Endocrine active compounds: from biology to dose response assessment

Endocrine active compounds (EACs) alter signaling processes responsible for regulation and coordination of physiological functions during development and adulthood. The potential that adverse effects of these compounds have gone unrecognized has focused attention on their toxicology. The primary response to this concern has been development of additional hazard identification methods. This review discusses issues for dose response (DR) analyses for EACs, including definitions of adversity, implications of alternative modes of action, the roles homeostatic and developmental regulatory feedback processes play in creating DR behaviors, uses of in vitro data in DR analyses, and induction of effects by natural and synthetic compounds in the context of endogenous hormone background. Current risk assessment guidance applicable to endocrine-mediated effects provide limited default methods for evaluating DR behaviors and making interspecies comparisons. Improved DR methods for EACs will be achieved through the use of mode of action and dosimetry data to better characterize potential human risks.     

A proton dose calculation algorithm for conformal therapy simulations based on Molière's theory of lateral deflections

An algorithm is developed for computing proton dose distributions in the therapeutic energy range (100-250 MeV). The goal is to provide accurate pencil beam dose distributions for two-dimensional or three-dimensional simulations of possible intensity-modulated proton therapy delivery schemes. The algorithm is based on Molière's theory of lateral deflections, which accurately describes the distribution of lateral deflections suffered by incident charged particles. The theory is applied to nonuniform targets through the usual pencil beam approximation which assumes that all protons from a given pencil beam pass through the same material at each depth. Fluence-to-dose conversion is made via Monte Carlo calculated broad-field central-axis depth-dose curves, which accounts for attenuation due to nuclear collisions and range straggling. Calculation speed is enhanced by using a best-fit Gaussian approximation of the radial distribution function at depth. Representative pencil beam and spread-out Bragg-peak computations are presented at 250 MeV and 160 MeV in water. Computed lateral full-widths-at-half-maximum's in water, at the Bragg peak, agree with the expected theoretical lateral values to within 1% at 160 MeV and to within 3% at 250 MeV. This algorithm differs from convolution methods in that the effect of the depth of any inhomogeneities in density or atomic composition are accounted for in a rigorous fashion. The algorithm differs from Fermi-Eyges based methods by accounting in a rigorous way for the effect of nonsmall-angle scattering and screening due to atomic electrons. The computational burden is only slightly greater than that expected using the less-rigorous Fermi-Eyges theory.     

On-line assessment of delivered dialysis dose

BACKGROUND: The adequacy of the delivered dialysis dose is essential to prevent patient morbidity and mortality. The determination of effective ionic dialysance (D) is easy, non-invasive and inexpensive, and its use instead of effective urea clearance (K) in kinetically determining apparent" urea distribution volume (Vt) is likely to lead to a correct Kt/V, even though the Vt value may be incorrect. The aim of this study was to test the possibility of using the measurement of D to monitor Kt/V on-line during each dialysis treatment. METHODS: Forty-four patients were dialyzed using a monitor equipped with specially designed "Diascan Module" (COT; Hospal) that measures effective D by means of a single conductivity probe. Vt was calculated according to the SPVV three BUN method urea kinetic model using D instead of K values. One month later, Kt/V was calculated as Dt/V, using actual D and T values and the predetermined Vt values updated for the current final body wt. Both the Dt/V and Kt/V determined according to the Smye and Daugirdas methods were compared with the Kt/V determined using the SPVV kinetic model (Kt/Veq) RESULTS: The Kt/V values calculated using ionic dialysance and predetermined Vt were approximately equivalent to those of Kt/Veq (1.14 +/- 0.16 vs. 1.14 +/- 0.17, mean difference 0.00 +/- 0.07), as were those determined according to the Smye and Daugirdas methods (1.10 +/- 0.18 and 1.13 +/- 0.17, mean difference -0.03 +/- 0.06 and 0.01 +/- 0.06, respectively). CONCLUSION: Once Vt has been determined, the evaluation of ionic dialysance in stable patients makes it possible to calculate the Kt/V accurately at each dialysis session without blood or dialysate sampling, and at no additional cost.     

Conformal proton therapy for prostate carcinoma

The suppression of apoptosis may contribute to the carcinogenicity of the peroxisome proliferators (PPs), a class of non-genotoxic rodent hepatocarcinogens. Our previous work demonstrated that the PP nafenopin suppressed both spontaneous and transforming growth factor beta1 (TGFbeta1)-induced hepatocyte apoptosis both in vivo and in vitro. Here, we extend these observations by demonstrating the ability of nafenopin to suppress apoptosis induced by other major candidates for the signalling of cell death in the liver. Treatment of rat or mouse hepatocyte monolayers with TGFbeta1 or the DNA damaging drugs etoposide or hydroxyurea induced high levels of apoptosis. Western blot analysis did not support a role for either p53 or p21waf1 in etoposide-induced apoptosis in rat hepatocytes. Treatment of mouse hepatocytes with an agonistic anti-Fas antibody also resulted in an induction of high levels of apoptosis. Pre-addition and continued exposure to nafenopin suppressed apoptosis induced by all three stimuli. Overall, our studies demonstrate that the ability of nafenopin to protect hepatocytes from apoptosis is not restricted to species or apoptotic stimulus. It is possible, therefore, that the PPs may suppress apoptosis by acting on diverse signalling pathways. However, it seems more likely that nafenopin suppresses hepatocyte apoptosis elicited by each death stimulus by impinging on a core apoptotic mechanism.     

Use of bronchopulmonary lavage for eliminating inhaled fume particles from a patient with arc welder's lung

A 42-year-old man, who had worked as a welder for 20 years, was admitted to our hospital complaining of a dry cough. A chest radiograph showed diffuse small nodular shadows and chest computed tomography revealed small patchy opacities. A transbronchial lung biopsy specimen showed welding fume particles mainly located in alveolar space with mild fibrosis of alveolar septa. In order to prevent further fibrosis, bronchopulmonary lavage (BPL) was performed to eliminate the fume particles. The amount of iron particles derived from the total lavage fluid was 911.7 mg.     

Howard Hughes Medical Institute dose assessment survey

Biomedical science researchers often express frustration that health physics practices vary widely between individual institutions. A survey examining both internal and external dose assessment practices was devised and mailed to fifty institutions supporting biomedical science research. The results indicate that health physics dose assessment practices and policies are highly variable. Factors which may contribute to the degree of variation are discussed.     

Reirradiation therapy for brain metastases from small cell lung cancer

Several evidences support the hypothesis that central catecholamines may play a significant role in the production and/or maintenance of different alterations that characterize portal hypertension. The aim of the present work was to study the possible modifications in norepinephrine (NE) metabolism in several telencephalic and diencephalic areas rich in NE in experimental prehepatic portal hypertension. NE uptake was studied as an index of NE metabolism. The experiments were carried out in vitro in encephalic areas and nuclei, obtained according to the punch-out technique. Results indicated that portal hypertensive rats showed an enhancement of NE uptake in olfactory bulb (OB), preoptic area (PA), and supraoptic, periventricular, paraventricular, and arcuate nuclei (SON, PeVN, PaVN, and AN, respectively) compared to sham-operated rats. However, no modifications on NE uptake was observed in the median eminence (ME). Present results suggest that the changes observed in central NE uptake may be related to the development and/or maintenance of the portal hypertensive state.     

Combination therapy: advantages and disadvantages of first-line fixed dose therapy

Phytotherapy is a medicinal and ancestral practice in Africa. It deals with all the fields of human pathology. We wanted to ascertain the efficacy of some plants used in odontology as Euphorbia balsamifera traditionally used as antalgic treatment of acute dental pulpitis. The latex of the plant was caught and treated as to get enough stable paste. We used that paste in the same conditions we use arsenical nerve caustics, a pulpal devitalizer widely used in dental offices. The study carried out on 37 teeth has shown that latex of Euphorbia balsamifera is an effective pulpal devitalizing in contact with the pulp. Its lifetime action was comparable to that of the pulpal nerve caustics. The active principles are not known, however the product seems attractive as a pulpal devitalizing agent.     

Regional lung hematocrit variation and assessment of acute lung injury

Estimating blood content in the lung remains a key step in calculating lung water volume and microvascular permeability. We studied the effect of regional lung hematocrit (Hct) variation on assessment of acute lung injury. Escherichia coli endotoxin was administered in guinea pigs intravenously. Lung injury was evaluated by measuring the wet-to-dry weight ratio (W/D) and transvascular 125I-labeled albumin leakage for 3 h [tissue-to-plasma 125I-albumin ratio (T/P)] in five tissue samples from each animal. Residual blood content was corrected using either 51Cr-red blood cells as a blood cell marker, 99mTc-albumin as a plasma marker, or both, injected 10 min before the guinea pigs were killed. Lung Hct, estimated from the marker counts of lung and peripheral blood samples, was lower than peripheral blood Hct; intraindividual variation, represented by the standard deviation in each subject, was 0.024 +/- 0.015 for the control group (coefficient of variation 8.0 +/- 5.1%) and 0.026 +/- 0.013 for the endotoxin group (coefficient of variation 8.5 +/- 4.1%). Uncorrected W/D for residual blood content was greater than the corrected W/D. 99mTc-albumin correction gave values closer to the W/D corrected by both markers. T/P corrected by 99mTc-albumin showed smaller data variations than the values obtained with 51Cr-red blood cell correction, which was affected by variations in lung Hct. We recommend using a plasma marker to correct for blood content in assessing acute lung injury by W/D and T/P.     

Phantom glucose calibration models from simulated noninvasive human near-infrared spectra

The validity of published reports claiming to have successfully measured in vivo blood glucose from noninvasive near-infrared spectra collected in a time-dependent manner is challenged on the basis of results obtained from a phantom glucose spectral data set. An in vitro model is used to simulate noninvasive human near-IR spectra. The phantom glucose data set is created by purposely omitting glucose in these modeled samples. Glucose values are then assigned to successive phantom glucose spectra, and multivariate calibration models are generated for glucose based on partial-least squares regression. As expected, calibration models are incapable of predicting glucose values when the glucose assignments are made randomly. Apparently functional models are obtained, however, when glucose assignments are made in a nonrandom, time-dependent manner. Prediction errors from these nonrandom models are essentially identical to those published by other as evidence of successful noninvasive blood glucose measurements. Chance temporal correlations between assigned glucose concentrations and some uncontrolled experimental parameter are responsible for this apparent model functionality.     

Forefront of lung cancer therapy

The differential urinary excretion of orally administered lactulose and mannitol is used to evaluate intestinal permeability. This test usually involves a 5- to 6-hr urine collection. We hypothesized that a shorter collection time would give an equivalent result. Forty-three patients with a variety of gastrointestinal symptoms and diagnoses (group 1) and 42 patients with Crohn's disease (group 2) had a standard lactulose/mannitol permeability test. The lactulose and mannitol urinary excretion was calculated using the first urine (group 1) or the 1-hr and 2-hr urine (group 2) and was compared to the values calculated from the routine 5- or 6-hr collection. Lactulose excretion kinetics, expressed as the percent of the total urinary excretion within a given time period, were as follows: 21% in first hour (group 2), 29% in second hour (group 2), and 46% in first 2.5 hr (group 1). Mannitol urinary excretion kinetics were 16%, 31%, and 44%, respectively. The lactulose/mannitol ratio based on a standard urine collection correlated well with the ratio based on just the first urine produced by the patient (R2 = 0.94; P < 0.001; group 1) and the 2-hr urine (R2 = 0.464; P < 0.001; group 2). Future use of the lactulose/mannitol ratio to assess intestinal permeability may be able to be simplified by shortening the urine collection time.     

Genetic risk after high dose radioiodine therapy with regard to gonadal dose

AIM: The genetic risk for the offspring of patients treated with high doses of radioiodine was to be assessed with special regard to the gonadal dose caused by diagnostic and therapeutic procedures. METHODS: 41 young females (aged between 19 and 39 years) and four young males (aged 26 to 36 years) treated with radioiodine because of a thyroid carcinoma were interviewed by use of a questionnaire. The course of pregnancy and birth history could be documented as well as the congenital and developmental conditions of 56 children. RESULTS: The amount of radioactivity applied for therapy and whole body scans ranged over 4.144 and 35.15 GBq 1-131; the individual gonadal dose was calculated based on the MIRD model and ranged over 0.2 and 2.2 Sv (0.51 Sv at a mean). The period of time between the last radioiodine application and confinement was at least 9 months, not exceeding 14 years. As to the course of pregnancy and birth two early abortions, one extrauterine gravidity and one premature birth due to an insufficiency of the placenta were stated. In one case a chromosomal translocation 7/14 occurred as a genetic defect which lead to an interruption. The children's development was unconspicuous except of two cases of neurodermatitis as well as multiple allergies and an early closure of the anterior fontanelle in one child each. CONCLUSION: Although the genetic risk is supposed to increase with the gonadal dose achieved (doubling dose 1 Sv) and the increased risk of any congenital anomaly was calculated as about 13% at a mean in our patients, the rate of genetic determined diseases was not elevated (1.8% or 1/57). Thus, no increase of genetic defects or congenital malformations was reported in a total of 408 children described in the literature and in our group.     

Treatment of lung metastases from malignant melanoma with IL-2 inhalation therapy

Seven patients with pulmonary metastases of malignant melanoma were treated with inhalation therapy with 36 million IU interleukin-2 for six months. Inhalation therapy was combined with four bolus infusions of DTIC at a dose of 850 mg/m2 once every four weeks. Response rates were 71.4% with 2 patients achieving a complete remission (CR), 2 partial remissions (PR), 1 stable disease (SD), and 2 progressing disease (PD). Therapy was well tolerated with low toxicity. Six of the patients developed cough; one patient was slightly feverish. We conclude that inhalation therapy of lung metastases is a promising addition to the therapeutic arsenal against malignant melanoma.     

Processing exhaust emissions from arc furnaces

A new treatment system for the exhaust emissions from arc furnaces is described. This system ensures complete combustion of CO and H₂, condensation of the steam, coagulation and spheroidization of the dust and slag particles, their cooling to sintering temperatures, and the utilization of 95% of the solid particles in the deposition chamber. That significantly reduces the erosional wear of the gas lines, extends their working life, and reduces water consumption.