A Opperhuizen

Maastricht University, Maestricht, Limburg, Netherlands

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Publications (57)102.03 Total impact

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    ABSTRACT: Tobacco smoke consists of thousands of harmful components. A major class of chemicals found in tobacco smoke is formed by aldehydes, in particular formaldehyde, acetaldehyde and acrolein. The present study investigates the gene expression changes in human lung alveolar epithelial cells upon exposure to formaldehyde, acrolein and acetaldehyde at sub-cytotoxic levels. We exposed A549 cells in vitro to aldehydes and non-aldehyde chemicals (nicotine, hydroquinone and 2,5-dimethylfuran) present in tobacco smoke and used microarrays to obtain a global view of the transcriptomic responses. We compared responses of the individual aldehydes with that of the non-aldehydes. We also studied the response of the aldehydes when present in a mixture at relative concentrations as present in cigarette smoke. Formaldehyde gave the strongest response; a total of 66 genes were more than 1.5-fold differentially expressed mostly involved in apoptosis and DNA damage related processes, followed by acetaldehyde (57 genes), hydroquinone (55 genes) and nicotine (8 genes). For acrolein and the mixture only one gene was upregulated involved in oxidative stress. No gene expression effect was found for exposure to 2,5-dimethylfuran. Overall, aldehyde responses are primarily indicative for genotoxicity and oxidative stress. These two toxicity mechanisms are linked to respiratory diseases such as cancer and COPD, respectively. The present findings could be important in providing further understanding of the role of aldehydes emitted from cigarette smoke in the onset of pulmonary diseases.
    Toxicology in Vitro 02/2013; · 2.65 Impact Factor
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    ABSTRACT: 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.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 12/2011; 49(12):3025-30. · 2.99 Impact Factor
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    ABSTRACT: Tobacco smoke is a toxic and carcinogenic mixture of more than 5,000 chemicals. The present article provides a list of 98 hazardous smoke components, based on an extensive literature search for known smoke components and their human health inhalation risks. An electronic database of smoke components containing more than 2,200 entries was generated. Emission levels in mainstream smoke have been found for 542 of the components and a human inhalation risk value for 98 components. As components with potential carcinogenic, cardiovascular and respiratory effects have been included, the three major smoke-related causes of death are all covered by the list. Given that the currently used Hoffmann list of hazardous smoke components is based on data from the 1990s and only includes carcinogens, it is recommended that the current list of 98 hazardous components is used for regulatory purposes instead. To enable risk assessment of components not covered by this list, thresholds of toxicological concern (TTC) have been established from the inhalation risk values found: 0.0018 μg day(-1) for all risks, and 1.2 μg day(-1) for all risks excluding carcinogenicity, the latter being similar to previously reported inhalation TTCs.
    International Journal of Environmental Research and Public Health 02/2011; 8(2):613-28. · 2.00 Impact Factor
  • Jan van Amsterdam, Antoon Opperhuizen, Wim van den Brink
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    ABSTRACT: In 2007, the Minister of Health of the Netherlands requested the CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of magic mushrooms. The present paper is an updated redraft of the review, written to support the assessment by CAM experts. It summarizes the literature on physical or psychological dependence, acute and chronic toxicity, risk for public health and criminal aspects related to the consumption of magic mushrooms. In the Netherlands, the prevalence of magic mushroom use was declining since 2000 (last year prevalence of 6.3% in 2000 to 2.9% in 2005), and further declined after possession and use became illegal in December 2008. The CAM concluded that the physical and psychological dependence potential of magic mushrooms was low, that acute toxicity was moderate, chronic toxicity low and public health and criminal aspects negligible. The combined use of mushrooms and alcohol and the quality of the setting in which magic mushrooms are used deserve, however, attention. In conclusion, the use of magic mushrooms is relatively safe as only few and relatively mild adverse effects have been reported. The low prevalent but unpredictable provocation of panic attacks and flash-backs remain, however, a point of concern.
    Regulatory Toxicology and Pharmacology 01/2011; 59(3):423-9. · 2.13 Impact Factor
  • Jan van Amsterdam, Antoon Opperhuizen, Fred Hartgens
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    ABSTRACT: Anabolic-androgenic steroids (AAS) are synthetic drugs derived from testosterone. Illegally, these drugs are regularly self-administered by body builders and power lifters to enhance their sportive performance. Adverse side effects of AAS include sexual dysfunction, alterations of the cardiovascular system, psyche and behavior, and liver toxicity. However, severe side effects appear only following prolonged use of AAS at high dose and their occurrence is limited. Occasionally, AAS abuse may be linked to certain social and psychological traits of the user, like low self-esteem, low self-confidence, suffered hostility, childhood conduct disorder, and tendency to high-risk behavior. The overwhelming stereotype about AAS is that these compounds cause aggressive behavior in males. However, the underlying personality traits of a specific subgroup of the AAS abusers, who show aggression and hostility, may be relevant, as well. Use of AAS in combination with alcohol largely increases the risk of violence and aggression. The dependence liability of AAS is very low, and withdrawal effects are relatively mild. Based on the scores for acute and chronic adverse health effects, the prevalence of use, social harm and criminality, AAS were ranked among 19 illicit drugs as a group of drugs with a relatively low harm.
    Regulatory Toxicology and Pharmacology 02/2010; 57(1):117-23. · 2.13 Impact Factor
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    ABSTRACT: Drug policy makers continuously face a changing pattern of drug use, i.e. new drugs appear on the market, the popularity of certain drugs changes or drugs are used in another way or another combination. For legislative purposes, drugs have mostly been classified according to their addictive potency. Such classifications, however, lack a scientific basis. The present study describes the results of a risk assessment study where 19 recreational drugs (17 illicit drugs plus alcohol and tobacco) used in the Netherlands have been ranked by a Dutch expert panel according to their harm based on the scientific state of the art. The study applies a similar approach as recently applied by Nutt et al. [Lancet 2007;369:1047-1053], so that the results of both studies could be compared. The harm indicators scored are acute and chronic toxicity, addictive potency and social harm. The aim of this study is to evaluate whether the legal classification of drugs in the Netherlands corresponds with the ranking of the drugs according to their science-based ranking of harm. Based on the results, recommendations are formulated about the legal classification of recreational drugs at national and international level which serves a rational approach for drug control.
    European Addiction Research 01/2010; 16(4):202-7. · 2.36 Impact Factor
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  • Toxicology Letters 10/2008; · 3.15 Impact Factor
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    ABSTRACT: In preparing a decision about the legal status of khat in the Netherlands, the Dutch Minister of Health requested CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of khat in the Netherlands. The present paper is a redraft of a report which formed the scientific basis of the risk evaluation procedure (October 2007). This report reviews the scientific data about khat available in the international literature. In addition, the report contains some information specific for the Netherlands (prevalence, availability of khat and public order aspects). The main psychoactive compounds in khat leaves are cathine and cathinone, which are some 2- to 10-fold less active than amphetamine. Acute health problems are rarely seen, and are usually related with malnutrition, social and financial problems. Khat has a low addictive potential. Chronic toxicity of khat is modest when used in low amounts, whereas at high levels, khat use is associated with adverse effects, like hypertension, heart rhythm disorders, insomnia and loss of appetite. In addition, khat users show a higher prevalence of cancers in the digestive tract. At population level, khat does not lead to specific health risks in the Netherlands, as its use is confined to East-African immigrants. A relationship between khat use and psychiatric disorders has been suggested, but the reports are contradictory, and such studies are presumably heavily confounded by posttraumatic and social stress. In the Netherlands (and other countries), khat use occasionally leads to minor disturbance of civil order in the public domain (loud talking, spitting), but is not related to criminal activities. Following the assessment, CAM estimated the overall risk potential of khat use in the Netherlands as very low. A similar conclusion may be drawn for countries with a comparable prevalence of khat use and khat related public order disturbance.
    Regulatory Toxicology and Pharmacology 09/2008; 52(3):199-207. · 2.13 Impact Factor
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    ABSTRACT: Decabromodiphenyl ether (decaBDE) is a widely used brominated flame retardant, considered to be of low toxicity. However, previous toxicity studies applied exposure methods with low bioavailability of this compound, and the actual hazard of decaBDE for humans, which are environmentally exposed to decaBDE, may thus be underestimated in current risk assessments. The present 28 days oral toxicity study in Wistar rats was designed to facilitate detection of endocrine and immune modulating effects of decaBDE using an exposure protocol with improved bioavailability. A technical preparation of high purity decaBDE was thus tested by daily exposure through gavage with an emulsion of soy phospholipon/lutrol as a carrier. Most sensitive effect in males were increased weight of seminal vesicle/coagulation gland with BMDL of 0.2mg/kg bw/day and increased expression of hepatic CYP1A and CYP2B (BMDLs 0.5-0.7 mg/kg bw/day). In females the most sensitive effect was decreased activity of P450c17 (CYP17), which is a key enzyme in the androgen synthesis pathway, in adrenals (BMDL 0.18 mg/kg bw/day). These results suggest that decaBDE may represent an as yet unreported hazard for reproductive health.
    Toxicology Letters 07/2008; 179(1):6-14. · 3.15 Impact Factor
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    Tobacco control 05/2008; 17(2):132-41. · 3.85 Impact Factor
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    ABSTRACT: We investigated whether inhaling peak concentrations of aldehydes several times daily is more damaging than semi-continuously inhaling low-dose aldehydes. We exposed Xpa-/-p53+/- knock-out mice either intermittently or semi-continuously to mixed acetaldehyde, formaldehyde, and acrolein. The intermittent regimen entailed exposure to the aldehydes 7 min every 45 min, 12 times/day, 5 days/week, corresponding to concentrations inhaled by smokers. Semi-continuously exposed animals received half the dose of aldehydes in 8h/day, 5 days/week. Some mice in each group were sacrificed after 13 weeks of exposure; the rest breathed clean air until the end of 1 year. Mice injected intratracheally with benzo[a]pyrene formed a positive control group. The nasal cavity, lungs, and any macroscopically abnormal organs of all mice were analysed histopathologically. After 13 weeks of exposure, the subacute, overall, histopathological changes induced by the inhalation differed noticeably between the intermittently and semi-continuously treated Xpa-/-p53+/- knock-out mice. After 13 weeks of mixed aldehyde exposure, atrophy of the olfactory epithelium generally appeared, but disappeared after 1 year (adaptation and/or recovery). Respiratory epithelial metaplasia of the olfactory epithelium occurred at a higher incidence at 1 year. Except for a significantly greater number of tumours observed in knock-out mice compared to wild mice (semi-continuous aldehyde exposure and controls), no differences between the semi-continuous and intermittent exposure groups were observed.
    Food and Chemical Toxicology 03/2008; 46(2):527-36. · 3.01 Impact Factor
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    ABSTRACT: This review evaluates the presumed contribution of acetaldehyde to tobacco smoke addiction. In rodents, acetaldehyde induces reinforcing effects, and acts in concert with nicotine. Harman and salsolinol, condensation products of acetaldehyde and biogenic amines, may be responsible for the observed reinforcing effect of acetaldehyde. Harman and salsolinol inhibit monoamine oxidase (MAO), and some MAO-inhibitors are known to increase nicotine self-administration and maintain behavioural sensitization to nicotine. Harman is formed in cigarette smoke, and blood harman levels appear to be 2-10 times higher compared to non-smokers. Since harman readily passes the blood-brain barrier and has sufficient MAO-inhibiting potency, it may contribute to the lower MAO-activity observed in the brain of smokers. In contrast, the minor amounts of salsolinol that can be formed in vivo most likely do not contribute to tobacco addiction. Thus, acetaldehyde may increase the addictive potential of tobacco products via the formation of acetaldehyde-biogenic amine adducts in cigarette smoke and/or in vivo, but further research is necessary to substantiate this hypothesis.
    European Neuropsychopharmacology 11/2007; 17(10):627-36. · 4.60 Impact Factor
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    ABSTRACT: Sugars are natural tobacco components, and are also frequently added to tobacco during the manufacturing process. This review describes the fate of sugars during tobacco smoking, in particular the effect of tobacco sugars on mainstream smoke composition. In natural tobacco, sugars can be present in levels up to 20 wt%. In addition, various sugars are added in tobacco manufacturing in amounts up to 4 wt% per sugar. The added sugars are usually reported to serve as flavour/casing and humectant. However, sugars also promote tobacco smoking, because they generate acids that neutralize the harsh taste and throat impact of tobacco smoke. Moreover, the sweet taste and the agreeable smell of caramelized sugar flavors are appreciated in particular by starting adolescent smokers. Finally, sugars generate acetaldehyde, which has addictive properties and acts synergistically with nicotine in rodents. Apart from these consumption-enhancing pyrolysis products, many toxic (including carcinogenic) smoke compounds are generated from sugars. In particular, sugars increase the level of formaldehyde, acetaldehyde, acetone, acrolein, and 2-furfural in tobacco smoke. It is concluded that sugars in tobacco significantly contribute to the adverse health effects of tobacco smoking.
    Food and Chemical Toxicology 12/2006; 44(11):1789-98. · 3.01 Impact Factor
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    ABSTRACT: Whole-body PET-scan studies in brains of tobacco smokers have shown a decrease in monoamine oxidase (MAO) activity, which reverts to control level when they quit smoking. The observed decrease in MAO activity in smokers is presumably due to their exposure to tobacco constituents that possess MAO-inhibiting properties. The inhibition of MAO activity seems, however, not to be a unique feature of tobacco smoking as subjects with Type II alcoholism have been reported to show a similar decrease in MAO activity that reverses when they cease to use alcohol. The present review summarizes the data on MAO-inhibiting tobacco constituents and explains that the decrease in MAO activity observed in alcoholics is probably due to concomitant tobacco use. It is concluded that the inhibition of MAO by constituents contained in tobacco and tobacco smoke, enhances the addiction induced by tobacco smoking.
    Life Sciences 11/2006; 79(21):1969-73. · 2.56 Impact Factor
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    ABSTRACT: The tobacco industry publicly contends that ammonia compounds are solely used as tobacco additive for purposes of tobacco flavoring, process conditioning and reduction of its subjective harshness and irritation. However, neither objective scientific reports, nor the contents of a large number of internal tobacco company documents support this contention. The present review focuses on the hypothesis that addition of ammonium compounds to tobacco enhances global tobacco use due to smoke alkalization and enhanced free-nicotine nicotine exposure. Obviously, ammonia enhances the alkalinity of tobacco smoke. Consequently, the equilibrium shifts from non-volatile nicotine salts to the volatile free base that is more readily absorbed from the airways. The observed change in the kinetics of nicotine (i.e., shorter t(1/2) and higher c(max)) after ammoniation is, however, predominantly due to the higher concentration of nicotine in the smoke, rather than to an increase in the absorption rate of free-base nicotine in the respiratory tract. Although several findings support the hypothesis, additional studies are required and suggested to provide a proper, objective and independent scientific judgment about the effect of tobacco ammoniation on nicotine bioavailability. Scientific and public awareness of the effects of tobacco-specific ammonia compounds may stimulate global control, legislation and restriction of their use in cigarette manufacture.
    Food and Chemical Toxicology 06/2006; 44(5):678-88. · 3.01 Impact Factor
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    ABSTRACT: Overweight and obesity lead to higher morbidity risks, which are alleviated even by mild weight loss. To gain insight in the molecular effects of weight loss in adipose tissue, we analyzed the effects of short-term dietary restriction (DR) on mice fed a low-fat diet (lean mice) or a high-fat diet (obese mice). Female C57Bl6/J mice on both diets were on DR until an average body weight loss of 20% , which was achieved in 8 to 12 days depending on body weight at the start of DR. Plasma free fatty acids and blood glucose levels decreased significantly on DR. In the (restricted) low-fat diet groups, gene expression analysis using adipose-enriched cDNA microarrays revealed only two transcripts to be significant differentially expressed by DR: up-regulation of malic enzyme (Mod1) and down-regulation of major urinary protein 1 (Mup1). Real-time polymerase chain reaction analysis confirmed these findings and showed, for the high-fat diet groups, an identical expression pattern for Mup1, whereas Mod1 showed an opposed gene expression pattern for the high-fat diet groups. In conclusion, initial weight loss induces transcriptional changes only in a very small number of adipose genes, which also depends on the (restricted) diet used.Keywords: microarray, caloric restriction, adipocyte, overweight
    Obesity 05/2006; 14(6):974-979. · 3.92 Impact Factor
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    ABSTRACT: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) have been associated with increased rates of tobacco usage as well as with dysregulations of the hypothalamus-pituitary-adrenal (HPA) axis. At the same time tobacco also affects the HPA axis. This paper examines the relationships between PTSD, posttraumatic MDD, smoking and levels of circadian cortisol 2-3 years postdisaster. Subjects were survivors of the Enschede fireworks disaster. The sample consisted of 38 healthy survivors, 40 subjects with PTSD, and 17 subjects with posttraumatic MDD. The Composite International Diagnostic Interview was used to determine mental disorders in accordance with DSM-IV criteria. Salivary cortisol samples were collected at home immediately upon awakening, 30 min after awakening, at noon, and at 10 p.m. Quantity of smoking was measured through self-report. The results of the study show that salivary cortisol concentrations were higher in smoking subjects. Survivors with MDD following the disaster had a flatter diurnal cortisol curve than subjects with PTSD or healthy survivors. In survivors with PTSD and healthy individuals the usual dynamic pattern of increase in cortisol past awakening was present, while we did not observe this in posttraumatic MDD. These survivors with MDD tended to use more tobacco per day, and the cortisol group differences could only be revealed when we adjusted for quantity of smoking. Smoking, which may be an important palliative coping style in dealing with posttraumatic arousal symptoms, seems to mediate the relationship between traumatic stress and the HPA-axis.
    International Journal of Psychophysiology 04/2006; 59(3):251-8. · 2.04 Impact Factor
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    ABSTRACT: 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.
    International Journal for Vitamin and Nutrition Research 10/2005; 75(5):327-31. · 1.27 Impact Factor
  • I Kooter, J Pennings, A Opperhuizen, F Cassee
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    ABSTRACT: Epidemiological studies show associations of short-term exposure to particulate matter with morbidity and mortality. Although many studies investigate the health effects of ambient particulate matter, the associated mechanisms, and the causality, they often focus on classical parameters. The objective of the present study was to gain insight into the roles of a wide range of genes in this process. Particular attention has been paid to immediate oxidative stress in the lung. We isolated total lung RNA from spontaneously hypertensive male rats 2-40 h after exposure to reference EHC-93 (10 mg/kg). Our results show that exposure to particulate matter generates a time-dependent pattern of gene expression. From the 8799 genes or expressed sequence tags tested, we see that 132 genes were up- or downregulated shortly after exposure (i.e., 2-6 h), whereas after 15-21 h and 24-40 h, 46 and 56 genes showed altered expression, respectively. Focusing on the earliest point, 99 of the 132 genes were identified as unique. They include genes involved in an oxidative stress response (hemeoxygenase-1, metallothioneins, and thioredoxin reductase), an inflammatory response macrophage inflammatory protein-2, and tumor necrosis factor alpha), transcription factors belonging to the activating protein-1 family, and genes involved in cardiovascular functions. The present study, although not representing an ambient situation, is used to identify the biological pathways implicated in the initial injury response to PM exposure. Using Affymetrix chips, this study shows time-dependent gene expression, it identifies many genes that can be affected by exposure to particulate matter, and it confirms the involvement of oxidative stress in particulate-matter-related effects.
    Inhalation Toxicology 02/2005; 17(1):53-65. · 1.89 Impact Factor