39 results on '"Hakkert BC"'
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2. Bisphenol A : Part 2. Recommendations for risk management
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ICH, M&V, Bakker J, Hakkert BC, Hessel EVS, Luit RJ, Piersma AH, Sijm DTHM, Rietveld AG, van Broekhuizen FA, van Loveren H, Verhoeven JK, ICH, M&V, Bakker J, Hakkert BC, Hessel EVS, Luit RJ, Piersma AH, Sijm DTHM, Rietveld AG, van Broekhuizen FA, van Loveren H, and Verhoeven JK
- Abstract
RIVM rapport:In 2014 en 2015 zijn de Europese normen voor een veilige blootstelling aan Bisfenol A (BPA) van werknemers en consumenten aangescherpt. Het RIVM concludeert dat nieuwe inzichten voldoende aanleiding vormen om verdere aanscherping van de normen te overwegen en stelt voor op korte termijn aanvullende maatregelen te treffen die de blootstelling aan BPA verder verminderen. Bisfenol A (BPA) is een stof die in veel producten zit, zoals kassabonnen, bouwmaterialen (verf en coatings), verpakkingsmateriaal van voedsel, speelgoed en medische hulpmiddelen. BPA is bij een te hoge blootstelling schadelijk voor de vruchtbaarheid en kan effect op het hormoonsysteem hebben. Nieuwe studies laten zien dat BPA het immuunsysteem van de ongeboren vrucht of jonge kinderen kan schaden bij een lager blootstellingsniveau dan het niveau waarop de huidige normen zijn gebaseerd. Dit lagere blootstellingsniveau is van ongeveer dezelfde grootte als de dagelijkse blootstelling van consumenten en werknemers aan BPA. Als gevolg van deze blootstelling hebben mensen mogelijk meer kans om voedselintoleranties te ontwikkelen en kunnen ze gevoeliger voor infectieziekten worden. Op basis van deze nieuwe inzichten wordt de rijksoverheid geadviseerd waar mogelijk op korte termijn de blootstelling aan BPA te verminderen. De bescherming van kleine kinderen, zwangeren en vrouwen die borstvoeding geven verdient hierbij bijzondere aandacht. Kleine en ongeboren kinderen zijn namelijk gevoeliger dan volwassenen voor de effecten van BPA doordat hun lichaam sterk in ontwikkeling is. De blootstelling kan bijvoorbeeld worden verminderd door veilige alternatieven te ontwikkelen, of ervoor te zorgen dat er minder BPA vrijkomt uit producten waar deze stof in wordt gebruikt. Daarnaast kunnen werknemers tegen blootstelling aan BPA worden beschermd. Een lagere blootstelling is ook van belang voor dieren in waterbodems, die nadelige effecten ondervinden bij de huidige BPA-concentratie- niveaus., More stringent European standards for safe exposure of workers and consumers to bisphenol A (BPA) were proposed in 2014 and 2015. The Dutch National Institute for Public Health and the Environment (RIVM) has concluded that new insights sufficiently warrant consideration of even more stringent standards and has recommended taking supplementary measures in the near future for a further reduction of BPA exposure. Bisphenol A (BPA) is a substance that occurs in numerous products, such as cash register receipts, building materials (paint and coatings), food packaging materials, toys and medical devices. Excessive BPA exposure is harmful to fertility and can affect the hormone system. New studies show that BPA can impair the immune system of unborn and young children at a lower exposure level than the one on which the current standards are based. This lower level is roughly comparable to the current every day BPA exposure level of workers and consumers. As a result of this exposure, people could have a greater probability of developing food intolerances and could become more susceptible to infectious diseases. Based on these new insights RIVM advises the national government to reduce BPA exposure in the short term wherever possible. Special attention needs to be devoted to protecting small children, pregnant women and women who breastfeed. This is because developing unborn and young children are more sensitive than adults to the effects of BPA. Ways to reduce exposure include developing safe alternatives or ensuring that less BPA is released from products. Additionally, workers can be protected against BPA exposure. Lower exposure is also important for sediment-dwelling animals that experience adverse effects due to current BPA concentration levels.
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- 2016
3. Assessment factors for human health risk assessment: a discussion paper
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Vermeire TG, Stevenson H, Pieters MN, Rennen M, Slob W, Hakkert BC, CSR, LEO, and TNO-ITV
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benchmark dose ,human limit value ,assessment factors ,human risk assessement ,margin of safety ,probabilistic - Abstract
TNO rapport V97.880
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- 2012
4. Assessment factors for human health risk assessment: a discussion paper
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Vermeire TG, Stevenson H, Pieters MN, Rennen M, Slob W, Hakkert BC, Nederlandse organisatie voor toegepast wetenschappelijk onderzoek (TNO), Zeist, CSR, LEO, and TNO-ITV
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benchmark dose ,human limit value ,assessment factors ,human risk assessement ,margin of safety ,probabilistic - Abstract
The general goal of this discussion paper is to contribute towards further harmonisation of the human health risk assessment. It discusses the development of a formal, harmonised set of default assessment factors. The status quo with regard to assessment factors is reviewed. Options are presented for a set of default values or probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabilistic distributions of assessment factors are described. The benchmark dose concept is proposed for better characterisation of the true human no-effect level in a probabilistic manner. It is shown how the probabilistic benchmark dose distribution can be combined with distributions of assessment factors to arrive at the distribution of a Human Limit Value.
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- 2007
5. Nanomaterials under REACH. Nanosilver as a case study
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SEC, SIR, LER, Pronk MEJ, Wijnhoven SWP, Bleeker EAJ, Heugens EHW, Peijnenburg WJGM, Luttik R, Hakkert BC, SEC, SIR, LER, Pronk MEJ, Wijnhoven SWP, Bleeker EAJ, Heugens EHW, Peijnenburg WJGM, Luttik R, and Hakkert BC
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RIVM rapport:Om de risico's van nanomaterialen te kunnen inschatten en beheersen, zijn enkele aanpassingen nodig in de Europese chemicalienwetgeving REACH. De gegevens over stoffen waar REACH standaard om vraagt, zijn namelijk onvoldoende om de specifieke eigenschappen van nanomaterialen te bepalen. Hetzelfde geldt voor het bepalen van de invloed van deze eigenschappen op het gedrag en de effecten van nanomaterialen in mens en milieu. Dit blijkt uit onderzoek van RIVM naar de geschiktheid van REACH voor nanomaterialen. Het instituut stelt daarom een aangepaste set minimum informatievereisten voor, voor alle te registreren nanomaterialen onder REACH, ongeacht de omvang van productie en import. Deze vereisten maken het mogelijk de risico's van nanomaterialen te beoordelen. Het gebruik van nanomaterialen neemt de laatste jaren sterk toe. Nanomaterialen worden vooralsnog gedefinieerd als stoffen waarvan de deeltjes minstens een dimensie kleiner dan honderd nanometer hebben. Vanwege hun afmeting hebben ze specifieke eigenschappen. Wetgeving moet erop gericht zijn de potentiele gevaren en risico's van deze nanomaterialen te beheersen. Aan de hand van een hypothetische registratie van nanozilver is onderzocht of REACH geschikt is om een veilig gebruik van nanomaterialen vast te stellen. Hieruit bleek onder andere dat een definitie van nanomateriaal ontbreekt, en dat de juiste maateenheid om de schadelijkheid en blootstelling in uit te drukken nog niet bekend is. Ook is de verplichte standaardinformatie ontoereikend om de blootstelling en gevaren in te kunnen schatten, en om het nanomateriaal goed te kunnen karakteriseren. Mede door de laatste beperking is niet vast te stellen in hoeverre de nanovorm van een stof overeenkomt met de niet-nanovorm van dezelfde stof. Bovendien is het onduidelijk of de huidige extrapolatiemethoden in de risicobeoordeling en de maatregelen om risico's te beheersen geschikt zijn voor nanomaterialen. Deze methoden en maatregelen zijn immers vastgesteld voor ni, Some adjustments are needed in the European chemicals legislation REACH to assess and control the risks of nanomaterials. The information on substances to be provided under REACH is not sufficient to determine the specific properties of nanomaterials, nor to assess how these properties affect their behaviour and effects in humans and the environment. RIVM concluded this following research into the suitability of REACH for nanomaterials. RIVM therefore proposes an adapted set of minimum information requirements, to be applied to all nanomaterials to be registered under REACH, independent of their volume of production and import. These requirements allow a risk assessment of nanomaterials. Over the last years the use of nanomaterials has strongly increased. As yet, nanomaterials are defined as substances of which the discrete parts have at least one dimension smaller than one hundred nanometres. Due to their nanosize they have specific properties. Legislation should focus on controlling the potential hazards and risks of these nanomaterials. By conducting a hypothetical registration of nanosilver it was investigated whether REACH is suitable for assessing the safe use of nanomaterials. From this it appeared that no definition of a nanomaterial is present, and that a relevant measure for expressing harmfulness and exposure is as yet not known. In addition, the standard information requirements are insufficient to assess hazard and exposure. They are also insufficient for a proper characterisation of the nanomaterial. Consequently, it cannot be determined to what extent the nanoform of a substance corresponds to the non-nanoform of the same substance. Furthermore, it is unclear whether current risk reduction measures and extrapolation methods in risk assessment, as established for non-nanomaterials, are applicable to nanomaterials.
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- 2009
6. Quantitative in vitro - in vivo extrapolation. Analysis of 19 compounds of varying embryotoxic potency
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SIR, GBO, SEC, Slob W, Janer G, Bessems JGM, Hakkert BC, Sips AJAM, Verhoef A, Wolterink G, Piersma AH, SIR, GBO, SEC, Slob W, Janer G, Bessems JGM, Hakkert BC, Sips AJAM, Verhoef A, Wolterink G, and Piersma AH
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RIVM rapport:Dierproeven zijn niet altijd eenvoudig te vervangen door in vitro testen (uitgevoerd in reageerbuizen of petrischaaltjes). Dat illustreert onderzoek van het RIVM. Bestaande onderzoeksgegevens uit een in vitro test gericht op ontwikkelingsstoornissen zijn getoetst op hun bruikbaarheid. Het gaat hierbij om stoornissen in de ontwikkeling van rattenembryo's als gevolg van blootstelling aan chemische stoffen. Dit soort alternatieven wordt ontwikkeld onder invloed van maatschappelijke bezwaren tegen dierproeven (in vivo) ten behoeve van kwantitatieve risicobeoordeling. In de onderzochte 'Whole Embryo Culture'-test worden rattenembryo's in vitro blootgesteld aan verschillende concentraties van een bepaalde stof. Vervolgens wordt bekeken bij welke concentratie (in vitro) de effecten overeenkomen met effecten in het intacte dier (in vivo). Dit werd voor 19 verschillende stoffen onderzocht. Er blijkt een duidelijke relatie te zijn tussen de gemeten potentie in in vitro- en in vivo testen, maar de ruis (onzekerheid) in deze relatie is erg groot (circa factor honderd). Dit wordt voor een deel veroorzaakt doordat de beschikbare in vivo studies op verschillende manieren zijn uitgevoerd (bijvoorbeeld doordat zwangere ratten op verschillende dagen van de dracht aan stoffen zijn blootgesteld). Ook zouden verschillen waarmee een lichaam stoffen opneemt of uitscheidt een rol kunnen spelen. Deze studie beschrijft een eerste aanzet om deze verschillen te verdisconteren. Zelfs als deze aspecten worden meegewogen blijft de onzekerheid in de uitkomst groot. Gegeven deze onzekerheid is het volledig vervangen van de in vivo dierstudie door de 'Whole Embryo Culture' test voor kwantitatieve risicobeoordeling vooralsnog niet haalbaar., Animal tests can not always simply be replaced by in vitro tests (carried out in test tubes or petri dishes). This is underlined by research at the National Institute for Public Health and the Environment (RIVM). Existing research data from an in vitro test on developmental effects have been evaluated for their usefulness. This concerns disturbances in the development of rat embryos due to exposure to chemicals. This kind of alternative tests are being developed due to the public objection to animal tests (in vivo) for the purpose of quantitative risk assessment. In the investigated 'Whole Embryo Culture' assay rat embryos are exposed to various concentrations of a particular chemical. Next, it is determined at which concentration (in vitro) effects occur that are similar to those in the whole animal (in vivo). This was investigated for 19 different substances. There appears to be a clear relationship between the determined potencies in the in vitro and in vivo tests, but the scatter (uncertainty) in this relationship is very large (about a factor of hundred). This can partially be explained by the different ways in which the in vivo tests have been performed (the pregnant rats are for example exposed at different days in the gestation). In addition, differences in the uptake or excretion of a substance by the body could play a role. This study describes a first initiative to account for these differences. Even if these aspects are taken into account, the uncertainty in the outcome remains large. Given this uncertainty, the full replacement of the in vivo animal test by the 'Whole Embryo Culture' assay for quantitative risk assessment is hitherto not feasible.
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- 2008
7. Workability of the guidance documents for the category or read-across approach for selected groups of chemicals
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SEC, SIR, Rila JP, Bos PMJ, Hulzebos E, Hakkert BC, SEC, SIR, Rila JP, Bos PMJ, Hulzebos E, and Hakkert BC
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RIVM rapport:De huidige internationale richtsnoeren om chemische stoffen van vergelijkbare structuur groepsgewijs te toetsen op mogelijke risico's hebben meer toelichting nodig om ze goed te kunnen toepassen. Dat blijkt uit een onderzoek van het RIVM naar de bruikbaarheid van deze richtsnoeren. Aanleiding voor het RIVM-onderzoek is de nieuwe Europese wetgeving voor productie, handel en gebruik van chemische stoffen (REACH), die halverwege 2007 in werking treedt. Die schrijft voor dat 30.000 chemische stoffen getoetst moeten worden op mogelijke gevaren. Om het grote aantal chemicalien te kunnen toetsen, zijn diverse dierproefvrije methoden ontwikkeld, zoals QSARS, in vitro-methoden en de categorie- of read-acrossbenadering. Van slechts een beperkt aantal chemische stoffen is bekend welke fysisch-chemische en toxicologische kenmerken ze vertonen; denk daarbij bijvoorbeeld aan huidirritatie, oplosbaarheid in water, afbreekbaarheid in het milieu. De categorie- of read-acrossbenadering maakt gebruik van beschikbare stofinformatie om chemische stoffen met een vergelijkbare structuur waarvoor weinig van deze data beschikbaar zijn, toch te kunnen toetsen. De huidige richtsnoeren voor deze benadering kunnen worden gebruikt als basisdocument. Enkele verbeterpunten zijn gewenst in de verdere ontwikkeling van de REACH-richtlijnen. Belangrijk aandachtspunt daarbij is een heldere definitie van de categorieen die voor read-acrossbenaderingen worden gebruikt om te voorkomen dat ongelijkwaardige data worden vergeleken. Die onderbouwing en een heldere documentatie van gegevens voor deze benadering bepalen in hoge mate de bruikbaarheid van het nieuwe systeem., The current international guidance documents for performing a group-based assessment of the possible risks caused by chemical substances with comparable structures need further elucidation if they are to be properly used. This was the result of RIVM research on the workability of guidance documents. This research was prompted by the upcoming European legislation on production, trade and use of chemical substances (REACH), which will come into force in mid-2007. This legislation stipulates that about 30,000 chemical substances are to be assessed on their possible risks. Several non-animal methods such as QSARs, in vitro methods and the category or read-across approach have been developed to assess this large number of chemicals. The physico-chemical and toxicological properties are only known for a minority of all chemical substances. These may for example include skin irritation, water solubility and degradation in the environment. The category or read-across approach uses available substance information to be able to assess chemical substances with comparable structures for which only few data are available. The current guidance document for this approach can be used as a basis, but several points still need more attention in the further development of the guidance document for REACH. One point of particular interest is establishing a clear definition of the categories for use in the read-across approach to avoid comparing unequal data. Data substantiated and clearly presented for this approach highly define the usefulness of this new system.
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- 2007
8. Assessment factors for human health risk assessment: a discussion paper
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CSR, LEO, TNO-ITV, Vermeire TG, Stevenson H, Pieters MN, Rennen M, Slob W, Hakkert BC, CSR, LEO, TNO-ITV, Vermeire TG, Stevenson H, Pieters MN, Rennen M, Slob W, and Hakkert BC
- Abstract
RIVM rapport:De algemene doelstelling van dit discussierapport is bij te dragen aan verdere harmonisatie van de humaan-toxicologische risicobeoordeling en aan de ontwikkeling van een formeel, geharmoniseerd stelsel van assessment factoren. De status quo van assessment factoren wordt geevalueerd. Opties worden aangeboden voor een stelsel van default waarden, of probabilistische verdelingen, van assessment factoren op basis van de huidige stand van de wetenschap. Methoden om deze default waarden of verdelingen te combineren worden beschreven. Het 'benchmark dose' concept wordt voorgesteld als een betere manier om het werkelijke geen-effectniveau voor de mens op probabilistische wijze te beschrijven. Gedemonstreerd wordt hoe de probabilistische verdeling van de benchmark dose gecombineerd kan worden met verdelingen van assessment factoren met als resultaat de waarschijnlijkheidsverdeling van een toxicologische grenswaarde voor de mens., The general goal of this discussion paper is to contribute towards further harmonisation of the human health risk assessment. It discusses the development of a formal, harmonised set of default assessment factors. The status quo with regard to assessment factors is reviewed. Options are presented for a set of default values or probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabilistic distributions of assessment factors are described. The benchmark dose concept is proposed for better characterisation of the true human no-effect level in a probabilistic manner. It is shown how the probabilistic benchmark dose distribution can be combined with distributions of assessment factors to arrive at the distribution of a Human Limit Value.
- Published
- 1998
9. Assessment factors for human health risk assessment: a discussion paper
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Nederlandse organisatie voor toegepast wetenschappelijk onderzoek (TNO), Zeist, CSR, LEO, TNO-ITV, Vermeire TG, Stevenson H, Pieters MN, Rennen M, Slob W, Hakkert BC, Nederlandse organisatie voor toegepast wetenschappelijk onderzoek (TNO), Zeist, CSR, LEO, TNO-ITV, Vermeire TG, Stevenson H, Pieters MN, Rennen M, Slob W, and Hakkert BC
- Abstract
RIVM rapport:The general goal of this discussion paper is to contribute towards further harmonisation of the human health risk assessment. It discusses the development of a formal, harmonised set of default assessment factors. The status quo with regard to assessment factors is reviewed. Options are presented for a set of default values or probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabilistic distributions of assessment factors are described. The benchmark dose concept is proposed for better characterisation of the true human no-effect level in a probabilistic manner. It is shown how the probabilistic benchmark dose distribution can be combined with distributions of assessment factors to arrive at the distribution of a Human Limit Value., De algemene doelstelling van dit discussierapport is bij te dragen aan verdere harmonisatie van de humaan-toxicologische risicobeoordeling en aan de ontwikkeling van een formeel, geharmoniseerd stelsel van assessment factoren. De status quo van assessment factoren wordt geevalueerd. Opties worden aangeboden voor een stelsel van default waarden, of probabilistische verdelingen, van assessment factoren op basis van de huidige stand van de wetenschap. Methoden om deze default waarden of verdelingen te combineren worden beschreven. Het 'benchmark dose' concept wordt voorgesteld als een betere manier om het werkelijke geen-effectniveau voor de mens op probabilistische wijze te beschrijven. Gedemonstreerd wordt hoe de probabilistische verdeling van de benchmark dose gecombineerd kan worden met verdelingen van assessment factoren met als resultaat de waarschijnlijkheidsverdeling van een toxicologische grenswaarde voor de mens.
- Published
- 1998
10. Neutrophil and monocyte adherence to and migration across monolayers of cytokine-activated endothelial cells: the contribution of CD18, ELAM-1, and VLA-4
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Hakkert, BC, primary, Kuijpers, TW, additional, Leeuwenberg, JF, additional, van Mourik, JA, additional, and Roos, D, additional
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- 1991
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11. Monocytes enhance the bidirectional release of type I plasminogen activator inhibitor by endothelial cells
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Hakkert, BC, primary, Rentenaar, JM, additional, and van Mourik, JA, additional
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- 1990
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12. Rebuttal to the letters to the editors by Terry et al. and Sewell et al. regarding.
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Heringa MB, Cnubben NHP, Slob W, Pronk MEJ, Muller A, Woutersen M, and Hakkert BC
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- 2020
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13. Rebuttal to the letter to the editors regarding Heringa et al. (2020).
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Heringa MB, Cnubben NHP, Slob W, Pronk MEJ, Muller A, Woutersen M, and Hakkert BC
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- 2020
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14. Regulating human safety: How dose selection in toxicity studies impacts human health hazard assessment and subsequent risk management options.
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Woutersen M, Muller A, Pronk MEJ, Cnubben NHP, and Hakkert BC
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- European Union, Humans, Endocrine Disruptors toxicity, Hazardous Substances toxicity, Risk Management, Toxicity Tests
- Abstract
In the EU, one of the key determinants in the regulation and management of substances to ensure adequate protection of human health is the outcome of toxicity studies. These studies should therefore be performed in a way that the data generated are adequate to fulfil all regulatory requirements. However, in recent years, an increasing number of toxicity studies use dose levels that induce only slight, or even no toxicity, while the top dose lies well below the limit dose of 1000 mg/kg bw/d. The results of these studies have limited value for the hazard and subsequent risk assessment and risk management of substances. This paper shows why conducting toxicity studies with too low doses has severe consequences for among others classification and labelling, identification of endocrine disruptors, health impact assessment, and incident management. With this paper we aim to raise awareness on this issue and want to stress the importance of the use of sufficiently high dosing in toxicity studies. Given their central role in toxicity testing, it is therefore key to adapt where necessary the descriptions in OECD test guidelines and guidance documents on requirements for dose level setting, to make sure they are as explicit and unambiguous as possible., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)
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- 2020
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15. Use of the kinetically-derived maximum dose concept in selection of top doses for toxicity studies hampers proper hazard assessment and risk management.
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Heringa MB, Cnubben NHP, Slob W, Pronk MEJ, Muller A, Woutersen M, and Hakkert BC
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- Dose-Response Relationship, Drug, European Union, Humans, Kinetics, Risk Management, Hazardous Substances administration & dosage, Hazardous Substances toxicity, Toxicity Tests
- Abstract
The KMD (kinetically-derived maximum dose) is an increasingly advocated concept that uses toxicokinetic data in the top dose selection for toxicity testing. Application of this concept may have serious regulatory implications though, especially in the European Union. The basic assumption is that the relationship between internal and external dose (IED) shows an inflection point where linearity transits into non-linearity due to saturation of underlying processes; top doses in toxicity tests should not be above the inflection point, provided human exposures are well below this point. A critical analysis of the KMD concept and its underlying assumptions shows, however, that the IED relationship is non-linear over the whole dose range, without any point of inflection. The KMD concept thus aims to estimate a non-existing point, rendering it invalid for use in toxicity testing. Moreover, the concept ignores the key question in toxicology: What kind of toxic effects occur at which doses? These and several other reservations against the KMD concept are discussed and illustrated with three existing applications of the KMD approach. Hence, we recommend to abolish the KMD concept for selecting top doses in toxicity testing. This requires the updating of regulations, guidance documents and OECD test guidelines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)
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- 2020
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16. Why Do Countries Regulate Environmental Health Risks Differently? A Theoretical Perspective.
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Clahsen SCS, van Kamp I, Hakkert BC, Vermeire TG, Piersma AH, and Lebret E
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- Cultural Characteristics, Electromagnetic Fields, Endocrine Disruptors toxicity, Health Policy, Humans, Internationality, Models, Theoretical, Psychometrics, Reproducibility of Results, Environmental Health legislation & jurisprudence, Environmental Monitoring legislation & jurisprudence, Public Policy, Risk Assessment methods, Risk Management methods
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Why do countries regulate, or prefer to regulate, environmental health risks such as radiofrequency electromagnetic fields and endocrine disruptors differently? A wide variety of theories, models, and frameworks can be used to help answer this question, though the resulting answer will strongly depend on the theoretical perspective that is applied. In this theoretical review, we will explore eight conceptual frameworks, from different areas of science, which will offer eight different potential explanations as to why international differences occur in environmental health risk management. We are particularly interested in frameworks that could shed light on the role of scientific expertise within risk management processes. The frameworks included in this review are the Risk Assessment Paradigm, research into the roles of experts as policy advisors, the Psychometric Paradigm, the Cultural Theory of Risk, participatory approaches to risk assessment and risk management, the Advocacy Coalition Framework, the Social Amplification of Risk Framework, and Hofstede's Model of National Cultures. We drew from our knowledge and experiences regarding a diverse set of academic disciplines to pragmatically assemble a multidisciplinary set of frameworks. From the ideas and concepts offered by the eight frameworks, we derive pertinent questions to be used in further empirical work and we present an overarching framework to depict the various links that could be drawn between the frameworks., (© 2018 The Authors Risk Analysis published by Wiley Periodicals, Inc. on behalf of Society for Risk Analysis.)
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- 2019
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17. An integrative test strategy for cancer hazard identification.
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Luijten M, Olthof ED, Hakkert BC, Rorije E, van der Laan JW, Woutersen RA, and van Benthem J
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- Animals, Biological Assay, Carcinogenicity Tests standards, Carcinogens toxicity, DNA Damage, Humans, Mutagenicity Tests methods, Mutagenicity Tests standards, Mutagens toxicity, Neoplasms, Risk Assessment methods, Carcinogenicity Tests methods
- Abstract
Assessment of genotoxic and carcinogenic potential is considered one of the basic requirements when evaluating possible human health risks associated with exposure to chemicals. Test strategies currently in place focus primarily on identifying genotoxic potential due to the strong association between the accumulation of genetic damage and cancer. Using genotoxicity assays to predict carcinogenic potential has the significant drawback that risks from non-genotoxic carcinogens remain largely undetected unless carcinogenicity studies are performed. Furthermore, test systems already developed to reduce animal use are not easily accepted and implemented by either industries or regulators. This manuscript reviews the test methods for cancer hazard identification that have been adopted by the regulatory authorities, and discusses the most promising alternative methods that have been developed to date. Based on these findings, a generally applicable tiered test strategy is proposed that can be considered capable of detecting both genotoxic as well as non-genotoxic carcinogens and will improve understanding of the underlying mode of action. Finally, strengths and weaknesses of this new integrative test strategy for cancer hazard identification are presented.
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- 2016
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18. International regulatory needs for development of an IATA for non-genotoxic carcinogenic chemical substances.
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Jacobs MN, Colacci A, Louekari K, Luijten M, Hakkert BC, Paparella M, and Vasseur P
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- Animals, Biological Assay methods, Mutagenicity Tests methods, Animal Testing Alternatives methods, Carcinogenicity Tests methods, Carcinogens toxicity, Hazardous Substances toxicity, Internationality
- Abstract
Although regulatory requirements for carcinogenicity testing of chemicals vary according to product sector and regulatory jurisdiction, the standard approach starts with a battery of genotoxicity tests. If any of the in vivo genotoxicity tests are positive, a lifetime rodent cancer bioassay may be requested, which allows the detection of non-genotoxic carcinogens (NGTxC). However, under most chemical regulations the cancer bioassay is rarely requested, specific requests to obtain information on non-genotoxic mechanisms of carcinogenicity are few, and there are no OECD approved screening methods. When the in vitro genotoxicity battery is negative, usually no further carcinogenicity testing is requested. Consequently NGTxC might remain unidentified and therefore the risks they may pose to human health will not be managed. In contrast to genotoxic carcinogens NGTxCact through a large variety of specific mechanisms, and a panel of tests covering multiple biological traits will be needed. The development of an Integrated Approach to Testing and Assessment (IATA) of NGTxC could assist regulatory decision makers. We examine what NGTxC are and discuss chemical regulatory requirements and limitations. With a strong drive to reduce animal testing and costs in mind, it is essential that proper and robust alternatives for animal testing (3Rs) methods for addressing non-genotoxic modes of action are developed and used. Therefore relevant in vitro mechanisms and assays are described and tentatively organized in levels of information, indicating both a possible structure of the future IATA for NGTxC and associated OECD Test Guideline development priorities.
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- 2016
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19. Evaluation of the performance of the reduced local lymph node assay for skin sensitization testing.
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Ezendam J, Muller A, Hakkert BC, and van Loveren H
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- Animals, Databases, Factual, Dose-Response Relationship, Drug, Irritants administration & dosage, Irritants classification, Mice, Skin pathology, Irritants toxicity, Local Lymph Node Assay, Skin drug effects
- Abstract
The local lymph node assay (LLNA) is the preferred method for classification of sensitizers within REACH. To reduce the number of mice for the identification of sensitizers the reduced LLNA was proposed, which uses only the high dose group of the LLNA. To evaluate the performance of this method for classification, LLNA data from REACH registrations were used and classification based on all dose groups was compared to classification based on the high dose group. We confirmed previous examinations of the reduced LLNA showing that this method is less sensitive compared to the LLNA. The reduced LLNA misclassified 3.3% of the sensitizers identified in the LLNA and misclassification occurred in all potency classes and that there was no clear association with irritant properties. It is therefore not possible to predict beforehand which substances might be misclassified. Another limitation of the reduced LLNA is that skin sensitizing potency cannot be assessed. For these reasons, it is not recommended to use the reduced LLNA as a stand-alone assay for skin sensitization testing within REACH. In the future, the reduced LLNA might be of added value in a weight of evidence approach to confirm negative results obtained with non-animal approaches., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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20. On the impact of second generation mating and offspring in multi-generation reproductive toxicity studies on classification and labelling of substances in Europe.
- Author
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Rorije E, Muller A, Beekhuijzen ME, Hass U, Heinrich-Hirsch B, Paparella M, Schenk E, Ulbrich B, Hakkert BC, and Piersma AH
- Subjects
- Animal Experimentation, Animals, Endocrine System drug effects, Europe, Female, Hazardous Substances classification, Male, Mice, Nervous System drug effects, Neurotoxicity Syndromes etiology, Pregnancy, Product Labeling methods, Rats, Cohort Effect, Hazardous Substances toxicity, Paternal Exposure adverse effects, Prenatal Exposure Delayed Effects, Reproduction drug effects, Toxicity Tests methods
- Abstract
The possible impact on classification and labelling decisions of effects observed in second generation parental (P1) and offspring (F2) parameters in multi-generation studies was investigated. This was done for 50 substances classified as reproductive toxicants in Europe, for which a multi-generation study was available. The P1 and F2 effects were compared to parental (P0) and first generation offspring (F1) effects with regard to type of effect as well as incidence, magnitude and severity (IMS), at any dose level. For every study with unique P1/F2 effects, or differences in IMS, the influence of the P1/F2 findings on the classification decision was investigated. Unique P1/F2 generation findings did not play a crucial role in the classification decision of any of the 50 classified substances, except for fenarimol. This substance however provided abundant alerts on the basis of its endocrine activity and developmental neurotoxicity and would therefore also be expected to be identified as a developmental neurotoxicant in an Extended One Generation Reproductive Toxicity Study (EOGRTS). These findings, in addition to the increased number of parameters analysed, increased statistical power and reduced animal use, provide strong further support for replacement of the classical two-generation reproductive toxicity study by the EOGRTS in regulatory reproductive toxicity assessment., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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21. Finding maximal transcriptome differences between reprotoxic and non-reprotoxic phthalate responses in rat testis.
- Author
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Yuan X, Jonker MJ, de Wilde J, Verhoef A, Wittink FR, van Benthem J, Bessems JG, Hakkert BC, Kuiper RV, van Steeg H, Breit TM, and Luijten M
- Subjects
- Administration, Oral, Animal Testing Alternatives, Animals, Gene Expression, Gene Expression Profiling, Hormone Antagonists classification, Male, Phthalic Acids classification, Protein Array Analysis, Rats, Rats, Inbred Strains, Reproduction genetics, Transcriptome genetics, Hormone Antagonists toxicity, Phthalic Acids toxicity, Reproduction drug effects, Testis drug effects, Toxicogenetics methods, Transcriptome drug effects
- Abstract
The chemical legislation of the EU, Registration, Evaluation, and Authorization of Chemicals (REACH), stipulates that about 30 000 chemical substances are to be assessed on their possible risks. Toxicological evaluation of these compounds will at least partly be based on animal testing. In particular, the assessment of reproductive toxicity is a very complicated, time-consuming and animal-demanding process. Introducing microarray-based technologies can potentially refine in vivo toxicity testing. If compounds of a distinct chemical class induce reproducible gene-expression responses with a recognizable overlap, these gene-expression signatures may indicate intrinsic features of certain compounds, including specific toxicity. In the present study, we have set out the first steps towards this approach for the reproductive toxicity of phthalates. Male rats were treated with a single dose of either reprotoxic or non-reprotoxic phthalates, and were analyzed 24 h afterwards. Subsequently, histopathological and gene-expression profiling analyses were performed. Despite ambiguous histopathological observations, we were able to identify genes with differential expression profiles between the reprotoxic phthalates and the non-reprotoxic counterparts. This shows that differences in gene-expression profiles, indicative of the type of exposure, may be detected earlier, or at lower doses, than classical pathological endpoints. These findings are promising for 'early warning' biomarker analyses and for using toxicogenomics in a category approach. Ultimately, this could lead to a more cost-effective approach for prioritizing the toxicity testing of large numbers of chemicals in a short period of time in hazard assessment of chemicals, which is one of the objectives of the REACH chemical legislation., (Copyright © 2010 John Wiley & Sons, Ltd.)
- Published
- 2011
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22. Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring.
- Author
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Piersma AH, Rorije E, Beekhuijzen ME, Cooper R, Dix DJ, Heinrich-Hirsch B, Martin MT, Mendez E, Muller A, Paparella M, Ramsingh D, Reaves E, Ridgway P, Schenk E, Stachiw L, Ulbrich B, and Hakkert BC
- Subjects
- Aging, Animals, Dose-Response Relationship, Drug, Embryonic Development drug effects, Endpoint Determination, Female, Fertility drug effects, Gestational Age, Lactation, Litter Size drug effects, Male, Maternal Exposure, Paternal Exposure, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Reproduction drug effects, Risk Assessment, Reproductive Physiological Phenomena drug effects, Research Design standards, Toxicity Tests standards
- Abstract
The multi-generation reproductive toxicity study (OECD TG 416 and USEPA 870.3800) has been extensively used internationally to assess the adverse effects of substances on reproduction. Recently the necessity of producing a second generation to assess the potential for human health risks has been questioned. The present standardized retrospective analysis of the impact of the second generation on overall study outcome combines earlier analyses and includes 498 rat multi-generation studies representing 438 different tested substances. Detailed assessment of study reports revealed no critical differences in sensitivities between the generations on the basis of a consideration of all endpoints evaluated. This analysis indicates that the second generation mating and offspring will very rarely provide critical information. These findings are consistent with the conclusions of previous retrospective analyses conducted by RIVM, USEPA and PMRA and support adoption of the proposed OECD extended one-generation reproductive toxicity study protocol in regulatory risk assessment testing strategies., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2011
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23. Retrospective analysis of relative parameter sensitivity in multi-generation reproductive toxicity studies.
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Dang ZC, Rorije E, Esch TH, Muller A, Hakkert BC, and Piersma AH
- Subjects
- Animal Use Alternatives, Animals, Body Weight drug effects, Dose-Response Relationship, Drug, European Union, Female, Genitalia drug effects, Genitalia pathology, Male, Mice, Organ Size drug effects, Rats, Reproduction physiology, Retrospective Studies, Risk Assessment, Sensitivity and Specificity, Toxicity Tests methods, Xenobiotics classification, Reproduction drug effects, Toxicity Tests statistics & numerical data, Xenobiotics toxicity
- Abstract
Current suggestions towards amending the OECD two-generation protocol include omission of the second generation and inclusion of additional parameters. This study analysed the relative parameter sensitivity in 18 individually published multi-generation studies with substances toxic to fertility. Among parameters that most often determined the reproductive LOAEL were weight of testis, dam and pup as well as litter size. Several other parameters were found to be unaffected in all studies evaluated. Some substances affected a specific set of parameters, indicating that rarely affected parameters may prove crucial in individual situations. This argues for the inclusion of a wide spectrum of parameters to cover all possible effects. Less sensitive parameters, mechanistically related to more sensitive ones, may be omitted as they will unlikely contribute to the overall LOAEL. This study gives first insights and needs follow-up by more extensive analyses before firm conclusions on the design of the two-generation study protocol can be drawn.
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- 2009
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24. A retrospective analysis of developmental toxicity studies in rat and rabbit: what is the added value of the rabbit as an additional test species?
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Janer G, Slob W, Hakkert BC, Vermeire T, and Piersma AH
- Subjects
- Animals, Environmental Pollutants toxicity, Female, Government Agencies, No-Observed-Adverse-Effect Level, Pregnancy, Rats, Retrospective Studies, Risk Assessment, Species Specificity, United States, Growth and Development drug effects, Rabbits physiology, Teratogens toxicity, Toxicity Tests methods
- Abstract
In contrast to most toxicological tests, developmental studies are usually required in both a rodent and a non-rodent species. This study retrospectively assessed the added value of the rabbit developmental test when a rat developmental test is available. In contrast with previous reviews, we looked at developmental toxicity instead of teratogenicity, and took into account maternal toxicity in the evaluation of developmental toxicity. We analyzed data for 54 substances classified for developmental toxicity and 73 substances considered to be teratogenic in the rabbit and not in the rat in two previous reviews. On average, the rat and the rabbit developmental toxicity studies were similarly sensitive: the average ratio of the NOAELs between the two species was about one, and for most compounds there were no differences between rat and rabbit studies in terms of classification for developmental toxicity. For certain substances the developmental study in either one of the two species appeared to be more sensitive than in the other species. However, these differences are partly due to differences between studies other than the test species used. Overall, our analysis does not clearly indicate that the evaluation of developmental toxicity, as opposed to other types of toxicity, would specifically require the rabbit as an additional test species. The discrimination between direct and indirect (i.e., as a consequence of maternal toxicity) developmental effects was often doubtful, and is one of the factors that could explain the apparent differences between the two species. A more accurate assessment of maternal toxicity might improve the reliability of the results from a single developmental toxicity study. More knowledge about the interaction between maternal and developmental effects is required before decisions on omitting the requirement for the developmental toxicity testing in a second species can be considered.
- Published
- 2008
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25. Quantitative extrapolation of in vitro whole embryo culture embryotoxicity data to developmental toxicity in vivo using the benchmark dose approach.
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Piersma AH, Janer G, Wolterink G, Bessems JG, Hakkert BC, and Slob W
- Subjects
- Abnormalities, Drug-Induced pathology, Animals, Dose-Response Relationship, Drug, Endpoint Determination, Female, Fetal Weight drug effects, Pharmacokinetics, Pregnancy, Rats, Reference Standards, Validation Studies as Topic, Embryo Culture Techniques, Teratogens toxicity, Toxicology methods
- Abstract
If in vitro data are to be used as a basis for hazard characterization, a translation of an in vitro concentration toward an in vivo dose must be made. In this study we examined the correlation between dose descriptors from the in vitro Whole Embryo Culture (WEC) test and in vivo developmental toxicity tests. We applied the Benchmark Dose (BMD) approach to estimate equipotent in vitro concentrations (Benchmark Concentrations [BMCs]) and equipotent in vivo doses (BMDs). Using the data generated in an European Center for the Validation of Alternative Methods validation study we found that the BMCs were highly reproducible among laboratories. The three endpoints analyzed (head length, crown-rump length, and total morphological score) were strongly correlated. A clear in vitro-in vivo correlation was found between BMCs and BMDs. However, a considerable uncertainty would remain if the BMDs were estimated from the BMC using this correlation: the confidence interval of such an in vivo dose estimate would span various orders of magnitude. Differences in toxicokinetic properties among the compounds explained at least part of the scatter of the in vitro-in vivo correlation. But also heterogeneity in the design of the available in vivo studies underlies much of the scatter, and this puts a limit on validating in vitro data as predictors of in vivo data. Further analysis of the in vitro-in vivo correlation would therefore require high-quality in vivo data, generated by appropriate (and similar) study designs.
- Published
- 2008
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26. A retrospective analysis of the two-generation study: what is the added value of the second generation?
- Author
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Janer G, Hakkert BC, Slob W, Vermeire T, and Piersma AH
- Subjects
- Animals, Body Weight drug effects, Dose-Response Relationship, Drug, Embryo Implantation drug effects, Environmental Pollutants classification, Epididymis drug effects, Female, Fertility drug effects, Growth and Development drug effects, Litter Size drug effects, Male, No-Observed-Adverse-Effect Level, Pesticides classification, Population Dynamics, Retrospective Studies, Risk Assessment, Spermatozoa drug effects, Time Factors, Environmental Pollutants toxicity, Germ Cells drug effects, Pesticides toxicity, Reproduction drug effects, Toxicity Tests, Chronic methods
- Abstract
Increasing pressure is exerted by some stakeholders to reduce the two-generation study to a one-generation study, a measure that would considerably reduce the number of animals and other costs involved in these lengthy studies. The present study retrospectively evaluates 176 multi-generation studies to assess potential differences between the first and the second generation, both in terms of the types of effects observed and in terms of the effective doses. All substances classified as reproductive toxicants by the Directive 92/32/EEC or considered as toxic to fertility by the California EPA for which we found a multi-generation study were included (n=58 studies). The second generation in the two-generation studies considered affected neither the overall NOAEL nor the critical effect. Therefore, it had no impact on the ensuing risk assessment, nor on classification and labeling. However, several substances did show an increased sensitivity of the F(1) adults in comparison to the P(0). These results support the proposal of replacing the current two-generation study by a one-generation study with a more extensive assessment of parameters at F(1) adulthood.
- Published
- 2007
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27. A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study.
- Author
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Janer G, Hakkert BC, Piersma AH, Vermeire T, and Slob W
- Subjects
- Animals, Dose-Response Relationship, Drug, Environmental Pollutants classification, Female, Fertility drug effects, Genitalia drug effects, Growth and Development drug effects, Male, No-Observed-Adverse-Effect Level, Population Dynamics, Rats, Retrospective Studies, Risk Assessment, Time Factors, Environmental Pollutants toxicity, Reproduction drug effects, Toxicity Tests methods, Toxicity Tests, Chronic
- Abstract
This study aims to evaluate the added value of the two-generation reproductive toxicity study when a subchronic study (90-day repeated dose toxicity study) is available. The analysis includes a total of 47 reproductive toxic and 75 non-reproductive toxic substances, for which a two-generation study was available. For each of these compounds the outcomes of both study types were compared, in view of the question what the impact would have been both for the derived NOAEL and for classification regarding toxicity to fertility. On average, only a small difference (less than twofold) in overall NOAELs was found between the rat two-generation study and the rat subchronic study. For individual compounds the differences could be larger (up to around a factor of 10), but differences of this magnitude equally occur between NOAELs of subchronic studies (testing the same substance). The two generation study did have an impact on classification for toxicity to fertility: about one-third of the substances shown to be toxic to fertility in the two-generation study did not show any sign of that in the 90-day study. If the subchronic study did show toxicity to reproductive organs this often occurred at (much) higher doses than other toxic effects in the same study. Therefore, apart from including more fertility endpoints, a larger dose spacing (or more dose groups) in the subchronic study might increase its detection rate of fertility toxic substances. The consequences that these findings may have for risk assessment and risk management are discussed, especially in the context of REACH.
- Published
- 2007
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28. Comparative in vitro-in vivo percutaneous penetration of the fungicide ortho-phenylphenol.
- Author
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Cnubben NH, Elliott GR, Hakkert BC, Meuling WJ, and van de Sandt JJ
- Subjects
- Administration, Cutaneous, Adult, Animals, Animals, Outbred Strains, Biphenyl Compounds administration & dosage, Dose-Response Relationship, Drug, Epidermis metabolism, Female, Fungicides, Industrial administration & dosage, Humans, In Vitro Techniques, Male, Membranes metabolism, Permeability, Rats, Rats, Wistar, Swine, Biphenyl Compounds pharmacokinetics, Fungicides, Industrial pharmacokinetics, Skin Absorption
- Abstract
The validity of in vitro and in vivo methods for the prediction of percutaneous penetration in humans was assessed using the fungicide ortho-phenylphenol (OPP) (log Po/w 3.28, MW 170.8, solubility in water 0.7 g/L). In vivo studies were performed in rats and human volunteers, applying the test compound to the dorsal skin and the volar aspect of the forearm, respectively. In vitro studies were performed using static diffusion cells with viable full-thickness skin membranes (rat and human), nonviable epidermal membranes (rat and human), and a perfused pig ear model. For the purpose of conducting in vitro/in vivo comparisons, standardized experimental conditions were used with respect to dose (120 microg OPP/cm(2)), vehicle (60% aqueous ethanol), and exposure duration (4 h). In human volunteers, the potentially absorbed dose (amount applied minus dislodged) was 105 microg/cm(2), while approximately 27% of the applied dose was excreted with urine within 48 h. In rats these values were 67 microg/cm(2) and 40%, respectively. In vitro methods accurately predicted human in vivo percutaneous absorption of OPP on the basis of the potential absorbed dose. With respect to the other parameters studied (amount systemically available, maximal flux), considerable differences were observed between the various in vitro models. In viable full-thickness skin membranes, the amount systemically available and the potentially absorbed dose correlated reasonably well with the human in vivo situation. In contrast the K(p)/maximal flux considerably underestimated the human in vivo situation. Although epidermal membranes overestimated human in vivo data, the species differences observed in vivo were reflected correctly in this model. The data generated in the perfused pig ear model were generally intermediate between viable skin membranes and epidermal membranes., ((c) 2002 Elsevier Science (USA).)
- Published
- 2002
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29. Refinement of risk assessment of dermally and intermittently exposed pesticide workers: a critique.
- Author
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Hakkert BC
- Subjects
- Administration, Cutaneous, Administration, Oral, Animals, Guidelines as Topic, Humans, Risk Assessment, Toxicity Tests methods, Occupational Exposure, Pesticides adverse effects
- Abstract
The regulatory requirements for the registration of pesticides are mainly evolved from concern about dietary exposure and risk, i.e. chronic oral exposure. Pesticide workers, however, are predominantly exposed dermally and intermittently. The present critique provides suggestions for improvement of toxicity studies to refine the risk assessment of pesticide workers. In this respect it is considered of utmost importance that toxicity studies (either toxicokinetic or toxicodynamic) should be tuned towards the anticipated exposure scenario. Apart from suggestions for improvement of dermal toxicokinetic and dynamic studies, recommendations for further research and guidance are given, amongst which the request for information on the robustness of in vitro dermal absorption studies and guidance on how to use these data. With respect to the intermittent exposure of pesticide workers it is recognised that both information on the anticipated exposure scenario as well as knowledge on the effect of intermittent exposure on the toxicity are needed. From a toxicological point of view, the setting of more than one Acceptable Operator Exposure Level (AOEL), covering effects that may arise after different periods of exposure, as well as the development of more robust acute and short term studies are strongly recommended.
- Published
- 2001
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30. Comparative in vitro-in vivo percutaneous absorption of the pesticide propoxur.
- Author
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van de Sandt JJ, Meuling WJ, Elliott GR, Cnubben NH, and Hakkert BC
- Subjects
- Animal Testing Alternatives, Animals, Ear, External blood supply, Ear, External metabolism, Humans, In Vitro Techniques, Male, Models, Animal, Perfusion, Rats, Rats, Wistar, Species Specificity, Swine, Epidermis metabolism, Insecticides pharmacokinetics, Propoxur pharmacokinetics, Skin Absorption
- Abstract
In vitro and in vivo skin absorption of the pesticide propoxur (2-isopropoxyphenyl N-methyl carbamate, commercially Baygon(TM) and Unden (TM); log Po/w 1.56, MW 209.2) was investigated. In vivo studies were performed in rats and human volunteers, applying the test compound to the dorsal skin and the volar aspect of the forearm, respectively. In vitro experiments were carried out in static diffusion cells using viable full-thickness skin membranes (rat and human), non-viable epidermal membranes (rat and human) and a perfused-pig-ear model. Percutaneous penetration of propoxur in human volunteers was measured by analysis of its metabolite (2-isopropoxyphenol) in blood and urine; in all other studies radiolabeled propoxur ([ring-U-(14)C]propoxur) was used. In order to allow for direct comparison, experimental conditions were standardized with respect to dose (150 microg propoxur per cm(2)), vehicle (60% aqueous ethanol) and exposure time (4 h). In human volunteers, it was found that approximately 6% of the applied dose was excreted via the urine after 24 h, while the potential absorbed dose (amount applied minus amount washed off) was 23 microg/cm(2). In rats these values were 21% and 88 microg/cm(2), respectively. Data obtained in vitro were almost always higher than those obtained in human volunteers. The most accurate in vitro prediction of the human in vivo percutaneous absorption of propoxur was obtained on the basis of the potential absorbed dose. The absorbed dose and the maximal flux in viable full-thickness skin membranes correlated reasonably well with the human in vivo situation (maximal overestimation by a factor of 3). Epidermal membranes overestimated the human in vivo data up to a factor of 8, but the species-differences observed in vivo were reflected correctly in this model. The data generated in the perfused-pig-ear model were generally intermediate between viable skin membranes and epidermal membranes.
- Published
- 2000
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31. Assessment factors for human health risk assessment: a discussion paper.
- Author
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Vermeire T, Stevenson H, Peiters MN, Rennen M, Slob W, and Hakkert BC
- Subjects
- Animals, Benchmarking, Dose-Response Relationship, Drug, Humans, No-Observed-Adverse-Effect Level, Probability, Risk Factors, Toxicity Tests, Health, Risk Assessment methods
- Abstract
The general goal of this discussion paper is to contribute toward the further harmonization of human health risk assessment. It first discusses the development of a formal, harmonized set of assessment factors. The status quo with regard to assessment factors is reviewed, that is, the type of factors to be identified, the range of values assigned, as well as the presence or absence of a scientific basis for these values. Options are presented for a set of default values and probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabilistic distributions of assessment factors are also described. Second, the effect parameter, the no-observed-adverse-effect level (NOAEL), is discussed. This NOAEL as selected from the toxicological database may be a poor substitute for the unknown, true no-adverse-effect level (NAEL). New developments are presented with respect to the estimation of the NAEL. The already widely discussed Benchmark Dose concept can be extended to obtain an uncertainty distribution of the Critical Effect Dose (CED). This CED distribution can be combined with estimated uncertainty distributions for assessment factors. In this way the full distribution of the Human Limit Value will be derived and not only a point estimate, whereas information on dose-response relations is taken into account. Finally, a strategy is proposed for implementation of the new developments into human health risk assessments.
- Published
- 1999
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32. Toxicological risk assessment of worker exposure to pesticides: some general principles.
- Author
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de Raat WK, Stevenson H, Hakkert BC, and van Hemmen JJ
- Subjects
- Humans, Occupational Health, Risk Assessment, Risk Factors, Sensitivity and Specificity, Occupational Exposure adverse effects, Pesticides toxicity
- Published
- 1997
- Full Text
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33. Neutrophil migration across monolayers of cytokine-prestimulated endothelial cells: a role for platelet-activating factor and IL-8.
- Author
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Kuijpers TW, Hakkert BC, Hart MH, and Roos D
- Subjects
- Antigens, Surface biosynthesis, Azepines pharmacology, Cells, Cultured, Endothelium, Vascular drug effects, Endothelium, Vascular growth & development, Female, Furans pharmacology, Humans, Interleukin-8 pharmacology, Platelet Activating Factor antagonists & inhibitors, Platelet Activating Factor metabolism, Pregnancy, Receptors, Cell Surface antagonists & inhibitors, Stimulation, Chemical, Triazoles pharmacology, Tumor Necrosis Factor-alpha pharmacology, Umbilical Veins, Cell Adhesion physiology, Cell Movement physiology, Endothelium, Vascular physiology, Neutrophils physiology, Platelet Membrane Glycoproteins, Receptors, Cell Surface physiology, Receptors, G-Protein-Coupled
- Abstract
In a previous study we observed that neutrophils respond with a rapid rise in [Ca2+]i during adherence to cytokine-activated endothelial cells (EC), caused by EC membrane-associated platelet-activating factor (PAF). In the present study, we investigated whether this form of PAF was important in neutrophil adherence and migration across monolayers of rIL-1 beta- or rTNF alpha-prestimulated EC. PAF receptor antagonists prevented neutrophil migration across cytokine-pretreated EC by approximately 60% (P less than 0.005) without interfering with the process of adherence. The antagonists WEB 2086 and L-652,731 had no effect on neutrophil migration across resting EC induced by formylmethionyl-leucyl-phenylalanine (FMLP). A murine anti-IL-8 antiserum was found to also partially inhibit the neutrophil transmigration across cytokine-activated EC. When the anti-IL-8 antiserum was used in combination with a PAF receptor antagonist, neutrophil migration across cytokine-pretreated monolayers of EC was completely prevented. During transmigration, LAM-1 and CD44 on the neutrophils were down-modulated; both WEB 2086 and anti-IL-8 antiserum partially prevented this down-modulation caused by cytokine-prestimulated EC. Our results indicate that human neutrophils are activated and guided by EC-associated PAF and EC-derived IL-8 during the in vitro diapedesis in between cytokine-stimulated EC.
- Published
- 1992
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34. Monocytes enhance endothelial von Willebrand factor release and prostacyclin production with different kinetics and dependency on intercellular contact between these two cell types.
- Author
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Hakkert BC, Rentenaar JM, and van Mourik JA
- Subjects
- Cell Communication physiology, Cells, Cultured, Endothelium, Vascular cytology, Humans, Kinetics, Leukocytes physiology, Endothelium, Vascular metabolism, Epoprostenol biosynthesis, Monocytes physiology, von Willebrand Factor metabolism
- Abstract
Human umbilical vein endothelial cells cultured on a collagen lattice were used to study the effects of the interaction between human monocytes and endothelial cells on endothelial von Willebrand Factor (vWF) release and prostacyclin (PGI2) production by these cells. The effects of monocytes were compared with those of other leucocytes, conditioned media from monocytes, and agonists such as interleukin 1 (IL-1) and the phorbol ester PMA. Because the cell culture system used allows simultaneous analysis of the lumenal and ablumenal compartment of endothelial cell monolayers, we also studied into which direction these products were released by endothelial cells. Under quiescent conditions the concentration of vWF in the ablumenal compartment was about three-fold higher than that in the lumenal compartment, whereas PGI2 was equally distributed between the two compartments. Direct cell-cell contact between purified monocytes and endothelial cells strongly enhanced both vWF release and PGI2 synthesis, in a dose-dependent and monocyte-specific manner. The monocyte-induced enhancement of PGI2 production, however, was much earlier in onset than that of vWF. Secretory products from monocytes also enhanced endothelial PGI2 synthesis, although to a lesser extent than with monocytes that were in direct contact with endothelial cells. In contrast, the monocyte-induced enhancement of endothelial vWF release was completely dependent on the direct interaction between monocytes and endothelial cells.
- Published
- 1992
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35. Role of endothelial leukocyte adhesion molecule-1 and platelet-activating factor in neutrophil adherence to IL-1-prestimulated endothelial cells. Endothelial leukocyte adhesion molecule-1-mediated CD18 activation.
- Author
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Kuijpers TW, Hakkert BC, Hoogerwerf M, Leeuwenberg JF, and Roos D
- Subjects
- CD18 Antigens, Calcium metabolism, Cell Adhesion, E-Selectin, Humans, L-Selectin, Recombinant Proteins pharmacology, Antigens, CD physiology, Cell Adhesion Molecules physiology, Endothelium, Vascular physiology, Interleukin-1 pharmacology, Neutrophils physiology, Platelet Activating Factor physiology
- Abstract
Adherence of neutrophils to endothelium is a key event in the sequence of inflammatory leukocyte responses. Double-color FACS analysis was used to determine the extent and kinetics of neutrophil adherence to rIL-1 beta-pretreated endothelial cells (EC). Neutrophils bound very avidly when the EC were prestimulated for 4 to 6 h with rIL-1 beta. Anti-ELAM-1 F(ab)2 fragments inhibited this adherence for more than 80%. On the other hand, anti-CD18 F(ab)2 fragments also inhibited the neutrophil adherence (40 to 50%). Combined use of anti-ELAM-1 and anti-CD18 F(ab)2 fragments completely prevented adherence. Neutrophils became activated as soon as they made contact with the rIL-1 beta-pretreated EC. First, neutrophils depleted of intracellular ATP showed a clearly decreased adherence completely dependent on ELAM-1-mediated binding, i.e., without additional effects of CD18 adhesion proteins. Thus, CD18 is activated during neutrophil adherence and then participates in the binding process. Secondly, the neutrophils responded with a transient rise in [Ca2+]i upon binding to rIL-1 beta-pretreated EC, which was demonstrated to be caused by endothelial cell-associated platelet-activating factor (PAF). However, the extent of neutrophil adherence to rIL-1 beta-pretreated EC was not affected by the use of the PAF-receptor antagonist WEB 2086, or removal of the EC-bound PAF. The only effect was a complete dependency of the neutrophil adherence on ELAM-1-mediated binding, although anti-CD18 mAb still induced 40 to 50% inhibition under these conditions. We therefore conclude that ELAM-1-mediated binding is the major mechanism for CD18 activation during neutrophil adherence to rIL-1 beta-pretreated EC.
- Published
- 1991
36. A three-dimensional model system to study the interactions between human leukocytes and endothelial cells.
- Author
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Hakkert BC, Rentenaar JM, Van Aken WG, Roos D, and Van Mourik JA
- Subjects
- Antibodies, Monoclonal, Antigens, CD physiology, Antigens, Differentiation physiology, CD11 Antigens, CD18 Antigens, Cells, Cultured, Collagen, Extracellular Matrix physiology, Humans, Interleukin-1 pharmacology, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Receptors, Leukocyte-Adhesion physiology, Time Factors, Cell Adhesion, Cell Movement, Endothelium, Vascular cytology, Leukocytes cytology
- Abstract
Leukocyte adhesion to endothelial cells and migration into the subendothelial matrix was studied with a three-dimensional model system, consisting of human endothelial cells cultured on a loose collagen matrix. We developed a new method to separate the endothelial cell monolayer and adhering leukocytes, from the subendothelial matrix, allowing simultaneous analysis of leukocyte adhesion and transendothelial migration. Monocytes adhered more avidly to untreated endothelial cells than did neutrophils (2.5 +/- 0.3 vs. 1.0 +/- 0.2 leukocytes per endothelial cell). Only a small fraction (10%-20%) of these leukocytes migrated into the subendothelium. Pretreatment of endothelial cells with interleukin 1 (IL 1) enhanced adhesion (20%), but not migration of monocytes. In contrast, neutrophil adhesion was markedly and in a time-dependent manner increased by IL 1 treatment (i.e. 200% after 6 h and 110% after 24 h of IL 1 treatment). Moreover, IL 1 pretreatment enhanced neutrophil migration twofold. Activation of leukocytes with formyl-methionyl-leucyl-phenylalanine (fMLP) enhanced both monocyte and neutrophil adhesion, but did not affect leukocyte migration. Under all conditions, monocyte adhesion was only partly (30%-40%) inhibited by monoclonal antibodies (mAb) against the common beta subunit of the leukocyte-cell adhesion molecules (LeuCAM: CD18) and 25%-30% by mAb against the alpha subunit of LFA-1 (CD11a). In contrast, mAb against the alpha subunits of Mac-1 (CD11b) and p150.95 (CD11c) were hardly effective. fMLP-mediated neutrophil adhesion was reduced to below baseline levels by anti-LeuCAM (CD18) mAb, whereas the LeuCAM contribution in IL 1-mediated neutrophil adhesion was less pronounced and varied in time. IL 1-mediated neutrophil migration, however, was completely blocked by anti-LeuCAM mAb. fMLP-mediated neutrophil adhesion was inhibited by mAb against the alpha subunits of Mac, while mAb against the alpha subunits of LFA-1 and Mac-1 both reduced IL 1-mediated adherence. In summary, we describe a novel leukocyte adhesion/migration method and demonstrate that the contribution of the LeuCAM complex in leukocyte-endothelium interaction varies depending on cell type and stimulus used.
- Published
- 1990
- Full Text
- View/download PDF
37. Distinct adhesive properties of granulocytes and monocytes to endothelial cells under static and stirred conditions.
- Author
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Kuijpers TW, Hakkert BC, van Mourik JA, and Roos D
- Subjects
- Cells, Cultured, Humans, In Vitro Techniques, Integrin alphaXbeta2 physiology, Intercellular Adhesion Molecule-1, Lymphocyte Function-Associated Antigen-1 physiology, Macrophage-1 Antigen physiology, Tetradecanoylphorbol Acetate pharmacology, Cell Adhesion drug effects, Cell Adhesion Molecules physiology, Endothelium, Vascular cytology, Granulocytes cytology, Monocytes cytology
- Abstract
Adherence of neutrophils and monocytes to endothelium is an important event in the sequence of leukocyte responses to inflammatory disease. Double-color flow microfluorimetry analysis was used to determine neutrophil and monocyte adherence to suspended endothelial cells under stirred conditions. The static adherence to endothelial cell monolayers was simultaneously determined. In both assays, neutrophils behaved in a similar way. Basal adherence of neutrophils was very low. Activation by PMA or by the chemoattractants platelet-activating factor and FMLP induced rapid binding, primarily mediated by CR3. Nonactivated neutrophils showed CD18-dependent (lymphocyte function-associated Ag-1 and CR3) and CD18-independent adherence to endothelial cells when the endothelial cells were prestimulated with rIL-1 beta. In contrast to neutrophils, nonactivated monocytes adhered avidly to resting endothelial cells. This adherence was partly CD18 dependent and partly CD18 independent. Whereas monocyte adherence under stirred conditions strongly increased upon activation by PMA, a significant decrease in adherence was found under static conditions, which was prevented by cytochalasin B. This decrease was limited to a distinct CD18-independent binding mechanism, and absent under stirred conditions. We conclude that monocytes adhere with (at least) three binding mechanisms to endothelial cells, a CD18-dependent and two CD18-independent mechanisms.
- Published
- 1990
38. Inhibitory effects of the phorbolester TPA and cigarette smoke condensate on the mutagenicity of benzo[a]pyrene in a co-cultivation system.
- Author
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Jongen WM, Hakkert BC, and van de Poll ML
- Subjects
- Animals, Benzo(a)pyrene metabolism, Biotransformation, Cell Communication drug effects, Chick Embryo, Cricetinae, Hypoxanthine Phosphoribosyltransferase genetics, Intercellular Junctions drug effects, Liver metabolism, Mutation drug effects, Plants, Toxic, Sister Chromatid Exchange drug effects, Nicotiana, Benzo(a)pyrene toxicity, Phorbols pharmacology, Smoke, Tetradecanoylphorbol Acetate pharmacology
- Abstract
The transport of reactive intermediates was studied in a co-cultivation system of primary chick embryo hepatocytes and V79 Chinese hamster cells. Two test systems with different genetic endpoints--sister-chromatid exchange (SCE) and gene mutation at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus--were used. Benzo[a]pyrene (B[a]P) was positive in both test systems. When the V79 cells were co-cultivated with the hepatocytes at a distance of 1 mm, only a slight increase in the number of SCEs was observed after exposure to benzo[a]pyrene. When the two cell types were in direct contact, addition of the phorbolester TPA or cigarette smoke condensate inhibited the mutagenic effects of B[a]P in both assays by 50%. No influence of TPA on the number of SCEs induced by B[a]P was observed in a preincubation assay using Aroclor-1254-induced rat liver homogenate. The results indicate that metabolic co-operation may play a role in the transport of reactive intermediates in this co-cultivation system. The mutagenic potential of compounds may be underestimated in systems using intact cells for metabolic activation if the compounds or their metabolites are capable of inhibiting metabolic co-operation.
- Published
- 1986
- Full Text
- View/download PDF
39. Genotoxicity testing of cigarette-smoke condensate in the SCE and HGPRT assays with V79 Chinese hamster cells.
- Author
-
Jongen WM, Hakkert BC, and van der Hoeven JC
- Subjects
- Animals, Biotransformation, Cells, Cultured, Chick Embryo, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, Male, Mutagenicity Tests, Rats, Rats, Inbred Strains, Hypoxanthine Phosphoribosyltransferase genetics, Mutagens metabolism, Plants, Toxic, Sister Chromatid Exchange drug effects, Smoke adverse effects, Nicotiana
- Abstract
The genotoxicity of cigarette-smoke condensate (CSC) was investigated using V79 Chinese hamster fibroblasts in the sister-chromatid exchange (SCE) and HGPRT (hypoxanthine-guanine-phosphoribosyl-transferase) tests. CSC was negative in the SCE test both with and without metabolic activation (co-cultivation with chick-embryo primary hepatocytes). In the HGPRT test no direct mutagenicity of CSC was observed but after metabolic activation there was a considerable increase in the number of mutants. Comparison of different metabolizing systems showed that non-induced chick hepatocytes, liver homogenate from non-induced chick embryos and liver homogenate from rats pretreated with Aroclor 1254 generated similar numbers of mutants in cells treated with CSC. In addition the capacity of CSC to inhibit metabolic co-operation between V79 cells was studied. A dose-related increase in the inhibition of metabolic co-operation was observed.
- Published
- 1985
- Full Text
- View/download PDF
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