Canadian Experience - Priority Setting and Screening of All Existing Substances under the Canadian Environmental Protection Act (CEPA)

Transcription

1 Canadian Experience - Priority Setting and Screening of All Existing Substances under the Canadian Environmental Protection Act (CEPA) ISRTP Workshop: Progress and Barriers to Incorporating Alternative Toxicological Methods in the U.S. Baltimore, MD November 18/05 Presented by: M.E. (Bette) Meek Existing Substances Division Health Canada

2 Outline Who we are Current Focus/Priorities & Why Overview of the tools, products and process meeting a significantly expanded mandate priority setting for > 20,000 chemicals screening assessments for several thousand full risk assessment on complex datasets Implications for risk assessment and testing/research Importance of systematic consideration of all substances and value of the predictive tools 2

3 Who Are We? - Existing Substances Division (EXSD) - Environmental Contaminants Bureau (ECB) - Safe Environments Programme (SEP) - Healthy Environments & Consumer Safety Branch (HECS) Address HC responsibilities for Existing Industrial Chemicals under the Canadian Environmental Protection Act (CEPA) 3

4 The Canadian Environmental Protection Act (CEPA 99) Progressive, encompassing legislation with a broad range of powers information gathering and reporting conduct of research, assessment and management, enforcement Primary authority to assess and manage the risks posed by toxic substances (health and environment) in Canada Federal jurisdiction and the provinces (through administrative agreement) Harmonization with international initiatives for pollution control Administered by Environment and Health Canada Introduced in 1988, renewed in 1999 and currently under review Encourages public participation 4

5 CEPA Key Activities Drivers Risk Assessment Research CEPA Registry Risk Management Mandated CEPA time-frames Program Management 5

6 Existing Substances under CEPA Approximately 23,000 substances (e.g., industrial chemicals) on the Domestic Substances List (DSL) The DSL was created for the purpose of defining a new substance under CEPA If notified, not considered new Includes substances grandfathered under the legislation i.e., those used for commercial manufacturing or manufactured or imported in Canada at >100 kg/year between January 1, 1984 and December 31, 1986 (n = approx. 23,000) Organics (50%), inorganics, polymers and substances of unknown or variable composition, complex reaction products and biologicals (UVCBs) 2

7 Assessment of CEPA Existing Substances the Mandate for Human Health Address both exposure and effect to set priorities for risk management Consumer & Environmental Exposure All age groups Multimedia Identifying most important media/sources of human exposure Publicly accountable transparent process, peer input/consultation/review, documented outcome Information gathering, reverse onus provisions, but Government responsibility in assessment considerable 7

8 Assessments under CEPA for Existing Substances Under CEPA 88, assessments focussed on limited numbers of Priority Substances ( n= 44 on PSL 1 and 25 on PSL 2) Assessments of large & complex datasets Robust process and methodology Contributed to formats/methodology internationally 60 CEPA Assessment Reports, approx. 100 published articles, 20 international assessments CEPA 99 extended our mandate to all Existing Substances in Canada (n=23,000) Categorization of the Domestic Substances List (DSL) by 2006, screening and full (Priority Substances) assessments Mandate is leading, internationally, though initiatives pending elsewhere EU Registration, Evaluation, Authorization of Chemicals (REACH) 8

9 Objectives of Categorization (Priority Setting) and Screening of All Existing Substances Short Term: To systematically set priorities for data generation and assessment for both human health and ecological effects of all Existing Substances Long Term: Greater consistency in consideration of New versus Existing Substances Why is this Important? Many, if not most Existing Substances pose greater risk than New Substances Widespread use, often higher toxicity Not systematically considered 9

10 Impact of Categorization under CEPA & Similar Programs (e.g., EU REACH program) Information gathering/global repositories for Existing Chemicals More data/information on existing chemicals in the public domain Development/refinement of predictive tools Exposure (modelling) Effect [Quantitative structure activity relationships (QSAR)] Significant learning based on profiling of large numbers of substances True versus perceived priorities Additionally focussing testing and research Much more intelligent testing strategies addressing true priorities Iterative approaches to priority setting and assessment that increase our efficiency and revolutionize the way we do business Integration of exposure and effect 10

11 CEPA Existing Substances Program CATEGORIZATION of the Domestic Substances List (DSL) by 2006 (First Phase) (n=23,000) Decisions of Other Jurisdictions Public Nominations STAGE 1 Greatest Potential for Human Exposure Substances that are Persistent or Bioaccumulative STAGE 2 Inherently Toxic to Humans Inherently Toxic to non-human Organisms STAGE 3 SCREENING ASSESSMENT (Second Phase) No further action under this program CEPA-Toxic Risk Management IN-DEPTH ASSESSMENT - Priority Substances List (Third Phase) No further action under this program CEPA-Toxic Risk Management STAGE N-1 STAGE N 11

12 Approach to Categorization & Screening Early recognition that program architecture required multiple stages of increasing complexity for all groups of compounds First stages to be simple/pragmatic to address all substances, based on limited information for each or many Simple tools Subsequent stages must be discriminating to set true priorities for further work Complex tools Cut for categorization determined by the timeline Protective approach, conservative in the absence of information, but with priorities specified, based on program experience Required significant technical capacity to develop / force the science for precedent setting mandate Consistent with but also influencing international priorities Peer input/consultation/review of technical components and release of robust proposals for public comment 12

13 Health Canada Milestones for DSL Categorization October 19, 2004 Release of Health Canada Draft Maximal List via ListServe November April 2004 Release of Proposed Initial GPE List for Comment June August 2005 Release of Proposed Integrated Framework for the Health-Related Components of DSL Categorization for Comment September 8, 2005 HC/EC DSL Prioritization Update Session Spring 2006 Release of Integrated Framework for the Health-Related Components of DSL Categorization March 8, 2004 Information Session June 1, 2005 HC/EC DSL Categorization Update Session July 28, 2005 HC/EC DSL Prioritization Update Session November 8, 2004 Peer Input Meeting Complex Exposure Tool November 22, 2004 Information Session December 30, 2004 Release of Health Canada Draft Maximal List & Sublists on Website 13

14 INTEGRATED FRAMEWORK DOMESTIC SUBSTANCES LIST HEALTH CANADA ENVIRONMENT CANADA Application of Simple Tools DSL Substances Identified as Hazardous to Human Health Highest Lowest Organic Substances that are Persistent and/or Bioaccumulative and Not Inherently Toxic to Non-human Organisms DSL Substances Ranked According to Potential For Exposure HC Maximal List (n=1896) Substances that are Persistent and/or Bioaccumulative According to the Regulations Substances that are Persistent and/or Bioaccumulative and Inherently Toxic to Non-human Organisms Application of Complex Tools No Further Action (Not 64c toxic ) Substances Prioritized & Identified For Full Screening Health Assessment EC Substances Identified for 14 Screening Assessment

15 DSL TOOLS - HEALTH Exposure SimET (Relative ranking of all DSL substances based on submitters (S),quantity (Q) and expert ranked use (ERU) 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 [High (H) or Low (L)] SimHaz (identification of high or low hazard compounds by various agencies based on weight of evidence for multiple endpoints) ComHaz (Hierarchical approach for multiple endpoints & data sources (e.g., QSAR) including weight of evidence without bias to data availability Hazard Quantification (Previously Exposure-Response) HazQ (measures of exposure-response developed (where possible) on the basis of measured or predicted carcinogenic potency, reference values or effect levels 15

16 The Simple Exposure Tool - SimET SimET is a relative ranking tool by which we have binned all 23,000 substances Based on three different lines of evidence, derived from the limited information provided for all substances on the DSL: quantity (estimated annual quantity of use, Q), number of submitters (S) use (sum of normalized expert ranked use codes, U), reflecting two workshops Ground-truthed against more robust and recent data on use Use far more important than volume as the critical driver Implications for testing & other programs (e.g. high production volume; REACH) 16

17 Criteria for Greatest, Intermediate and Lowest Potential for Exposure (GPE, IPE & LPE) Quantity (kg/year) Number of Submitters Sum of the Expert Ranked Use Code Indices GPE > Top 10% Top 10% IPE > n.a. Top 30% LPE All All All 17

18 The Complex Exposure Tool (ComET) Being applied to thousands of prioritized substances Provides quantitative plausible maximum estimates of exposure of individuals in the general population by age group for consumer (nearfield) & multimedia environmental (far-field) exposure based on readily available generic data Near-field exposure Frequency and duration of product use Sentinel product scenarios Sentinel product - consumer product that yields the highest exposure to an individual for one of its component substances as compared to other consumer products containing that substance Far-field exposure Concentrations in environmental media estimated from fugacity modelling (generic unit world model that can be scaled) Exposure for all age groups 18 Contributes considerably to available product exposure scenarios

19 Overview of ComET Chemical Identity Measures of Dose- Response for Critical Effects Physical/ Chemical Properties Near-field Substance Profile Far-field Production Quantity Production Quantity Bin + Release Factor Emissions Sentinel Products Far Field SP 1 SP 2 SP 3 SP n Age Specific Variables Human Exposure Priority for Assessment 19

20 The Far-field Model Substance Calculate Unit Emissions Phys-Chem properties and use information (Substance Profile) Transformation Migration into media and fate for uptake Ambient Concentrations Scale unit concentrations using actual emissions, production quantities and use information Integrate with Near-field Component 20

21 ComET Input Parameters Readily Available Information Use Profiling Near-field Selection of sentinel products, based on use for specific function in generic products (e.g., surfactant in paint, solvent in paint, pigment in paint) Maximum proportion generically used for a specific function in a product (e.g % of surfactant in paint, etc.) Frequency and duration of product use Amount transferred during use Bioavailability Far-field (Fugacity Modelling to Intake Media) Emissions/Release Physical/Chemical properties Intake of relevant media 21

22 Exposure Tools What We ve Learned Value of use profiling in focussing resources & increasing efficiency Much of the information is publically available Robust search strategy for use profiling which includes approx. 60 sources Information exists to set exposure-based priorities, though labour intensive to identify Volume a poor surrogate for exposure Many high volume production chemicals present lowest potential for exposure Environment and health priorities diverging Greater influence of use profile, toxicokinetics in designating priorities for human health than persistence (P) and bioaccumulation (B) Priorities vary from what we would have expected Value of systematic consideration of all substances 22

23 DSL TOOLS - HEALTH Exposure SimET (Relative ranking of all DSL substances based on submitters (S),quantity (Q) and expert ranked use (ERU) 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 [High (H) or Low (L)] SimHaz (identification of high or low hazard compounds by various agencies based on weight of evidence for multiple endpoints) ComHaz (Hierarchical approach for multiple endpoints & data sources (e.g., QSAR) including weight of evidence without bias to data availability Hazard Quantification (Previously Exposure-Response) HazQ (measures of exposure-response developed (where possible) on the basis of 23 measured or predicted carcinogenic potency, reference values or effect levels

24 Simple Hazard (SimHaz) Tool Classifications of other agencies, selected based on comprehensiveness, peer review, etc. Applied to all 23,000 substances on the DSL High Hazard Lists/Endpoints Cancer (IARC, EU, HC, US EPA etc.) Genotoxicity (EU) Developmental Toxicity (EU) Reproductive Toxicity (EU) Respiratory Sensitization (EU) Low Hazard Lists PMRA 4a/US EPA OECD Low Concern 24

25 Complex Hazard (ComHaz) Tool Being applied to thousands of prioritized substances Hierarchical approach for multiple endpoints & data sources including weight of evidence Qualitative/quantitative endpoints; conservative Weight of evidence for qualitative endpoints Sources of Information Considered Hierarchically Comprehensive literature searching (electronic & hardcopy resources) Reviews or secondary accounts of toxicological or epidemiological studies Original Toxicological and Epidemiological Studies [(Quantitative) Structure Activity Relationship (QSAR)]Models (TOPKAT, CASETOX) Chemical structures of concern, Structure Activity Relationship (SAR) models (DEREK), surrogate/analogue approaches (Leadscope, visual grouping) 25

26 ComHaz Tool Criteria Endpoint Information Source Criteria Cancer Data or (Q)SAR No hits/wt of Evidence Genotoxicity Data or (Q)SAR No hits/wt of Evidence Regulatory/Reference Value International & National Assessments Ref Value 0.1 mg/kg bw/day Developmental Toxicity Data NO(A)EL 90 mg/kg bw/day Data or (Q)SAR (where appropriate) Weight of evidence Reproductive Toxicity Data NO(A)EL 10 mg/kg bw/day Longer Term Toxicity Data or (Q)SAR (where appropriate) NO(A)EL 10 mg/kg bw/day Short Term Toxicity Data NO(A)EL 30 mg/kg bw/day Acute Toxicity Data or (Q)SAR (where appropriate) LD mg/kg bw 26

27 Complex Hazard (ComHaz) Tool CHEMICAL X MEETS CRITERIA CARCINOGENICITY? DOES NOT MEET CRITERIA OR INSUFFICIENT DATA GENOTOXICITY? MEETS CRITERIA WEIGHT OF EVIDENCE FOR GENOTOXIC CARCINOGENICITY? NO MEETS CRITERIA REFERENCE / REGULATORY VALUES INSUFFICIENT DATA DOES NOT MEET CRITERIA YES MEETS CRITERIA DEVELOPMENTAL TOXICITY? DOES NOT MEET CRITERIA OR INSUFFICIENT DATA EXPOSURE -RESPONSE CHARACTERIZATION MEETS CRITERIA MEETS CRITERIA MEETS CRITERIA MEETS CRITERIA REPRODUCTIVE TOXICITY? LONGER TERM TOXICITY? INSUFFICIENT DATA INSUFFICIENT DATA SHORT TERM TOXICITY? ACUTE TOXICITY? DOES NOT MEET CRITERIA OR INSUFFICIENT DATA DOES NOT MEET CRITERIA DOES NOT MEET CRITERIA DOES NOT MEET CRITERIA SET ASIDE FROM FURTHER CONSIDERATION AT THIS TIME 27

28 Preliminary Weight of Evidence Framework (Q)SAR Models TOPKAT* (version 6.2) NTP Carcinogenicity Male Rat (195 chemicals) (v 3.2) Female Rat (162 chemicals) (v 3.2) Male Mouse (208 chemicals) (v 3.2) Female Mouse (229 chemicals) (v 3.2) CARCINOGENICITY (Q)SAR MODELS CASETOX** (version 1.56) (Multicase PC Version) NTP Rodent Carcinogenicity(A07) (v 1.5) (313 chemicals) FDA-CDER Rodent Carcinogenicity (proprietary) Male Rat (AG3) (v 1.7) (1301 chemicals) Female Rat (AG4) (v 1.7) (1293 chemicals) Male Mouse (AG1) (v 1.7) (1182 chemicals) Female Mouse (AG2) (v 1.7) (1189 chemicals) DEREK FOR WINDOWS*** (version 8.0.1) TOPKAT* (version 6.2) 49 Structural Alerts for Carcinogenicity Ames Mutagenicity (v 3.1) (1835 chemicals) CASETOX** (version 1.56) (Multicase PC Version) GENOTOXICITY (Q)SAR MODELS) Salmonella Mutagencity (A2H) (v 1.7) (5864 chemicals) Somatic Mutations in Drosophila (A2D) (v 1.7) (289 chemicals) Mutations in Mouse Lymphoma Cells In Vitro (A2F) (v 1.5) (270 ch emicals) Chromosomal Aberrations in CHO cells In Vitro (A61) (v 1.7) (805 chemicals) Induction of Micronuclei in Mouse Bone Marrow In Vivo (A62) (v 1.5) (238 chemicals) Unscheduled DNA Synthesis in Rat Hepatocytes In Vitro (A64) (v 1.5) (299 chemicals) DEREK FOR WINDOWS*** (version 8.0.1) 97 Structural Alerts for Genotoxicity * Accelrys. Burlington, MA USA ** Multicase Incorporated. Beachwood, OH USA *** LHASA Ltd. Leeds, UK 28

29 The Predictive Component of ComHaz Developing Better Tools & Understanding Transparency/Capacity Building Developing Better (Q)SAR Models Integrating toxicological, risk assessment and modelling expertise Weight of Evidence Approach for Cancer/Genotoxicity Data/(Q)SAR/Analogues Developmental Toxicity Model Development ILSI Project Collaborative Effort with OECD/EU Validation Principles for Application Setubal Decision Support System 29

30 Robust Summaries of Modelled Results Transparency & Capacity Building What? Comparable to robust summary for data but including information relevant to interpretation of model output Clear delineation of input and output of the model Includes both chemical-specific and model-generic information TOPKAT, Multicase, DEREK for Windows Why? Critically important to transparency, increased understanding and capacity building Provides information to assist in interpreting conflicting model predictions, difficult wt of evidence calls, etc. 30

31 Robust (Q)SAR Model Summary - Example Chemical structure, SMILES Pred probability, detailed results of univariate/multivariate/similarity analyses (TopKat) Including id of similar structures ExSD criteria for interpretation of predictions Model identification (name, version) Size of database and distribution of pos/neg compounds Source of studies for database and criteria for inclusion Sample validation data 31

32 Preliminary Weight of Evidence Framework Cancer/Genotoxicity - Process Draft approach developed and revised based on operational experience through consideration of large numbers of individual compounds Concomitant internal consultation with internal genetox specialists Endpoint specific external peer consultation genetox External peer consultation on proposed weight of evidence approach to data/(q)sar/analogues Go to: Additional developmental work on analogues/surrogates/categories 32

33 DATA (Q)SAR ANALOGUES/SURROGATES CANCER DATA NEGATIVE PREDICTIONS ANALOGUE/SURROGATE IDENTIFICATION TOOLS ANALYTICAL EPIDEMIOLOGY CANCER BIOASSAYS TOPKAT CASETOX DEREK IN HOUSE DATABASE (ACCESS/ACCORD) LEADSCOPE OTHER TOOLS CANCER BIOASSAYS POSITIVE PREDICTIONS ROUTE OF ADMINISTRATION DEREK TOPKAT CASETOX Oral, Dermal & Inhalation Studies IV, IP, SC, etc. Studies GENOTOXICITY BIOASSAYS & (Q)SAR PREDICTIONS IN VIVO IN VITRO Clast/Mut DNA Damage Indicator Assays Clast/Mut* DNA Damage Indicator Assays *Consider Grouping of Ames/Salmonella Assays Into Frameshift and Base-pair substitution classes for Weighting purposes HIGH Confidence LOW 33

34 ILSI RSI Project on QSAR for Developmental Toxicity Sponsored by U.S. EPA and Health Canada Working Group includes model developers, developmental toxicologists (>20, currently)/biologists, risk assessors Objective: Endpoint specialists (i.e., developmental toxicologists) to systematically consider appropriate content of test database as a basis to meaningfully define (Q)SAR algorithms Go to: rsi.ilsi.org 34

35 QSAR for DSL/Health What We ve Learned The value of (Q)SAR for specific endpoints Not only where we don t have data but where we have contradictory data Another tool relevant to both priority setting and assessment The need for transparency and public availability of global models for human health endpoints The need for consistent consideration and transparent documentation of output as a basis for decision making Covert expert judgment won t advance understanding and acceptance (capacity building) Robust summaries for documentation of (Q)SAR output and approach to weight of evidence are key 35

36 QSAR for DSL/Health What We ve Learned (Cont d) The need for capacity building and broader engagement of toxicologists and risk assessors in development of better models for specific health endpoints The need to consider appropriate chemical space in testing strategies in order to optimize efficiency Testing for hazard on the basis of uncharacterized chemical space vs. individual substances 36

37 Small Priority Substances Assessment More Focussed Screening Assessment Number of Substances Large (Phase III) Issue Identification for Health Priorities (Phase II) Tools-Based Priority Setting and Assessment of Non-Health Priorities (Phase I) Substances Identified for Screening Health Assessment No. of Substances Assessment Complexity & Extent of Documentation Less Review of Decisions of Other Jurisdictions Categorization of the Domestic Substances List (DSL) Public Nominations 37

38 Principle/Nature of Assessments and Associated Documentation No more assessment and/or documentation than is necessary to identify non-priorities; robust advice/process for priorities with efficiencies gained in early issue identification Tools based screening assessments for non-priorities: Defensibility relates principally to the robustness of the tools and completeness of the search strategies Concise, tabular documentation of output, with more complete supporting information available on request Full, focussed screening assessments for high priorities: Brief assessment report focussing on critical information Currently, supporting document with limited text content and considerable tabular presentation, which documents how critical data were identified In future, for health assessments, supporting documents will be principally tabular output - use and hazard profiles, Issue Identifications and any documentation prepared to address critical issues 38

39 Implications for Testing Strategies The importance of systematic consideration of all existing substances in setting priorities for both testing and assessment Outcome varied from what we might have expected Profiling across many compounds and application of robust, predictive tools obviates the need in some cases to additionally fill datagaps The need for intelligent testing strategies integrating both potential exposure & predictive hazard tools E.g., inadequate role of volume in designating priorities Value of use profiling Health vs. environment priorities Implications for minimum datasets Screening Initial Datasets 39

40 Implications (Cont d) The importance of considering uncharacterized chemical space in testing versus individual substances In some cases, risk management may be preferable to generation of critical data Importance of an iterative approach which is fit for purpose to increase efficiency Preliminary versus full consideration of the data for nonpriorities Several models of increasingly explicit documentation Clear delineations of confidence/uncertainty at all stages but with increasing detail Need for increased cooperation internationally to meet the demanding requirements to develop the tools, set priorities/test and assess risk for all Existing Substances Global expertise is limiting 40

41 More Information? Health Canada Existing Substances Division Website Health Canada Maximal List and Integrated Framework Proposal Health Canada Existing Substances Mailing List CEPA Registry 41