Đang tải... (xem toàn văn)
Outline • Evolution of Chemicals Legislation – Addressing much larger numbers of substances in Canada, Europe, U.S. • Predictive Tools – Physiologically Based Pharmacokinetic (PBPK) Modelling – Hazard • Combined Exposure to Multiple Chemicals • The Need for More Efficient Testing Strategies • ReadingInformation Sources Evolving Legislative Mandates for Industrial Chemicals • Most chemicals already in use at the time of introduction of modern chemicals legislation in Europe and North America (late 1980’s) were “grandfathered” – No testing, assessment were required • New chemicals required assessment • Between the late 1980s and late 1990s, countries focussed assessments on approx. 100 out of the tens to hundreds of thousands of industrial chemicals in use (i.e., 0.1% to 1%)
Developments in Chemical Risk Assessment Legislative Trends, Advances in Testing & Predictive Tools M.E. (Bette) Meek McLaughlin Centre University of Ottawa bmeek@uottawa.ca CRI Bangkok 1 Outline • Evolution of Chemicals Legislation – Addressing much larger numbers of substances in Canada, Europe, U.S. • Predictive Tools – Physiologically Based Pharmacokinetic (PBPK) Modelling – Hazard • Combined Exposure to Multiple Chemicals • The Need for More Efficient Testing Strategies • Reading/Information Sources 2 Evolving Legislative Mandates for Industrial Chemicals • Most chemicals already in use at the time of introduction of modern chemicals legislation in Europe and North America (late 1980’s) were “grandfathered” – No testing, assessment were required • New chemicals required assessment • Between the late 1980s and late 1990s, countries focussed assessments on approx. 100 out of the tens to hundreds of thousands of industrial chemicals in use (i.e., 0.1% to 1%) 100 100,000 3 Evolving Legislative Mandates for Industrial Chemicals (Cont’d) • Chemicals which were considered: – E.g , Benzene, – formaldehyde, – asbestos, etc. • Increasingly, legislation is requiring consideration of all chemicals – E.g., 23, 000 in Canada – 130, 000 in Europe 4 Evolving Legislative Mandates for Existing Chemicals (Cont’d) • Canada – “Categorization” (i.e., systematic priority setting) for 23, 000 chemicals by Sept., 2006 under the Canadian Environmental Protection Act (CEPA) • Europe – Registration, Evaluation and Authorization of Chemicals (REACH) (2007) • Volume trigger and hazard based • Consistency between Existing (n = 130, 000) and New Chemicals • Industry Responsibility • U.S. – Voluntary Testing Initiatives – Renewal of legislation 5 Comparing U.S., Canada and EU Approaches U.S. ChAMP Canada Chemical Management Plan 2 EU REACH Registration & Authorization Candidate List Announce Challenge Notice to Obtain More Info DSL Categorization/ Prioritization 500 High Priority Chemicals Substance Profiles Risk Assessments Risk Management Chemicals with Identified Info Needs Registration Dossier Registration Dossier ≥ 1,000 t ≥ 1 t ≥ 100 t Registered (2008-2018) 2008 and Ongoing 2011 Evaluation Restriction Candidate List Authorization 2015 2013 2011 2009 20182013 2010 Starts in 2009 2006 2006 REACH New Chemicals ≥ 1 t Pre-REACH Existing Chemicals in Commerce ≥ 1 t 1 DSL = Canadian Environmental Protection Act Domestic Substances List 2 Other aspects of the CMP are not shown on this figure. 1,000 t = 2.2 M lbs.; 100 t = 220k lbs.; 1 t = 2.2k lbs. Current TSCA Inventory Resetting the Inventory IUR Chemicals Organics SPP Inorganics HPV Challenge Assess & Initiate Follow- Up Action Assess & Initiate Follow- Up Action 2012 2012 – 2014? Non-IUR Chemicals 6 The Canadian Environmental Protection Act (CEPA) • Under CEPA ’88, assessments for specified numbers of Priority Substances (5 yr timeframe) – N= 44 on Priority Substances List (PSL) 1 – N= 25 on PSL 2 – Risk management now implemented for most considered “toxic” under CEPA • CEPA ’99 extended our mandate to all Existing Substances in Canada (n=23,000) – Categorization of the Domestic Substances List (DSL) by September, 2006 (priority setting), – screening, – full (Priority Substances) assessment 7 CATEGORIZATION of the Domestic Substances List (DSL) (First Phase) (n=23,000) Decisions of Other Jurisdictions Public Nominations No further action under this program CEPA-Toxic No further action under this program CEPA-Toxic IN-DEPTH ASSESSMENT - Priority Substances List (Third Phase) Risk Management Risk Management Greatest Potential for Human Exposure Substances that are Persistent or Bioaccumulative “Inherently Toxic” to Humans “Inherently Toxic” to non-Human Organisms SCREENING ASSESSMENT (Second Phase) CEPA 1999 Existing Substances Program INCREASING REFINEMENT OF PRIORITIES + COMPLEXITY OF ASSESSMENT 8 DECREASING NUMBERS OF SUBSTANCES DECREASING UNCERTAINTY 9 Simple and Complex Priority Setting Tools EXPOSURE Simple Exposure Tool (SimET) - Relative ranking of all DSL substances based on submitters (S),quantity (Q) and expert ranked use (ERU) Complex Exposure Tool (ComET) - Quantitative plausible maximum age-specific estimates of environmental and consumer exposure for individuals based on use scenario (sentinel products), phys/chem properties & bioavailability HAZARD Simple Hazard Tool (SimHaz) - Identification of high or low hazard compounds by various agencies based on weight of evidence and expert opinion/consensus Complex Hazard Tool (ComHaz) - Hierarchical approach for multiple endpoints & data sources (e.g., (Q)SAR) including preliminary weight of evidence framework Potential for exposure influential in setting priorities Included simple use profiling for all 23, 000 chemicals, more complex use profiling for priorities Registration, Evaluation, Authorization of Chemicals (REACH) within Europe • Registration of manufactured/imported chemical substances > 1 tonne/year (Industry) • Increased information and communication throughout the supply chain • Evaluation of some registration dossiers (Agency & Member States) • Authorisation for use of substances of very high concern (CMR, PBT, vPvB, similar properties) • Restrictions: “Safety net” (Can be initiated by Member States and the Commission) -> European Chemicals Agency to manage the system [...]... for increased efficiency in risk assessment – Processing much larger numbers of substances • More/better predictive tools & more efficient toxicity testing –Drawing on new technologies such as the genomics 13 Predictive Tools M.E (Bette) Meek McLaughlin Centre University of Ottawa bmeek@uottawa.ca CRI Bangkok 14 Physiologically Based Pharmacokinetic (PBPK) Models in Risk Assessment • Estimating internal... “Verified” against experimental data PBPK modeling Venous Blood GI Liver Arterial Blood Oral dose Lungs Tissues Skin Chemical in air Rate of change = Input - Output (Krishnan and Andersen 2007) 16 Value of PBPK Models • Increasing accuracy of risk estimates and understanding of uncertainty and variability • Help to interpret biomonitoring data – X ug/L of chemical X in blood = ???? risk for the individual... blood = ???? risk for the individual or population • Reducing reliance on animal testing – Biologically meaningful quantitative framework in which in vitro data can be more effectively utilized Computational (Predictive) Hazard Tools • Increasingly, computerized analysis is being applied: – to draw upon the significant amounts of genomic data being generated, and – to make maximum use of the results... Compounds of same class included in the Database 00 DOSE 30 History of the TTC • Introduced and used principally in the food area (regulatory use – mid 90’s) – food contact materials • US Food and Drug Administration (FDA) • European Food Safety Agency (EFSA) – flavouring agents • Joint FAO/WHO Expert Committee on Food Additives (JECFA), • Being considered for other areas – E.g., industrial chemicals,... categories • Integrate metabolism/mechanisms with categories/(Q)SAR • Assist in the estimation of missing values for chemicals 26 Example Questions in the (Q)SAR Toolbox • Is the chemical included in regulatory inventories or existing chemical categories? • Has the chemical already been assessed by other agencies/organizations? • Would you like to search for available data on assessment endpoints for each... Structural fragments? Log Kow? Electronic States? Interatomic Distances? Other? Toxic? 23 The Need for Combining Output of Predictive Models • Because we don’t know exactly which characteristics best predict toxicity, we use a combination of models – “weight of evidence” • Comprehensive, integrated judgment of all relevant information supporting conclusions regarding potential toxicological effects –Consistency,... genotoxicity of quinones is associated with their ability to undergo enzymatic and non-enzymatic redox cycling with their corresponding semiquinone radical [Bolton et al] As a result they generate superoxide anion radicals that can be converted to powerfully oxidising hydroxyl radicals that can cause oxidative damage to DNA In addition … » (Source: DfW report) Which Descriptors are Important to Distinguish between... substances in preparations) obtain/generate information on their substances and • Use this knowledge to ensure responsible and wellinformed management of the risks of chemicals throughout their life cycle Documentation • Technical Dossier: starting at 1 tonne / year per manufacturer or importer • Chemical Safety Report: starting at 10 tonnes / year – Documentation of assessment – Communication in Safety... toxicological effects –Consistency, specificity, biological plausibility 24 How do Predictive Hazard Tools Contribute? • For human health-related effects, they contribute most in the consideration of cancer/genotoxicity data – Wider range of supporting data from in vitro studies of genotoxicity – Some mechanistic basis (i.e., interaction with DNA) 25 Organization for Economic Co-operation and Development... Cannot be Used for: • • • • • Local (site of contact) and lung (via inhalation) effects Dermal irritation or sensitization Proteins / allergenicity Metals and metal containing compounds Compounds with structural alerts for high potency carcinogenicity (must be evaluated separately) • Compounds expected to be bioaccumulative (e.g., dioxins) • Others 34 Application of the TTC - Steps • 1 Check to see if . Developments in Chemical Risk Assessment Legislative Trends, Advances in Testing & Predictive Tools M.E. (Bette) Meek McLaughlin Centre University of Ottawa bmeek@uottawa.ca CRI Bangkok 1 Outline •. Reducing reliance on animal testing – Biologically meaningful quantitative framework in which in vitro data can be more effectively utilized Computational (Predictive) Hazard Tools • Increasingly,. for More Efficient Testing Strategies • Reading/Information Sources 2 Evolving Legislative Mandates for Industrial Chemicals • Most chemicals already in use at the time of introduction of modern