Source term calculation and validation for 18F-production with a cyclotron for medical applications at HZDR.

In this document we present the calculation and experimental validation of a source term for 18F-production with a cyclotron for medical applications operating at 18 MeV proton energy and 30 µA proton current. The Monte Carlo codes MCNP6 and FLUKA were used for the calculation of the source term. In addition, the radiation field around the 18O-enriched water target was simulated with the two codes. To validate the radiation field obtained in the simulation, an experimental program has been started using activation samples which are placed close to the water target during an 18F-production run of the cyclotron. After the irradiation, the samples are analysed and the resulting activation is compared to Monte Carlo calculations of the expected sample activation. We find good agreement between simulations and experimental results, with most calculation to experiment (C/E) ratios well between 0.6 and 1.4.

Source terms, shielding calculations and soil activation for a medical cyclotron.

Calculations of the shielding and estimates of soil activation for a medical cyclotron are presented in this work. Based on the neutron source term from the 18O(p,n)18F reaction produced by a 28 MeV proton beam, neutron and gamma dose rates outside the building were estimated with the Monte Carlo code MCNP6 (Goorley et al 2012 Nucl. Technol. 180 298-315). The neutron source term was calculated with the MCNP6 code and FLUKA (Ferrari et al 2005 INFN/TC_05/11, SLAC-R-773) code as well as with supplied data by the manufacturer. MCNP and FLUKA calculations yielded comparable results, while the neutron yield obtained using the manufacturer-supplied information is about a factor of 5 smaller. The difference is attributed to the missing channels in the manufacturer-supplied neutron source terms which considers only the 18O(p,n)18F reaction, whereas the MCNP and FLUKA calculations include additional neutron reaction channels. Soil activation was performed using the FLUKA code. The estimated dose rate based on MCNP6 calculations in the public area is about 0.035 µSv h-1 and thus significantly below the reference value of 0.5 µSv h-1 (2011 Strahlenschutzverordnung, 9 Auflage vom 01.11.2011, Bundesanzeiger Verlag). After 5 years of continuous beam operation and a subsequent decay time of 30 d, the activity concentration of the soil is about 0.34 Bq g-1.

The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits.

The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit-setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties-typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical-specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has the benefit of increasing the transparency of occupational exposure limit derivation. Improved characterization of the scientific basis for uncertainty factors has led to increasing rigor and transparency in their application as part of the overall occupational exposure limit derivation process.

[Quality assurance of rehabilitation by the German pension insurance: an overview]. / Ein aktueller Überblick zur Reha-Qualitätssicherung der Rentenversicherung.

The German pension insurance has in recent years developed a comprehensive programme for quality assurance in rehabilitation, and has implemented the programme into routine practice. Different aspects of rehabilitation are evaluated with differentiated instruments. Issues dealt with inter alia include the quality of rehabilitative care in a narrower sense, the structure and organisation of the rehabilitation centres, as well as quality from the patients' perspective. On the whole, positive results predominate. Big differences in quality however have been found between the rehabilitation centres. The data collections and data evaluations carried out make a continuous process of quality assurance reporting possible for use by rehabilitation centres and pension insurance agencies. This will enable targeted initiatives for quality improvement. The methods and procedures of quality assurance are enhanced at regular intervals, and the scope of quality assurance is extended. Thus, rehab quality assurance is also expanded to cover ambulant rehabilitation or rehabilitation of children and young people.

Enhancement of Rb fine-structure transfer in 4He due to three-body collisions.

Using ultrafast laser excitation and time-correlated single-photon counting techniques, we have measured the collisional mixing rates between the rubidium 5(2)P fine-structure levels in the presence of (4)He gas. A nonlinear dependence of the mixing rate with (4)He density is observed. We find Rb fine-structure transfer is primarily due to binary collisions at (4)He densities of < or = 10(19) cm(-3), while at greater densities, three-body collisions become significant. We determine a three-body collisional transfer rate coefficient (5(2)P(3/2) --> 5(2)P(1/2)) of 1.25(9)x10(-32) cm(6)/s at 22 degrees C.

Guidelines for application of chemical-specific adjustment factors in dose/concentration-response assessment.

This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose-response assessment for regulatory purposes (IPCS, 2001).

Occupational hazard evaluation of p-bromobenzyl bromide from tests for genotoxicity.

As part of an occupational hazard evaluation, p-bromobenzyl bromide (p-BBB) was evaluated for genotoxic activity in the Ames microbial mutagenicity assay, the alkaline elution assay for DNA strand breaks in rat hepatocytes and the in vitro chromosome aberration assay in Chinese hamster ovary cells. The compound produced equivocal results in the microbial mutagenicity assay but was negative in the alkaline elution assay for DNA strand breaks in rat hepatocytes. The compound produced weakly positive results in the in vitro chromosome aberration assay. There was substantial cytotoxicity in all three assays. It is concluded that p-BBB is weakly genotoxic.

[Palliative measures in the hepatobiliary-pancreatic system]. / Palliative Massnahmen im hepatobiliopankreatischen System.

Malignant tumors of the hepatobiliopancreatic system are not curable in > 60%. For this reason, palliation plays an important therapeutic role. Indications are mainly obstructive jaundice, duodenal obstruction and pain. Assessment of the tumor's morphology and resectability is often possible only by surgical exploration. If necessary and feasible, non-curable malignancies are treated synchronously during this operation. In preoperatively proven distant metastases or local non-resectability, interventional procedures are preferred. They are efficient, at least primarily, and mostly correlated with little patient discomfort. A surgical biliary bypass obviously leads to improved long-term palliation. Especially in Klatskin tumors, palliative resection may be useful. Generally the patients benefit from palliation depends on minor therapeutic discomfort and long-lasting control of symptoms.

Setting occupational exposure limits for pharmaceuticals.

The active ingredients used in the pharmaceutical industry's products are designed to modify biological processes; thus, if not adequately controlled, they can place employees at risk. This chapter provides an historical look at the need for occupational exposure limits, as well as an overview of the limit-setting process.

Performance-based exposure control limits for pharmaceutical active ingredients.

For many years pharmaceutical companies have established employee exposure limits for the active ingredients used in their products. Historically these limits were derived using traditional risk assessment methods. Because the trend in the pharmaceutical industry is to identify and develop more selective drugs of increasing potency, and because of the difficulty in identifying no-effect levels for certain drugs, a new performance-based approach for setting limits was developed. This method involves assigning materials into one of five hazard categories according to their inherent toxicological and pharmacological properties. The criteria used to assign compounds into performance-based exposure control limit (PB-ECL) categories focus on the degree to which exposure impacts human health. These assignments dictate the level of containment required to assure employee safety that is achieved through the use of engineering controls and safe handling practices. Several matrices were developed to specify general design concepts and controls for unit operations in laboratory and manufacturing operations. Containment options range from conventional handling practices for low potency (PB-ECL Category 1) materials, to technologically advanced systems that result in essentially no open handling for potent or toxic (PB-ECL Category 3) materials, to state-of-the-art facilities employing closed processes and use of robotics for extremely potent (PB-ECL Category 5) materials.

Setting health-based residue limits for contaminants in pharmaceuticals and medical devices.

A procedure for determining health-based residue limits for impurities in drug substances and medical devices is described. The procedure is based upon the concept of setting residue limits that correspond to the intended usage of the drug or device, i.e., short-term use, prolonged use, and/or lifetime use. Data pertaining to chemical and physical properties, occurrence and use, biodisposition, pharmacology, toxicology, and effects in people are used. After evaluation of these data, acceptable daily intake (ADI) values are derived using a safety margin approach for short-term and prolonged exposure limits. The safety margin approach combines the use of safety factors and professional judgment. ADI values for lifetime exposure are calculated using the safety margin approach for noncarcinogens and for some carcinogens, and they are calculated using risk assessment procedures that provide ADI values corresponding to no more than a 1 in 10,000 excess lifetime cancer risk based upon maximum likelihood risk levels for other carcinogens. A weight-of-evidence test determines the use of each approach. Finally, ADI values from relevant routes and endpoints are compared and a residue limit or residue limits are estimated. The standard is expressed in terms of maximum dose per exposure period and/or dose per day and is applicable to medical products intended for short-term use, for prolonged use, and/or for lifetime use as a major clinical indications dictate.

Measurement of particle clearance from the alveolar region of the rabbit respiratory tract.

This paper describes a method for the measurement of the clearance of inert, insoluble radioactively tagged tracer particles from the alveolar region of the rabbit respiratory tract. The technique uses a fixed detector for noninvasive, external monitoring. Validation of the method is presented, as is the clearance pattern of 3.5-micron latex particles as measured for 56 days postexposure. The clearance of latex deposited within the alveolar region can be described by two phases within this time frame, having half-times of 4.9 and 30.1 days, respectively. Clearance of latex initially deposited on the tracheobronchial tree was essentially complete by 2 days after exposure.

Assessment of early alveolar particle clearance and macrophage function following an acute inhalation of sulfuric acid mist.

Rabbits were exposed to submicrometer sulfuric acid mist at 1 mg/m3 for 1 hr to assess effects on alveolar region clearance of a polystyrene latex tracer aerosol. Bronchopulmonary lavage was performed at selected times after exposure for functional characterization of alveolar macrophages. In vivo, clearance was accelerated in acid exposed animals relative to sham controls. Acid exposure produced no change in the viability or numbers of macrophages recovered. Although an increase in the number of polymorphonuclear leukocytes, primary neutrophils, was observed by 1 hr in both acid and sham groups, compared to nonexposed controls, levels were normal by 12 hr in shams but continued elevated in the acid group through 24 hr. Reduced in vitro macrophage adherence was observed after acid exposure. In vivo uptake of the tracer particles by macrophages was enhanced during the first 3 hr after acid exposure and in vitro phagocytosis by polymorphonuclear leukocytes was increased through 48 hr post-exposure. The results indicate some functional alterations in free cells after in vivo exposure to H2SO4 and the production of a mild inflammatory response. This latter was associated with an acceleration of inert particle clearance from the alveolar region.

Physiological and histological alterations in the bronchial mucociliary clearance system of rabbits following intermittent oral or nasal inhalation of sulfuric acid mist.

Rabbits were exposed to submicometer sulfuric acid mist (H2SO4) for 1 h/d, 5 d/w for 4 wk, during which time mucociliary clearance was monitored by external in vivo measurements of tagged tracer aerosol retention. One group was exposed orally to 250 micrograms/m3, another to the same concentration via the nose, and a third to 500 micrograms/m3 also via nasal breathing. Clearance was accelerated on specific individual days during the course of the acid exposures, especially at 500 micrograms/m3. In all series, clearance was significantly faster, compared to preexposure controls, during a 2-wk follow-up period after acid exposures had ceased. At the end of this period, the rabbits were sacrificed, and histological sections were obtained from the tracheobronchial tree. Significantly increased epithelial thickness of small conducting airways, compared to sham exposure controls, occurred in rabbits exposed orally at 250 micrograms/m3 or nasally at 500 micrograms/m3, and additionally the lumen of the smallest airways of the former group was narrower than control. The number of airways containing epithelial secretory cells was also significantly greater in these acid exposure groups compared to sham controls. The only change in the rabbits exposed nasally at 250 micrograms/m3 was a significant increase in the number of airways with epithelial secretory cells in the smallest airway classification. The histological alterations provide a basis for observed changes in clearance, and are similar to those found in chronic bronchitis in humans and experimental animals. Differences in site and degree of histological response and degree of physiological change between the two groups exposed to identical acid concentrations appear to have been due to differences in exposure mode, with resultant effects on breathing pattern, aerosol size distribution, and concentration penetrating beyond the upper respiratory tract to specific lung sites.