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.

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).

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.

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.

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.

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.

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.

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)