and adults who regularly consume oatmeal porridge sprinkled with cinnamon may exceed the TDI by several folds depending on the frequency of consumption and the amount of cinnamon used. Small children (1- and 2-years old) who have a mean or high consumption of oatmeal porridge may exceed the TDI even if they use moderate amounts of cinnamon powder on the porridge. In a worst case scenario with high consumption of porridge and use of high amounts of cinnamon powder, the estimated coumarin intake could exceed the TDI by about 20-fold. This intake is similar to dose levels of coumarin used in medical treatment of adults and where cases of liver toxicity have been reported. Drinking of cinnamon-based tea, which may have a high content of coumarin, can also result in a total intake of coumarin that exceeds the TDI both for children and adults. Other relevant sources of coumarin are cosmetics and food supplements with cinnamon. The recommended dose of two cinnamon supplements sold on the Norwegian market can lead to an exceedance of TDI in adults. It is not anticipated that children will consume supplements with cinnamon. Cosmetic products (shower gels, body lotions, deodorants and oils) are important sources of coumarin exposure both for children and adults, but quantification of the coumarin exposure from cosmetics was not possible due to lack of data. The VKM Panel concludes that based on the available data, the possibility of an adverse health effect by exceeding the TDI 3-fold for 1-2 times per week for several years cannot be assessed. Generally, a minor or an occasional exceedance of TDI is not considered to increase the risk of adverse health effects. The coumarin intake could exceed the TDI by 7-20 fold in some instances. Liver toxicity may occur shortly after the start of coumarin exposure. Such large daily exceedances of TDI, even for a limited time period of 1-2 weeks, cause concern of adverse health effects.

Tratamiento restaurador de lesiones dentales traumáticas. Reporte de tres casos clínicos / Restorative treatment of traumatic dental injuries. Report of three clinical cases

RESUMEN: Las lesiones dentales traumáticas (LDT) son comunes, siendo las principales causas: golpes por caídas u objetos, traumatismos deportivos, actividades físicas de ocio y accidentes automovilísticos. Casi todos los casos abarcan los dientes anteriores, con mayor frecuencia los incisivos centrales superiores. De las clasificaciones de LDT, se describe la propuesta por Andreassen y aceptada por la OMS en su «Clasificación internacional de las enfermedades¼ desde 1978. Sumando tecnologías a la práctica odontológica, el diseño asistido por computadora y la fabricación asistida por computadora (CAD/CAM), proporcionan al rehabilitador nuevas modalidades de tratamiento, mejorando el diseño y la aplicación de restauraciones cerámicas libres de metal, que a lo largo de la última década ha demostrado un buen desempeño clínico. Se presentan a la clínica de la Especialidad de Odontología Restauradora Avanzada, tres pacientes, de los cuales el primero se presentó en las primeras 48 horas luego de la LDT en centrales y lateral derecho; dos pacientes presentaban LDT de uno de los incisivos centrales, el primero un adulto de 28 años de edad con una evolución de cinco años y sin ningún tratamiento ejecutado aún; el segundo caso, un niño de nueve años de edad que se presenta con un tratamiento de sistemas de conductos con una evolución de seis meses.

ABSTRACT: Traumatic dental injuries (TDI) are very common, they are mainly originated from blows caused by objects or due to falls, sport injuries as well as injuries sustained during leisure activities and car accidents. Most cases involve anterior teeth, of which upper central incisors are more frequently affected. Andreassen's TDI classification, sanctioned by WHO in 1978 in «International disease classification ¼, is described here. When new technologies are incorporated into dental practice, computer-assisted design and computer-assisted manufacture (CAD/CAM) provide the restorative clinician with new treatment options, thus improving design and application of metal-free ceramic restorations, which, along last decade, have haven proven to provide suitable clinical performance. Three patients were treated at the Advanced Restorative Dental Graduate Program clinic. The first one sought treatment within the first 48 hours after TDI, in central and right lateral teeth; two patients exhibited TDI in one central incisor, the first one was a 28 year old male with a five year evolution of the injury and no previous treatment, the second case was a nine year old child who arrived having been subjected to root canal treatment, with a six month evolution.

Effect of ethyl pyruvate on E-cadherin of airway epithelium in a TDI-induced mouse asthma / 实用医学杂志

Objective To explore the role of ethyl pyruvate (EP) on E-cadherin of airway epithelium and airway inflammation in a TDI-induced mouse asthma model. Methods 30 male BALB/c mice were randomly divided into control group , asthma group and EP group. On day 1 and 8 , mice in asthma group and EP group were treated with 0.3%TDI on the dorsum of both ears for sensitization. And on day 15 , 18 and 21 the mice underwent an aerosol inhalation of 3% TDI, and saline (100 mg/kg) was injected intraperitoneally 1 hour before inhalation. The control group underwent acetone and olive oil (AOO) sensitization on day 1 and 8, AOO challenge on day 15, 18 and 21. Saline (100 mg/kg) was injected intraperitoneally 1 hour before challenge. One hour before each challenge, mice were given EP (100mg/kg) or vehicle via intraperitoneal injection. On day 22, airway reactivity, IL-4 , IFN-γand IgE in the serum were detected , immunohistochemistry and WB were used to assess E-cadherin levels. Results Airway reactivity, IL-4, IFN-γin and IgE in the serum in asthma group are significantly higher than that in control group (P<0.05). Treatment with EP dramatically decreased airway hyperresponsiveness in TDI-challenged mice, as well as IL-4, IFN-γ and IgE (P < 0.05). E-cadherin in control group was distributed evenly at the connection of epithelial cells. E-cadherinin distribution was chaotic and its expression was decreased in asthma group. EP intervention can ameliorate the damage of E-cadherinin. Conclusions EP can ameliorate the destruction of E-cadherin in airway epithilum by TDI.

Inhibition of CYP3A4 and CYP2C9 by podophyllotoxin: Implication for clinical drug–drug interactions.

Podophyllotoxin (PPT) and its derivatives exert significant anti-cancer activities, and one derivative etoposide is often utilized to treat various cancers in the clinic. The aim of the present study is to investigate the inhibitory effects of PPT on major cytochrome P450 (CYP) isoforms in human livers. Inhibition of CYP3A4, CYP2C9, CYP2C8, CYP2D6, CYP2E1 and CYP2A6 by PPT was investigated in the human liver microsomal system. Time-dependent inhibition of CYP3A4 by PPT was also evaluated. The results showed that PPT strongly exhibited inhibitory effects on CYP3A4 and CYP2C9 in a concentration-dependent manner. Half inhibition concentration (IC50) was 1.1±0.3 and 4.6±0.3 μM for CYP3A4 and CYP2C9, respectively. Inhibition kinetic analysis showed that PPT exhibited competitive inhibition towards CYP3A4 and CYP2C9 with Ki of 1.6 and 2.0 μM, respectively. Additionally, PPT exerted time-dependent inhibition towards CYP3A4 and the kinetic parameters were 4.4±2.1 μM and 0.06±0.01 min–1 for KI and kinact, respectively. Our experimental data indicate that potential drug–drug interaction (DDI) might exist when PPT is co-administered with the substrates which mainly undergo CYP3A4- or CYP2C9-mediated metabolism.

Mesenchymal Stem Cell Transfer Suppresses Airway Remodeling in a Toluene Diisocyanate-Induced Murine Asthma Model

PURPOSE: Severe asthma is characterized by high medication requirements to maintain good disease control or by persistent symptoms despite high medication use. The transfer of bone marrow-derived mesenchymal stem cells (BMDMSCs) to the injured lungs is a possible treatment for severe asthma. This study investigated the therapeutic effects of BMDMSCs in airway remodeling and inflammation in an experimental toluene diisocyanate (TDI)-induced asthma animal model of severe asthma. METHODS: BMDMSCs were transferred into rats after TDI inhalation. Bronchoalveolar lavage (BAL) cell profiles, histological changes including an inflammatory index and goblet cell hyperplasia, and the airway response to methacholine using plethysmography were analyzed. Smooth muscle actin (SMA) and proliferating cell nuclear antigen (PCNA) protein expression were observed in lung tissue using immunohistochemical staining. The collagen content was measured in lung tissue sections and lung extracts using Masson's trichrome staining and an immunoassay kit. RESULTS: The numbers of inflammatory cells in BAL fluid, histological inflammatory index, airway response to methacholine, number of goblet cells, and amount of collagen were increased in TDI-treated rats compared with sham rats (P=0.05-0.002). BMDMSC transfer significantly reduced the TDI-induced increase in the inflammatory index and numbers of eosinophils and neutrophils in BAL fluid to levels seen in sham-treated rats (P<0.05). BMDMSC transfer significantly reduced the number of goblet cells, collagen deposition, and immune staining for SMA and PCNA with concomitant normalization of the airway response to methacholine. CONCLUSIONS: The systemic transfer of BMDMSCs effectively reduced experimental TDI-induced airway inflammation and remodeling and airway hyperreactivity.

The Value of Conventional Echocardiographic and Tissue Doppler Imaging in the Diagnosis of Cardiac Amyloidosis / 华中科技大学学报（医学）（英德文版）

Transthoracic echocardiographic characteristics of 17 cases of cardiac amyloidosis (CA),a rare disease in China, were analyzed in order to improve the understanding of the disease. Seventeen cases of biopsy-proven CA, admitted to Wuhan Union Hospital from June 1994 to September 2008 were retrospectively reviewed. Twenty normal volunteers served as control group. Left atrial and ventricular functions and mitral inflow velocity were measured by two-dimensional, and Doppler echocardiography, and tissue Doppler imaging (TDI)-derived peak systolic wall motion velocities (Sv), peak early diastolic wall motion velocities (Ev), and peak late diastolic wall motion (Av) were measured at the septunm. Lateral, inferior and anterior comers of mitral annulus from the apical 4- and 2 chamber views. Compared with the control group, the interventricular septal thickness (IVSd), the left ventricular posterior wall (LVPWd), right ventricular transverse diameter (RVTDd) near the end of diastole and the interauricular septum thickness (IASs), left atrial anteroposterior diameter (LAADs), right atrial transverse diameter (RATDs) near the end of systole were increased significantly (all P<0.05) and left ventricular ejection fraction (LVEF) decreased (P<0.05) in the CA group.Compared with the control group, Sv, Ev at each wall and Av at almost all walls were significantly decreased in the CA group. In the CA group, Myocardial echoes of interventricular septum and free wall of left ventricle were enhanced evidently and distributed unevenly. The echoes presented as ground glass-like images, with some spotty hyper echoes. Both atria were enlarged, and LVEF decreased, with diastolic function impaired, and mild-moderate hydropericardium found in the CA group. It was concluded that echocardiography was a relatively sensitive and highly specific non-invasive method for the diagnosis of CA.

Prevalence of Occupational Asthma in TDI-Exposed Workers / 대한산업의학회지

OBJECTIVES: This study was carried out to estimate the prevalence of isocyanate-induced occupational asthma in toluene diisocyanate (TDI) exposed workers. METHODS: We examined 170 workers who had been directly exposed to TDI through a medical questionnaire, physical examination, and pulmonary function test. Based on screening examination, workers with suspected occupational asthma were selected for further evaluation such as methacholine and TDI challenge tests. RESULTS: Eleven (6.9%) among 170 workers complained of symptoms of occupational asthma, and 7 among these 11 symptomatic workers showed positive responses to the methacholine challenge test (4.1%). One spray painter was confirmed as having the TDI induced occupational asthma following a positive response to TDI challenge test. CONCLUSIONS: The prevalence of TDI-induced asthma was at 0.58% was lower than that for former studies (2-20%). Improved workplace environment, lower level of TDI exposure compared to the past, and the healthy workers effect may have contributed to this low rate of asthma prevalence in workers with TDI exposure.

Exposure to Toluene Diisocyanate (TDI) Induces IL-8 Production from Bronchial Epithelial Cells: Effect of Pro-inflammatory Cytokines

This investigation was designed to confirm IL-8 production from human bronchial epithelial cells with toluene diisocyanate (TDI) exposure and to examine the effects of pro-inflammatory cytokine and dexamethasone. We cultured Beas-2B, a bronchial epithelial cell line with TDI-HSA conjugate and compared with those without conjugate. IL-8 in the supernatant was measured by ELISA. To evaluate the effect of proinflammatory cytokines, peripheral blood mononuclear cells (PBMC) were collected from TDI- and non-TDI asthma patients, and were added to the epithelial cell culture. Dexamethasone or antibodies to TNF-alpha and IL-1beta were pre-incubated with PBMC supernatant. There was a significant production of IL-8 from bronchial epithelial cells with addition of TDI-HSA conjugate in a dose-dependent manner, which was significantly augmented with addition of PBMC supernatant. Higher production of IL-8 was noted with addition of PBMC supernatant from TDI-asthma patients than in those from non-TDI asthma patients. IL-1beta and IL-1beta/TFNalpha antibodies were able to suppress the IL-8 productions. Pre-treatment of dexamethasone induced dose-dependent inhibition of the IL-8 production. These results suggest that the IL-8 production from bronchial epithelial cells contribute to neutrophil recruitment occurring in TDIinduced airway inflammation. IL-1beta released from PBMC of TDI-induced asthma patients may be one of the pro-inflammatory cytokines to enhance IL-8 production.

Characteristics of Occupational Asthma Reported by Surveillance System in Incheon / 대한산업의학회지

OBJECTIVES: This study was carried out to estimate the magnitude of occupational asthma and to determine its characteristics. METHODS: We collected and analyzed 121 cases of occupational asthma reported by a surveillance system in Incheon for 5 years. The cases were classified according to industry and causing gent. We attached the data to worker's compensation records to establish the degree of agreement between the two sources. RESULTS: The industry of musical instrument manufacture was the most common (31 cases, 25.6%), followed by furniture manufacture, dye making, and machinery manufacture. TDI was the most common causing agents (52 cases, 43%), followed by reactive dye, wood dust, and organic dust. There was poor agreement with the worker's compensation records (2 cases, 8%). CONCLUSIONS: TDI and reactive dyes were the major materials causing occupational asthma. Most cases reported by the surveillance system were not applied to the worker's compensation system. Therefore, the surveillance system should be used to estimate the magnitude of occupational asthma and to determine its characteristics.

Role of Matrix Metalloproteinase in the Pathogenesis of Bronchial Asthma / 결핵

BACKGROUND: Toluene diisocyanate(TDI) is a leading cause of occupational asthma. However, the pathogenesis of TDI-induced asthma is largely unknown because there is no suitable animal model. METHODS: We developed a murine model of TDI-induced asthma by performing two sensitization with 3% TDI and one challenge with 1% TDI using ultrasonic nebulization. RESULTS: Similar to occupational asthma in humans, murine TDI-induced asthma includes findings 1) increased inflammatory cells, including neutrophils and eosinophils, 2) histologic changes, including infiltration of inflammatory cells around bronchioles, thickened airway epithelium, contraction of bronchioles, and accumulation of mucus and debris in the bronchioles, 3) increased MMP-9 activity in inflammatory cells in the airway lumen, 4) airway hyperresponsiveness. Administration of an MMP inhibitor, MMPI-I, remarkably reduced all these pathophysiological findings. CONCLUSION: Therefore, we conclude that TDI-induced occupational asthma is associated with the induction of MMP-9 in inflammatory cells, and the inhibition of MMP-9 may be a good therapeutic strategy.

Expression of epidermal growth factor receptor (EGFR) and transforming growth factor beta1 (TGF beta1) in airway mucosa of toluene diisocyanate (TDI)-induced asthma patients / 천식및알레르기

BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor(EGFR) and TGF beta1 have been known as a central regulator in airway remodeling. There have been some reports demonstrating expression of EGFR and TGF beta1 in airway mucosa of asthmatic patients. However, the expression of EGFR and TGF beta1 in bronchial epithelium of TDI-induced asthmatics has not been observed. The aim of this study was to observe expression of EGFR and TGF beta1 and evaluate their roles in pathogenic mechanism of TDI-induced asthma. METHODS: EGFR and TGF beta1 expression were compared using immunohistochemistry technique in bronchial mucosa from 22 subjects with TDI-induced asthma(group I: 10 newly diagnosed, group II: 12 TDI-induced asthma patients with persistent asthma symptoms for more than 5 years after diagnosis), 7 non-asthmatics undergoing pneumonectomy from lung tumor, and 3 healthy subjects. The intensity of expression was analyzed by two observers. The grade of intensity was presented from 0 to 3. Subepithelial basement membrane (SBM) thickness was measured using an image analyzer. RESULTS: EGFR expression was significantly higher in asthmatic patients than in wntrois (p>0.05), while no significant difference were nosed in TGF beta1 expression (p>0.05). There was no significant difference in EGFR expression between group I and II (p>0.05). However, grade of TGF beta1 expression was significantly higher in group II than those of group I (p0.05). CONCLUSION: These findings suggest that EGFR and TGF beta1 may contribute to pathogenesis of TDI-induced asthma. However, further studies are required to evaluate the role of EGFR and TGF beta1 in the pathogenesis of TDI-induced asthma.

Longitudinal study of specific antibodies to toluene diisocyanate (TDI)-human serum albumin (HSA) conjugate in patients with TDI-induced asthma

BACKGROUND: An appreciable number of patients with toluene diisocyanate (TDI)-induced asthma have high serum levels of specific IgE (sIgE) antibody to TDI-human serum albumin conjugate (HSA). A recent investigation suggested a role of specific IgG (sIgG) in the development of TDI asthma. METHODS: We observed the changes in the levels of specific IgE and IgG antibodies to TDIHSA conjugate in TDI-induced asthmatic patients during seven years avoidance. RESULTS: Six subjects with high sIgE and five with high sIgG were enrolled. All of them had taken anti-asthmatic medications with complete avoidance. Serum levels of sIgE and sIgG to TDI-HSA conjugate were detected by ELISA. The level of sIgE continued to decline up to 7 years and the mean half-life was 3.9 years. The mean half-life of sIgG was 4.5 yrs. CONCLUSION: These findings suggest that both sIgE and sIgG to TDI-HSA conjugate may persist for several years after the last exposure to TDI.

Localization of transforming growth factor beta1 in airway mucosa of toluene diisocyanate-induced asthma / 천식및알레르기

BACKGROUND AND OBJECTIVE: There have been some reports on the expression of TGF beta-an anti-inflammatory and fibrosing cytokine in airway mucosa of asthmatics. However, the ex- pression of TGF beta1 in bronchial mucosa of TDI-induced asthma is not known. The aim of this study was to observe immunolocalization of TGF beta1 in airway mucosa of TDI-induced asthma. METHODS: TGF beta1 expressions were compared using immunohistochemistry in bronchial muco- sa from 22 subjects with TDI-induced asthma (group I: 10 newly diagnosed, group II: 12 subjects with persistent asthma symptoms for more than 4 years after diagnosis), and 8 non- asthmatics undergoing pneumonectomy from lung tumor. The distribution and intensity of expression were analyzed by two observers in four areas of bronchial tissue-epithelium(EP), vascular endothelium(VE), smooth muscle(SM), and mucous glands(MG). RESULTS: Positive rates of TGF beta1 expression for groups I and II in the four areas were as follows; EP (50% vs 100%, p0.05). Grades of TGF beta1 expression of EP, VE, and SM were significantly higher in group II than in group I(p0.05, respectively). CONCLUSION: TGF beta1 expressions of EP, VE, SM and MG were noted in airway mucosa of TDI-induced asthma and expressions of EP, VE, and SM were more intense and frequent in patients with persistent asthma symptoms.

Expression of transforming growth factorbeta1 (TGFbeta1) and TGFbeta receptor II (R II) in airway mucosa of toluene diisocyanate (TDI)-induced asthma: relationships with persistent asthmatic symptoms / 대한내과학회지

BACKGROUND: The underlying mechanism to explain the poor prognosis of TDI-induced asthma is unknown. We performed this study to evaluate the role of TGFbeta1 and its receptor, TFGbeta receptor II (RII) in TDI-induced asthma. METHODS: We applied immunohistochemistry with monoclonal antibodies to TGFbeta1 and RII in bronchial mucosa from 22 subjects with TDI-induced asthma (group I: 10 newly diagnosed, group II: 12 subjects with persistent asthma symptoms for more than 4 years after diagnosis) and 8 non-asthmatics undergoing pneumonectomy from lung tumor. The expression was analyzed in 4 areas of bronchial tissue-epithelium (EP), vascular endothelium (VE), smooth muscle (SM), mucous gland (MG). The grade of intensity was presented from 0 to 3. Subepithelial basement memberane (SBM) and submucosal extracellular matrix (SECM) thickness were measured using an image analyzer. Serum specific IgE and IgG antibody levels to TDI- human serum albumin (HSA) conjugate were detected by ELISA. RESULTS: Grade of TGFbeta1 expression was significantly higher in EP, VE and SM in group II than those of group I of TDI-induced asthma (p0.05). Significant correlations were noted between asthma duration after diagonsis and intensity of TGFbeta1 expression in EP, VE and SM (p0.05). TGF 1 expression was significantly higher in EP, VE and SM in subjects with specific IgG antibody to TDI-HSA than those without it (p<0.05). CONCLUSION: These findings suggest that TGFbeta1 may contribute to develop persistent asthma symptoms in TDI-induced asthma.

Diverse profiles of specific IgE response to toluene diisocyanate (TDI)-human serum albumin conjugate in TDI-induced asthma patients

The prevalence studies on specific IgE to toluene diisocyanate (TDI)-human serum albumin (HSA) conjugate in TDI-induced asthma have shown variable results. In this study, we attempted to compare specific IgE bindings to TDI-HSA conjugate and its specificity using 3 different conjugates. Sera were collected from 20 TDI-induced asthma and 10 controls. Specific IgE were measured by ELISA using three TDI-HSA conjugates; two from Carnegie Mellon (CM; 98 and 99 CM conjugates) and one from Ajou University. To evaluate specificity and cross-reactivity, ELISA inhibition tests were applied. Positive and negative predictive values between Ajou conjugate and 98 CM conjugate were 75% and 100%. Those between Ajou and 99 CM were 100% and 93.8%. One patient showed an isolated positive response to the Ajou with negative responses to the other two conjugates. ELISA inhibition test using this patient's serum revealed the significant inhibitions by the Ajou and minimal inhibitions by the others. On the other hand, another patient showed an isolated positive response to 99 CM with negative responses to the others, and ELISA inhibition test showed significant inhibition by 99 CM with minimal inhibitions by the others. These results suggest that specific IgE bindings to a new antigenic determinant of TDI-HSA conjugate can be heterogeneous and differ from one individual to another.

A status of occupational asthma in Korea through the cases reported to the Occupational Asthma Surveillance Center / 천식및알레르기

BACKGROUND: Since asthma caused by toluene diisocyanate (TDI) was reported at a polyurethane paint factory, occupational asthma there has been increasing concern of in both allergic and occupational health. However, the statistics of occupational asthma did not reflected its seriousness because of many barriers related to legal reporting. Since fild a voluntary report from a clinician sent directly to a surveillance center would allow more cases to be filed without any disadvantage to workers and employers, we developed a surveillance system to facilitate the reporting of occupational asthma. METHODS: Allergists and pulmonary physicians were asked to report to the Occupational Asthma Surveillance Center (OASC) using a mail, fax or e-mail if work-related asthma was diagnosed. A claimed case for occupational asthma to the Occupational Health Research Institute was also included. The OASC contacted the workers by phone and investigated the workplace if necessary. The reported cases from October, 1998 to November, 1999 were analysed. RESULTS: Thirty-three cases were reported with 29 males and four females. The mean age was 44 and the mean latency period was 5.4 years. Twenty-one cases were caused by a known allergen inducer with objective evidence. The causative agents included TDI in 45.5 % (15), followed by reactive dye in 24.2 % (8), welding fume (2), formaldehyde (1), paint (1), toluene (1), styrene (1), exhaustive gas (1), and wood dust (1). Among these cases, there were seven dyers, four painters, three machine operators and furniture finishers, two assemblers and tanneries. Eighteen cases had claimed Workers Compensation Insurance and all were accepted. The reasons for not claiming Insurance included ignorance (28.5 %), feat of job dismissal (23.8%), other reasons (9.5 %), agreement with the employer (14.3 %) and employer himself (9.5 %). CONCLUSION: The OASC by allergists was an effective system to find unreported cases and to provide a prevention strategy of occupational asthma. Occupational asthma was mostly caused by TDI and reactive dye. Painters and dyers were the most common occupations causing occupational asthma. Only half of occupational asthma patients claimed compensation because of workers' ignorance and fear of being fired.

Treatment of iron deficiency anemia by total dose infusion (TDI) of iron dextran

Twenty-eight patients received intravenous iron-dextran (TDI) for correction of iron deficiency anemia. One experienced a systemic reaction but recovered without untoward effects, another developed uterine contraction and both of this case were not included in this studiesThe rise in hemoglobin and hematocrit were noted after two weeks and was rapid over a period of six weeks. No delayed reactions were seen in all the casesWe believe that, although not without danger, the use of Iron-Dextran Infusion (TDI) by the method and techniques described should find a useful place in correction of severe iron deficiency anemia. (Summary)

Regulation of CC Chemokines in TDI-Induced Nasal Hyperreactive Rats: Expression of RANTES and Eotaxin mRNA Examined Using Competitive PCR / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Chemokines are effective leukocyte chemoattractants and may play an important role in mediating eosinophil recruitment in various allergic conditions in human. Eotaxin is an eosinophil-specific chemokine associated with the recruitment of eosinophils to the site of allergic inflammation. However, it is not yet known as to whether or not RANTES is associated with selective tissue eosinophilia. The aim of this study is to understand the events involved in selective eosinophil migration into inflammatory sites. MATERIALS AND METHODS: We performed the quantitative analysis of RANTES and eotaxin mRNA expression levels in TDI-induced nasal hyper-reactive rats. Expression levels of RANTES and eotaxin mRNA from inferior turbinate mucosa were examined using competitive PCR in 35 experimental rats and 5 control rats compared with infiltrated eosinophil counts. RESULTS: The quantity of RANTES mRNA increased 3 folds 2 day after provocation, and the infiltrating eosinophils were correlated with the expression levels of RANTES mRNA (p<0.01). The quantity of eotaxin mRNA increased 15 folds 1 day after provocation. These results suggest that RANTES and eotaxin play a role in controlling antigen-induced eosinophil recruitment into the tissue. Eotaxin is a more potent and selective chemoattractant for eosinophils than infiltrating eosinophils, and were correlated with the expression levels of eotaxin mRNA (p<0.01). CONCLUSIONS: Further investigations for chemokine receptor related to eosinophils will provide better understanding of the mechanism involved in selective tissue eosinophilia.

Clinical significance of specific IgG and IgE antibodies to toluene diisocyanate ( TDi ) - human - serum albumin ( HSA ) conjugate in TDI - induceed occupational asthma / 천식및알레르기

BACKGROUND AND OBJECTIVE: TDI is known to be the most prevalent cause of occupational asthma ( OA ) in Korea. However, the pathogenesis of TDI - induced occupational asthma still remains to be further clarified. So, we evaluated clinical significance of serum specific IgG and IgE antibodies to TDI - HSA conjugate in TDI - induced occupational asthma. Subjects and METHODS: Serum specific IgG and IgE antibodies to TDI - HSA conjugate were measured by enzyme linked immunosorbent assay. Serum was collected from 50 TDI- induced OA patients ( classified as group I ), and was compared with that from 13 asthmatic subjects with negative TDI - bronchoprovocation test ( BPT, group II ), allergic asthmatics ( group III ), and unexposed healthy controls ( group IV ). RESULTS: The prevalence of specific IgG was significantly higher in group I than in group II (p = 0.01) or group III (p 0.05). However, the prevalence of specific IgE was not different between group I and group II (p> 0.05 ) or group II and group III( p> 0.05 ). There was no significant difference in prevalence of specific IgG according to the asthmatic response during TDI bronchoprovocation test ( p> 0.05 ). No statistical significance was noted between specific IgG and IgE antibodies in group I subjects ( p> 0.05 ). CONCLUSION: These findings demonstrate that presence of specific IgG to TDI - HSA conjugate is closely related to TDI - BPT results and it may contribute to the development of TDI - induced asthma.

Exposure to toluene diisocyanate ( TDI) induces IL - 8 and RANTES production from bronchial epithelial cell / 천식및알레르기

BACKGROUND: There have been a few reports suggesting involvement of neutrophil as well as eosinophil in inducing bronchoconstriction aft,er inhalation of TDI. OBJECTIVE: In order to observe the source of chemokines in TDI-induced asthma, this investigation was designed to determine whether IL-8 and RANTES could be produced by human bronchial epithelial cells and whether dexamethasone had any effects on their production. Materials and METHODS: We cultured Beas-2B, a bronchial epithelial cell line, with five concentrations of TDI-human serum albumin (HSA) conjugate and compared them with those having no conjugate. The levels of IL-8 and RANTES in the supernatant were measured by ELISA. To evaluate the effect of pro-inflammatory cytokines, cells were incubated with peripheral blood mononuclear cell (PBMC) culture supernatant, which was derived from PBMC culture of a TDI -induced asthmatic subject under exposure to TDI-HSA conjugate, and then compared to those without PBMC supernatant addition. To evaluate the effect of dexamethasone, four concentrations of dexamethasone were pre-incubated and the same steps were repeated. RESULTS: There was significant production of IL-8 from bronchial epithelial cells with addition of TDI-HSA conjugate in a dose-dependent manner (p<0.05, respectively), which was significantly augmented with additions of PBMC supernatant (p<0.05, respectively) at each concentration. RANTES production was negligible, however, it increased significantly with addition of PBMC supernatant and TDI-HSA conjugate in a dose response manner(p<0.05, respectively). Compared to the untreated sample, pre-treatment of dexamethasone induced remarkable inhibitions of IL-8 and RANTES production. CONCLUSION: These results suggest that IL-8 and RANTES released from bronchial epithelial cells may contribute to neutrophil and eosinophil recruitment occurring in TDI-induced airway.