Substantivity of Carbodiimide Inhibition on Dentinal Enzyme Activity over Time.

The use of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl (EDC) has recently been investigated for its effectiveness in the prevention of collagen degradation over time and the improvement of resin-dentin bond durability. The objective of the present study was to evaluate the effects of a 0.3 M EDC-containing conditioner on endogenous enzymatic activities within the hybrid layer (HL) created by a self-etch or an etch-and-rinse adhesive after 1 y. The activity within the HL was examined using in situ zymography and confocal laser scanning microscopy after 24 h or 1-y storage in artificial saliva. Dentin specimens were bonded with Clearfil SE Bond (CSE) or XP Bond (XPB). For CSE, the self-etching primer was applied and treated with 0.3 M EDC for 1 min, and then the bonding agent was applied. For XPB, dentin was etched and treated with 0.3 M EDC for 1 min and then bonded with the primer-bonding agent. Control specimens were prepared without EDC treatment. Slices containing the adhesive-dentin interface were covered with fluorescein-conjugated gelatin and observed with a multiphoton confocal microscope. Fluorescence intensity emitted by hydrolyzed fluorescein-conjugated gelatin was quantified, and the amount of gelatinolytic activity was represented by the percentage of green fluorescence emitted within the HL. After 24 h of storage, enzymatic activity was detected by in situ zymography within the HLs of both tested adhesives, with XPB higher than CSE ( P < 0.05). Almost no fluorescence signal was detected when specimens were pretreated with EDC compared to controls ( P < 0.05). After 1 y of storage, enzymatic activities significantly increased for all groups (excluding XPB control) compared to 24-h storage ( P < 0.05), with EDC pretreated specimens exhibiting significantly lower activity than controls ( P < 0.05). The present study showed, for the first time, that the use of EDC for both the self-etch and the etch-and-rinse approaches results in the reduction but not complete inhibition of matrix-bound collagenolytic enzyme activities over time in the HL.

Clinical effectiveness of a hydrophobic coating used in conjunction with a one-step self-etch adhesive: an 18-month evaluation.

The purpose of this randomized clinical trial was to evaluate the clinical performance of a one-step self-etch adhesive in noncarious cervical lesions with inclusion of a hydrophobic bonding layer not included in the original bonding system as a test of potentially improved bonding. Patients with noncarious cervical lesions received two or four restorations after being randomly assigned to two adhesive technique protocols (n=32): EB, application of Adper Easy Bond (3M ESPE) following manufacturer's instructions; and EB+B, application of Adper Easy Bond, immediately followed by the application of a hydrophobic resin coat (Scotchbond Multi-Purpose Bonding Agent, 3M ESPE). All restorations were restored with a microhybrid composite (Filtek Z250, 3M ESPE). Clinical effectiveness was recorded in terms of retention, marginal discoloration, marginal integrity, postoperative sensitivity, recurrent caries, periodontal health, and pulpal vitality, according to the modified USPHS criteria, for 18 months. Data were analyzed using chi-square, Fisher exact, and McNemar tests at α=0.05. Two restorations of each group were debonded after six months, leading to an overall clinical success rate of 93.8% for both groups. At the 18-month evaluation period, no new restoration was debonded. However, one restoration of the EB group displayed recurrent caries at the dentin margin, decreasing the overall success rate to 90.6% in comparison to 93.8% of EB+B. The success rate between EB and EB+B was not statistically significant (p=0.5). The application of a hydrophobic resin coat over EB did not increase bonding effectiveness in noncarious cervical lesions after 18 months.

Electronic determination of root canal working length in primary molar teeth: an in vivo and ex vivo study.

AIM: To evaluate in vivo and ex vivo the accuracy of an electronic apex locator in primary molar teeth with or without root resorption. METHODOLOGY: Fifteen primary molar teeth with 30 root canals were divided into two groups: roots without resorption (n = 13) and roots with resorption (n = 17). Root canals were measured with the Root ZX apex locator in vivo, and then after tooth extraction, each canal was measured electronically ex vivo. The actual root canal length was measured visually, with the placement of a K-file into the most cervical edge of either apical foramen or resorption. The Student's t-test was applied for statistical analysis at a 5% significance level. RESULTS: The electronic apex locator was precise in 69% and 65% of the cases with and without root resorption, respectively (tolerance = ± 0.5 mm), in vivo and 69% and 77%ex vivo. When the tolerance was ± 1 mm, however, these figures increased to 92% and 94% for root canals with and without resorption, respectively, in vivo and ex vivo. No significant difference was observed between the resorbed and non-resorbed root canals measured using the Root ZX. CONCLUSION: The Root ZX apex locator was accurate in determining in vivo and ex vivo the working length ± 1 mm in primary molar teeth in over 90% of roots regardless of the presence of root resorption.

Pancreatic cystic tumors.

Cystic tumors of the pancreas are less frequent than other tumors in neoplastic pancreatic pathology, but in recent years the literature has reported an increasing number. After the first report by Becourt in 1830, cystic tumors were classified into 2 different types by Compagno and Oertel in 1978: benign tumors with glycogen-rich cells and mucinous cystic neoplasms with overt and latent malignancy. The WHO classification of exocrine tumors of the pancreas, published in 1996, is based on the histopathological features of the epithelial wall, which are the main factor in differential diagnosis with cystic lesions of the pancreas. Thanks to the knowledge acquired up to now, a surgical procedure is not always required because the therapeutic choice is conditioned by the correct classification of this heterogeneous group of tumors. Clinical signs are not really useful in the clinical work up, most patients have no symptoms and when clinical signs are present, they may help us to pinpoint the organ of origin but never to identify the type of pathology. In the last few years, the great improvement in imaging has enabled us not only to discriminate cystic from solid lesions, but also to identify the features of the lesions and label them preoperatively. More invasive diagnostic procedures such as fine needle aspiration and intracystic fluid tumor marker level are not really useful because they are not sensitive and the cystic wall can show different degrees of dysplasia and de-epithelialization. These are the reasons for sending the entire specimen to pathology. Good cooperation between surgeons, pathologists, radiologists and gastroenterologists is mandatory to increase the chances of making a proper diagnosis. Therefore, we must analyze all the information we have, such as age, sex, clinical history, location of the tumor and radiological features, in order to avoid the mistake of treating a cystic neoplasm as a benign lesion or as a pseudocyst, as described in the literature. Except for inoperable cases due to the critical condition of the patient or non-resectable lesions, surgical treatment differs with the diagnosis. Cystic tumors of the pancreas, therefore, are a heterogeneous group of tumors, with a real problem regarding differential diagnosis between neoplastic and inflammatory lesions. Even with a proper work up, some perplexity may remain about the nature of the lesion and in these cases the surgical procedure has a therapeutic value as well as playing a diagnostic role. The role of surgery is central in the treatment of these tumors because it could be curative when complete resection is possible. In this way, the lack of good therapeutic results with chemotherapy and radiotherapy force the surgeon to go ahead with the procedure. Intraductal papillary mucinous neoplasms represent a new and, from the epidemiological point of view, important chapter in the world of cystic tumors. The margin of resection is important and the surgeon has to be aware that in order to have a curative resection, total pancreatectomy is sometimes required. In the last few years the therapeutic approach has changed thanks to new knowledge of the biological behavior of these tumors. In fact, from a surgical approach in all cases, we are now discussing the possibility of a follow-up not only for asymptomatic serous cystadenomas but also for the little branch side intraductal papillary mucinous neoplasms (IPMNs) in critical patients. A follow-up could be planned even for solid pseudopapillary tumors but it seems risky to leave untreated big tumors in young patients without a certain diagnosis and with so few studies reported in the literature.

Role of unlabelled somatostatin analogues in the prevention of complications after elective pancreatic and peripancreatic surgery: a critical review.

Although studies on the use of the somatostatin analogues in the elective pancreatic surgery are mostly prospective, double blind and randomised, the results are contradictory and not univocally interpretable. Through the examination of all randomised perspective works published on this subject, a critical interpretation is attempted which may give relevant suggestions for further studies. A new clinical, randomised, double blind and multicentric prospective trial should take into proper consideration even the changes which have occurred in the care of the patients. Over the years a significant decrease of postoperative hospital stay and a deeper awareness of the medical expenses have been observed. Moreover, since the drug has a potential advantage on specific pancreatic complications, only these must be considered among the end points of the study and the population studied will be limited exclusively to patients who underwent resection of the pancreatic head or of the periampullar region because of neoplastic disease. Finally, the selection of the centres that enrol the patients must be considered, since the expertise of each operator or of the team, affects, as an independent variable, both morbidity and mortality.

Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD).

We performed an analysis of All cancer and Lung cancer mortality in relation to estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) in the cohort of chemical workers at 12 US plants assembled by the US National Institute for Occupational Safety and Health (NIOSH) (n = 5172). Estimates of cumulative exposure to TCDD were based on a minimal physiologic toxicokinetic model (MPTK) that accounts for inter- and intra-individual variations in body mass index (BMI) over time. Population-level parameters related to liver elimination and background (input or concentration) of TCDD were estimated from separate data with repeated measures of serum TCDD (US Air Force Health Study). An occupational TCDD input parameter was estimated based on one-point-in-time TCDD data available for a subset (n = 253) of the NIOSH cohort. Model-based time-dependent cumulative dose estimates (area under the curve (AUC) of the lipid-adjusted serum TCDD concentration over time) were obtained for members of the full cohort with recorded body height and weight (n = 4049), as this information is required by the MPTK model to compute dose. Missing-value problems arose in the estimation of the occupational input parameter (n = 42) and in TCDD-dose calculation in the full cohort (n = 886) and they were handled with multiple imputation methods. Risk-regression analyses were based on Cox log-linear models including age at entry, year of entry and duration of employment as categorical covariates in addition to the logarithm of cumulative TCDD dose in ppt-years. Risk sets were stratified on birth cohort. Estimates of the unlagged exposure coefficient in these models were 0.1249 [95% confidence interval (CI) 0.0144, 0.2354] for All cancer and 0.2158 (95% CI 0.02376, 0.4078) for lung cancer. A 10-year lag produced an increase in the estimate for all cancer (0.1539, 95% CI 0.0387, 0.2691), whereas, the estimate for lung cancer was not affected much (0.2125, 95% CI 0.0138, 0.4112). At a dose level of 100 times the background the estimates obtained with a 10-year lag translate into a relative risk of 2.03 (95% CI 1.19-3.45) for all cancer and of 2.66 (95% CI 1.07-6.64) for lung cancer. Higher estimates of the exposure coefficients were obtained after imputation of missing values. This increase in risk seemed due to the inclusion of short-term workers, who may exhibit a higher mortality for reasons other than dioxin exposure.

[Does locoregional chemotherapy improve survival in patients with non-resectable pancreatic carcinoma? Results of an open controlled study]. / La chemioterapia locoregionale migliora la sopravvivenza dei pazienti affetti da carcinoma pancreatico non resecabile? Risultati di uno studio aperto, controllato.

About 90% of patients suffering from pancreatic carcinoma are diagnosed with disease that is not amenable to surgical intervention due to local infiltration or the presence of hepatic metastases. Palliative intra-arterial chemotherapy was developed to improve the response in these patients by increasing the antiblastic dose and minimizing the side effects. The aim of this study is to evaluate the efficacy of this treatment comparison to a control group. From December 1994 to February 1997, 135 patients with ductal carcinoma, in whom 68 were stage III and 67 stage IV, with a median age of 63.3 years (range 38.4-79), were enrolled in an open study. Sixty four patients were subjected to a median of 3.5 cycles, according to intra-arterial FLEC protocol. Four patients had a partial response (6.3%), 27 enjoyed a stabilization of their disease (42.2%) and 13 showed disease progression (20.3%). The toxicity was mild. The overall survival was 8.3 months, better in the treated group (9.6 months) in respect to the control one (7.1 months), although this was not statistically significant. The treatment reported here, therefore, does not seem to change the prognosis of patients affected by no resectable pancreatic carcinoma, but it may demonstrate good tolerability and minimal toxicity.

[Gabexate mesilate vs gabexate mesilate combined with octreotide in the prevention of postoperative complications of pancreatic surgery: preliminary results]. / Confronto fra gabesato mesilato da solo e in associazione con octreotide nella prevenzione delle complicanze postoperatorie in chirurgia pancreatica: risultati preliminari.

To date, gabexate mesilate, a synthetic protease inhibitor, has been used in the prophylaxis and treatment of acute pancreatitis, but has yet to be tested in preventing the postoperative complications of pancreatic surgery. For this purpose we planned a pilot study based on two treatment groups, each numbering 25 patients, submitted to high-risk pancreatic resection. In the first group, all patients received a continuous infusion of gabexate mesilate 1 g/day up to postoperative day 4; the second group of patients received the same treatment plus octreotide 0.1 mg every 8 hours for 5 days after surgery. All patients were followed until discharge with clinical and instrumental investigations to detect the onset of postoperative complications. The overall incidences of an uneventful course were 40% (10/25) and 32% (8/25), respectively. We found 12 complications closely related to pancreatic surgery in the former and 8 in the latter group. In the combined treatment group therefore we observe a 33% reduction in the incidence of related abdominal complications (12 vs 8). This favourable trend, however, needs to be confirmed in a larger multicentre trial.

Changes in pancreatic resection for chronic pancreatitis over 28 years in a single institution.

BACKGROUND: Because of advances in knowledge over recent years there is reason to believe that surgical attitudes towards patients with chronic pancreatitis may have changed. METHODS: Some 547 patients were treated surgically for chronic pancreatitis from 1971 to June 1998. Anastomoses were performed in 80 per cent (438 patients) and resections in 20 per cent (109 patients). Indications and type of operation were analysed, as were mortality and morbidity rates and long-term follow-up results, in patients undergoing resection both over the period as a whole and after dividing the series into two subperiods of 14 years. RESULTS: In the second 14-year period, there was a significant reduction in the percentage of resections compared with anastomoses (28 per cent (69 of 244 patients) versus 13 per cent (40 of 303); P < 0.0001), and a significant change in the type of resection with a substantial increase in resections of the head compared with those of the body and tail. Statistically significant reductions occurred in operating times, number of units of blood transfused (mean(s.d.) 4.7(3.6) versus 1.2(1.6) units; P = 0.0001) and mean hospital stay (18 versus 14 days for pylorus-preserving and 12 versus 8 days for left pancreatectomy with splenectomy; P < 0. 01); mortality and morbidity rates also tended to decrease, but not significantly. CONCLUSION: A different pattern has emerged over the years as regards both the type and number of resections performed.

Cytoreductive surgery in advanced endocrine tumours of the pancreas.

Surgery still plays an important role even in advanced endocrine tumours of the pancreas, owing to their biological behaviour. Sometimes it is possible to attempt a radical approach, but more often only cytoreduction is feasible. In fact, when the malignancy is not completely resectable on account of vessel involvement or extensive liver metastases, surgical reduction of the tumour burden (debulking) can be proposed, aimed at improving the clinical conditions and survival of these patients. Forty-one patients suffering from advanced endocrine tumour of the pancreas were observed from 1985 to 1996. In 13 patients, the disease was locally advanced as far as concerns lymph node metastases and/or vessel involvement, while the other 28 patients presented liver metastases. In the former group, we performed 6 radical resections, in the latter we submitted 2 patients to radical resection and 12 patients to cytoreductive surgery, with complete removal of the pancreatic malignancy. The overall survival of the resected patients was 87% (7/8). Three patients (37.5%) are alive and free of disease, while the other 4 have subsequently developed liver metastases. One patient died with hepatic recurrence. Half the patients (6/12) undergoing cytoreductive surgery are alive, 3 with stable and 3 with progressive disease. The other 6 patients have died due to liver progression of the disease. As data in the literature concerning the role of debulking as regards the survival are conflicting, we have modified our surgical approach in patients with advanced disease. We perform cytoreductive surgery whenever complete removal of the pancreatic tumour is feasible. The rationale of this approach is to leave only a liver with residual disease, with a view to giving targeted adjuvant treatment.

Management of digestive tract fistulas. A review.

Digestive tract fistulas are a complex subject in terms both of classification and management. There is still a lack of firm epidemiological data regarding the their incidence, though the prognostic factors conditioning the prognosis of these patients are now well known. They are related mainly to the nutritional status of the patients and to the presence or otherwise of sepsis. Instrumental investigations should be aimed not merely at identifying the complication, but also at guiding clinicians in their choice of therapeutic management. According to the various situations arising, the treatment will be surgical, endoscopic or conservative medical. In the latter case, the clinician should establish first of all whether, as a result of the site of the fistula or the nutritional status, the patient requires total parenteral or enteral artificial nutrition, whenever possible. In those cases in which parenteral nutrition is indicated, the ideal drug with the best proven ability to shorten healing times and reduce the number of complications when used in combination with parenteral nutrition is naturally occurring somatostatin at the dose of 250 micrograms/h over 24 h. In all other cases, if the fistula is clinically important, its synthetic analogue, octreotide, should be the drug of choice and can be administered subcutaneously. The amount of octreotide administered ranges from 300 to 600 micrograms/day in 3 or 4 daily doses.

Early detection of pancreatic cancer following the diagnosis of chronic pancreatitis.

AIM: To assess whether patients with misdiagnoses of chronic pancreatitis (CP), followed at an early stage by a diagnosis of pancreatic cancer (PCr), present different epidemiological characteristics from patients suffering either from CP alone or from CP with late degeneration to PCr. METHODS: We arbitrarily subdivided our patient series into three groups: (1) 12 CP who developed PCr within 4 years after onset of symptoms; (2) 12 CP developing PCr after the 4th year, and (3) 701 CP with no subsequent development of PCr. The variables studied were age, sex, drinking and smoking habits, tumor localization, and presence of intraductal calcifications and diabetes mellitus at the time of diagnosis of CP. RESULTS: There were no significant differences between CP and 'late' PCr in any of the study variables considered. As compared with the CP group, the 'early' PCr cases were older (58.7 vs. 40.7 years; p < 0.0001), with a lower proportion of males (58 vs. 88%; p < 0.01), smaller proportions of both smokers (42 vs. 88%; p < 0.0001) and subjects drinking more than 40 g of alcohol/day (42 vs. 86%; p < 0. 0001), and a greater incidence of non-insulin-dependent diabetics at the time of diagnosis of CP (25 vs. 3.7%; p < 0.012). As compared with the 'late' PCr group, the malignancies in the 'early' PCr cases were more often located in the head of the pancreas (100 vs. 50%; p < 0.01). Multivariate logistic regression analysis selected age over 50 (odds ratio OR 13.5, 95% confidence interval CI 2.79-65.5; p < 0. 001), smoking habits (OR 0.14, 95% CI 0.04-0.49; p < 0.002), and non-insulin-dependent diabetes (OR 5.91, 95% CI 1.20-29.1; p < 0. 028) as variables identifying subjects with 'early' PCr. CONCLUSIONS: A high suspicion of a pancreatic tumor is necessary when CP is diagnosed in a patient with atypical epidemiological characteristics for this condition, possibly female, aged over 50, who is not a smoker or drinker, and suffers from non-insulin-dependent diabetes.

Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer.

The aim of this study was to compare alcohol and smoking as risk factors in the development of chronic pancreatitis and pancreatic cancer. We considered only male subjects: (1) 630 patients with chronic pancreatitis who developed 12 pancreatic and 47 extrapancreatic cancers; (2) 69 patients with histologically well documented pancreatic cancer and no clinical history of chronic pancreatitis; and (3) 700 random controls taken from the Verona polling list and submitted to a complete medical check-up. Chronic pancreatitis subjects drink more than control subjects and more than subjects with pancreatic cancer without chronic pancreatitis (P<0.001). The percentage of smokers in the group with chronic pancreatitis is significantly higher than that in the control group [odds ratio (OR) 17.3; 95% CI 12.6-23.8; P<0.001] and in the group with pancreatic carcinomas but with no history of chronic pancreatitis (OR 5.3; 95% CI 3.0-9.4; P<0.001). In conclusion, our study shows that: (1) the risk of chronic pancreatitis correlates both with alcohol intake and with cigarette smoking with a trend indicating that the risk increases with increased alcohol intake and cigarette consumption; (2) alcohol and smoking are statistically independent risk factors for chronic pancreatitis; and (3) the risk of pancreatic cancer correlates positively with cigarette smoking but not with drinking.

Incidence of cancer in the course of chronic pancreatitis.

OBJECTIVE: Chronic pancreatitis patients appear to present an increased incidence of pancreatic cancer. The aim of the study was to compare the incidence of cancer, whether pancreatic or extrapancreatic, in our chronic pancreatitis cases with that in the population of our region. METHODS: We analyzed 715 cases of chronic pancreatitis with a median follow-up of 10 yr (7287 person-years); during this observation period they developed 61 neoplasms, 14 of which were pancreatic cancers. The cancer incidence rates were compared, after correction for age and gender, with those of a tumour registry. RESULTS: We documented a significant increase in incidence of both extrapancreatic (Standardized Incidence Ratio [SIR], 1.5; 95% confidence interval [CI], 1.1-2.0; p <0.003) and pancreatic cancer (SIR, 18.5; 95% CI, 10-30; p <0.0001) in chronic pancreatitis patients. Even when excluding from the analysis the four cases of pancreatic cancer that occurred within 4 yr of clinical onset of chronic pancreatitis, the SIR is 13.3 (95% CI, 6.4-24.5; p <0.0001). If we exclude these early-onset cancers, there would appear to be no increased risk of pancreatic cancer in nonsmokers, whereas in smokers this risk increases 15.6-fold. CONCLUSIONS: The risks of pancreatic and nonpancreatic cancers are increased in the course of chronic pancreatitis, the former being significantly higher than the latter. The very high incidence of pancreatic cancer in smokers probably suggests that, in addition to cigarette smoking, some other factor linked to chronic inflammation of the pancreas may be responsible for the increased risk.

Role of chemoembolization in synchronous liver metastases from pancreatic endocrine tumours.

Endocrine tumours of the pancreas, even in case of liver involvement, are generally characterized by a slower evolution and a better prognosis, if compared with ductal carcinoma. This fact gives reason to a radical surgical approach, whenever possible, and to the research of any effective adjuvant treatment. For this purpose, hepatic transarterial chemoembolization (TACE) has been proposed in recent years for the treatment of metastatic endocrine tumours. Out of 80 patients suffering from endocrine tumours of the pancreas, observed between January 1985 and December 1996, 28 (35%) presented liver metastases at the time of diagnosis. Twelve of these patients were submitted to palliative resection of pancreatic tumour and one or more cycles of TACE. Overall survival was 50% (6/12); median survival was 35.4 months (range 4-75). These results suggest that chemoembolization, combined with surgical resection of primary malignancy, appears to be able to control the disease for a certain time and to increase the survival rate.

Assessment and treatment of severe pancreatitis. Protease inhibitor.

From the theoretical point of view, antiproteolytic therapy would seem to be the rationale for acute pancreatitis management. Unfortunately, clinical human trials studying the role of antiproteases in the treatment of acute pancreatitis differ in several respects in terms of their basic design. As a consequence, any form of homogeneous analysis of the reported data as a whole is impossible. Considering the data emerging from a meta-analysis of five trials a rational use of antiproteases may result in a reduction of complications requiring surgery and of patient management costs only in selected cases, meaning by that severe and necrotic forms. As regards presumptive applications, over 400 patients were prospectively tested versus placebo in a double-blind trial with the aim of preventing acute pancreatitis after ERCP. The complication incidence was significantly lower among the pretreated patients; anyway, also in this field of protease inhibitor clinical application it is necessary to identify the patients with the greatest risk to develop post-ERCP acute pancreatitis. In conclusion, antiproteases can still play a role when given prophylactically or when used in the very early phases of the disease; moreover a 'multiple drugs approach' (including, for example, suitable antibiotics) seems to represent nowadays the most modern and rational treatment of acute pancreatitis.

Gastroprotective effect from Calophyllum brasiliense Camb. bark on experimental gastric lesions in rats and mice.

In order to establish the pharmacological basis for the ethnomedicinal use of stem bark extracts of Calophyllum brasiliense Camb. in gastrointestinal affections, this study examined the effects of a dichloromethane fraction (DCMF), obtained from the hexane extract of bark, on ethanol, indomethacin and hypothermic restraint stress-induced gastric lesions in mice and rats, respectively. Oral administration of DCMF at doses ranging from 12.5-250 mg/kg significantly inhibited the development of gastric lesions in all the three test models. It caused significant decreases of the pyloric-ligation and bethanechol-stimulated gastric secretion, and also the free and total acidities. Besides, DCMF offered protection against ethanol-induced depletion of stomach wall mucus and reduction in nonprotein sulfhydryl concentration. The results indicate that DCMF from C. brasiliense possesses antisecretory, antiulcer and cytoprotective properties.

Uncertainty in estimating exposure using a toxicokinetic model. The example of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

This paper deals with sources of uncertainty in the use of a minimal physiological toxicokinetic model to obtain dose estimates for a dose-response analysis of cancer in an occupational cohort. Toxicokinetic models make it possible to construct exposure parameters that are more closely related to the individual dose than traditional measures of exposures to toxic agents. However, the process introduces a wide array of sources of uncertainty. Selecting a model structure to describe the kinetics of a toxic agent implies necessarily making simplifications and assumptions that influence the range of applicability of the model. Once a model has been selected, the value of certain model parameters (constants) must be assigned, for example, from anthropometric data. The question then arises of how sensitive the model predictions are to variations in the values of these constants. Other model parameters, typically those describing the kinetics of the agent, are next estimated from actual data. There may be limitations in the data concerning, for example, sparseness (too few observations per subject) or missing values. The methods used for parameter estimation carry their own set of assumptions that need to be appropriate to the situation at hand. In summary, the dioxin example is used to characterize the sources of uncertainty at different levels, such as model structure, methods and data used for parameter estimation, estimation of occupational exposure, and imputation of missing values in exposure indices derived from the kinetic model.