Effect of ammonia in cigarette tobacco on nicotine absorption in human smokers.

The function of ammonia as tobacco additive is subject of scientific debate. It is argued that ammonia, by increasing the proportion of free nicotine, increases the absorption of nicotine in smokers. As a result of the addition of ammonia to cigarettes, smokers get exposed to higher internal nicotine doses and become more addicted to the product. On two occasions, the nicotine absorption in blood was measured after smoking a commercial cigarette of either brand 1 or brand 2, which differed 3.8-fold in ammonium salt content. Using a standardized smoking regime (six puffs, 30 s puff interval, 7 s breath hold before exhalation), 51 regular smokers smoked brand 1 (Caballero Smooth Flavor; 0.89 mg ammonium per gram tobacco) and brand 2 (Gauloise Brunes; 3.43 mg ammonium per gram tobacco). Puff volumes and cardiovascular parameters were monitored during and following smoking, respectively. Measurement of serum nicotine level in the blood samples collected over time following smoking of the two brands, showed that total amount of nicotine absorbed did not differ between the two brands. Present results demonstrate that smoking tobacco containing a higher amount of the tobacco additive ammonium does not increase the absorption of nicotine in the smoker's body.

Changes in serum markers indicative of health effects in vineyard workers following exposure to the fungicide mancozeb: an Italian study.

The aim of this study was to investigate the health effects induced by exposure to the fungicide mancozeb in Italian vineyard workers. Ninety-three Italian subjects entered the study - 48 vine-growers intermittently exposed to mancozeb and 45 healthy controls. The subjects were investigated three times: before the seasonal application of pesticides (T0), 30 days after the beginning of the application period (T30), and 45 days after T0 (T45). At T0 the comparison between agricultural workers and controls showed a higher prevalence of cold or flu symptoms, a statistically significant lower percentage of monocytes, higher absolute count of T lymphocytes, CD4 and natural killer cells, and lower plasma levels of IgA and IgM in workers. Such differences were not confirmed at T30 and T45. In fact at T30 in exposed workers, besides a significant increase of urinary ethylenethiourea, confirming mancozeb exposure, T lymphocytes, CD4 and natural killer cells, IgA and IgM returned to values comparable to those observed in controls. Moreover, no other differences in clinical signs, haematological, and immune parameters, such as the immune functional capability evaluated as a response to hepatitis B vaccination, was observed. Altogether the differences between exposed and controls were not consistently correlated to any clinical impairment and suggest that the seasonal application of mancozeb does not pose a significant health risk to exposed subjects.

Relation between sources of particulate air pollution and biological effect parameters in samples from four European cities: an exploratory study.

Given that there are widely different prevalence rates of respiratory allergies and asthma between the countries of Europe and that exposure to ambient particulate matter (PM) is substantial in urban environments throughout Europe, an EU project entitled "Respiratory Allergy and Inflammation Due to Ambient Particles" (RAIAP) was set up. The project focused on the role of physical and chemical composition of PM on release of cytokines of cells in vitro, on respiratory inflammation in vivo, and on adjuvant potency in allergy animal models. Coarse (2.5-10 microm) and fine (0.15-2.5 microm) particles were collected during the spring, summer and winter in Rome (I), Oslo (N), Lodz (PL), and Amsterdam (NL). Markers within the same model were often well correlated. Markers of inflammation in the in vitro and in vivo models also showed a high degree of correlation. In contrast, correlation between parameters in the different allergy models and between allergy and inflammation markers was generally poor. This suggests that various bioassays are needed to assess the potential hazard of PM. The present study also showed that by clustering chemical constituents of PM based on the overall response pattern in the bioassays, five distinct groups could be identified. The clusters of traffic, industrial combustion and/or incinerators (TICI), and combustion of black and brown coal/wood smoke (BBCW) were associated primarily with adjuvant activity for respiratory allergy, whereas clusters of crustal of material (CM) and sea spray (SS) are predominantly associated with measures for inflammation and acute toxicity. The cluster of secondary inorganic aerosol and long-range transport aerosol (SIALT) was exclusive associated with systemic allergy. The present study has shown that biological effect of PM can be linked to one or more PM emission sources and that this linkage requires a wide range of bioassays.

No adaptation to UV-induced immunosuppression and DNA damage following exposure of mice to chronic UV-exposure.

It is well known that ultraviolet (UV) radiation induces erythema, immunosuppression and carcinogenesis. We hypothesized that chronic exposure to solar UV radiation induces adaptation that eventually prevents the suppression of acquired immunity. We studied adaptation for UV-induced immunosuppression after chronic exposure of mice to a suberythemal dose of solar simulated radiation (SSR) with Cleo Natural lamps, and subsequent exposure to an immunosuppressive dose of solar or UVB radiation (TL12). After UV dosing, the mice were sensitized and challenged with either diphenylcyclopropenone (DPCP) or picryl chloride (PCl). To assess the adaptation induced by solar simulated radiation, we measured the proliferative response and cytokine production of skin-draining lymph node cells after immunization to DPCP, the contact hypersensitivity (CHS) response to PCl, and thymine-thymine (T-T) cyclobutane dimers in the skin of mice. After induction of immunosuppression by SSR or by TL12 lamps, the proliferative response of draining lymph node cells after challenge with DPCP, or the CHS after challenge with PCl, showed significant suppression of the immune response. Chronic irradiation from SSR preceding the immunosuppressive dose of UV failed to restore the suppressed immune response. Reduced lipopolysaccharide-triggered cytokine production (of IL-12p40, IFN-gamma, IL-6 and TNF-alpha) by draining lymph node cells of mice sensitized and challenged with DPCP indicated that no adaptation is induced. In addition, the mice were not protected from T-T dimer DNA damage after chronic solar irradiation. Our studies reveal no evidence that chronic exposure to low doses of SSR induces adaptation to UV-induced suppression of acquired immunity.

The effect of vitamin E supplementation on serum DHEA and neopterin levels in elderly subjects.

Contradictory results have been published on the immune-stimulating effects of vitamin E. Using a randomized placebo-controlled design, the effect of 15 month's daily supplementation with 200 mg vitamin E on two biomarkers of immunocompetence, i.e. serum DHEA sulfate ester (DHEA-S) and neopterin, was studied. Of the 100 relatively healthy Dutch elderly subjects included in the study, 50 were supplemented with vitamin E and 50 received placebo. As compared to placebo, vitamin E supplementation affected neither serum DHEA-S nor serum neopterin level. This corroborates with the finding that vitamin E supplementation did not affect infection-related severity measures, i.e. total number of days with respiratory infection, and total duration of the infections. It is concluded that vitamin E supplementation does not substantially alter the immunocompetence markers DHEA and neopterin in elderly subjects, and may explain our recently reported failure of vitamin E supplementation to afford protection against acute respiratory infections.

Measurement of exhaled nitric oxide.

Assessment of the value of exhaled NO (eNO) is an attractive tool for studying pulmonary disease, considering its wide advantages (i.e., fast analysis, noninvasive sampling, ability to measure large numbers of subjects [including children], and inexpensive in use). Increased concentrations of eNO have been observed in asthmatic patients' airway infections, allergic rhinitis, and bronchiectasis. During inflammation, specific and nonspecific stimuli elicit expression and de novo synthesis of inducible nitric oxide (iNOS). Once generated in the bronchiolar cells, NO is released from the tissue and diffuses to the lumen of the bronchiolis. Of the two sampling ways (on-line and off-line), the off-line method is suitable for monitoring environmental health effects of air pollution and for obtaining an impression of the prevalence of atopy in epidemiological surveys. For this off-line measurement, a balloon method is developed (sampling exhaled air at location) that includes a sample device assuring inflation of balloons at a controlled flow rate and back-pressure. Cigarette smoking and alcohol consumption significantly reduces NO levels in exhaled air because of downregulation of iNOS. Although eNO can be reliably measured and analyzed, the prospective value to detect asthma or allergy is rather low (low sensitivity and low specificity), which makes the diagnostic value of eNO for predicting either allergy or asthma doubtful. Promising results have, however, been observed in corticoid-sparing therapies under guidance of eNO. In addition, measurement of eNO helps to understand the mechanisms of pulmonary disease and may be useful in detecting adverse effects of air pollution.

Persistent hematologic and immunologic disturbances in 8-year-old Dutch children associated with perinatal dioxin exposure.

Perinatal exposure to Dutch "background" dioxin levels in 1990 was high, but comparable with that of other industrialized Western European countries. Exposure during the sensitive perinatal period may cause permanent disturbances. Therefore, we assessed the health status and various hematologic and immunologic parameters among our longitudinal cohort. A medical history was taken and venipuncture performed in a longitudinal cohort of 27 healthy 8-year-old children who had documented perinatal dioxin exposure. Linear regression revealed a decrease in allergy in relation to prenatal (p = 0.02) and postnatal (p = 0.03) dioxin exposure. Increases in CD4+ T-helper cells (p = 0.006) and in CD45RA+ cells (p = 0.02) were seen in relation to postnatal exposure. A persistently decreased platelet count (p = 0.04) and increased thrombopoietin concentration (p = 0.03) were seen in relation to postnatal exposure. This follow-up has shown a decrease in allergy, persistently decreased thrombocytes, increased thrombopoietin, and increased CD4+ T-helper and increased CD45RA+ cell counts. This study provides indications of effects at the stem cell level of perinatal dioxin exposure, persisting until minimally 8 years after birth.

Testing therapeutic potency of anticancer drugs in animal studies: a commentary.

Regulatory authorities for medicines in European countries deal with many applications for admission to the market of anticancer drugs. Each application must be supported by preclinical and clinical data, among which testing of the therapeutic activity of drugs in animals is important. Recently, the Committee for Proprietary Medicinal Products (CPMP) has released a note for guidance on the preclinical evaluation of anticancer medicinal products. This note provides only general statements regarding tests of anticancer drugs in rodents. This stimulates considerations on how to organize and how to evaluate these tests. In this article we describe our considerations regarding these items based on our experience with applications in The Netherlands since 1993.