Identification of emerging safety and sustainability issues of advanced materials: Proposal for a systematic approach.

The EU Chemicals Strategy for Sustainability is a first step to achieve the Green Deal ambition for a toxic-free environment, and ensure that chemicals are produced and used in a way that maximises their contribution to society while avoiding harm to our planet and to future generations. Advanced materials are predicted to play a pivotal role in achieving this ambition and the underlying sustainability goals, and considerable efforts are invested in designing new classes of materials. Examples of such materials are metamaterials, artificially architectured materials designed to have material properties beyond those of the individual ingredient materials, or active materials at the boundary between materials and devices (e.g., new biomedical soft materials). Such innovative advanced materials raise concern about possible future safety and sustainability issues and would benefit from appropriate risk governance that promotes innovation, while pushing for safety and sustainability. To balance these aspects, a methodology is proposed for the early-stage identification of emerging safety and sustainability issues of advanced materials. As exemplified by two case studies, the methodology aims to be of use for innovators, risk assessors, and regulators. Extension of the methodology is highlighted, as well as implementation in broader initiatives like the EU's industrial policy approach.

Risk assessment of chemicals and pharmaceuticals in the pediatric population: a workshop report.

ATSDR and RIVM organized an Expert Panel Workshop on the Differences Between Children and Adults and Their Relevance to Risk Assessment. The workshop was held in June 2003, in Brussels, Belgium. The purpose of the workshop was to identify data gaps in current scientific knowledge related to children's health and to recognize areas of mutual interest that would serve as the basis for upcoming ATSDR/RIVM cooperative projects. The aim for both agencies is a better understanding of the issues related to children's health, and the improvement of scientifically based (chemical) risk assessment in children. Topics discussed included clinical trials/toxicity studies, testing in juvenile animals, PBPK modeling in children, and children's risk assessment.

Profiles of measured and perceived bronchodilation. A placebo-controlled cross-over trial comparing formoterol and salmeterol in moderate persistent asthma.

BACKGROUND AND OBJECTIVE: Long-acting beta(2)-agonists have acquired an indispensable position in the management of bronchial symptoms in patients with asthma. The objective of this study was to compare onset-of-action and clinical effectiveness of formoterol and salmeterol during 2 weeks of treatment. We also investigated the association between bronchodilator effects and perceived relieve of dyspnoea. METHODS: A multi-centre randomized double-blind placebo-controlled cross-over trial was performed in 35 subjects with moderate persistent asthma. Treatment periods existed of 2 weeks formoterol (12 microg bid), salmeterol (50 microg bid) and placebo, all administered by pressurized metered dose inhaler. FEV(1) and Visual Analogue Scale (VAS) scores were repeatedly measured until 180 min post-bronchodilation (post-BD), before as well as after each treatment period. Onset-of-action was defined as a >/=15% increase in FEV(1). Subjects kept diaries of morning and evening PEFR values and use of rescue bronchodilator. RESULTS: Formoterol and salmeterol both caused a significant increase in FEV(1) (0.45L [95% CI 0.01, 0.80] and 0.27L [95% CI 0.08, 0.62] respectively). At 3' post-BD, three times as many subjects demonstrated onset-of-action on formoterol compared to salmeterol (36% versus 13%, P = 0.063), at 6' post-BD 42% versus 27% (P = 0.063). VAS scores were similar for formoterol and salmeterol at pre-treatment assessment, but tended to be higher for formoterol after 2weeks treatment. No differences between formoterol and salmeterol were observed for PEFR values or use of rescue medication. 50% of the subjects preferred formoterol, 29% salmeterol (P < 0.001). Significant associations between FEV(1) and VAS ratings existed only at 10', 15' and 30' post-BD, not before or after these time points. CONCLUSION: The earlier described faster onset-of-action of formoterol as compared to a equipotent dosage of salmeterol was confirmed in this study. Perception of decreasing airflow obstruction may be delayed after acute bronchodilation.

Role of biokinetics in risk assessment of drugs and chemicals in children.

Whether children incur different risks from xenobiotics than adults will depend on the exposure, biokinetics, and dynamics of compound. In this paper, current knowledge on developmental physiology and possible effects on biokinetics are evaluated and the role of biokinetics in risk assessment both for drugs and chemicals is discussed. It is concluded that most dramatic age-related physiological changes that may affect biokinetics occur in the first 6-12 months of age. The difference in internal exposure between children and adults can generally be predicted from already known developmental physiological differences. However, for risk assessment it will also be necessary to determine whether internal exposure is within the drug's therapeutic window or if it will exceed the NOAEL of a chemical. Furthermore, the effects of internal exposure of potentially harmful compounds on developing organ systems is of utmost importance. However, knowledge on this aspect is very limited. Risk assessment in children could be improved by: (1) application of pediatric PBPK-models in order to gain insight into internal exposure in children, (2) studies in juvenile animals for studying effects on developing systems, and (3) extrapolation of knowledge on the relationship between internal exposure and dynamics for drugs to other chemicals.

Effect of bile type on the bioaccessibility of soil contaminants in an in vitro digestion model.

Soil ingestion is an important pathway of exposure for many nonvolatile contaminants for man and in particular for children. A fraction of the ingested contaminant may not dissociate from the soil particles during digestion in the gastrointestinal tract, and is thus not available for transport across the intestinal epithelium. In order to estimate the contaminant fraction that is mobilized from soil, i.e., the bioaccessible fraction, several in vitro digestion models have been developed. The currently existing digestion models display many differences. One aspect that may affect bioaccessibility and may induce differences between digestion models is the bile that is used. Often freeze-dried bile of animal origin is preferred to purified bile salts. However, also the animal origin of bile may give rise to differences in bioaccessibility because bile composition appears to be species dependent. In the present study, we compared the bioaccessibility of benzo[a]pyrene, arsenic, cadmium, and lead of four different soils after digestion with ox bile from two different suppliers, pig bile, and chicken bile. Bioaccessibility appeared to vary amongst the different soils and contaminants. Only chicken bile increased the bioaccessibility of lead and cadmium significantly and relevantly for one of four soils. For chicken bile, the bioaccessibility of lead was 3-5.5 times greater than for the other bile types and the bioaccessibility of cadmium was 1.5 times greater. In all other cases, the bioaccessibility differences were less than 10%, which is considered irrelevant for risk assessment purposes.

Comparable efficacy and tolerability of formoterol (Foradil) administered via a novel multi-dose dry powder inhaler (Certihaler) or the Aerolizer dry powder inhaler in patients with persistent asthma.

BACKGROUND: For maximum treatment compliance there is a need to provide asthma patients with devices that suit their particular preferences. The Foradil Certihaler is a novel multi-dose dry powder inhaler developed to increase the choice of devices available. OBJECTIVES: To evaluate the safety and efficacy of formoterol administered via the Foradil Certihaler, or via the single-dose inhaler Foradil Aerolizer. METHODS: This was a randomized, placebo-controlled, double-dummy, incomplete block crossover, dose-ranging and pharmacokinetic study in patients with persistent asthma. Sixty-seven patients (mean 48.0 years) were randomized to formoterol 5, 10, 15 and 30 microg twice daily via the Certihaler, 12 microg formoterol b.i.d. via the Aerolizer, or placebo in four 1-week double-blind treatment periods separated by 1-week single-blind washouts. RESULTS All formoterol doses delivered via the Certihaler or the Aerolizer significantly increased FEV(1) compared with placebo (p < 0.0001). Formoterol demonstrated an onset of action of <3 min. All active treatments were well tolerated. Tremor was the most common adverse event and was more pronounced at high doses. At lower doses the incidence of tremor with the Certihaler was similar to that observed with placebo or the Aerolizer. The pharmacokinetic evaluation comprised 41 patients (mean 45.9 years). Urinary excretion of unchanged formoterol and total formoterol increased with dose delivered via the Certihaler. The optimum dose of formoterol via the Certihaler was 10 microg. CONCLUSION: Delivery of formoterol via the Certihaler or Aerolizer combines rapid relief with enduring control and provides convenient bronchodilation in patients with persistent asthma.

Development of an in vitro digestion model for estimating the bioaccessibility of soil contaminants.

Soil ingestion can be a major route of human exposure to many immobile soil contaminants. The present risk assessment is based on toxicity studies in which contaminants are typically ingested in liquid or food matrices. The difference in bioavailability of contaminants ingested in a soil matrix is not taken into account. To become bioavailable, contaminants first need to become bioaccessible, i.e., they must be mobilized from the soil during digestion. Soil contaminants may be less bioaccessible than contaminants from liquid or food, so that the risks can be overestimated. This article describes the development of an in vitro human digestion model that is physiologically based. It can be used as a tool to assess bioaccessibility. We explain the rationale behind the experimental design of the model. We address the aspects of the simulated compartments of the gastrointestinal tract, temperature, soil-to-fluid ratio, ratio of digestive juices, transit times, centrifugation, pH values, mixing, constituents and their concentrations, and bile. The optimized in vitro digestion model was applied in a case study. The bioaccessibility of lead in pottery flakes with glazing was determined and compared to the bioaccessibility of lead in the soil from which the pottery flakes were removed. The data indicate that pottery flake lead is considerably less bioaccessible (0.3 +/- 0.2%) than lead in soil without pottery flakes (42-66% at the same site, and 28-73% at other sites in the same town). Furthermore, bioaccessibility values of lead in soil appear to be less than calculated bioaccessibility values for dietary lead (which are based on the criterion used by the Dutch risk assessment and on literature absorption data). This indicates that accounting for the matrix of ingestion can affect the exposure assessment for lead. The in vitro digestion model is a promising tool for studying the effect of the ingestion matrix on bioaccessibility.

Lead speciation in artificial human digestive fluid.

For children, soil ingestion via hand-to-mouth behavior can be a main route of exposure to contaminants such as lead. The ingested lead can be mobilized from the soil and form new species during the digestion process. Speciation is known to affect the availability of metals for transport across biological membranes. In the present study, in vitro digestions were performed with (artificially contaminated) standard soil. Lead speciation was investigated in the artificial human intestinal fluid, i.e., chyme, to gain insight into the lead species and lead fractions that may be available for transport across the intestinal epithelium. To that end, both a lead ion selective electrode (Pb-ISE) and a voltammetric technique (differential pulse anodic stripping voltammetry, DPASV) were used. The results indicate that in chyme only a negligible lead fraction is present as free Pb(2+), whereas lead phosphate and lead bile complexes are important fractions. The lead phosphate complexes appear to be voltammetrically labile, i.e., in dynamic equilibrium with Pb(2+). Labile complexes can dissociate and the produced metal ions can subsequently be transported across the intestinal epithelium. Lead bile complexes may behave in a similar manner, or this organometal complex may be able to traverse the intestinal membrane. Therefore, substantially more than only the free metal ion should be considered available for transport across the intestinal epithelium.

In vitro intestinal lead uptake and transport in relation to speciation.

Children might be exposed substantially to contaminants such as lead via soil ingestion. In risk assessment of soil contaminants there is a need for information on oral bioavailability of soilborne lead. Oral bioavailability can be seen as the result of four steps: (1) soil ingestion; (2) mobilization from soil during digestion, i.e., bioaccessibility; (3) transport across the intestinal epithelium; and (4) first-pass effect. Lead bioaccessibility and speciation in artificial human small intestinal fluid, i.e., chyme, have been investigated in previous studies. In the present study, transport of bioaccessible lead across the intestinal epithelium was investigated using the Caco-2 cell line. Cell monolayers were exposed to (diluted) artificial chyme. In 24 h, approximately 27% of the lead were associated to the cells and 3% were transported across the cell monolayer, without signs of approaching equilibrium. Lead associated to the cells showed a linear relationship with the total amount of lead in the system. Bile levels did not affect the fraction of lead associated to Caco-2 cells. Extrapolation of the lead flux across the Caco-2 monolayer to the in vivo situation indicates that only a fraction of the bioaccessible lead is transported across the intestinal epithelium. Furthermore, the results indicate that as the free Pb(2+) concentration in chyme was negligible, lead species other than the free metal ion must have contributed to the lead flux toward the cells. On the basis of lead speciation in chyme, this can be attributed to dissociation of labile lead species, such as lead phosphate and lead bile complexes, and subsequent transport of the released free metal ions toward the intestinal membrane.

The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling.

Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. In addition, it is of clinical interest for possible treatment of chronic hepatitis C. In some highly exposed subjects, side effects such as hypertension and symptoms associated with electrolyte disturbances have been reported. To analyze the relationship between the pharmacokinetics of glycyrrhizic acid in its toxicity, the kinetics of glycyrrhizic acid and its biologically active metabolite glycyrrhetic acid were evaluated. Glycyrrhizic acid is mainly absorbed after presystemic hydrolysis as glycyrrhetic acid. Because glycyrrhetic acid is a 200-1000 times more potent inhibitor of 11-beta-hydroxysteroid dehydrogenase compared to glycyrrhizic acid, the kinetics of glycyrrhetic acid are relevant in a toxicological perspective. Once absorbed, glycyrrhetic acid is transported, mainly taken up into the liver by capacity-limited carriers, where it is metabolized into glucuronide and sulfate conjugates. These conjugates are transported efficiently into the bile. After outflow of the bile into the duodenum, the conjugates are hydrolyzed to glycyrrhetic acid by commensal bacteria; glycyrrhetic acid is subsequently reabsorbed, causing a pronounced delay in the terminal plasma clearance. Physiologically based pharmacokinetic modeling indicated that, in humans, the transit rate of gastrointestinal contents through the small and large intestines predominantly determines to what extent glycyrrhetic acid conjugates will be reabsorbed. This parameter, which can be estimated noninvasively, may serve as a useful risk estimator for glycyrrhizic-acid-induced adverse effects, because in subjects with prolonged gastrointestinal transit times, glycyrrhetic acid might accumulate after repeated intake.

Availability of polychlorinated biphenyls (PCBs) and lindane for uptake by intestinal Caco-2 cells.

Children may ingest contaminated soil from hand to mouth. To assess this exposure route, we need to know the oral bioavailability of the contaminants. Two determining steps in bioavailability of soil-borne contaminants are mobilization from soil during digestion, which is followed by intestinal absorption. The first step has been investigated in previous studies that showed that a substantial fraction of PCBs and lindane is mobilized from soil during artificial digestion. Furthermore, almost all contaminants are sorbed to constituents of artificial human small intestinal fluid (i.e., chyme), whereas only a small fraction is freely dissolved. In this study, we examine the second step using intestinal epithelial Caco-2 cells. The composition of the apical exposure medium was varied by addition of artificial chyme, bile, or oleic acid at similar or increasing total contaminant concentrations. The uptake curves were described by rate constants. The uptake flux seemed to be dose-dependent. Furthermore, different exposure media with similar total contaminant concentrations resulted in various uptake rates. This can be attributed to different freely dissolved concentrations and carrier effects. In addition, the large fractions of contaminants in the cells indicate that PCBs and lindane sorbed to bile, oleic acid, and digestive proteins contributed to the uptake flux toward the cells. These results can be extrapolated qualitatively to in vivo conditions. Because the sorbed contaminants should be considered available for absorption, the first step of mobilization from soil is the most important step for oral bioavailability of the presently investigated soil-borne contaminants.

A population physiologically based pharmacokinetic/pharmacodynamic model for the inhibition of 11-beta-hydroxysteroid dehydrogenase activity by glycyrrhetic acid.

Glycyrrhizic acid is widely applied as a sweetener in food products and chewing tobacco. Habitual consumption of this compound may lead to hypertension and electrolyte disturbances due to inhibition of 11-beta-hydroxysteroid dehydrogenase by the metabolite glycyrrhetic acid. The effect of 130 mg glycyrrhetic acid/day for 5 days on 11-beta-hydroxysteroid dehydrogenase activity was studied by measuring the cortisol-cortisone ratio in 24-h urine. A twofold increase in this ratio was observed. It took 4 days for the elevated urinary cortisol-cortisone ratio to return to the baseline ratio after cessation of the treatment. The pharmacokinetics of glycyrrhetic acid were studied after the first and last dose. Using data from a previously performed single-dose study and present multiple-dose treatment, a physiologically based pharmacokinetic model for glycyrrhetic acid was developed. The variability of the pharmacokinetics of glycyrrhetic acid in the population studied could be explained for a considerable part by interindividual differences in gastrointestinal transit of glycyrrhetic acid metabolites. The relationship between glycyrrhetic acid exposure and changes in urinary cortisol-cortisone ratio was described by a pharmacodynamic model, using nonlinear mixed-effect modeling. Literature data on the inhibitory effect of glycyrrhetic acid on 11-beta-hydroxysteroid dehydrogenase activity under various exposure scenarios could be adequately described by the model. Due to the relationship between the pharmacokinetics of glycyrrhetic acid and its inhibitory effect on 11-beta-hydroxysteroid dehydrogenase activity, reflected by a change in the urinary cortisol-cortisone ratio, this ratio might serve as a noninvasive marker to identify individuals at risk for glycyrrhizic acid over-consumption.

A human physiologically-based model for glycyrrhzic acid, a compound subject to presystemic metabolism and enterohepatic cycling.

PURPOSE: To analyze the role of the kinetics of glycyrrhizic acid (GD) in its toxicity. A physiologically-based pharmacokinetic (PBPK) model that has been developed for humans. METHODS: The kinetics of GD, which is absorbed as glycyrrhetic acid (GA), were described by a human PBPK model, which is based on a rat model. After rat to human extrapolation, the model was validated on plasma concentration data after ingestion of GA and GD solutions or licorice confectionery, and an additional data derived from the literature. Observed interindividual variability in kinetics was quantified by deriving an optimal set of parameters for each individual. RESULTS: The a-priori defined model successfully forecasted GA kinetics in humans, which is characterized by a second absorption peak in the terminal elimination phase. This peak is subscribed to enterohepatic cycling of GA metabolites. The optimized model explained most of the interindividual variance, observed in the clinical study, and adequately described data from the literature. CONCLUSIONS: Preclinical information on GD kinetics could be incorporated in the human PBPK model. Model simulations demonstrate that especially in subjects with prolonged gastrointestinal residence times, GA may accumulate after repeated licorice consumption, thus increasing the health risk of this specific subgroup of individuals.

Intestinal calcium absorption and bone metabolism in young adult men with childhood-onset growth hormone deficiency.

Suboptimal growth hormone (GH) replacement therapy during childhood is a major cause of osteopenia in young adults with childhood-onset GH deficiency (CO-GHD). This is primarily attributed to reduced bone formation in childhood. It is currently not known whether GHD also has adverse effects on bone metabolism in adult life. To examine the impact of GHD on calcium and bone metabolism in adults, we evaluated 50 men with CO pituitary failure at a mean age of 28.2+/-4.5 years, i.e., 8.8+/-4.1 years after the discontinuation of previous GH treatment for short stature. Thirty-three patients had multiple pituitary hormone deficiencies (MPHD) for which they received conventional replacement therapy, seventeen patients had isolated GHD (IGHD), and forty-nine age-matched men served as controls. Intestinal calcium absorption, serum calcium concentration, serum phosphate levels, and renal calcium and phosphate excretion were normal in IGHD and MPHD patients. IGHD patients had marginally elevated serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen (ICTP: 5.0+/-1.2 vs. 4.2+/-1.2 microg/l, p < 0.05), but other indices of bone turnover were normal. In contrast, MPHD patients had reduced levels of the carboxy-terminal propeptide of type I procollagen (PICP: 137+/-76 vs. 179+/-72 microg/l, p < 0.01), elevated serum ICTP levels (6.0+/-3.8 vs. 4.2+/-1.2 microg/l, p < 0.001), and reduced serum 1,25-dihydroxyvitamin D levels (55.1+/-16.7 vs. 73.0+/-23.0 pmol/l, p < 0.001). Multivariate regression analysis showed that the serum levels of bone resorption and bone formation markers in MPHD patients were correlated with the hydrocortisone, thyroxine, and testosterone replacement doses. There was no relationship with serum insulin-like growth factor I concentration. Panhypopituitary adults receiving conventional hormone replacement therapy are at risk to develop osteopenia either caused by reduced bone formation or by increased bone resorption activity. Predominantly, these abnormalities result from nonoptimal thyroid, gonadal, or adrenal hormone replacement therapy. GHD is not an important factor. In adults, GHD does not adversely affect intestinal calcium absorption or bone formation activity. Bone resorption activity may be slightly higher than normal, but the abnormality is too small to expect substantial bone loss as a consequence of GHD.

Preclinical screening of the applicability of strontium as a marker for intestinal calcium absorption.

The applicability of stable strontium as a marker for measuring intestinal calcium absorption is mainly dependent on the validity of the assumption that calcium and strontium are absorbed with a constant ratio. Up to now, it is not clear whether this ratio is affected by intervention therapy. Therefore, preclinical screening of this ratio before and after treatment is indispensable for a clinical calcium absorption test based on the use of stable strontium as a marker. We studied the effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D(3)], a potent enhancer of active intestinal calcium absorption, on the pharmacokinetics of both calcium-45 and strontium in adult male rats, in a short-term dose-finding study [0-50 ng 1,25(OH)2D(3)/100 g body weight] and also in a placebo-controlled study in which 12.5 ng 1,25(OH)2D(3)/100 g body weight were applied to assess the long-term pharmacokinetics. The mean bioavailability (true absorption) was 33% for calcium and 19% for strontium (ratio 1.7:1), whereas, after 1,25(OH)2D(3) pretreatment, it was 73 and 43% (ratio 1.7:1), respectively. These findings demonstrate that intestinal strontium absorption has, like intestinal calcium absorption, an active component. Moreover, they underscore the applicability of stable strontium as a tool for investigating calcium absorption under various conditions.

Intestinal absorption of strontium chloride in healthy volunteers: pharmacokinetics and reproducibility.

1. The absorption kinetics of orally administered strontium chloride and its reproducibility were investigated in healthy volunteers after administering strontium either under fasting conditions (study I, n = 8) or in combination with a standardized meal (study II, n = 8). Each subject received strontium orally at day 0, 14, and 28 and intravenously at day 42. The study was performed as part of a project in which a simple clinical test for measuring intestinal calcium absorption is being developed, based on the use of stable strontium as a marker. 2. Plasma strontium concentration-time curves were analysed by noncompartment analysis and a four compartment disposition model. Within a volunteer each oral curve was fitted simultaneously with the intravenous curve, by which means a two segment model for absorption was revealed. 3. Mean absolute bioavailability of strontium was 25% without a meal and 19% with a meal, whereas the intraindividual variation was 24% and 20%, respectively. 4. Various limited sampling absorption parameters were determined in order to select a potential test parameter for measuring intestinal calcium absorption using strontium as a marker. Fractional absorption at 4 h (Fc240), obtained after co-ingestion of strontium with a meal, appeared to be the best test parameter, because it represented bioavailability well (r = 0.90).

A blinded comparison of fluticasone propionate with budesonide via powder devices in adult patients with moderate-to-severe asthma: a clinical evaluation.

In Vitro and in vivo data have demonstrated that there are detectable differences between inhaled corticosteroids commonly used to treat asthma. However, controversy still remains as to whether these differences translate into clinical benefits. This 12-week, international, randomized, doubleblind, parallel-group study was undertaken to compare the efficacy and safety of fluticasone propionate (FP) 800 mug daily, administered as a powder via the Diskhaler((R)), and budesonide (BUD) 1600 mug daily, administered using the Turbuhaler((R)), in adult patients with moderate-tosevere asthma. A total of 518 patients participated in the study, 256 of whom received FP and 262 BUD. Assessment of mean morning peak expiratory flow (PEF) over the 12-week treatment period revealed a statistically significant difference in efficacy between FP 800 mug daily and BUD 1600 mug daily in favour of FP (p = 0.003), with an overall improvement of 20.9 l/min with FP compared with 12.4 l/min on BUD. Statistically significant differences in favour of FP were seen over the 12 weeks for mean evening PEF (p = 0.04), diurnal PEF variation (p = 0.03) and percentage predicted PEF (p = 0.003), as well as forced expiratory volume (p = 0.008), forced vital capacity (p = 0.02) and PEF (p = 0.005) measured at clinic visits. The median percentage of symptom-free nights increased over the 12-week study period in both treatment groups, with similar changes seen for the median percentage of days with symptom score < 2, rescue medication use and exacerbations of asthma. The incidence of adverse events was found to be comparable in the two treatment groups. The geometric mean ratios of serum cortisol levels were found to be 1.03 for FP, indicating no mean hypothalamic-pituitary-adrenal axis suppression from baseline, and 0.93 for BUD (p = 0.0002 compared with FP). In summary, FP 800 mug daily showed a greater efficacy/safety ratio in the treatment of moderate-to-severe asthma than BUD 1600 mug daily.

Intestinal strontium absorption: from bioavailability to validation of a simple test representative for intestinal calcium absorption.

Calcium absorption tests have rarely been validated for being representative for absolute bioavailability (true absorption) or for intraindividual variation. Therefore, we investigated the reproducibility of the absolute bioavailability of strontium chloride, a marker for intestinal calcium absorption, in healthy male volunteers (n = 8) by measuring the area under the plasma strontium concentration-time curve after oral and intravenous administration of strontium. Subsequently, we selected a simple test variable as being representative of absolute bioavailability. The mean absolute bioavailability (+/- SD) was 25% +/- 7%. The best test variable appeared to be the fractional absorption at 240 min (Fc240) after oral intake, which demonstrated the highest correlation with absolute bioavailability (r = 0.66). The intraindividual variations of the data for this variable and for the absolute bioavailability are similar to those described for various absorption tests based on the use of calcium isotopes. Thus, the Fc240 of strontium offers the potential of a simple clinical test for use as a measure of intestinal calcium absorption and its modulation.

Sensitive method for analysis of strontium in human and animal plasma by graphite furnace atomic absorption spectrophotometry.

For long-term pharmacokinetic studies in humans as well as in experimental animals, an analysis of strontium (Sr) with a low detection limit and high sensitivity is necessary. The data presented here describe the optimization of the furnace program and sample handling for measuring Sr in plasma by using graphite furnace atomic absorption spectrophotometry. The method was validated and applied to studies on the pharmacokinetics of SrCl2 in humans and rats. Calibration curves were linear up to 57.1 nmol/L. The limit of detection and lower limit of quantification were 0.21 and 0.57 nmol/L, respectively. Reciprocal sensitivity was 0.53 nmol/L Sr at A = 0.0044. The intraassay precision was 2.2%, 1.5%, and 1.1% (n = 6) at 4.57, 22.7, and 49.2 nmol/L Sr, respectively. At these concentrations, the interassay precision and recovery were 0.7%, 1.5%, and 1.8% and 100.4%, 99.1%, and 100.6% (n = 12), respectively. The endogenous Sr concentration in human plasma samples was 0.27 +/- 0.07 mumol/L (n = 18). Pharmacokinetic studies in a human volunteer and in rats demonstrated that this procedure was suited for measuring low Sr concentrations and was applicable to small sample volumes.