13.50 dhr de Jong


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  • How can you define a nanoparticles dose To give you an impression how size, particle number and surface area are related to each other, i can show you 3 times a cube of one by one centimetre. The first is only 1 particle with in total 6 square cm. If the cube is build up from little 1 mm cubes, then 1000 cubes are needed with a total surface area of 60 square cm. If the particles are 1 nm cubes, then …. A lot particles would be needed to fill the cube with a total surface area of 600 square kilometres. Inside the body, the surface of particles is in contact with the tissue
  • 13.50 dhr de Jong

    1. 1. Nanotechnology What about safety, is there a risk? Evaluation of risk Wim de Jong
    2. 2. Increase in consumer products with nanoclaim Number of total products listed, by date of inventory update, with regression analysis. August 2009 Nanotechnology Consumer Products Inventory, Woodrow Wilson International Center for Scholars, Washington, USA
    3. 3. Most commonly used nanomaterials in consumer products Nanotechnology Consumer Products Inventory, August 2009, Woodrow Wilson International Center for Scholars, Washington, USA
    4. 4. Consumer products with nanoclaim
    5. 5. Why are we concerned? Nanomaterials (nanoparticles) can have sizes similar to structures at subcellular level. Reminder, chemicals (molecules) also do this. nanopore, dendrimer, nanoshell, fullerene, nanotube, nanowire, nanocrystalls cantilevers, microneedles Nanotechnology lab-on-a-chip erythrocyte apple water molecule virus DNA Nature Nanometres 10 -1 1 10 1 10 2 10 3 10 4 10 5 10 6 10 7 10 8
    6. 6. Increase in reactivity due to increase in surface All: 1 x 1 cm Decrease in size results in (enormous) increase in surface area 6,000cm 2 1 x 10 12 1 µm 60.000.000 cm 2 (600km 2 ) 1 x 10 21 1 nm 60 cm 2 1,000 1 mm 6 cm 2 1 1 cm Total Surface area number size
    7. 7. Existing problems in safety evaluation of nanomaterials/nanoparticles <ul><li>Various crystal forms of same material </li></ul><ul><ul><li>Titanium dioxide; rutile, anatase, brookite crystals) </li></ul></ul><ul><li>Problems with dispersion </li></ul><ul><li>Protein adherence, effect of protein corona </li></ul><ul><li>Dose metrics (mass, number of particles, surface area, …) </li></ul>
    8. 8. Problems with dispersion in toxicity testing Gold nanoparticles in PBS, A and B 10 nm, C 50 nm, and D 100 nm diamater) De Jong et al., Biomaterials 29, 1912, 2008
    9. 9. Nanoparticles do not exist as single particle entity, they adsorbe “things”. <ul><li>What do we know </li></ul><ul><ul><li>Protein corona is important for biological interactions </li></ul></ul><ul><ul><li>Corona is not static, proteins get on and off </li></ul></ul><ul><li>What do we not know </li></ul><ul><ul><li>Dependence on nanomaterial? </li></ul></ul><ul><ul><li>Dependence on size? </li></ul></ul><ul><ul><li>How does it affect biological activity of nanomaterial </li></ul></ul>EU FP6 project NanoInteract, courtesy of Prof Kenneth Dawson, UCD, Dublin, Ireland
    10. 10. Is nano more toxic than micro material? Depends on the dose metric used for particle toxicity Oberd ö rster et al., Environ Health Perspect 113, 823, 2005 This was demonstrated for local effects in the lung after inhalation exposure. What about other routes of exposure (oral, dermal, intravenous)?
    11. 11. Risk Assessment Risk characterization Hazard characterization Internal dose Hazard identification Dose response assessment Exposure assessment
    12. 12. Safety evaluation is not only toxicology <ul><li>Toxicology is detection of toxic = harmful effect and study mechanisms of toxicity. </li></ul><ul><li>Safety evaluation is using toxicology for </li></ul><ul><li>determination of no-effect levels </li></ul><ul><li>which can be used in risk assessment . </li></ul><ul><li>You need toxic dose to determine non toxic level </li></ul>
    13. 13. What about safety? <ul><li>Safety evaluation is done by performing a risk assessment (RA) </li></ul><ul><ul><li>Identification of substance </li></ul></ul><ul><ul><li>Hazard characterization </li></ul></ul><ul><ul><ul><li>Hazard identification </li></ul></ul></ul><ul><ul><ul><li>Dose response effect (no effect level) </li></ul></ul></ul><ul><ul><li>Exposure assessment </li></ul></ul><ul><ul><li>Risk characterization </li></ul></ul><ul><li>What is risk? </li></ul><ul><ul><li>Risk, combination of likelyhood of occurrence of harm to health and </li></ul></ul><ul><ul><li>the severity of that harm </li></ul></ul><ul><ul><li>Margin of safety (no effect level/exposure level) </li></ul></ul><ul><ul><li>No exposure >>>>> No risk </li></ul></ul><ul><li>Risk is a possibility, not an absolute value !!! </li></ul>
    14. 14. Some issues/problems associated with engineered nanomaterials
    15. 15. Nanofibres, issue on CNT versus asbestos Scientific publications on possible cancer risk Sakamoto Y, Nakae D, Fukumori N, Tayama K, Maekawa A, Imai K, Hirose A, Nishimura T, Ohashi N, Ogata A. Induction of mesothelioma by a single intrascrotal administration of multi-wall carbon nanotube in intact male Fisher 344 rats. The Journal of Toxicological Sciences, 34, 65-76, 2009 nature nanotechnology | VOL 3 | JULY 2008 | 423
    16. 16. Poland et al 2008 MWCNT induce chronic inflammation Takagi et al 2008, Sakamoto et 2009 MWCNT induce tumors in P53 mice and F344 rats Muller et al 2009 MWCNT do NOT induce tumors in 2 year study Nygaard et al 2009 CNT act as adjuvant
    17. 17. Nanofibres, the MWCNT issue <ul><li>There are different types of MWCNT!!! </li></ul><ul><li>“ when a fibre has characteristics of brown/blue asbestos </li></ul><ul><li>(rigid, non degradable, length >20 µ m) </li></ul><ul><li>it behaves like brown/blue asbestos” (Poland et al., 2008) </li></ul><ul><li>Lesson is NOT </li></ul><ul><li>MWCNT behave like asbestos but.... </li></ul><ul><li>Manufacturer....when producing MWCNT </li></ul><ul><li>Check for these specific characteristics </li></ul><ul><li>(rigidity, degradability, fibre length) </li></ul><ul><li>Perform proper safety evaluation to exclude this specific hazard associated with a certain types of fibres </li></ul>
    18. 19. Song et al., Exposure to nanoparticles is related to pleural effusion, pulmonary fibrosis and granuloma <ul><li>Case report on 8 workers (age 18-47 yrs) </li></ul><ul><ul><li>One with working period of 3 months free of symptoms, 7 with symptoms and working period 5-13 months (2 deaths) </li></ul></ul><ul><li>Clinical symptoms </li></ul><ul><ul><li>Shortness of breath, dyspnea </li></ul></ul><ul><ul><li>Pleural effusions (n=7), pericardial effusions (n=5, 2 died) </li></ul></ul><ul><ul><li>Rash with itching on face, hands, and forearms </li></ul></ul><ul><li>Clinical tests </li></ul><ul><ul><li>Bronchoscopy </li></ul></ul><ul><ul><li>Thoracoscopy </li></ul></ul><ul><ul><li>Thoracic surgery </li></ul></ul><ul><ul><li>Pleural effusion, no malignant cells, TEM presence of ~30nm particles </li></ul></ul><ul><ul><li>Histopathology TEM of lung tissue, presence of clusters of ~30nm particles </li></ul></ul><ul><li>Clinical tests with mainly negative results </li></ul><ul><ul><li>Bacteriology </li></ul></ul><ul><ul><li>Virology </li></ul></ul><ul><ul><li>Tumor markers </li></ul></ul>
    19. 20. Nanostructures in pleural fluid and in pulmonary epithelial cell Song et al, Eur Resp J 34, 559-567, 2009 Bar represents 200 nm
    20. 21. Song et al., Exposure to nanoparticles is related to pleural effusion, pulmonary fibrosis and granuloma <ul><li>Diagnosis </li></ul><ul><ul><li>Histopathology </li></ul></ul><ul><ul><ul><li>Nonspecific pulmonary inflammation </li></ul></ul></ul><ul><ul><ul><li>Pulmonary fibrosis </li></ul></ul></ul><ul><ul><ul><li>Foreign body granulomas in pleura </li></ul></ul></ul><ul><ul><li>TEM analysis </li></ul></ul><ul><ul><ul><li>Nanoparticles present in pulmonary cells and chest fluid </li></ul></ul></ul><ul><li>Workplace survey </li></ul><ul><ul><li>Closed room, one door, no windows (door closed due to cold outdoor temperatures) </li></ul></ul><ul><ul><li>One machine used to air spray materials starting with a paste material </li></ul></ul><ul><ul><ul><li>Polyacrylate ester </li></ul></ul></ul><ul><ul><ul><li>Defect exhauster/ventilation unit (5 months before complaints started) </li></ul></ul></ul><ul><ul><li>Gas chromatography/mass spectrometry and EM evaluation </li></ul></ul><ul><ul><ul><li>Presence of nanoparticles in paste used for spraying </li></ul></ul></ul><ul><ul><ul><li>Presence of nanoparticles in dust particles obtained from intake of gas exhauster </li></ul></ul></ul>
    21. 22. Song et al., Exposure to nanoparticles is related to pleural effusion, pulmonary fibrosis and granuloma <ul><li>Conclusions </li></ul><ul><ul><li>Severe lung and thoracic problems in patients </li></ul></ul><ul><ul><li>No plausible cause found </li></ul></ul><ul><ul><ul><li>Extensive clinical investigation resulted in exclusion of possible causes (infectious disease) </li></ul></ul></ul><ul><ul><li>Polyacrylate nanoparticles as cause seems likely </li></ul></ul><ul><li>Comments </li></ul><ul><ul><li>No definitive cause response relationship was established </li></ul></ul><ul><ul><ul><li>Causative confirmation (animal studies, identification of NP in pleural effusions) is lacking </li></ul></ul></ul><ul><ul><li>Extensive description of case reports </li></ul></ul><ul><ul><li>Hygienic conditions of very low quality </li></ul></ul>
    22. 23. Where do we stand with nanotechnology? <ul><li>Multitude of products available on the market </li></ul><ul><ul><li>Some labeled, others not </li></ul></ul><ul><li>Various hazards (toxic effects) identified </li></ul><ul><ul><li>Inhalation exposure most severe hazard and highest risk </li></ul></ul><ul><ul><li>But risk of inhalation of dust is well known (silicosis) </li></ul></ul><ul><li>Exposure estimation remains a problem </li></ul><ul><li>Case by case approach for risk assessment advocated </li></ul>
    23. 24. <ul><li>Nanotechnology does not exist by itself. </li></ul><ul><li>It is an area with a multitude of applications and possibilities </li></ul><ul><li>We are dealing with various </li></ul><ul><li>NANOTECHNOLOGIES </li></ul><ul><li>each with its own use and application </li></ul><ul><li>AND ITS OWN RISKS </li></ul><ul><li>A balanced risk communication to the public is needed to avoid......... </li></ul>
    24. 25. Societal fear for ………technology. <ul><li>Information Technology </li></ul><ul><ul><li>Artificial intelligence dominating man </li></ul></ul><ul><ul><li>Big Brother is watching you (1984, George Orwell, 1949) </li></ul></ul><ul><li>Biotechnology/Genetic modification </li></ul><ul><ul><li>Manipulation of organisms/man (BBC news 1998) </li></ul></ul><ul><ul><li>Jurassic Park (Michael Crichton, 2005) </li></ul></ul><ul><li>Nanotechnology </li></ul><ul><ul><li>Prey (Michael Crichton, 2002) Self assembling nanostructures become alive and thinking </li></ul></ul><ul><ul><li>Privacy, personal tracking by electronic nanodevices </li></ul></ul>