Progress Made on Tox21: A Framework for the Next Generation of Risk Science
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1 Progress Made on Tox21: A Framework for the Next Generation of Risk Science Daniel Krewski, PhD, MHA Professor and Director McLaughlin Centre for Population Heath Risk Assessment & Risk Sciences International October 1, 2014
2 Outline NexGen: The next generation of risk science TT21C: Toxicity testing in the 21 st century (NRC, 2007) New Risk Assessment Methodologies (NRC, 2009) Population heath risk assessment (Krewski et al., 2007; Chiu et al., 2011) Principles of risk management (Krewski et al., 2014) Case study prototypes (Krewski et al., 2014) Exposure assessment in the 21 st Century (NRC, 2013) Future perspectives McLaughlin Centre for Population Health Risk Assessment
3 Next generation risk assessment McLaughlin Centre for Population Health Risk Assessment
4 Three Cornerstones New paradigm for toxicity testing (TT21C), based on perturbation of toxicity pathways Advanced risk assessment methodologies, including those addressed in Science and Decisions Population health approach: multiple health determinants and multiple interventions McLaughlin Centre for Population Health Risk Assessment
5 Three Cornerstones New paradigm for toxicity testing (TT21C), based on perturbation of toxicity pathways Advanced risk assessment methodologies, including those addressed in Science and Decisions Population health approach: multiple health determinants and multiple interventions McLaughlin Centre for Population Health Risk Assessment
6 Toxicity Testing in the 21 st Century
7 Building the Scientific Toolbox (Andersen & Krewski, 2009, Tox. Sci)
8 Human Toxicology Project Consortium Hamburg, M. (2011), Science (Editorial). Vol p. 987 Collins, F.S., Gray, G.M. & Bucher, J.R. (2008), Science (Policy Forum). Vol pp McLaughlin Centre for Population Health Risk Assessment
9 Reaction from Experts in Toxicology 8 +1 Invited Commentaries Reaction from Experts in Risk Assessment 6 Invited Commentaries 2009 McLaughlin Centre for Population Health Risk Assessment
10 International Perspectives Expert Panel on the Integrated Testing of Pesticides
11 Canada-China collaboration in toxicological risk assessment... McLaughlin Centre for Population Health Risk Assessment
12 McLaughlin Centre for Population Krewski Health et al. Risk (2011), Assessment ARPH
13 Mapping Toxicity Pathways McLaughlin Centre for Population Health Risk Assessment
14 TT21C: Toxicity Pathway and Network Biology Program at The Hamner Using Case Studies to implement NRC- TT21C report 1. Select a group of well-studied prototype compounds/pathways 2. Design & validate human/rodent cell or tissue surrogate based toxicity pathway assays 3. Examine results from the panel of assays to assess adversity 4. Refine quantitative risk assessment tools, i.e., computational systems biology pathway (CSBP) models and in vitro-in vivo extrapolation (IVIVE). 5. Integrate results into proposed health safety/risk assessments. Show the entire process in practice. 6. Take a look at results and modify steps to insure the process assist quantitative safety assessment
15 Specific TT21C Pathway Projects at Hamner Receptor mediated pathways PPARa liver responses Estrogen Pathway uterine and breast tissue responses Aryl-hydrocarbon receptor in liver Stress Pathways involving chemical reactivity DNA damage (p53-mdm2) creating a computational model Oxidative stress (Nrf2-Keap1) Mitochondrial damage See Mid-year report: (
16 Mapping the Human Toxome by Systems Toxicology Endocrine disruption Use omics to map PoT for endocrine disruption Develop software tools Identify PoT Develop a process for PoT annotation, validation Establish public database on PoT. NIH Transformative Research Project Hewitt et al., Science, 307:
17 Three Cornerstones New paradigm for toxicity testing (TT21C), based on perturbation of toxicity pathways Advanced risk assessment methodologies, including those addressed in Science and Decisions Population health approach: multiple health determinants and multiple interventions McLaughlin Centre for Population Health Risk Assessment
18 KEY MESSAGES Enhanced framework Formative focus Four steps still core Matching analysis to decisions Clearer estimates of population risk Advancing cumulative assessments People and capacity building
19 Not OK OK Risk-Based Decision-Making Framework Phase I Formulating and Scoping Problem For environmental condition: What s the problem? What are the options for altering? What assessments are needed to evaluate options? Phase II Planning and Risk Assessing Stage 1: Planning for: Options Assessment Uncertainty and Variability Analysis Stage 2: Assessing Stage 3: Confirming Utility of Assessment Phase III Risk Management Relative benefits of proposed options? How are other factors (e.g., costs) affected by options? Which option is chosen? What s the uncertainty and justification? How to communicate it? Should decision effectiveness be evaluated? If so, how? Stakeholder involvement at each phase
20 Methodological Issues Adversity Variability Susceptible populations Dose and species extrapolation Mixtures and multiple stressors Uncertainty analysis McLaughlin Centre for Population Health Risk Assessment
21 Methodological Issues: (1) Adversity Issue Current Approach NexGen Approach Adverse outcomes Apical outcomes in mammalian systems, or precursors to these outcomes, serve as the basis for risk assessment. In vitro assays identify critical toxicity pathway perturbations, which serve as the basis for risk assessment, even in the absence of a direct link with an apical outcome.
22 McLaughlin Centre for Population Health Risk Assessment.
23 Methodological Issues: (2) Dose-response Issue Current Approach NexGen Approach Doseresponse assessment Empirical or biologically-based models describe apical endpoints, and determine an appropriate point of departure (such as the benchmark dose) for establishing a reference dose. Computational systems biology pathway models describe dose-response relationships for pathway perturbations, reflecting dosedependent transitions throughout the dose range of interest.
24 Signal-to-Noise Crossover Dose (SNCD) Sand, Portier & Krewski (2011), EHP McLaughlin Centre for Population Health Risk Assessment A WHO/PAHO Collaborating Centre
25 Methodological Issues: (3) Variability Issue Current Approach NexGen Approach Interindividual variability Adjustment factors used in establishing reference doses account for interindividual variability in PK and PD. Variability in exposure is also taken into account. Variability in biological response is characterized through the use of a diverse range of human cell lines. Dosimetry models link variation in human exposure with corresponding in vitro doses.
26 From Zeise et al. (2012): Assessing Human Variability in the Next Generation Health Assessments of Environmental Chemicals
27 Methodological Issues: (4) Susceptibility Issue Current Approach NexGen Approach Susceptible populations Life-stage, genetics, and socioeconomic and lifestyle factors determine susceptible population groups. Molecular and genetic epidemiology defines susceptible populations in terms of critical pathway perturbations.
28 How susceptibility arises from variability (from Zeise et al., 2012)
29 Methodological Issues: (5) Extrapolation Issue Current Approach NexGen Approach Dose and species extrapolation Dose and species extrapolation translate animal test results to humans. Cellular assays provide direct measures of toxicity pathway perturbations in humans. IVIVE techniques and pathway modeling calibrate in vitro and in vivo exposures. Sensitive in vitro tests are used to evaluate risk directly at environmental exposure levels.
30 Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, Lecluyse EL, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117: McLaughlin Centre for Population Health Risk Assessment
31 Methodological Issues: (6) Mixtures Issue Current Approach NexGen Approach Mixtures and multiple stressors Common experimental protocols include testing of mixtures and factorial experiments with joint exposures. However, there are only a limited number of such studies because of cost and complexity of experimental design. Cost-effective high throughput technologies permit expanded testing of mixtures and multiple stressors.
32 Methodological Issues: (7) Uncertainty Issue Current Approach NexGen Approach Uncertainty analysis Uncertainty considerations include species differences in susceptibility, lowdose and route-toroute extrapolation, and exposure ascertainment. Probabilistic risk assessments characterize overall uncertainty, and identify the most important sources of uncertainty that guide value-of-information decisions.
33 MOA Reverse Toxicokinetics (rtk): in vitro concentration to in vivo dose Pharmacodynamics Adverse Effect Key Events Pharmacokinetics Dose-to-Concentration Scaling Function (C ss /DR) Probability Distribution Toxicity Pathway BPADL HTS Assays Probability Distribution for Dose that Activates Biological Pathway PK Model Populations Biological Pathway Activating Concentration (BPAC) Probability Distribution Intrinsic Clearance Plasma Protein Binding
34 Three Cornerstones New paradigm for toxicity testing (TT21C), based on perturbation of toxicity pathways Advanced risk assessment methodologies, including those addressed in Science and Decisions Population health approach: multiple health determinants and multiple interventions McLaughlin Centre for Population Health Risk Assessment
35 Population Health Regulatory Economic Advisory Community Technological Multiple Interventions Health Risk Policy Analysis Evidence Based Policy Health Risk Science Determinants and Interactions Biology-environment interactions Environment-social interactions Biology and Genetics Environment and Occupation Social and Behavioural Biology-social interactions
36 Chiu, W.A., et al., Approaches to advancing quantitative human health risk assessment of environmental chemicals in the post-genomic era, Toxicol. Appl. Pharmacol. (2010), doi: /j.taap
37 Social-Environment Interaction Darby et al. (2005), Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies. BMJ 330: McLaughlin Centre for Population Health Risk Assessment
38 Social-Genetic Interaction McLaughlin Centre for Population Health Risk Assessment
39 Risk Management McLaughlin Centre for Population Health Risk Assessment
40 Risk Management Principles (1/2) Beneficence and non-maleficence (do more good than harm) Natural justice (a fair process of decision making) Equity (ensure an equitable distribution of risk) Utility (seek optimal use of limited risk management resources) Honesty (be clear on what can and cannot be done to reduce risk) McLaughlin Centre for Population Health Risk Assessment
41 Risk Management Principles (2/2) Acceptability of risk (do not impose risks that are unacceptable to society) Precaution (be cautious in the face of uncertainty) Autonomy (foster informed risk decision-making for all stakeholders) Flexibility (continually adapt to new knowledge and understanding) Practicality (the complete elimination of risk is not possible) McLaughlin Centre for Population Health Risk Assessment
42 Case Study Prototypes McLaughlin Centre for Population Health Risk Assessment
43 NexGen Tiered Approach to Risk Assessment
44 Tier 1: Screening and Ranking
45 Judson et al. (2010), EST
46
47 Tier 2: Limited Scope Assessment
48 Traditional versus Toxicogenomics Determination of BMD Thomas et al. (2012), Mutation Research
49 Thomas et al. (2012) found a strong correlation between transcriptional BMDs for specific pathways and traditional BMDs
50 Tier 3: Major Assessment Lung Injury and Ozone To identify toxicity pathways using omics data To determine accuracy of predicting in vivo responses from in vitro toxicity pathway induction from toxicants To develop a biologically-based dose-response (BBDR) based on the integration of diverse data sets McLaughlin Centre for Population Health Risk Assessment
51 IL8 Fold-Change 3 IL8 RNA Expression Time Course Relative to Mean Air Value 1 ppm O ppm O ppm O ppm O3 Air Time (hrs) Response time course of IL8 RNA expression, relative to mean air value. Peak response occurs 3 hours post exposure cessation.
52 Lung Injury and Ozone Conclusion NF-κB signaling is seen early during ozone exposure, and there is a clear dose-response with the cytokine IL-8. McLaughlin Centre for Population Health Risk Assessment
53
54 Three Cornerstones New paradigm for toxicity testing (TT21C), based on perturbation of toxicity pathways Advanced risk assessment methodologies, including those addressed in Science and Decisions Population health approach: multiple health determinants and multiple interventions McLaughlin Centre for Population Health Risk Assessment
55 Exposure Assessment McLaughlin Centre for Population Health Risk Assessment
56 Hubal et al., 2010, JTEH 13:299
57 Exposomics McLaughlin Centre for Population Health Risk Assessment
58 ``The exposome represents the combined exposures from all sources that reach the internal chemical environment. Toxicologically important classes of exposome chemicals are shown. Signatures and biomarkers can detect these agents in blood or serum.``
59 Two Approaches to Exposomics Rappaport et al., 2011 J.Exp. Sc. & Envir. Epi. 21:5
60 Biomarkers of Exposure McLaughlin Centre for Population Health Risk Assessment
61 NRC Report McLaughlin Centre for Population Health Risk Assessment
62
63 NHANES National Health and Nutrition Examination Survey Human Biomonitoring Programs Canadian Health Measures Survey (CHMS) McLaughlin Centre for Population Health Risk Assessment
64
65 Mapping toxicity pathways is key to identifying biomarkers Toxicity Pathways at Multiple Levels of Biological Organization
66 Balshaw, NIH
67 Biomonitoring Equivalents McLaughlin Centre for Population Health Risk Assessment
68 Establishing Biomonitoring Equivalents McLaughlin Centre for Population Health Risk Assessment
69 Biomonitoring Equivalents (BEs) Hayes et al., 2008 Biomonitoring Equivalents (BEs) are defined as the concentration of a chemical (or metabolite) in a biological medium (blood, urine, human milk, etc.) consistent with defined exposure guidance values or toxicity criteria including reference doses and reference concentrations (RfD and RfCs), minimal risk levels (MRLs), or tolerable daily intakes (TDIs) [Hays, Regul. Toxicol. Pharmacol. 47(1), ].
70 2,4-D Acrylamide Cadmium Cyfluthrin Di(2-ethylhexyl)phthalate Phthalate Esters: Diethyl phthalate Di-n-butyl phthalate Benzylbutyl phthalate Polychlorinated dibenzo-pdioxins and dibenzofurans Toluene Trihalomethanes: Chloroform Dibromochloromethane Bromodichloromethane Bromoform McLaughlin Centre for Population Health Risk Assessment
71 Reverse Toxicokinetics (rtk) McLaughlin Centre for Population Health Risk Assessment
72 Incorporating Human Dosimetry and Exposure Into High-Throughput In Vitro Toxicity Screening Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, Lecluyse EL, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117:
73 Reverse Toxicokinetics (rtk): in vitro concentration to in vivo dose (Dix, 2011) Pharmacodynamics MOA Adverse Effect Key Events Pharmacokinetics Dose-to-Concentration Scaling Function (C ss /DR) Probability Distribution Toxicity Pathway BPADL HTS Assays Probability Distribution for Dose that Activates Biological Pathway PK Model Populations Biological Pathway Activating Concentration (BPAC) Probability Distribution Intrinsic Clearance Plasma Protein Binding
74 Example: Bisphenol A Estrogenicity In Vitro vs. In Vivo Reproductive Toxicity Rat reproduction tests resulted in a NOEL of 50 mg/kg/day, with a corresponding RfD of 0.5 mg/kg/day HTRA lower limit BPADL99 is 0.16 mg/kg/day, derived from six ToxCast estrogen receptor assays Actual human exposure is estimated to be mg/kg/day McLaughlin Centre for Population Health Risk Assessment
75 Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, Lecluyse EL, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117: McLaughlin Centre for Population Health Risk Assessment
76 Exposure Science in the 21 st Century An NRC committee will develop a longrange vision for exposure science.... It will include development of a unifying conceptual framework for advancement of exposure science to study and assess human and ecological contact with chemical, biological, and physical stressors in their environments. concern.
77 Conclusions and Future Directions TT21C (NRC, 2007) has received widespread support, both in the United States and internationally: progress towards the implementation of TT21C ahead of projected timetable NexGen (EPA, 2014) integrates three cornerstones of the future of risk science: TT21C, new assessment methodologies, and a population health perspective High-throughput exposomics: assess toxicity pathway perturbations measured directly in humans RS21C: a coordinated international approach needed to chart the future of risk science, building on the powerful new tools, technologies, and methodologies now available to the scientific community McLaughlin Centre for Population Health Risk Assessment
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