A physiologically-based kinetic (PBK) model for work-related diisocyanate exposure: Relevance for the design and reporting of biomonitoring studies.

Diisocyanates are highly reactive substances and known causes of occupational asthma. Exposure occurs mainly in the occupational setting and can be assessed through biomonitoring which accounts for inhalation and dermal exposure and potential effects of protective equipment. However the interpretation of biomonitoring data can be challenging for chemicals with complex kinetic behavior and multiple exposure routes, as is the case for diisocyanates. To better understand the relation between external exposure and urinary concentrations of metabolites of diisocyanates, we developed a physiologically based kinetic (PBK) model for methylene bisphenyl isocyanate (MDI) and toluene di-isocyanate (TDI). The PBK model covers both inhalation and dermal exposure, and can be used to estimate biomarker levels after either single or chronic exposures. Key parameters such as absorption and elimination rates of diisocyanates were based on results from human controlled exposure studies. A global sensitivity analysis was performed on model predictions after assigning distributions reflecting a mixture of parameter uncertainty and population variability. Although model-based predictions of urinary concentrations of the degradation products of MDI and TDI for longer-term exposure scenarios compared relatively well to empirical results for a limited set of biomonitoring studies in the peer-reviewed literature, validation of model predictions was difficult because of the many uncertainties regarding the precise exposure scenarios that were used. Sensitivity analyses indicated that parameters with a relatively large impact on model estimates included the fraction of diisocyanates absorbed and the binding rate of diisocyanates to albumin relative to other macro molecules.We additionally investigated the effects of timing of exposure and intermittent urination, and found that both had a considerable impact on estimated urinary biomarker levels. This suggests that these factors should be taken into account when interpreting biomonitoring data and included in the standard reporting of isocyanate biomonitoring studies.

Target development for diversified irradiations at a medical cyclotron.

The irradiation facility at an old medical cyclotron (Ep=17 MeV; Ed=10 MeV) was upgraded by extending the beam line and incorporation of solid state targetry. Tests performed to check the quality of the available beam are outlined. Results on nuclear data measurements and improvement of radiochemical separations are described. Using solid targets, with the proton beam falling at a slanting angle of 20°, a few radionuclides, e.g. (75)Se, (120)I, (124)I, etc. were produced with medium currents (up to 20 µA) in no-carrier-added form in quantities sufficient for local use. The extended irradiation facility has considerably enhanced the utility of the medical cyclotron.

Time course and mechanisms of the anti-hypertensive and renal effects of liraglutide treatment.

AIMS: Glucagon-like peptide-1 receptor agonist studies have revealed clinically significant reductions in systolic blood pressure (SBP). The aim was to investigate the time course of the anti-hypertensive effect of liraglutide treatment and potential underlying mechanisms. METHODS: We used an open-label, single-centre trial; 31 participants with Type 2 diabetes and hypertension completed the study. All participants were treated with liraglutide escalated to a maximum dose of 1.8 mg/day for 7 weeks, followed by a 21-day washout period. The primary outcome was a change in 24-h SBP. RESULTS: Twenty-four-h SBP increased by 10 mmHg on day 3 (P = 0.008) and 7 mmHg on day 7 (P = 0.033, 0.6 mg/day). On day 29, (1.8 mg/day), 24-h SBP was 7 mmHg lower compared with baseline (P = 0.11). Following the treatment period (day 49) and after washout (day 70), 24-h BP was equivalent to baseline. In addition, extracellular volume (ECV) was reduced by 2.0 l [95% confidence interval (CI) = 1.0-3.1 l, P < 0.001] and midregional-pro-atrial natriuretic peptide (MR-proANP) was reduced by 20% (95% CI = 12-28%, P < 0.001). Also, urinary albumin excretion declined by 30% (95% CI = 12-44%, P = 0.003), GFR by 11 ml/min/1.73 m(2) (95% CI = 7.2-14.4 ml/min/1.73 m(2) , P < 0.001) and fractional albumin excretion by 29% (95% CI = 3-48%, P = 0.032). CONCLUSIONS: Liraglutide treatment was associated with an initial increase in 24-h SBP, followed by a 7 mmHg reduction after escalation to 1.8 mg/day. This effect subsided after 4 weeks of maximum dose. Reductions in ECV and MR-proANP may explain the anti-hypertensive potential. Liraglutide treatment was associated with reversible reductions in albuminuria and GFR, which has to be confirmed in randomized trials.

Evaluation of excitation functions of 100Mo(p,d+pn)99Mo and 100Mo (p,2n)99mTc reactions: Estimation of long-lived Tc-impurity and its implication on the specific activity of cyclotron-produced (99m)Tc.

Excitation functions were calculated by the code TALYS for 10 proton-induced reactions on (100)Mo. For (100)Mo(p,d+pn)(99)Mo and (100)Mo(p,2n)(99m)Tc, calculations were also performed using the code STAPRE. Furthermore, for those two reactions and (nat)Mo(p,x)(96)Tc, evaluation of available experimental data was also carried out. The production of (99m)Tc via the (100)Mo(p,2n)-process is discussed. The ratio of atoms of long-lived (99g)Tc and (98)Tc to those of (99m)Tc is appreciably higher in cyclotron production than in generator production of (99m)Tc; this may adversely affect the preparation of (99m)Tc-chelates.

Excitation functions of α-particle induced reactions on enriched 123Sb and (nat)Sb for production of 124I.

Excitation functions of (α,xn) reactions on 98.28% enriched (123)Sb and on (nat)Sb were measured from 9 to 40 MeV. The data could be described well in terms of statistical and precompound models using the code TALYS. The discrepancies in the literature data for the formation of (125)I and (126)I were solved. The nuclear reaction (123)Sb(α,3n)(124)I on an enriched target appears to be interesting for the production of (124)I (T(1/2)=4.18 d) over the energy range E(α)=42→32 MeV, its yield being 11.7 MBq/µAh. The levels of the radionuclidic impurities (125)I and (126)I amount to 1.8% and 0.6%, respectively. The use of (nat)Sb as target material for (124)I production is unsuitable due to the high level of (123)I impurity.

Radiochemical determination of cross sections of alpha-particle induced reactions on 192Os for the production of the therapeutic radionuclide 193mPt.

For determination of cross sections of alpha-particle induced reactions on 99.65% enriched (192)Os, the methods for electrolytic preparation of thin samples and radiochemical separation of radioplatinum were optimized. The excitation functions of the (192)Os(alpha,n)(195m)Pt and (192)Os(alpha,3n) (193m)Pt reactions were measured from 20 to 39 MeV. The cross section of the latter reaction reaches a maximum value of about 1.5b at an energy around 36 MeV. The results of nuclear model calculations using the codes TALYS and STAPRE agreed well with the measured data. The optimum energy range for the production of no-carrier-added (193m)Pt (T(1/2)=4.33 d) was found to be E(alpha)=40-->30 MeV. The thick target yield amounts to 10 MBq/microA h and a possible batch yield of 2 GBq should be sufficient for Auger electron therapy on a wide scale.

PET imaging problems with the non-standard positron emitters Yttrium-86 and Iodine-124.

AIM: Positron emission tomography (PET) imaging of non-standard positron emitters is influenced by gamma-coincidences, i.e. false coincidences produced by the coincident detection of an annihilation photon and a gamma-ray simultaneously emitted with the positron. The extent to which the PET study is disturbed by this effect is dependent on the kind of the positron emitter used, the kind and position of the object, the acquisition mode, i.e. the optional use of septa, and the reconstruction program. In order to demonstrate and study imaging problems with non-standard positron emitters, a phantom was scanned containing non-radioactive rods with different absorption materials and filled with either (124)I or (86)Y in the bidimensional (2D) as well as tridimensional (3D) acquisition mode. METHODS: For reconstruction, the PET manufacturer's standard software without any modification was used. To reduce errors caused by the gamma-coincidences, a simple linear background subtraction, estimated from the counts at the scanner's external radius, was applied. RESULTS: Without background subtraction, apparent positive and negative ''radioactivity concentrations'' were found in regions of interest positioned over the non-radioactive rods with values higher for (86)Y compared to (124)I and also higher for 3D compared to 2D. A complete subtraction of the background led to erroneous RESULTS: The errors in the phantom's non-radioactive rods and the difference between measured and true radioactivity became minimum, when about 75% of the background was subtracted. This refers to both the 2D and 3D mode. CONCLUSION: Quantitation problems with the non-standard positron emitters (124)I and (86)Y could be minimized in the phantom study examined here by using a simple background subtraction together with the manufacturer's standard correction and reconstruction procedures.

Excitation functions of (alpha,xn) reactions on (nat)Rb and (nat)Sr from threshold up to 26 MeV: possibility of production of (87)Y, (88)Y and (89)Zr.

Excitation functions were measured by the stacked-foil technique for (nat)Rb(alpha,xn)(87m,87m+g,88)Y and (nat)Sr(alpha,xn)(86,88,89)Zr reactions from their respective thresholds up to 26 MeV. The samples for irradiation were prepared by sedimentation and pellet pressing techniques. The measured data were compared with those available in the literature. From the excitation functions, integral yields of the products were calculated. The suitable energy ranges for the production of (87)Y and (88)Y via (nat)Rb(alpha,xn) processes and of (89)Zr via the (nat)Sr(alpha,xn) process are E(alpha)=26-->20 MeV, E(alpha)=26-->5 MeV and E(alpha)=20-->8.5 MeV, respectively. The respective yields amount to 8.2, 0.08 and 0.9 MBq/microA h. Production of (88)Y is feasible if a waiting time of about 2 months is allowed to let the impurities decay out. Also, (87)Y can be produced with a relatively low impurity of (88)Y. The yields of both (88)Y and (87)Y via the present routes are, however, appreciably lower than those via the (nat)Sr(p,xn) processes. There is a possibility to produce (89)Zr via the alpha-particle irradiation of (nat)Sr. The yield is rather low but would be considerably increased if enriched (86)Sr would be used as target material. The radionuclidic impurity levels in all the three products are discussed.

Some optimisation studies relevant to the production of high-purity 124I and 120gI at a small-sized cyclotron.

Optimisation experiments on the production of the positron emitting radionuclides 124I(T(1/2) = 4.18d) and (120g)I (T(1/2) = 1.35 h) were carried out. The TeO(2)-target technology and dry distillation method of radioiodine separation were used. The removal of radioiodine was studied as a function of time and the loss of TeO(2) from the target as a function of oven temperature and time of distillation. A distillation time of 15 min at 750 degrees C was found to be ideal. Using a very pure source and comparing the intensities of the annihilation and X-ray radiation, a value of 22.0 +/- 0.5% for the beta(+) branching in 124I was obtained. Production of 124I was done using 200 mg/cm(2) targets of 99.8% enriched 124TeO(2) on Pt-backing, 16 MeV proton beam intensities of 10 microA, and irradiation times of about 8 h. The average yield of 124I at EOB was 470 MBq(12.7 mCi). At the time of application (about 70 h after EOB) the radionuclidic impurity 123I (T(1/2) = 13.2 h) was <1%. The levels of other impurities were negligible (126I < 0.0001%;125I = 0.01%). Special care was taken to determine the 125I impurity. For the production of (120g)I only a thin 30 mg target (on 0.5 cm(2) area) of 99.9% enriched 120TeO(2) was available. Irradiations were done with 16 MeV protons for 80 min at beam currents of 7 microA. The 120gI yield achieved at EOB was 700 MBq(19 mCi), and the only impurity detected was the isomeric state 120 mI(T(1/2) = 53 min) at a level of 4.0%. The radiochemical purity of both 124I and 120gI was checked via HPLC and TLC. The radioiodine collected in 0.02 M NaOH solution existed >98% as iodide. The amount of inactive Te found in radioiodine was <1 microg. High purity 124I and 120gI can thus be advantageously produced on a medium scale using the low-energy (p,n) reaction at a small-sized cyclotron.

Excitation functions of 125Te(p, xn)-reactions from their respective thresholds up to 100 MeV with special reference to the production of 124I.

Excitation functions of the nuclear reactions 125Te(p, xn) (119,120m, 120g, 121,122,123,124,125)I were measured for the first time from their respective thresholds up to 100 MeV using the stacked-foil technique. Thin samples were prepared by electrolytic deposition of 98.3% enriched 125Te on Ti-backing. In addition to experimental studies, excitation functions were calculated by the modified hybrid model code ALICE-IPPE. The experimental and theoretical data generally showed good agreement. From the measured cross section data, integral yields of (123,124,125)I were calculated. The energy range Ep 21 --> 15 MeV appears to be very suitable for the production of the medically interesting radionuclide 124I (T(1/2) = 4.18 d; I(beta)+ = 25%). The thick target yield of 124I amounts to 81 MBq/microA h and the level of 125I-impurity to 0.9%. The 125Te(p,2n)124I reaction gives 124I yield about four times higher than the commonly used 124Te(p,n)124I and 124Te(d,2n)124I reactions. The proposed production energy range is too high for small cyclotrons but large quantities of 124I can be produced with medium-sized commercial machines.