Challenges of Regulation and Risk Assessment of Nanomaterials

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Challenges in nanomaterials human health risk assessment Aschberger K. 1 , Burello E. 1 , Christensen F.M. 1 1 European Commission, Joint Research Centre, Institute for Health and Consumer Protection, Ispra, Italy Nanomaterials risk assessment is still hampered by lack of data for both, hazard and exposure assessment. Moreover, current technical guidance documents for preparing risk assessments have only limited focus on substances in particulate and/or in nanoform. Within the ENRHES project and follow up investigations, we have prepared basic human health risk assessment appraisals for 4 types of nanomaterials: carbon nanotubes, fullerenes, nano-silver and nano-titanium dioxide. These risk assessment appraisals followed the structure of a regulatory risk assessment and, where possible, we attempted to derive indicative human no-effect levels from key studies by applying assessment factors as suggested in the REACH guidance on "Information Requirements and Chemical Safety Assessment". Consequently we compared these values to available exposure values. Our investigations showed that based on current information, occupational inhalation risks cannot be excluded, but no generalisations on risks of nanomaterials are possible. It is thus recommended to perform the risk assessment on a case-by-case basis. The results from our approach to derive indicative human no-effect levels were compared to other approaches that have recently been published. The main divergence was observed when evaluating the differences between animal and human exposure situations (including duration), when accounting for interspecies (rat to human) differences and in applying assessment factors for intraspecies differences for local effects. The REACH guidance gives preference to chemical specific assessment factors over default assessment factors if data allow and if scientifically justified. Deviations from default assessment factors thus require extensive chemical specific data and a good understanding of the fundamentals of the biological response to the material. A step forward, moving to grouping of nanomaterials and read across among different nanomaterials and to bulk-materials requires likewise a profound understanding of the properties of nanomaterials and their mechanism of action in biological systems. As a starting point we will show a hypothesis model as an example for a basic approach for using QSARs for predicting nanomaterials mode of action and adverse effects based on their different properties. 54
Variation in acute toxicity for 9 engineered nanoparticles in murine lungs Gosens I. 1 , Jacobson N.R. 2 , Stoeger T. 3 , de Jong W.H. 4 , Cassee F.R. 1 1Center Environmental Health, RIVM, Bilthoven, The Netherlands; 2 National Research Centre for the Working Environment, Copenhagen, Denmark; 3 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Germany; 4 Laboratory for Health Protection Research, RIVM, Bilthoven, The Netherlands Within the EU project ENPRA (Engineered NanoParticles Risk Assessment), hazard identification for a panel of 9 different engineered nanoparticles is being performed after a single exposure via the airways. Dose-response curves were generated for a number of endpoints and target organs. From these relationships, a benchmark dose (BMD) for each endpoint was derived to assess acute toxicity. The biological endpoints include oxidative stress, inflammation, cytotoxicity, genotoxicity and developmental toxicity. Overlap between these endpoints and cell culture assays representative for target organs should allow in vivo validation of in vitro results generated elsewhere in this project. All nanoparticles were well characterized for physico-chemical parameters. In addition a dispersion protocol has been developed and was essentially the same for in vitro and in vivo studies. Female C57BL/6 mice were exposed via intratracheal instillation for 24 hours to 0, 4, 8, 16, 32, 64 and 128 µg/mouse with 3 animals per group. Four different types of titanium dioxide (TiO2), a coated and uncoated Zinc Oxide (ZnO), nanosilver (Ag) and two types of multiwall carbon nanotubes (MWCNT) were used and adverse effects were determined in lung, liver, spleen, kidney and cardiovascular system. The most toxic particles (per µg) from this panel are both types of ZnO, based on reduced body weight and pulmonary and systemic inflammation. The TiO2 nanoparticles were not acutely toxic at most endpoints, except for some pulmonary cytotoxicity for a 10 nm rutile type of TiO2. Nanosilver was not acutely toxic at the dose-range tested here, while MWCNTs showed a trend towards some lung inflammation only at the highest doses. The BMDs will be used for extrapolation of in vitro to in vivo results and serves as an alternative for the NOAEL in the risk assessment process. 55
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Challenges of Regulation and Risk A
Page 3 and 4: TABLE OF CONTENTS 1. INTRODUCTION .
Page 5 and 6: 2. REGULATORY DEVELOPMENTS 2.1. Sum
Page 7 and 8: into risk assessments and risk mana
Page 9 and 10: Nanomaterials in the Regulatory Dev
Page 11 and 12: Guidance on the risk assessment of
Page 13 and 14: Current Progress of activity and ef
Page 15 and 16: of the Sponsorship programme and pr
Page 17 and 18: exposure using new metrics and to d
Page 19 and 20: and risks would increase the probab
Page 21 and 22: OECD Working Party on Manufactured
Page 23 and 24: REACH Implementation Project on Nan
Page 25 and 26: Industry experience with conducting
Page 27 and 28: Health, Safety, and Environment: As
Page 29 and 30: 4. CHARACTERISATION AND DETECTION O
Page 31 and 32: 4.2. Abstracts 31
Page 33 and 34: Primary and secondary characterizat
Page 35 and 36: 5. EXPOSURE ASSESSMENT 5.1. Summary
Page 39 and 40: Application and adaptation of expos
Page 41 and 42: areas. The final remark was that th
Page 45 and 46: Integrating test strategy for ecoto
Page 47 and 48: Ageing and Toxicity of real NM in a
Page 49 and 50: The bioavailability and trophic tra
Page 51 and 52: 7. HUMAN TOXICITY 7.1. Summary reco
Page 53: 7.2. Abstracts 53
Page 57 and 58: In conclusion, the in vitro hepatoc
Page 59 and 60: Acknowledgements The editors would
Page 61 and 62: 24 FURUNO Shoko Association (NIA) A
Page 63 and 64: 76 VOM BROCKE Jochen German Federal
Page 65 and 66: 05. NANEX: development of Exposure
Page 68 and 69: European Commission JRC 67654- Join
Page 70: The mission of the JRC is to provid
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