Effects of sub-chronic nitrate exposure on the thyroidal function in humans.

No experimental data exist on the thyroid toxicity of nitrate among humans. We aimed to show that no significant antithyroid effect could be observed after exposure to a three times the acceptable daily intake of nitrate in humans. In a randomized controlled non-inferiority trial, 10 volunteers received 15 mg/kg sodium nitrate during 28 days whereas 10 control participants received distilled water. We performed 5- and 24-h measurements of thyroidal (131)I uptake (RAIU) before and at the end of the exposure period. Thyroid hormone plasma concentrations of T3, rT3, T4, TSH were also measured prior to and after exposure. Differences in RAIU between the intervention and the control groups at 4 weeks were 3.4% (95% confidence interval -0.5 to 7.3, and 4.8% (95% confidence interval -1.4 to 11.0, respectively, for the 5- and 24-h RAIU measurement. Plasma concentrations of thyroid hormones stayed normal. In conclusion, no significant effects on thyroidal (131)I uptake and thyroid hormones plasma concentrations were observed after sub-chronic exposition to 15 mg/kg sodium nitrate among humans.

Non-professional paint stripping, model prediction and experimental validation of indoor dichloromethane levels.

We have experimentally quantified exposure to dichloromethane during non-professional paint stripping and validated the mathematical paint exposure model of van Veen et al. (1999). The model innovates the prediction of the dichloromethane evaporation rate and room concentration by accounting for transport in the paint stripper matrix. The experiments show that peak concentrations range from 600 to 1600 mg/m3, increasing to 2000 mg/m3 when direct sun radiation increases evaporation. A naive model prediction, using a priori parameter values from the experimental set-up and a previous experiment with alkanes, accurately predicts the upper range of the experimental values, but overpredicted four out of six experiments. Statistical fit of the two paint stripper layer parameters to the experimental data resulted in a good coincidence of predicted and experimental data. Model and experiment indicate that 10-30% of dichloromethane is immediately available for evaporation.

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.

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.

Bioavailability of carbamazepine from four different products and the occurrence of side effects.

The relative bioavailability of four different carbamazepine products, showing large differences in in vitro dissolution profiles, was studied in healthy volunteers to correlate the occurrence of side effects with a measure of the rate of absorption in vivo for bioequivalence testing. Two of the three generic products investigated showed bioequivalence with respect to the extent of absorption with Tegretol. In vivo, the differences found in absorption rate were reflected in the occurrence of side effects, especially dizziness. As a measure for the rate of absorption, the partial AUC did not seem to be a good characteristic to test bioequivalence, as the variability is very high and dependent on the AUC taken. The Cmax/AUCpart seems more promising, especially the partial AUC directly after completion of the absorption process. The variability is low in the case of carbamazepine after a single dose. However, as long as no consensus on the use of other metrics and the objective (clinical or quality control aspects) of bioequivalence testing is reached, and no other pharmacokinetic characteristic is validated, Cmax should be the characteristic of choice for the rate of absorption in single-dose studies with carbamazepine products.

Healthy volunteer studies in toxicology.

In the future there will be an increasing need for quantitative human risk assessment in order to develop soundly-based risk level regulations. Human volunteer studies can contribute to gain essential data needed for this risk assessment. Volunteer studies are especially relevant to study the biokinetics and metabolism of a compound. Comparison of these data with those of laboratory animals can increase the accuracy in extrapolation study results from animals to man. Furthermore, the results of volunteer studies can be used to fill in the gaps of knowledge which cannot be solved with in vitro or animal studies in order to develop adequate physiologically-based biokinetic or biodynamic models for human risk assessment.

IPV-Vero vaccine induces a strong booster reaction and is well tolerated in adults.

A phase 1-2 trial was conducted in 48 adults to study safety and immunogenicity of an inactivated poliovirus vaccine produced using Vero cells (IPV-Vero). Participants received 2 intramuscular injections with IPV-Vero (40-8-32 D-Ag units) 4 weeks apart. IPV-Vero was well tolerated, and induced strong antibody responses in all participants. At least an 8-fold titre rise against all 3 types of poliovirus was found within 1 week of the first vaccination, indicating a strong secondary response in primed individuals. Two days after the first vaccination, there was no indication for such a booster reaction. The second vaccination 4 weeks after the first dose did not further increase antibody levels, indicating that an immune plateau had been achieved after the first vaccination. The second vaccination was not reactogenic despite the presence of these high pre-vaccination antibody levels. We conclude that IPV-Vero is well tolerated and strongly immunogenic in adults. In pre-immune adults 1 dose is enough to induce an impressive booster reaction.

Host factors and environmental determinants associated with skin test reactivity and eosinophilia in a community-based population study.

We examined the relationship of host factors (age, gender) and environmental determinants (smoking status, area of residence) to indicators of allergy (skin test reactivity and eosinophil count) in a random population sample in the Netherlands. Positive skin test reactivity was associated with age (decreasing with increasing age), with male gender (versus female gender), and with urban residence (versus rural residence). Positive skin test reactivity was not associated with smoking. Elevated eosinophil counts were associated with male gender (versus female gender), with urban residence (versus rural residence), and with current smoking (versus never smoking). Elevated eosinophil counts were not clearly associated with age (if adjusted for the age-related effects of skin test reactivity). Additionally, this study specifically demonstrates that skin test reactivity increases with increasing eosinophil count and vice versa, indicating that the two traits are interrelated. Furthermore, this interrelationship was demonstrated to be age-dependent (decreasing with increasing age).

Factors associated with bronchial responsiveness to histamine in a population sample of adults.

The association of age, gender, number of eosinophils, area of residence, cigarette smoking, respiratory symptom prevalence, and FEV1 with the level of bronchial responsiveness was studied in a random sample of 2,216 subjects aged 15 to 72 yr. Subjects participated in the Dutch longitudinal study on chronic obstructive pulmonary disease. In 18 yr of follow-up, 5,012 observations were collected. Interviewers used a standardized questionnaire to assess the presence of respiratory symptoms. Bronchial responsiveness was measured by a histamine challenge test. Because multiple measurements within a subject are correlated, multivariate regression methods for correlated outcome were used. A greater number of eosinophils, skin test positivity, and living in a rural area (Vlagtwedde) were associated with increased responsiveness, independently of the level of FEV1 and the presence of respiratory symptoms. Older age was associated with increased responsiveness, and this was even more so in subjects with symptoms. Cigarette smokers were more responsive than nonsmokers, but this association was not significant if the level of FEV1 was taken into account. Hyperresponsiveness was more likely to be present if the amount of cigarettes smoked per day was greater. The level of responsiveness did not differ significantly between males and females. For the same degree of obstruction, however, expressed as the FEV1/VC ratio, males tended to be less responsive than females. The analyses were repeated using the dose-response slope as a continuous measure of responsiveness and by applying a method to adjust for censoring the responsiveness data. These analyses yielded identical results.

Relationship of skin test reactivity and eosinophilia to level of pulmonary function in a community-based population study.

We studied the relationship of skin test reactivity (sumscore greater than or equal to 3) and eosinophilia (greater than or equal to 275 cells/mm3 blood), separately and combined, to the level of FEV1 in a community cohort. We used the regression analysis technique, adjusting for age and area of residence, and stratifying by gender and cigarette smoking. Eosinophilia, among men, was associated with lower levels of FEV1 in skin test negative subjects with moderate cigarette smoking (greater than or equal to 10 pack-yr: beta = -250 ml, p = 0.02; greater than or equal to 10 pack-yr: beta = -234 ml, p less than 0.01) and in skin test positive subjects who either never smoked (beta = -228 ml, p = 0.06) or had only a brief history of smoking (beta = -428 ml, p less than 0.01). Eosinophilia, among women, was significantly associated with lower levels of FEV1 in never smokers (beta = -95 ml, p less than 0.01), especially if subjects were skin test positive as well (beta = -289 ml, p less than 0.01). Moderate cigarette smoking was uncommon in women. These data suggest an association of indices of inflammation (eosinophilia alone) and allergic inflammation (eosinophilia combined with skin test reactivity) with lower levels of FEV1, independent of the effect of cigarette smoking.

The relationship of eosinophilia and positive skin test reactivity to respiratory symptom prevalence in a community-based population study.

We studied the relationship of the prevalence of a variety of respiratory symptoms to positive skin test reactivity (skin test index greater than or equal to 3) and/or eosinophilia (greater than or equal to 275 eosinophilic cells per cubic millimeter of blood) in a community-based population sample (N = 2805), adjusting for age, gender, area of residence, and cigarette smoking. We considered subjects with neither positive skin test reactivity nor eosinophilia to be the reference group. Positive skin test reactivity without eosinophilia (N = 487; 17.3%) was significantly associated with persistent wheeze (odds ratio value (OR) = 1.6; 95% confidence interval of the odds ratio value (CI) = 1.0 to 2.6) and with asthmatic attacks (OR = 3.2; CI = 2.0 to 5.3). Positive skin test reactivity in combination with eosinophilia (N = 92; 3.3%) was also significantly associated with persistent wheeze (OR = 2.7; CI = 1.2 to 6.0) and with asthmatic attacks (OR = 10.4; CI = 5.3 to 20.2), however, with a stronger association than in subjects with positive skin test reactivity alone. Finally, eosinophilia without positive skin test reactivity (N = 170; 6.1%) was significantly associated with chronic cough (OR = 1.8; CI = 1.2 to 2.7), bronchitis episodes (OR = 2.1; CI = 1.4 to 3.2), dyspnea grade greater than or equal to III (OR = 1.7; CI = 1.0 to 2.8), and asthmatic attacks (OR = 3.0; CI = 1.5 to 6.6).(ABSTRACT TRUNCATED AT 250 WORDS)