08 rita schoeny
Upcoming SlideShare
Loading in...5
×
 

08 rita schoeny

on

  • 613 views

Seminário Nacional do Benzeno (5 e 6 dez/12) - NOVOS PARADIGMAS PARA O GERENCIAMENTO DO RISCO CARCINOGÊNICO - rita schoeny

Seminário Nacional do Benzeno (5 e 6 dez/12) - NOVOS PARADIGMAS PARA O GERENCIAMENTO DO RISCO CARCINOGÊNICO - rita schoeny

Statistics

Views

Total Views
613
Views on SlideShare
613
Embed Views
0

Actions

Likes
0
Downloads
17
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • May show in the amMake distinction between DA which is particular – to answer are DNA adducts causal. Not retro fitted risk assessments or dataThis is a pieces of the larger context for RA RMRisk assessment is not a linear process; one goes back and forth among the stepsOne size does not fit all; risk assessments should be designed to fit a purpose or purposesUnderstanding of available risk management options informs risk assessment planningStakeholder involvement will vary with assessment purpose, complexity, resourcesPeer review may be needed at several steps
  • I
  • Conceptual models are used to plan the risk assessment and associated data collection activities and are often revised periodically as data become available.  They consist of two principal components: (1) a set of risk hypotheses that describe predicted relationships among stressor, exposure and health endpoint/response, along with the rationale for their selection; and (2) a diagram that illustrates the relationships presented in
  • Evaluate WOE across study but for a particular endpoint
  • Slides from Doug Wolf
  • Policy for any endpoint.

08 rita schoeny 08 rita schoeny Presentation Transcript

  • Brazilian Benzene Seminar Brasilia, Brazil December 5, 2012Rita Schoeny, Ph.D.Senior Science Advisor,Office of Science Policy, Office of Research and DevelopmentU.S. EPA 1
  • Disclaimer The views expressed in this presentation are those do the author and do not represent the policy of the U.S. EPA. Some of this is EPA policy 2
  • So What Is EPA Policy?  Science Policy  Defaults, methods, Guidelines  Used when there are data or methodology gaps  Peer reviewed  Lots of documentation, which is publicly available  Policy based on science  May be set by EPA Executive Level  Generally involves regulations or other risk management choices; science is peer reviewed, action involves public comment; May be subject to Federal Advisory Committee Act  Lots of documentation; may be docket; publicly available 3
  • Examples Science policy  Cancer Guidelines 2005  Set a reference dose for effects which are likely to have a threshold  Quantitative adjustment to cancer risk for early life exposure  Animal data are relevant to humans unless demonstrated otherwise 4
  • Examples Policy set on science  Drinking Water Regulations are set as close as feasible to a Maximum Contaminant Level Goal  Consideration of residual risk after setting and air regulation requiring Maximum Achievable Control Technology ○ What we are currently doing for electrical power plants  Cost / benefit choices 5
  • SDWA ‗96 Does the contaminant adversely affect Regulate with public health? NPDWR Is the contaminant known or likely to occur in PWSs with a frequency and at levels posing a threat to public health? These are questions,Will regulation of the contaminant present a demonstrations of riskmeaningful opportunity for health risk reduction? 6
  • ‘83 Risk Assessment Paradigm ‘12? Risk Assessment Risk Management Statutory, legal Mode of considerations Dose Response Action Assessment Politics Risk Hazard Risk Management Identification Characterization Options Social Factors Exposure Available Assessment Technology Economics 7
  • A lot has changed since ‗83 Exposure Science in the 21st Century: A Vision and A Strategy IPCS FRAMEWORK FOR ANALYSING THERELEVANCE OF A CANCER MODE OF ACTION FOR HUMANS 8
  • NRC Silver BookRecommendation  NRC Silver Book recommendation (Chapter 8 ―Improving Utility of Risk Assessment‖)  To make risk assessments most useful for risk management decisions, the committee recommends that EPA adopt a framework for risk- based decision-making . . . that embeds the Red Book risk assessment paradigm into a process with initial problem formulation and scoping, upfront identification of risk-management options and use of risk assessment to discriminate among these options. 9
  • Draft HHRA Framework Silver Book on Utility “Risk assessments Planning & Scoping and Problem Formulation should not be Conceptual Analysis conducted unless it is clear that they are Confirmation of Utility Model Plan Risk Assessment designed to answer Public/ Community/ specific questions, and Effects Assessment Stakeholder Exposure Hazard Identification that the level of Assessment Involvement Dose Response technical detail and Risk Characterization uncertainty and variability analysis is appropriate to the Informing Decisions decision context” (NRC 2009, p. 247). 10
  • 12/10/2012 11
  • 12
  • NRC Scheme for Biomarkers(Schulte, 1989) 13
  • A Generalized Conceptual Model (adapted from USEPA, 2002; 2003) Sources Stressors Exposure Pathways/Routes Receptors Endpoints Risk MetricsActivities thatgenerate/releaseStressors or Chemical,types of stressor physical orreleases biological agents Physical processes that cause or interactions by which an effect a stressor is brought into to contact with Populations receptor and/or lifestages exposed to Measures of the stressor stressor effects or biological systems Metrics by affected which risk is quantified (e.g., disease cases, hazard quotients, magnitude of effect)
  • Sources Stressors Exposure Receptors Endpoints Risk Pathways/ Metrics Drinking water disinfection Routes Variable mixture nitrosamines; dependent on Conceptual Model treatment & Nitrosamines in Drinking Water source water. Ingestion of nitrosamine mixture in drinking water Consumers of drinking water; includes sensitive populations & life stages Cancer, any site or type Combined risk of cancer from subset nitrosamines in mixture
  • Cancer Guidelines: What‘s Differentfrom 1986? Analyze data before invoking default options. Mode of action is key in decisions Weight-of-evidence narrative replaces the previous ―A-B-C-D-E‖ classification scheme. Two step dose response assessment  Model in observed range  Extrapolate from point of departure Consider linear and non-linear extrapolation Address differential risks to children12/10/2012 16
  • Risk Assessment Science Use Data Before Invoking Defaults Analyze the available data Is there too much uncertainty or Invoke a is critical information lacking? default option Y N Conduct risk assessment 17
  • Cancer Guidelines: What‘s Differentfrom 1986? Analyze data before invoking default options. Mode of action is key in decisions Weight-of-evidence narrative replaces the previous ―A-B-C-D-E‖ classification scheme. Two step dose response assessment  Model in observed range  Extrapolate from point of departure Consider linear and non-linear extrapolation Address differential risks to children12/10/2012 18
  • Human Animal Indirect, Other IARC US EPA NTPSufficient -- -- Carcinogenic to Strong human Carcinogenic to Known to Be Human humans mechanistic humans Carcinogen (Group 1)Limited Sufficient data -- Probably carcinogenic to Sufficient Strong humans (Group 2A)Inadequate Limited Strong Likely to be Sufficient -- carcinogenic to Reasonably humans Anticipated to BeLimited Limited -- Possibly Human Carcinogen carcinogenic to Strong & same humans class as other (Group 2B)Inadequate Inadequate carcinogens Strong/ Inadequate convincing Information to AssessInadequate Limited -- Not classifiable Suggestive Not classified 19 Zeise EEA Copenhagen Sept 3, 2010
  • Cancer Guidelines: What‘s Differentfrom 1986? Analyze data before invoking default options. Mode of action is key in decisions Weight-of-evidence narrative replaces the previous ―A-B-C-D-E‖ classification scheme. Two step dose response assessment  Model in observed range  Extrapolate from point of departure Consider linear and non-linear extrapolation Address differential risks to children12/10/2012 20
  • Mode of Action and CancerAssessment MOA is the keystone to all aspects of the assessment process True for other endpoints and is the major factor in harmonization among risk assessments 21
  • Why Do You Care aboutMOA ? MOA is key in Hazard Identification  Helps describe circumstances under which agent is carcinogenic (High dose? Route?)  Relevance of data for humans MOA determines choice of Low Dose Extrapolation Life stage risk R esponse (T u m o r o r N on tu m o r D ata) e) os D on it m Li ce x en e) E n v iro n m e n ta l E m p iric a l fid at E x p o s u re L e v e ls on R ange of ti m C 5% Es o f In te re s t 9 O b s e rv a tio n st al tr e ow en (L (C x x 10% lt fau De R ange of ear E x tra p o la tio n L in x x 0% L E D 10 E D 10 MOE x N O AEL N o n lin e a r D e fa u lt D ose x LO AEL 22
  • Breaking Down the Dichotomy Cancer Non-Cancer  Threshold  Non-Threshold  Reversible  Irreversible  Safety Value  Risk value  RfD/RfC  Slope Factor  ADI/TDI  Unit Risk  MRL  Risk-Specific Dose 23
  • Mode of Action Exposure ―. . . a sequence of key Key event events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting in cancer Key event formation. . . Mode of action is contrasted with ―mechanism of action,‖ which implies a more detailed understanding and description of events, often at the molecular level, than is meant by mode of action‖ Key event Toxicity 24
  • Mode of Action Frameworks U.S. EPA IPCS  Postulated mode of action Hypothesized MOA: summary (theory of the case) description and identification  Key events of key events  Concordance of dose- Experimental support: response relationships  Strength, consistency,  Temporal association specificity of association  Strength, consistency and  Dose-response specificity of association of concordance tumour response with key  Temporal relationship events  Biological plausibility and  Biological plausibility and coherence coherence  Other modes of action Consideration of the  Uncertainties, possibility of other MOAs Inconsistencies, and Data Relevance to humans Gaps  Assessment of postulated mode of action 25
  • MOA/Human Relevancy ILSI/IPCS NO Is the weight of evidence Proceed with sufficient to establish a mode risk assessment of action (MOA) in animals? YES Can human relevancy of the MOA be YES reasonably excluded on the basis of MOA not fundamental, qualitative differences in Relevant key events between animals and humans? NO Can human relevancy of the MOA be reasonably excluded on the basis of NO YES MOA not quantitative differences in either Proceed with Relevant kinetic or dynamic factors between Risk assessment animals and humans? 26
  • Key Event  A “key event” is an empirically observable precursor step that is itself a necessary element of the mode of action or is a biologically based marker for such an element.Key event is necessary, but not sufficientIf a key event doesn‘t occur, there is nocancerIf one key event occurs, there may or maynot be cancer 27
  • Postulated Mode Of Action Chloroform Sustained Toxicity Regenerative Cell ProliferationKey Events Tumor Development 28
  • Postulated Mode Of Action Metabolism CP DNA damageTumorDevelopment Mutations 29
  • Mode of Action Framework Hypothesized MOA: summary description and identification of key events Experimental support:  Strength, consistency, specificity of association  Dose-response concordance  Temporal relationship  Biological plausibility and coherence Consideration of the possibility of other MOAs Relevance to humans12/10/2012 30
  • Based on ―Hill Criteria‖ for Causality ―None of my nine viewpoints Experimental support: can bring indisputable  Strength, consistency, evidence for or against the cause-and-effect hypothesis specificity of and none can be required association as a sine qua non. What they can do, with greater or  Dose-response less strength, is to help us concordance to make up our minds on the fundamental question —  Temporal relationship is there any other way of explaining the set of facts  Biological plausibility before us, is there any other and coherence answer equally, or more, likely than cause and effect?‖ Hill (1965) 12/10/2012 31
  • Experimental Support for MOA  Strength, consistency, specificity of association  What is the level of statistical and biological significance for each event and for cancer?  Do independent studies and different experimental hypothesis-testing approaches produce the same associations?  Does the agent produce effects other than those hypothesized?  Is the key event associated with precursor lesions? Section 2.4.3.212/10/2012 32
  • Experimental Support forMOA Dose Response Concordance ○ Is precursor induced at lower dose than tumors? ○ If greater incidence of the precursor occurs, does incidence of tumor increase? ○ If the precursor event is more severe is there an increase in tumor incidence?12/10/2012 33
  • Experimental Support forMOA Temporal Relationship ○ Do the precursor events occur before tumors are observed? ○ Is this observed in independent studies?12/10/2012 34
  • Mode of Action: Bladder Tumors, Key Events Cytotoxicity and Regenerative Hyperplasia DMAIII Measurable Key Metabolite Events in Target Tissue SEM Urothelial Toxicity BrdUSustained BrdU Labeling Labeling Regenerative Proliferation Hyperplasia Tumor
  • Association of Key Precursor Events & Bladder Tumors in F344 Rats Temporal Dose Metabolism Transitional Urothelial Regenerative Urothelial (mg/kg DMAVDMAI Cell II Toxicity Proliferation Hyperplasia bw/day) Carcinoma 0.2 + + (2 ppm) (wk 3-0.03 ± (wk 10-6/10, - - -Dose Response Concordance 0.01 uM) grade 3 or 4) + + 1 (wk 3-2/7, grade slight (10 ppm) (wk 3-0.12 ± 3) (wk- 10; 8/10, (wk 10-1.5X inc) - - 0.02 uM) grade 3 or 4) + + 4 (wk 3-0.28 ± (wk 3-7/7, grade + + - (40 ppm) 3) (wk 10-5/10, (wk 10-4.3X inc) (wk 10- 4/10) 0.09 uM) grade 3 or 4) + (6 hrs-6/7, grade 3) + + 9.4 + (24 hrs-4/7, grade 3 (wk 1- 2.2X inc) + (papilloma first (100 ppm) (wk 3-0.55 ± or 4) (wk 8-7/10) obs at wk 107; (wk 2 6/10, grade (wk 2-3.9X inc) (wk carcinoma first 0.15 uM) (wk 10-9/10) 5)(wk 10-0/10, grade 10-4.2X inc) obs at wk 87) 4 or 5) 12/10/2012 36
  • Experimental Support forMOA Biological plausibility and coherence ○ Does the MOA make sense given what is known about carcinogenesis in general, and for the case specifically? ○ Are carcinogenic effects and events consistent across structural analogues? ○ Is the database on the agent internally consistent in supporting the MOA, including relevant non-cancer toxicities?12/10/2012 37
  • Nuclear Receptor WorkshopPossible Key Strength Consistency Specificity Temporal Biological Biological Coherence Key EventEvents Reproducibility Gradient Plausibility (Causal) Dose- Associated Response (Marker?) Modulatory ? NeitherCAR activation High, Required High High Earliest Not Yes High Causal for tumors1,2 2 In vivo Knock out event, in determine Fits in a (DWolf) Bear in mind studies1,2 studies1,2 vivo and in d logical (RPeffer) that both ref #1 In vitro nuclear vitro14 (any sequence (RBars) & #2 involve translocation3,4 Perhaps data?) No (RSchoeny) initiation with PB- data that I (CElcombe) den and a induced am aware Causal, under rather short activation of. the period of of the Only in experimental treatment with phosphatas vitro (93, conditions pb, 32 wk in e that 58) outlined in ref #1 & 30 wk appears to Ref #1 & #2 in ref #2, we facilitate (JGoodman) do not know the what would translocati happen in car on of CAR ko mice if they from the were treated cytoplasm with pb for 2 to the years nucleus is (JGoodman) the very earliest event? 12/10/2012 38
  • MOA/Human Relevancy ILSI/IPCS NO Is the weight of evidence Proceed with sufficient to establish a mode risk assessment of action (MOA) in animals? YES Can human relevancy of the MOA be YES reasonably excluded on the basis of MOA not fundamental, qualitative differences in Relevant key events between animals and humans? NO Can human relevancy of the MOA be reasonably excluded on the basis of NO YES MOA not quantitative differences in either Proceed with Relevant kinetic or dynamic factors between Risk assessment animals and humans? 39
  • Concordance Analysis of Key Events:Cytotoxic Mode of ActionKey Event Rodents Humans Concordance analysisPresence of of key events is for Yes Yesmetabolite the MOA and notPersistent Yes Possible necessarilycytototoxicity chemical specificPersistent Chemical specific andregenerative Yes Possible generic informationproliferation relevant to adverseTumors Yes Possible outcome is useful
  • α2μ Globulin and Male Rat Kidney Tumors Chemical- a2u-Globulin a2u -Globulin "Complex" Renal Reabsorption Renal Reabsorption Nucleus NucleusHeterolysosome Amino Acids Heterolysosome Circulation Circulation
  • α2u-Globulin  The main story  Protein produced by male rats  MOA– functional changes in epithelial cells of proximal tubules•Hyaline droplets accumulate•Tubule cell degeneration•Regenerative cell proliferation•Expansion of initiated renal tubule cells 12/10/2012 42
  • Human Relevance of α2u-globulinnephropathy – U.S. EPA Humans do not possess a protein that is similar to α2u in abundance or binding characteristics; thus, humans would not be at risk of developing a chemically induced protein-mediated nephrotoxic response. Borghoff SJ and Lagarde WH, Toxicol Appl Pharmacol. 1993 Apr;119(2):228-35. If male rat kidney tumors develop In the absence of female rat kidney tumors Male rats have increased hyaline droplets Hyaline droplets contain a2u-Globulin Characteristic nephrotoxicity The male rat kidney tumors are not relevant for human health risk and would not be included in a risk assessment.
  • Is the MoA for phenobarbital plausible inhumans? Key event in MoA Plausible in humans? Activation of CAR Induction of CYP2B Increase via CAR can occur Hypertrophy Yes Cell proliferation Not likely, based on in vitro and in vivo data Inhibition of apoptosis Possible but not likely, based on limited in vitro data Selective clonal expansion Possible but not likely, none reported Occurrence of liver tumors No, based on epidemiological data
  • Cancer Guidelines: What‘sDifferent from 1986? Analyze data before invoking default options. Mode of action is key in decisions Weight-of-evidence narrative replaces the previous ―A-B-C-D-E‖ classification scheme. Two step dose response assessment  Model in observed range  Extrapolate from point of departure Consider linear and non-linear extrapolation Address differential risks to children12/10/2012 45
  • MOA and Kids Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens  Effects observed in childhood  Early life exposures that contribute to later life effects  MOA determines whether quantitative adjustment is made 46
  • Supplemental Guidance Use age-specific values for exposure and potency When data permit, develop separate potency estimates for childhood exposure In risk characterization, mutagenic MOA risk is increased by age-dependent adjustment factor (used with exposure info for age group) ○ <2 yrs old, 10 fold ○ 2 to < 16yrs, 3 fold No MOA, linear extrapolation without ADAF; non-linear MOA, no ADAF 47
  • Framework for Determining  This may actually geta Mutagenic Mode of published at someAction for Carcinogenicity point in timeUsing EPA‘s 2005 CancerGuidelines and SupplementalGuidance for AssessingSusceptibility from Early-LifeExposure to Carcinogens 48
  • Framework on Default MOA ― It should also be noted that there is no ‗default MOA.‘ The Cancer Guidelines offer some default procedures to use when no MOA can be determined.‖ •No MOA is not the same as a Mutagenic MOA Determination of mutagenic MOA is as scientifically rigorous as any other MOA I found nothing in IPCS on a default MOA 49
  • To boldly go where no regulatorytoxicologist has gone before . . .Mutagenicity is the induction of permanent,transmissible changes in the amount,chemical properties, or structure of thegenetic material. These changes may involve asingle gene or gene segment, a block of genes, parts ofchromosomes, or whole chromosomes. Effects on wholechromosomes may be structural and/or numerical (e.g.,aberrations and/or aneuploidy). 50 5012/10/2012
  • Boldly part 2 Genotoxicity is the induction of alterations to genetic material. It is a broader term than mutagenicity in that genotoxicity refers to potentially harmful effects on genetic material, which are not necessarily persistent and transmissible. Genotoxicity may be mediated directly or indirectly by chemical or physical agents, and may or may not be associated with mutagenicity. Tests for genotoxicity include tests for mutagenicity, as well as other tests which provide an indication of induced damage to DNA. For example, such tests may include unscheduled DNA synthesis (UDS), sister chromatid exchange (SCE), mitotic recombination, DNA adduct formation, or DNA strand breaks. 51 12/10/2012
  • What does this definitiondo? Distinguishes between genotoxic and mutagenic (U.S. EPA Guidelines refer to ―mutagenic MOA‖; Europe deals with genotoxic). Includes numeric changes in chromosome as mutagenic  But not likely to be linear at low dose Includes agents that generate reactive oxygen species (ROS)  But need to consider low dose response 52
  • Framework: Multi-stepProcess Risk assessment is an iterative process Visualize the Framework as series of linear steps  Assemble data  Assess, weigh data quality  WOE for mutagenicity  WOE for MOA 53
  • Step 2: Evaluate DataQuality Look at primary papers Judge against current acceptability criteria Cites publications for evaluating quality (e.g. Cimino 2006, OECD, ICH, IWGT, DHHS 2006) Keep, but weigh 54
  • Step 3 Gene- tox Tests Measure Different Events Genotoxicity Assays Mouse Chromosome Ames BacterialType of Damage Lymphoma Aberrations CHO cells MutagenicityPoint mutation Yes No YesOligonucleotideinsertion or deletion Yes No YesAllele Loss Yes No NoSmall Chromosomealteration Yes ? NoLarge Chromosomealteration Yes Yes NoAneuploidy ? Yes No Adapted from M. Moore (2004) Cancer Hazard ID TERA’s Dose-Response Assessment Boot Camp 55 55
  • Step 3: WOE for MutagenicActivity Categorize data – suggest use of our table in Appendix A.  Put in all data with notes on quality  Use consistent terms for assay types or endpoints: positive, negative, inconclusive, contradictory  Present summary of database 56
  • Concen- Cytotoxicity Duration of Results With Results Without Conform to RefIn vitro Assays trations observed Exposure metabolic metabolic relevantTest System activation (+ S9) activation (- S9) guidelineGene MutationBacterialSalmonella, reverse mutationE. coli, reverse mutationMammalianCHO gene mutation, hprt locusMouse L5178Y, tk locusChromosomeMutationMicronucleus assayChromosomal aberrationsDNA EffectsMammalianUnscheduled DNA synthesisSister chromatid exchangesComet assayDNA adduct analysisLower EukaryoteSaccharomyces cerevisiae, geneconversion 57
  • WOE for Mutagenic Activity  Conclusions across endpoints: some endpoints carry more weight than others ○ e.g. Sperm head morphology may be caused by modification of protein structure ○ Morphologic cell transformation does not measure mutation  WOE for mutagenic activity: negative, data are inadequate, data are of questionable quality, data are equivocal, data are positive 58
  • Apply MOA FrameworkMutagenicity + carcinogenicity ≠ Mutagenic MOAMutagenic Carcinogen Initiating Multiple events Tumor Mutation Nonmutagenic CarcinogenToxicityAltered Gene Initiating Multiple eventsExpression Mutation TumorCell Proliferation 59
  • Data Preference: WOE Mutagenic MOA Cancer-relevant oncogene or tumor suppressor gene mutations detected in target tissue after chemical exposure. Surrogate gene mutations detected in target tissue after chemical exposure. Chemical-specific DNA adducts (known to be mutagenic adducts) in target tissue after chemical exposure. Primary DNA damage in target tissue after chemical exposure. Gene mutations or chromosome aberrations in surrogate tissues after in vivo exposure. DNA adducts or other measures of DNA damage and/or repair or in surrogate tissues after in vivo exposure. Mutations, cytogentic damage, DNA adducts and/or primary DNA damage in vitro. 60 12/10/2012
  • What Has a Mutagenic MOA?Cyclophosphamide Cytotoxic, alkylating Alkylating Cytotoxic 61
  • Source Application to Levels of Organization Based on Source to OutcomeEnvironmentalContaminant Exposure Molecular Initiating Event Cellular Effects Individual Population Community Toxicity Pathway Mode of Action Adverse Outcome Pathway Source to Outcome Pathway 62
  • Application to Levels of Organization Based on Source to OutcomeSource Community Environmental Contaminant Population Exposure Individual Molecular Initiating Event Cellular Effects Toxicity Pathway Mode of Action Adverse Outcome Pathway Source to Outcome Pathway 63
  • Cancer Guidelines: What‘s Differentfrom 1986? Analyze data before invoking default options. Mode of action is key in decisions Weight-of-evidence narrative replaces the previous ―A-B-C-D-E‖ classification scheme. Two step dose response assessment  Model in observed range  Extrapolate from point of departure Consider linear and non-linear extrapolation Address differential risks to children12/10/2012 64
  • High dose data – what do theytell us? Response Dose 65
  • Take home message In science, data before defaults Scientifically based low dose extrapolation before defaults Science may inform policy; policy should never affect science 66
  • Possibilities Response Dose Interspecies 67
  • Two Step Approach  Model data in the observed range – to a R e s p o n s e (T u m o r o r N o n tu m o r D a ta ) it o n D o se ) point of departure im L ce x  Extrapolate below the en e) E nv ironm e ntal d E m pirical fi at n E xpo sure Lev els C o im R ange of st of In terest 5% O b serv ation lE t9 tr a es w POD en o (L (C x x 1 0% lt fa u R ange of r De ea L in E xtrapo lation x x 0% L E D 10 E D 10 UF x NOAEL N on lin ear D efau lt D o se x LOAEL 68
  • Extend the Observed Range UsingPrecursor Data Objective of choosing POD is to set it as close to environmental levels as  Supported by data  Appropriate to model Cancer Guidelines say precursor data are useful for this Must have MOA Section 3.2.2 69
  • Cacodylic Acid: BMDs and BMDLs Feeding Drinking water 10% 1% 10% 1%Endpoint Duration Duration BMD BMDL BMD BMDL BMD BMDL BMD BMDL (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) (mg/kg/d) 104 104Tumor weeks 7.74 5.96 6.80 2.22 weeks 1.92 1.21 0.88 0.14 10 weeks 1.36 1.04 0.42 0.32 104Hyperplasia weeks 1.63 1.04 0.74 0.14 104 weeks 1.97 1.61 0.93 0.66BrdU 10 weeks 0.65 0.29 0.54 0.07 Not determined. Available data not suitable for modeling.labeling 3 weeks 0.68 0.18 0.31 0.02Cytotoxicity No reliable dose-response data available 10 weeks 0.02 0.008 0.002 0.0007 70
  • Linear or Non-linear? Two Step Dose Response Process R e sp on se (Tum o r o r No n tu m o r D ata ) e) os D on it Another Question First en ce Li m x e) E n v iro n m e n ta l E m p iric a l fid at E x p o s u re L e v e ls on R ange of t im C Es o f In te re s t 5% O b s e rv a tio n t9 al es tr ow en (L (C x x 1 0% lt fa u De R ange of e ar L in E x tra p o la tio n x x 0% L E D 10 E D 10 UF x NOAEL N on lin ear D efau lt D ose x LOAEL 71
  • Is There Something Better? Analyze the available data Is there too much uncertainty or is Invoke a critical information lacking? Y default option* N Conduct risk assessment 72
  • Specify the sequence(s) of keyevents dosimetry Key event B1 Key event B2 Key event A1 Mode of Action Assessment endpoint Key event A2 Key event A3 73
  • Source Exposure PBPK Tissue dose BBDR Mode of actionBiologically BasedDose ResponseModel Response 74
  • AppliedDose of Phenobarbital (PBPK) 75
  • Reality check (I) There are always data gaps  Arsenic  Formaldehyde  TCDD  phenobarbital A BBDR model is a description of biological structure with embedded empirical linkages that cover the parts of the overall exposure- dose-response linkage for which data are missing. 76
  • Reality check (II) As research improves our understanding of the overall exposure-dose-response linkage, the sophistication of the description of the mode of action increases. Corresponding iteration of the BBDR model leads to more accurate predictions of dose- response and time-course behaviors. Will always be some degree of residual uncertainty. But is the default more uncertain? 77
  • And if no BBDR? Two Step Dose Response Process R e sp on se (Tum o r o r No n tu m o r D ata ) e) os D on it m Linear or Non-linear Li ce x en e) E n v iro n m e n ta l E m p iric a l fid at E x p o s u re L e v e ls on R ange of t im C Es o f In te re s t 5% O b s e rv a tio n t9 al es tr ow en (L (C x x 1 0% lt fa u De R ange of e ar L in E x tra p o la tio n x x 0% L E D 10 E D 10 UF x NOAEL N on lin ear D efau lt D ose x LOAEL 78
  • Mutagenesis Paradigm Mutagens/Spontaneous DNA Damaged DNA Damage Sensing Cellular Response DNA Repair Incorrect No repair Repair/ReplicationRepaired DNA Mutant DNA Dead Cell Demarini 70 79
  • Threshold? Demonstrated  Based on MOA  By inspection of the  Mutagenic MOA has dose response been linear curve  But should consider  Fitting models and biology of mutation checking goodness of fit  Statistical tests for one model or another Does mutagenic MOA mean low dose linear? BBDR should be first choice 80
  • In vitro Mutation Dose-Response: MMS & MNU Doak et al., 2007 HPRT MF MMS MMS NOEL = 1 mg/ml MNU MNU No NOEL 2011 EMS Annual Meeting Pottenger 81
  • In vitro Mutation Dose-Response: ENU Johnson et al., 2009 HPRT MFENU threshold dose-response (Lutz & Lutz model) Slide from Pottenger 82
  • Take Home Message MOA informs dose response assessment DNA damage is not mutation Mutation is not cancer Some genotoxicity endpoints may be reasonable biomarkers  May be useful for extending the lower end of dose response curve  Useful in MOA 83
  • Take home message 2 In science, data before defaults Scientifically based low dose extrapolation before defaults Science may inform policy; policy should never affect science 84
  • 85
  • NRC 2009 Silver Book 1 Framing questions and design step. Risk Assessment is not an end in itself. Characterize uncertainty and variability Default before data? These are strictly my own opinions 86
  • NRC 2009 Silver Book 2 Dose response  Additivity to background is a major theme ○ How differentiate between exogenous and endogenous damage? ○ DNA adducts biomarkers, could have major role ○ Does this mean linear all the time?  EPA has expressed preference for BBDR ○ Low dose data for adduct formation ○ Low dose data for mutation ○ Low dose data for other markers Again my own opinions 87
  • Breaking Down the Dichotomy Cancer Non-Cancer  Threshold  Non-Threshold  Reversible  Irreversible  Safety Value  Risk value  RfD/RfC  Slope Factor  ADI/TDI  Unit Risk  MRL  Risk-Specific Dose 88