Stefan Willers

Urinary cotinine in children and adults during and after semiexperimental exposure to environmental tobacco smoke

Urinary cotinine (U-cotinine) as a biomarker of environmental tobacco smoke exposure was evaluated in 14 children (age 4-11 y) and in 7 adults who were exposed to environmental tobacco smoke at an air nicotine level of 110 mg/m3 for 2 h in a bus. Nicotine in air and U-cotinine were measured by gas chromatography/mass spectrometry before, during, and after the experiment. U-cotinine rose rapidly to a maximum after a median of 6 h following the end of exposure; remained at an apparent plateau for half a day; and then decreased exponentially, with a mean half-time of 19 h (95% confidence interval 18-20 h; no significant difference between children and adults). The maximum U-cotinine was higher in the children (mean = 22 mg/l) than in the adults (13 mg/l; p = .005); decreased with age among the children (r = -.74; p = .002); and increased as the estimated inhaled nicotine dose increased. Therefore, the findings of the present study showed that young children had higher U-cotinine than adults at the same experimental environmental tobacco smoke exposure, probably because they had a higher relative nicotine dose because of a higher relative ventilation rate, and possibly also because of metabolic differences; the elimination rate did not differ. The long half-time makes U-cotinine a good biomarker of environmental tobacco smoke exposure; the time of sampling is not very critical. Dilution-adjusted concentrations should be employed, and in children, preferably by density correction. A certain urinary cotinine level indicates a lower environmental tobacco smoke exposure in a small child than in an adult.

Exposure to Environmental Tobacco Smoke in the Household and Urinary Cotinine Excretion, Heavy Metals Retention, and Lung Function

The relationship between urinary levels of cotinine (U-cotinine) and arsenic (U-As), blood levels of cadmium (B-Cd), blood levels of lead (B-Pb), lung function, and questionnaire data on smoking habits were studied in 107 parents and their 46 children (7-10 y of age). There was a statistically significant relationship between the reported amount of tobacco smoked and U-cotinine levels. Nonsmokers who were married to persons who smoked had three times higher U-cotinine levels than nonsmokers whose spouses did not smoke. There was a significant association between the number of parents who smoked in the family and the U-cotinine levels of children. If only one parent smoked, maternal smoking was of greater importance than paternal smoking. There was also an association between U-cotinine and B-Cd. A study of lung function in the children revealed that vital capacity and functional residual capacity (corrected for sex, age, and height) increased as the number of parents who smoked increased. Therefore, the present study showed that (1) U-cotinine was a useful index of active smoking and environmental tobacco smoke exposure in adults and children, (2) U-cotinine was associated with the blood concentration of cadmium, and (3) environmental tobacco smoke exposure was associated with changes in lung function of children.

Assessment of environmental tobacco smoke exposure in children with asthmatic symptoms by questionnaire and cotinine concentrations in plasma, saliva, and urine

To validate a detailed questionnaire for assessment of environmental tobacco smoke (ETS) exposure by the biomarker cotinine in various media, a population-based study in the urban area of Malmö, Sweden was performed in children aged 8-13 years with and without asthmatic symptoms. There were strong correlations between urinary and saliva cotinine concentrations and also, though to a lesser extent, between these media and plasma. Even a detailed questionnaire gave only a rough picture of the ETS exposure, as indicated by the biomarkers. In a multivariate model, the most significant questionnaire-derived predictor of the cotinine levels was the maternal smoking habits; other questionnaire variables gave only a minimal explained variance. Children with a history of asthmatic symptoms had statistically significantly lower median cotinine levels in urine and saliva compared to referent children, most likely because of the antismoking information to their parents. This should be considered in epidemiological studies of ETS risks.

Passive smoking and childhood asthma. Urinary cotinine levels in children with asthma and in referents

Passive exposure to tobacco smoke was assessed in children with asthma (age 3‐15) and in referents. There was statistically significantly (P < 0.0005) higher excretion of the nicotine metabolite, cotinine, in the urine of 49 children with asthma (geometric mean 10 ng/ml) compared with 77 referents (4.8 ng/ml). Maternal smoking was statistically significantly more prevalent among the asthmatics than among the referents (relative risk = RR = 2.6, 95% Cl = 1.2‐5.3). In conclusion, the exposure to environmental tobacco smoke in asthmatic children was higher than among healthy children, indicating that passive smoking may be a predisposing and/or aggravating factor for childhood asthma.

Determination of cotinine in urine using glass capillary gas chromatography and selective detection, with special reference to the biological monitoring of passive smoking

A capillary gas chromatographic (GC) method using selected-ion monitoring (SIM) was developed for the analysis of cotinine (C.A.S. No. 486-56-6) in human urine. The method is based on basic extraction of cotinine from 2 ml of urine into dichloromethane. After evaporation of the dichloromethane solution to dryness, 100 microliters of toluene were added, prior to GC-mass spectrometric (MS) analysis. Trideuterated cotinine (C.A.S. No. 97664-65-8) was used as the internal standard. More than 1000 automatic chromatographic analyses were made without column degradation. Molecular ions (M) of cotinine and trideuterated cotinine, (m/e = 176 and 179), were monitored in the electron impact (EI) mode and m/e = 177 (M + 1) and m/e = 180 (M + 1) in the chemical ionization (CI) mode with isobutane. The correlation coefficient with SIM and EI was 0.998 (5-20 ng/ml) and with CI was (0.2-2 ng/ml). For thermionic specific detection the correlation coefficient was 0.998 (10-510 ng/ml). Only capillary columns with an apolar bonded stationary phase film thickness of 1 micron showed sufficient inertness for cotinine analysis at the sub ng/ml level. The relative standard deviations for 5 and 20 ng/ml were 5.2 and 3.5% respectively (n = 12) using EI. Spiked urine samples from six non-smokers (5 ng/ml) showed a relative standard deviation of 5%. The overall recovery (25 ng/ml) was 100 +/- 4%. The minimum detectable concentration, using SIM, was ca. 2 ng/ml in the EI mode and ca. 0.2 ng/ml in the CI mode. The half-time for cotinine was ca. 18 h for both active smokers and non-smokers.

Varenicline as compared to bupropion in smoking-cessation therapy--cost-utility results for Sweden 2003.

STUDY OBJECTIVES To calculate incremental cost-utility ratios (cost per QALY gained) for varenicline (Champix; Pfizer), as compared to bupropion, in smoking-cessation programmes for a lifetime follow-up period. DESIGN The Benefits of Smoking Cessation on Outcomes (BENESCO) simulation model was used for a male and female cohort, respectively, as a point of departure but further extended in order to include the indirect effects of smoking-cessation on production and consumption in the economy. All calculations were performed in 2003 Swedish prices. SETTING Sweden in 2003. PATIENTS OR PARTICIPANTS Model cohort consisting of 25% of all smokers among men and women (168,844 males and 208,737 females), distributed by age, 18 and older, as in the Swedish population of 2003. INTERVENTIONS Varenicline as compared to bupropion, in smoking-cessation programmes for 20-year, 50-year, and lifetime follow-up periods. MEASUREMENTS AND RESULTS When the indirect effects on production and consumption were included, the incremental costs per QALY gained were euro2056 (euro14,743) for men and euro1193 (euro14,214) for women, in comparison to bupropion and computed for a time horizon of 20 and 50 years (1euro approximately euroSEK9.12). Excluding the indirect effects on production and consumption, varenicline was cost-saving in comparison to bupropion. Sensitivity analysis indicated that the results are robust. Variation of treatment efficiency and intervention costs, respectively, had a larger effect on cost per QALY gained than other variables. CONCLUSIONS Estimated costs per QALY gained rated smoking-cessation intervention using varenicline among the most cost-effective life-saving medical treatments.

Environmental exposure to lead and arsenic among children living near a glassworks

Concentrations of lead (Pb) in blood (B-Pb, geometric mean 34.6 micrograms l-1, n = 127) and inorganic arsenic (As) and its metabolites in urine (U-As, mean 5.1 micrograms/g creatinine, n = 35) did not differ between children living in a village close to a glassworks emitting both Pb and As and children living in a reference area. There was no significant effect on B-Pb and U-As related to parents working at the glassworks or consumption of domestically grown vegetables. Neither was there any significant effect upon B-Pb of sex, age, potentially lead-exposing hobbies, or consumption of canned foods. Boys had higher U-As than girls (5.8 vs 4.2 micrograms/g creatinine, p = 0.005), and there was a decrease with age (range 8.4-10.4 years, 27% per year, p = 0.01). Further, parental smoking habits had a significant effect on both B-Pb and U-As. In children of non-smoking parents the B-Pb was 30 micrograms l-1, in children with one parent who smoked 39 micrograms l-1 (smoking father 37, smoking mother 41 micrograms l-1) and in children with two parents who smoked 47 micrograms l-1 (p less than 0.001). The corresponding values for U-As were 4.2, 5.5, and 13 micrograms/g creatinine, respectively (p = 0.01).

Development of allergy to laboratory animals is associated with particular Gm and HLA genes

To find out whether IgG genes are involved in atopy we studied 26 of 101 laboratory technicians who had developed laboratory animal allergy (LAA). The genes for the constant region of the heavy chains of IgG subclasses were analyzed by serum Gm allotypes, representing products on allelic level of the IGHCG1, IGHCG2 and IGHCG3 on chromosome 14q32. There was a significantly increased frequency of the GM(f,f;n,n;b,b) genotype (57.7 instead of 22.3%, p < 0.001) representing IgG1, IgG2 and IgG3 molecules and in particular increased frequency of Gm genotypes with the homozygous expression of G2m (n,n) (69.2 instead of 27.4%, p < 0.001) and of the Gm(f,n,b) haplotype (75 instead of 44.8%, p < 0.001) compared to a normal Caucasian population. An increased HLA-DR4 content of the LAA group (61.5 instead of 33.7%, p < 0.01) was further investigated for Gm allotypes. Among 16 HLA-DR4 LAA individuals, the Gm(f,f;n,n;b,b) genotype (56.3 instead of 22.3%, p < 0.01) and the Gm genotypes with the homozygous expression G2m(n,n) (62.6 instead of 27.4%, p < 0.01) dominated. However, the HLA-DR4 frequency among Gm(f,f;n,n;b,b) of LAA patients did not deviate from the frequency of healthy individuals of the same Gm genotype. The increased frequency of HLA-DR4 antigen in LAA patients might be due to its association to the Gm(f,f;n,n;b,b) genotype. This study supports the following concept: the susceptibility of developing LAA is associated with Gm allotypes Glm(f) expressed from IGHCG1, G2m(n) from IGHCG2 and G3m(b) from IGHCG3 on both alleles situated close to IGHCE on chromosome 14q32. The association of LAA to Gm allotypes [Gm(f,f;n,n;b,b)] expressed from chromosome 14q32 and of HLA class II antigens (HLA-DR4) expressed from chromosome 6p21.3 further confirms the polygenic inheritance of the immune response in atopy.

Cadmium and Lead Levels in House Dust from Smokers' and Non-Smokers' Homes Related to Nicotine Levels

In children there is an association between environmental tobacco smoke exposure and blood lead levels. One possible explanation is a contamination of house dust by cigarette ash and smoke, since several studies have shown that house dust is a source of lead exposure. Thus, house dust samples from the vacuum cleaner sacks from 72 homes in the city of Copenhagen were ana lysed for cadmium (Cd) and lead (Pb). The lead concentration was higher in fine than in coarse fraction (medians 190 vs. 140 μg/g; p = 0.0001). For cad mium the median concentrations were 5.0 μg/g in both fractions. No statisti cally significant association was found between the smoking habits, the socio- economic status of the residents, the presence of wall-to-wall carpets, or dust nicotine levels, on the one hand, and the metal levels in the house dust, on the other. Thus, tobacco is not an important source of contamination of house dust with lead and cadmium. However, high levels found in some samples indicate that house dust may be a significant source of lead and cadmium exposure, in some small children.

Sensitization to Laboratory Animals and Small-Airway Hyperreactivity

Fifty-six laboratory-animal workers were investigated regarding allergy and lung function. Thirty percent had at least one positive skin prick test against laboratory animals. RAST® test was positive in 25 %. Thirty-two percent had laboratory-animal allergy (LAA; rhinoconjunctivitis and/or asthma). Associa tion with an increased risk for LAA was found for atopy, as indicated by a family history of allergy, positive skin prick test against nonlaboratory envi ronmental allergens, positive Phadiatop®, and increased levels of serum IgE. The entire group of laboratory workers did not significantly differ from a ref erence group in airway reactivity. However, subgrouping of the workers showed that sensitized cases had significantly increased levels of volume of trapped gas (VTG), a measure of the small-airway function, after pulmonary provocation with methacholine at a concentration of 0.1 %, as compared to both a reference group and nonsensitized workers. Thus, animal allergen sen sitization was found to be associated with small-airway hyperreactivity. Also, a positive Phadiatop was associated with increased levels of VTG.