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Summary
INTRODUCTION
Terms of reference
Background
Definition of `poorly soluble particles of low toxicity`
PHYSICO-CHEMICAL ASPECTS ASSOCIATED WITH `LUNG OVERLOAD`
Dose metrics
Particle mass
Particle volume
Particle surface area
Particle properties
Particle density
Particle size (fine, ultrafine, nano)
Particle shape
Surface reactivity
Dosimetry
Conclusion
BIOSOLUBILITY
Definition for (bio)solubility
Impact of biosolubility on clearance of deposited particular matter
Clearance classes
Case study on zinc oxide (ZnO)
Case study on amorphous silica
Case study on cobalt oxide (Co3O4)
Guidance on assess bio-solubility
Conclusion
PATHOBIOLOGY OF ʽLUNG OVERLOADʼ
Relevance of alveolar macrophages
Relevance of inflammation
Relevance of cell proliferation
Relevance of oxidative stress
Particle translocation
UFP show a rapid translocation from the site of deposition
Translocation is determined by solubility and size
GI tract may contribute to particle burden in organs
Source of UFP may influence translocation
Target organs for translocation
Summary
SPECIES DIFFERENCES AND MECHANISMS OF LUNG TUMOuR FORMATION IN RATS
Subchronic inhalation studies
Pigment-grade TiO2
Ultrafine TiO2 particles
Carbon black particles
Chronic inhalation studies
Pigment-grade TiO2
Ultra-fine grade TiO2
Carbon black
Other mammalian species responses to inhaled particulates
Understanding the mechanisms of the unique neoplastic rat lung responses to particle overload
Conclusions
Adverse outcome pathway
(AOP) rat
(AOP) mouse and hamster
Relevance of `Lung Overload` for humans
Biomathematical modelling of respirable dust in human lungs
INFLUENCE OF METHODOLOGY USED
Inhalation
Instillation
Pros and cons of instillation and inhalation
In vitro methods
HUMAN DATA, INCLUDING EPIDEMIOLOGY
Existing data inclusive epidemiology
Various dusts
Toner
Carbon black
Carbon black evaluation IARC (2010)
Titanium dioxide
Titanium dioxide IARC evaluation (2010)
Conclusion
REGULATORY CONSIDERATIONS
Carcinogen classifications of relevance to inhalation exposure to PSP
United Nation’s Globally Harmonized System (UN GHS) and its European implementation law EU regulation (EC) 1272/2008 (`CLP`)
International Agency for Research on Cancer (IARC)
German MAK-Commission
Other non-tumorigenic classifications of relevance to PSP inhalation exposure
United Nation’s Globally Harmonized System (`UN GHS`) and its European implementation law EU Regulation (EC) 1272/2008 (`CLP`)
Proposed approaches to derive health based exposure limits for PSPs
Generic versus substance specific approaches
Specific DNEL derivation for PSPs following inhalation exposure
Conclusions on the rat lung overload issue from a regulatory perspective
Recommendation from a regulatory perspective for classification and DNEL derivation
Classification for tumorigenic and non-tumorigenic effects
REACH DNEL establishment for PSP
CONCLUSIONS/DATA GAPS
Current knowledge regarding lung overload
Existing data gaps & proposed way forward (to be addressed at a workshop)
ABBREVIATIONS
APPENDIX A: Test Methodology: BALF Study
APPENDIX B: Derivation of a human no effect level (‘DNEL’) under REACH’
BIBLIOGRAPHY
MEMBERS OF THE TASK FORCE
MEMBERS OF THE SCIENTIFIC COMMITTEE
MEMBERS OF THE SCIENTIFIC COMMITTEE (cont’d)
Technical report 122
HUMAN DATA, INCLUDING EPIDEMIOLOGY
