The conversion of exposures due to radon into the effective dose: the epidemiological approach.

The risks and dose conversion coefficients for residential and occupational exposures due to radon were determined with applying the epidemiological risk models to ICRP representative populations. The dose conversion coefficient for residential radon was estimated with a value of 1.6 mSv year-1 per 100 Bq m-3 (3.6 mSv per WLM), which is significantly lower than the corresponding value derived from the biokinetic and dosimetric models. The dose conversion coefficient for occupational exposures with applying the risk models for miners was estimated with a value of 14 mSv per WLM, which is in good accordance with the results of the dosimetric models. To resolve the discrepancy regarding residential radon, the ICRP approaches for the determination of risks and doses were reviewed. It could be shown that ICRP overestimates the risk for lung cancer caused by residential radon. This can be attributed to a wrong population weighting of the radon-induced risks in its epidemiological approach. With the approach in this work, the average risks for lung cancer were determined, taking into account the age-specific risk contributions of all individuals in the population. As a result, a lower risk coefficient for residential radon was obtained. The results from the ICRP biokinetic and dosimetric models for both, the occupationally exposed working age population and the whole population exposed to residential radon, can be brought in better accordance with the corresponding results of the epidemiological approach, if the respective relative radiation detriments and a radiation-weighting factor for alpha particles of about ten are used.

RISKS AND RADIATION DOSES DUE TO RESIDENTIAL RADON IN GERMANY.

The population-averaged risk rate and the annual average effective dose due to residential radon in Germany were calculated. The calculations were based on an epidemiological approach taking into account the age- and gender-specific lung cancer incidence rates for the German population and the excess relative risk of 0.16 per 100 Bq·m-3 for residential radon. In addition, the risk estimates adjusted for the smoking habits were determined. The population-averaged risk rate for the whole population was estimated with 4.1·10-5 y-1 (95% confidence interval (CI) 1.4·10-5-7.6·10-5 y-1). Residential radon causes a detriment per year of 3.3·10-5 y-1 (95% CI 1.1·10-5-6.0·10-5 y-1), which corresponds to an annual average effective dose of 0.6 mSv (95% CI 0.2-1.1 mSv). Annually, ~3400 lung cancer incidences are attributed to residential radon. The results from the epidemiological approach exercised in this study are considerably lower than the effective dose, which would be obtained from the dose conversion coefficient calculated using biokinetic and dosimetric models.

THE CONVERSION OF EXPOSURES DUE TO RADON INTO THE EFFECTIVE DOSE TAKING INTO ACCOUNT THE EQUIVALENCE OF RISKS FROM SHORT- AND LONG-TERM EXPOSURES.

The theoretical basis for comparing risks from short- and long-term exposures is developed aiming at implementing long-term exposures into a unique and consistent system of radiation protection. Based on system-analytical considerations, the equivalence of population-averaged risk rates due to prolonged exposures and population-averaged lifetime risks due to short-term exposures is shown. The consequences of this risk analysis are discussed, focussing on long-term exposures due to residential radon. Equations for the dose conversion of exposures due to radon into the effective dose are derived.

The measurement accuracy of passive radon instruments.

This paper analyses the data having been gathered from interlaboratory comparisons of passive radon instruments over 10 y with respect to the measurement accuracy. The measurement accuracy is discussed in terms of the systematic and the random measurement error. The analysis shows that the systematic measurement error of the most instruments issued by professional laboratory services can be within a range of ±10 % from the true value. A single radon measurement has an additional random measurement error, which is in the range of up to ±15 % for high exposures to radon (>2000 kBq h m(-3)). The random measurement error increases for lower exposures. The analysis especially applies to instruments with solid-state nuclear track detectors and results in proposing criteria for testing the measurement accuracy. Instruments with electrets and charcoal have also been considered, but the low stock of data enables only a qualitative discussion.

Performance tests for instruments measuring radon activity concentration.

Performance tests of electronic instruments measuring the activity concentration of (222)Rn have been carried out with respect to the standard IEC 61577-2. In total, 9 types of instrument operating with ionization chambers or electrostatic collection have been tested for the influence of different climatic and radiological factors on the measurement characteristics. It is concluded that all types of instrument, which are commercially available, are suitable for indoor radon measurements. Because of the dependence on climatic conditions, the outdoor use is partly limited.

Interlaboratory comparisons for passive radon measuring devices at BfS.

Since 2003, the German Federal Office for Radiation Protection (BfS) has conducted annual interlaboratory comparisons for passive radon measuring devices in order to ensure the quality of these measurements. Passive radon devices which use solid state nuclear track detectors, electrets or activated charcoal can be tested. The exposures of radon devices are carried out in the radon calibration laboratory at BfS. Radon activity concentrations are traced back to the national standard, being established at the National Institute of Physics and Metrology (PTB). According to the national guideline, radon services which offer radon monitoring at workplaces have to participate in the intercomparisons and prove the suitability of their radon devices for the measurements.

Clinical experience with intravenous fenoldopam.

Fenoldopam (Corlopam), a new dopaminergic agent in clinical development by SmithKline Beecham Pharmaceuticals, is a dopamine-1 (DA1) agonist at post-synaptic dopamine receptors. Preclinical and clinical studies have demonstrated that it is a potent renal vasodilator as well as a peripheral vasodilator. In both normal volunteers and hypertensive patients intravenous fenoldopam causes dose-related decreases in blood pressure and important increases in renal hemodynamics and function including increased renal blood flow, diuresis and natriuresis. Fenoldopam does not alter glomerular filtration. Intravenous fenoldopam has been demonstrated to be efficacious in severe hypertensive patients in several multicenter, multinational trials. In severe hypertension efficacy trials fenoldopam was judged to be as effective as sodium nitroprusside and to produce less serious side effects. In patients with moderate to severe heart failure, fenoldopam has been demonstrated to produce dose-related acute increases in cardiac output, stroke volume and work index, decreased systemic vascular resistance but no important changes in pulmonary wedge pressure or right atrial pressure. In CHF patients fenoldopam has been demonstrated to be as efficacious as sodium nitroprusside. Fenoldopam, as a specific (DA1) agonist resulting in decreased peripheral and renal vascular resistance, diuresis, natriuresis and increases in cardiac hemodynamics on intravenous administration, appears to be an efficacious agent which offers a reasonable alternative in the treatment of severe hypertension and acute congestive heart failure.

The effect of selective dopamine-1 receptor stimulation on renal and adrenal function in man.

We studied the actions of iv fenoldopam, a selective dopamine-1 (DA-1) receptor agonist, in 10 normal men eating a diet containing 150 meq sodium and 60 meq potassium per day. During DA-1 receptor stimulation systemic hemodynamic function did not change. Fenoldopam resulted in an increase in urine flow rate from 13 +/- 1 (+/- SE) to a peak of 17 +/- 2 mL/min (P less than 0.05) and an increase in renal plasma flow from 344 +/- 39 to 481 +/- 44 mL/min (P less than 0.05). Urinary sodium excretion and fractional excretion of sodium both increased. Urinary sodium excretion rose to a maximum of 0.32 +/- 0.05 compared with a control value of 0.21 +/- 0.03 meq/min (P less than 0.01), while fractional excretion of sodium rose to 2.7 +/- 0.6 compared with a control value of 1.6 +/- 0.1% (P less than 0.05). The glomerular filtration rate did not change. Administration of a predominantly DA-2 antagonist during continuous DA-1 receptor stimulation did not block the fenoldopam-induced natriuresis. The rise in plasma aldosterone concentration after metoclopramide administration was blunted by DA-1 receptor activation [19.2 +/- 2.9 during control compared with 12.7 +/- 1.3 ng/dL (P less than 0.01) during fenoldopam]. No change occurred in serum potassium, plasma cortisol, or PRA. We conclude that selective DA-1 receptor stimulation in man produces sustained natriuresis and inhibition of aldosterone release by direct renal and adrenal effects.

Continuous intragastric delivery of fenoldopam: relationship between plasma concentration and effects on renal function.

1. The pharmacodynamics of the dopamine DA1 agonist fenoldopam were examined in six healthy male volunteers after constant intragastric infusions of fenoldopam at dosages of 0, 10, 25, 50 and 75 mg h-1 for 6 h. 2. Hourly p-aminohippurate (PAH) clearance was used to assess fenoldopam induced renal plasma flow changes. Marked dose-related increases in renal plasma flow were noted with a maximal increase of 65% over baseline values of 711 ml min-1 being seen at the 75 mg h-1 rate. No changes in sodium excretion and glomerular filtration rate were observed. 3. Mean steady-state fenoldopam plasma concentrations were related to mean PAH clearance based on an Emax model (r = 0.996) with an Emax of 1350 ml min-1 and an EC50 of 6.2 ng ml-1. 4. Mean steady-state plasma concentrations of fenoldopam-7-sulphate and fenoldopam-8-sulphate failed to increase with dose but were linearly correlated to mean PAH changes (r = 0.998, r = 0.981 respectively). 5. These results support the concept of extending fenoldopam's duration of action through the development of an oral sustained delivery system.

Selective dopamine-1 receptor stimulation produces natriuresis by a direct tubular action.

Fenoldopam mesylate, a selective dopamine-1 (DA-1) receptor agonist, was infused intravenously in 10 normal male subjects in metabolic balance. The study was designed to determine the mechanism of dopamine-induced natriuresis. During fenoldopam infusion renal plasma flow (RPF) and urine flow rate manifested a biphasic response. The RPF rose from 344 +/- 39 to 481 +/- 44 ml/min (P less than 0.05), decreased to control levels, and then rose to 497 +/- 38 ml/min (P less than 0.05). Urinary sodium excretion (UNaV) and fractional excretion of sodium (FENa) demonstrated a sustained increase during DA-1 receptor activation. The FENa rose from 1.6 +/- 0.1 to 2.7 +/- 0.6% (P less than 0.05). Glomerular filtration rate (GFR), blood pressure and heart rate were unchanged. Our results, specifically the dissociation of RPF from UNaV and FENa, demonstrate in man that stimulation of renal tubular DA-1 receptors causes natriuresis.

Calculations of the pH changes produced in body tissue by a spherical stimulation electrode.

A mathematical description of pH excursions produced in interstitial fluid by a spherical stimulation electrode is presented. The pH is calculated as a function of current density, electrode radius, distance, time, and pulsing regimen for an electrode driven by biphasic current pulses. Calculations indicate that large pH excursions occur around electrodes pulsed at current densities used for neural stimulation. For an electrode with a radius of about 1 micron these transient pH changes extend only a few micrometers from the electrode surface. The practical importance of these pH changes remains to be determined.

Calculations of temperature rise produced in body tissue by a spherical electrode.

Two estimates of temperature rise produced in body tissue when a spherical electrode passes current have been calculated. The estimates bracket the expected temperature rise. Time-transient and steady-state results have been obtained. The effects of heat transfer through the highly conductive metal electrode and irreversible Faradaic reactions have been considered. The calculations indicate that electrodes smaller than about 2 micron in radius produce a peak temperature rise of about 1 degree C when driven by typical square current pulses of 25 microA intensity and 200 microseconds duration. The results are presented in a graphic form allowing for quick estimation of the expected peak temperature rise around electrodes of a specific radius, which are driven with a pulse of known current density and duration.

Prostaglandins inhibit renal ammoniagenesis in the rat.

We describe the inhibitory effect of prostaglandins (PGs) on in vivo rat renal ammonia synthesis. The influence of systemic pH upon urinary PG excretion and ammoniagenesis was also investigated. Finally, PG production by incubated rat renal cortical slices was suppressed to investigate the PG-ammonia interplay in the absence of changes in renal blood flow, glomerular filtration rate, ambient electrolyte concentrations or extrarenal hormonal factors. In vivo ammonia synthesis doubled and PG excretion fell by 44% in normal rats, after intravenous administration of 1 mg/kg of meclofenamate. Higher doses of meclofenamate further augmented ammonia production and further reduced PG excretion. PG depletion was also associated with an increase in fractional excretion of ammonia (FENH3) that was independent of changes in urine flow rate or pH. Acute metabolic acidosis (AMA) increased total ammonia synthesis but also stimulated PG production. Administration of meclofenamate to rats with mild AMA markedly reduced urinary PG excretion, further augmented ammonia synthesis, and significantly increased the FENH3. Inhibition of stimulated PG synthesis during severe AMA did not increase ammoniagenesis or FENH3. Acute metabolic alkalosis did not alter production of PGs or ammonia, but reduced the FENH3 by 42%. Meclofenamate nearly normalized the FENH3 but stimulated synthesis to a lesser degree than was seen in nonalkalotic rats that received meclofenamate. Inhibition of PG synthesis in incubated rat renal cortical slices also stimulated ammoniagenesis. Conversely, stimulation of PG synthesis decreased ammonia production and acidification of the incubation medium increased prostaglandin F2 alpha production. Thus, in vitro findings support the in vivo results. We conclude that PGs inhibit ammonia synthesis in normal rats and in those undergoing mild AMA. Severe acidosis overrides this inhibitory effect of PGs, whereas metabolic alkalosis suppresses the stimulatory effect of PG synthesis inhibition.

The effect of arginine vasopressin and its analogs on the synthesis of prostaglandin E2 by rat renal medullary interstitial cells in culture.

Arginine vasopressin (AVP) stimulates renal prostaglandin (PG) production which is thought to inhibit vasopressins' antidiuretic action. Using rat renal medullary cells in culture (RMIC), we compared the ability of the following peptides which possess different biological activities to stimulate prostaglandin biosynthesis: AVP (high antidiuretic and pressor activities); 1-desamino-8-D-arginine vasopressin (a synthetic peptide with high antidiuretic and no pressor activity); and oxytocin (intermediate pressor, low antidiuretic activity). Radiometric thin-layer chromatography of supernatant media from cells incubated with octatritiated or [14C]arachidonic acid revealed only one radiolabeled peak which co-migrated with PGE2. Radioimmunoassay confirmed that PGE2 was the only prostaglandin synthesized by RMIC. Incubation of cells with AVP (1 nM to 3 microM) increased PGE2 synthesis measured by radioimmunoassay in a concentration-dependent fashion up to 2 1/2-fold over control; 1-desamino-8-D-arginine did not increase PGE2 synthesis. Oxytocin stimulated PGE2 synthesis, but was less potent than AVP. Preincubation of RMIC with [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid)-4-valine, 8-D-arginine]vasopressin, a synthetic nonpressor, nonantidiuretic antagonists of AVP's pressor activity, completely blocked the ability of AVP to stimulate PGE2 synthesis. We conclude that the ability of AVP to stimulate PGE2 synthesis in RMIC is related to its pressor, not its antidiuretic, activity.