A framework for fit-for-purpose dose response assessment

Regulatory Toxicology and Pharmacology 66 (2013) 234–240

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Workshop Report

A framework for fit-for-purpose dose response assessment M.E. Bette Meek a,⇑, Michael Bolger b,1, James S. Bus c,2, John Christopher d, Rory B. Conolly e, R. Jeffrey Lewis f, Gregory M. Paolini g, Rita Schoeny h, Lynne T. Haber i, Amy B. Rosenstein j, Michael L. Dourson i a

R. Samuel McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, One Stewart Street, Suite 309, Ottawa, ON, Canada K1N 6N5 Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, 5100 Pain Branch Parkway, College Park, MD 20740, USA c Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Building 1803 Washington St., Midland, MI 48674, USA d Independent Consultant, 8173 Suarez Way, Elk Grove, CA 95757, USA e U.S. Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA f ExxonMobil Biomedical Sciences, Inc., 1545 Route 22 East, Annandale, NJ 08801, USA g Risk Sciences International, 325 Dalhousie Street, Ottawa, ON, Canada K1N 7G2 h U.S. Environmental Protection Agency, 1200 Pennsylvania Ave., Washington, DC 20460, USA i Toxicology Excellence for Risk Assessment, 2300 Montana Ave., Suite 409, Cincinnati, OH 45211, USA j Independent Consultant, 18 Ames Ave., Lexington, MA 02421, USA b

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Article history: Received 11 September 2012 Available online 6 April 2013 Special note: This paper is dedicated to the memory of Dr. Randall Manning of the Georgia Department of Natural Resources. Dr. Manning was an early and avid supporter of this collaborative effort, making constructive comments during its 3rd meeting, and listening well and supporting others in their efforts to find common scientific ground on seemingly intractable risk assessment issues. His humor, kindness and intellect are sorely missed. Keywords: Mode of action Fit-for-purpose Problem formulation Framework Tier Endogenous Methods compendium

a b s t r a c t The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose–response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two broad elements: improving technical analysis and utility for decision making. To advance the discussions in the NRC report, in three multi-stakeholder workshops organized by the Alliance for Risk Assessment, available and evolving risk assessment methodologies were considered through the development and application of case studies. A key product was a framework (http://www.allianceforrisk.org/Workshop/Framework/ProblemFormulation.html) to guide risk assessors and managers to various dose–response assessment methods relevant to a range of decision contexts ranging from priority setting to full assessment, as illustrated by case studies. It is designed to facilitate selection of appropriate methodology for a variety of problem formulations and includes a variety of methods with supporting case studies, for areas flagged specifically by the NRC committee for consideration – e.g., susceptible sub-populations, population variability and background. The framewok contributes to organization and communication about methodologies for incorporating increasingly biologically informed and chemical specific knowledge into dose–response analysis, which is considered critical in evolving fit-for-purpose assessment to address relevant problem formulations. Ó 2013 Elsevier Inc. All rights reserved.

Abbreviations: ARA, alliance for risk assessment; CPF, chlorpyrifos; MOA, mode of action; NAS, National Academy of Sciences; NGO, non-governmental organization; NRC, National Research Council; PBPK/PD, physiologically-based pharmacokinetic/pharmacodynamic; RfD, reference dose; VOI, value of information. ⇑ Corresponding author. Address: Chemical Risk Assessment, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, One Stewart Street, Suite 309, Ottawa, ON, Canada K1N 6N5. Fax: +1 613 562 5380. E-mail addresses: [email protected] (M.E. Bette Meek), [email protected] (M. Bolger), [email protected] (J.S. Bus), [email protected] (J. Christopher), [email protected] (R.B. Conolly), [email protected] (R.J. Lewis), [email protected] (G.M. Paolini), [email protected] (R. Schoeny), [email protected] (L.T. Haber), [email protected] (A.B. Rosenstein), [email protected] (M.L. Dourson). 1 Current address: Center for Chemical Regulation and Food Safety Exponent, 1150 Connecticut Ave. NW, Washington, DC 20036, USA. 2 Current address: Senior Managing Scientist, Center for Toxicology and Mechanistic Biology, Health Sciences Group, Exponent, USA. 0273-2300/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yrtph.2013.03.012

1. Introduction In 2009, the National Research Council of the National Academy of Sciences (NAS) released a report entitled Science and Decisions: Advancing Risk Assessment (NRC, 2009 also known as the Silver Book). Recommendations encompassed two broad elements: (1) improving technical analysis, namely developing and using scientific knowledge and information to promote more accurate characterization of risk; and (2) ensuring that risk assessments provide meaningful support to allow discrimination among risk management options. Specifically, recommendations addressed the following areas: design of risk assessments, uncertainty and variability, selection and use of defaults, a unified approach to dose–response assessment, cumulative risk assessment, improving

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the utility of risk assessment and stakeholder involvement and capacity-building within the U.S. Environmental Protection Agency (U.S. EPA). As illustrated in Figure S-1 of NRC (2009), the authors of the report expanded the risk assessment paradigm of NRC (1983), principally through inclusion of a problem formulation step including framing of the assessment to address specific risk management options, explicit consideration of stakeholder input, and confirmation that the assessment addressed the issues identified in the problem formulation. The report (see Figure 5–8) provided additional guidance on considerations for dose–response assessment, including endpoint assessment, assessment of mode of action (MOA), vulnerable populations and background exposure, conceptual model selection, and dose–response method selection. In response to recommendations of this report and other NRC and international initiatives (e.g., NRC, 2007; IPCS, 2006, 2007; Meek and Armstrong, 2007; Meek et al., 2011), improvement of risk assessment practice continues to be explored in a series of initiatives, including the workshops described here, organized by the Alliance for Risk Assessment (ARA, a coalition of non-profit organizations). The purpose of the workshop series, entitled ‘‘Beyond Science and Decisions: From Problem Formulation to Dose–Response Assessment’’ (henceforth, the ARA workshop series) was to extend these discussions, with the goal of developing a practical compendium of dose response assessment methods for fit-for-purpose dose–response analysis and potentially in future, other components of risk assessment. While not referenced in the NRC report, the concept of fit-for-purpose assessment has been widely adopted recently in legislative mandates requiring greater efficiency in consideration of much larger numbers of substances (see for example, Meek and Armstrong, 2007) and in research initiatives, for example in Lee et al. (2006), who described a fit-for-purpose approach for biomarker method development and validation. Fit-for-purpose dose–response analysis encourages application of a level of rigor commensurate with the intended purpose and use of an assessment. As recommended by the NRC (2009) report, the nature and extent of the assessment needs to be considered in the problem formulation stage, with level and complexity to be no greater than that needed to identify the best choice among risk management options (i.e., ‘‘fit for purpose’’). In practice, this is accomplished by having a variety of available tools (e.g., tools for acute vs. chronic exposures) and using tiered approaches, proceeding down the tiering only as far as necessary to set an issue, exposure or chemical aside (as not of concern) or to target it for further assessment and/or management. Three multi-stakeholder workshops were held in 2010 and 2011. The workshops explored available and evolving methodologies through the development and application of case studies. While these case studies covered a number of important aspects of the NAS text, particular attention was focused on problem formulation, use of information on MOA and endogenous and background exposure during solicited speaker presentations and panel discussions. This paper summarizes the outcome of the ARA workshops and the resulting ARA fit-for-purpose dose response assessment methods framework. This framework, which is illustrated by case studies, is designed for use by risk managers and scientists in a variety of settings (e.g., government agencies, industry), for a range of applications and/or levels of analysis including distributional, non-threshold methods for estimating risk-specific doses for toxic effects other than cancer. Case studies were selected to be illustrative of various approaches rather than as assessments for any specific environmental contaminant. However, the scope and variety of included case studies are anticipated to assist in the determination of appropriate assessment strategies and relevant risk management options. Additional case studies are

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also being sought for consideration in the context of the framework. 2. Description of the workshop series 2.1. Workshop objectives and structure The Dose–Response Advisory Committee (DRAC), which includes state, federal, industry, and NGO representatives, organized the workshop series on behalf of the now more than 50 workshop sponsors. The DRAC determined the agendas in consultation with the Science Panel. The Steering Committee of the ARA, which includes representatives from state, tribal, the federal government, academia, and environmental NGOs (www.allianceforrisk.org/ ARA_Steering_Committee.htm) provided oversight of the workshop series. The workshops were designed to address technical aspects (methods development) based on robust process (stakeholder engagement), as described in Table 1. Important aspects included (1) broadly advertising the workshops; (2) providing for webbased participation; (3) posting all workshop-related materials on the web; (4) providing an open process for interested parties to develop and submit case studies; and, (5) sponsorship by a group of more than 50 diverse organizations. The first workshop included two primary elements. About half of this workshop was devoted to presentations by thought leaders from various sectors on activities related to issues raised in the NRC (2009) report, as well as perspectives on the NRC report. The other half of the workshop was devoted to brainstorming and evaluation of the impact for the NRC recommendations of 27 submitted proposals for case studies developed by volunteer teams of scientists from numerous organizations. Some of the case studies reflected previously published work, while others were designed to evolve specific methodological issues identified in the NRC (2009) Science and Decisions report, such as approaches for low-dose extrapolation. Based on the recommendations from Workshop 1, case studies were developed and presented to the Science Panel at Workshop 2 for their review, recommendations, and consideration for incorporation into the Framework (see Section 3.1). Workshop 3 was organized primarily around three cross-cutting topics identified by the Science panel: (1) problem formulation, (2) use of mode of action information, and (3) endogenous/ background exposure. Discussion of each of these themes was initiated by a presentation by an expert on the topic, followed by Science Panel discussion in the context of the case studies presented. Presentations, meeting material and reports from all three of the workshops are available at, http://www.allianceforrisk.org/ ARA_Dose-Response.htm.

2.2. The science panel Following an open nomination process, the ARA Steering Committee selected a Science Panel designed to reflect a range of affiliations, perspectives, and expertise (e.g., biology, risk assessment, modeling). Particular effort was made to include representatives from the NRC Science and Decisions committee and environmental NGOs. Invitations were sent to 27 nominees, with 13 individuals accepting the invitation. The Science Panel members for Workshops 2 and 3 are listed at http://www.allianceforrisk.org/ Workshop/Panel.htm. Science Panel members provided input on the utility of the case study methods to address specific problem formulations, and identified areas for additional development of the case study and/or method. After the first three workshops, a

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Table 1 Workshop Objectives. General workshop objectives:  Additionally develop the content of the NAS (2009) report on improving the risk assessment process to develop a compendium of practical, problem-driven approaches for ‘‘fit for purpose’’ risk assessments, linking methods with specific problem formulations (e.g., prioritization, screening, and in-depth assessment) for use by risk managers at a variety of levels (e.g., states, regional managers, people in a variety of agencies, and in the private sector).  Implement a multi-stakeholder approach to share information, ideas and techniques in support of developing practical problem-driven risk assessment methods compendium. Specific workshop objectives:  Identify useful dose–response techniques for specific issues, including consideration of relevant data, characterization of assumptions, strengths and limitations, and how the techniques address key considerations in the dose–response.  These techniques should appropriately reflect the relevant biology (including the biology of thresholds), and mode of action information, at a level of detail appropriate for the identified issue.  Provide methods to explicitly address human variability in cancer assessment, and enhance the consideration of human variability in noncancer assessment, including explicit consideration of underlying disease processes, as appropriate for the relevant risk assessment context.  Identify methods for calculating the probability of response for noncancer endpoints, as appropriate for the relevant risk assessment context.  Develop a risk methods compendium that will serve as a resource for regulators and scientists on key considerations for applying selected dose– response techniques for various problem formulations, with suggested techniques and resources.

similar open nominations process was followed, and the ARA Steering Committee selected a standing Science Panel to serve for 2–3 years. 3. Results and discussion This section describes issues related to three cross-cutting topics that were the focus of the third workshop: (1) problem formulation, (2) use of mode of action information, and (3) endogenous and background exposure. In addition, it describes the development of the framework to organize and provide access to dose response assessment methods, as illustrated by the case studies. 3.1. Framework for identifying context specific methods for dose– response analysis A key product of the ARA workshops was a framework to guide risk assessors to different dose response methods relevant to a variety of decision contexts ranging from priority setting or screening to full assessment, and illustrated by case studies. The framework is designed for use by risk managers and scientists at the problem formulation stage, to aid in selecting appropriate dose response assessment methodology, based on the objectives of any specific assessment taking into account factors such as time and resource constraints. This central resource for access to methods and guidance from many organizations was considered helpful as a basis to promote better planning for different levels of analysis required for specific risk assessment applications. The framework is available on-line at http://www.allianceforrisk.org/Workshop/Framework/ProblemFormulation.html and on the National Library of Medicine’s Enviro Health Links suite of databases at http://sis.nlm.nih.gov/enviro/toxweblinks.html. The current version is derived from the general structure of the dose–response portion of the risk assessment framework presented in the NRC (2009) report (Figures S-1 and 5–8 of the

NRC report). Based on need, the user chooses from amongst a number of methods options for different decision contexts (e.g., priority setting, screening and full assessment); the ARA framework also references case studies illustrating methods that can address the topics and questions in the NRC report. Case studies were selected based on the Science Panel’s evaluation of the utility of the method to address a practical application. Inclusion of a method or case study as an illustration of a useful technique does not imply Science Panel consideration or acceptance of the chemical-specific outcome. It is expected that the framework will continue to be updated with new and evolving methods. For example, areas where additional methods or tools exist are identified, even if case studies have not yet been presented for consideration. Additional case studies illustrating these and other methods are expected to be added to the framework as they are submitted and considered by the Science Panel. 3.2. Major themes discussed at workshop 3 Although the NRC (2009) report focused primarily on approaches to dose–response analysis for in-depth assessments of hazard from chronic exposure, the case studies addressed a broader range of methods relevant to a variety of different decision contexts, including those for short term exposures and screening assessments (e.g., see Case Study #1 below). In addition to populating the framework with individual case studies, the Science Panel focused its discussions in the final workshop on three cross-cutting topics: problem formulation, use of MOA information, and the issue of how to address endogenous/ background exposures. Discussions concerning those cross-cutting topics are summarized here and illustrated by representative case studies. Additional details on these case studies including strengths, weaknesses and minimum data needs, are available at: http://www.allianceforrisk.org/Workshop/WS3/CaseStudiesWS3. html. The case studies presented here address some of the major themes from Workshop 3, as well as illustrating the range of variety in data requirements, approaches, and sophistication of analysis. 3.2.1. Theme 1: Problem formulation – consideration of the risk management Objectives and Options The NRC (2009) report emphasized that the level and complexity of a risk assessment should be no greater than what is needed to identify the best choice among risk management options. Thus, in order to optimize requirements for data generation and/or identification, available risk management options need to be considered at the earliest stage of an assessment and re-considered in an iterative fashion throughout the process, based on additional complexities uncovered during initial phases involving consultation with stakeholders. The extent of formal problem formulation in risk assessment varies among different programs, stakeholders and institutions, depending on decision context. Value-of-information (VOI) analysis is a decision analytic method that characterizes the relative contribution (in a specific decision context) of specific information in reducing various uncertainties in an assessment (Yokota and Thompson, 2004). VOI analysis can be part of the problem formulation step, as well as contributing to consideration of whether or not more information would meaningfully inform an assessment. While there are a number of challenges in instituting formal VOI analysis (including the need to specify prior distributions and the need to know the sensitivity of decision-makers’ choices to risk assessment outcomes), the panel considered that informal (qualitative) VOI analysis could potentially assist in focusing resources on issues and

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analyses that are fit-for-purpose for the relevant decision context as a basis for increasing efficiency. Since there are few published examples of informal VOI analysis the panel recommended development of a case study to explore this avenue. The panel noted that tiered approaches, such as summarized in Case Study #1 below (see the full framework for further details), also contribute to efficiency, with assessment proceeding to the next tier only if needed to inform the risk management decision. Prior problem formulation is helpful, then, in deciding which of a series of approaches incorporating increasingly biologically informed and chemical specific knowledge would meaningfully address the choice among potential risk management options, taking into account the potential impact of the decision and time and resource constraints. Case Study Box #1 Tiered Approach to Screening Level Development Key point: A tiered approach appropriate for the decision context, namely to set screening levels for acute exposures for as many air contaminants as possible, for ‘‘air permitting’’ for emissions from new or modified facilities. Method: For chemicals with limited toxicity data, interim screening levels for acute exposures can be derived using a tiered approach. This includes application of either default screening levels or derivation of generic healthbased screening levels, depending on the availability of toxicity information and time and resource constraints. Tier I assessments are based on a Threshold of Regulation approach, using a default value of 2 lg/m3 (TCEQ, 2012; the original case study was based on the then-current default of 1 lg/m3). Tier II assessments can be based on either (1) categorizing the chemical based on its LC50 and identifying an appropriate Threshold of Concern for that chemical category; or (2) using a conservative estimate of a NOAEL-to-LC50 ratio based on a distributional analysis of such ratios for known chemicals to extrapolate from the LC50 for the chemical of interest to a health-protective limit (Grant et al., 2007). Tier III assessments are based on a relative toxicity/potency approach to extrapolate from related chemicals (TCEQ, 2012). Conclusions: Tiered strategies provide flexible and efficient approaches, taking into account the decision context, data availability and resource constraints. Screening assessments use conservative default approaches with the goal of providing health-protective results where the assessment is resource-limited and/or the screening indicates that further action and analysis are not needed. An important aspect of using such tiered approaches is that if a potential problem is indicated in a lower tier, and if important for risk management, then the assessment is advanced to a subsequent, more informed, tier.

Consideration of the nature of decisions to be made in the problem formulation is also critical to selection of the appropriate form of expression of hazard for health-related endpoints; that is whether or not to calculate a dose corresponding to a specified risk level, such as the daily dose that, over a lifetime, would result in a 1  10 5 population risk. The calculation of risk-specific doses for any suitable endpoint (not just cancer incidence) was noted by NRC (2009) as desirable, and of high importance for cost-benefit analyses. However, the panel recommended that this might be most useful when the measured or predicted exposure approaches recommended limits such as a

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Reference Dose (RfD). In other words, the panel recommended that calculating a risk-specific dose may be helpful if exposure is near an RfD or similar value, but it may be of much less interest if the measured or estimated exposure is well below (or well above) a safe dose, or if the application considered in problem formulation requires the estimation of an RfD or similar value. Case Study #2 summarizes an approach developed by Hattis et al. (2002) that could be used potentially to predict risk levels at any dose of interest, if risk management options are best informed by such analyses (e.g., cost benefit considerations). This approach also draws on non-chemical-specific broadly based information sources (i.e., for other chemicals and pharmaceuticals) to improve the traditional uncertainty factor framework, but draws on more generic (i.e., non chemical specific) information and as such is likely to have greater relative uncertainty than, for example, Chemical Specific Adjustment Factors (CSAF) (IPCS, 2005). Case Study Box #2 Use of Hattis ‘‘Straw Man’’ Approach for Dose–Response Evaluation Key point: Chemical-specific dose–response data and generic distributional data are used to estimate risk for noncancer endpoints, based on the assumption of a distribution of individual thresholds of toxicity. Method: The Straw Man model provides a distribution of risks at specified doses, and for illustrative purposes, defines the reference value as the 5th percentile value of the dose corresponding to a 1 in 100,000 increase in risk of mildly adverse effects (Hattis and Lynch, 2007). Other percentiles and risk levels could be used. The model initially estimates an uncertainty distribution for the effective animal dose expected to yield a 50% response (animal ED50). It then applies a series of uncertainty distributions based on specific chemical data, or empirical data for other compounds to transform the animal ED50 to a human ED50 uncertainty distribution (e.g., subchronic-tochronic, database deficiency, animal-to-human.) Next, separate distributions based on specific chemical data, or empirical data for other compounds of human pharmacokinetic and pharmacodynamic variability specific to the organ system affected and the severity of effect are used to account for human variability. The uncertainty distributions are combined in a Monte Carlo simulation to predict a distribution of doses corresponding to a target risk level. MOA data could be used in determining the relevant set of reference chemicals for deriving the distributions. Conclusions: The Straw Man approach draws on non-chemical-specific broadly based information sources (i.e., for other chemicals and pharmaceuticals) to improve the traditional uncertainty factor framework. Science Panel members recommended that further refinement would be based on, for example, chemical-, endpoint- or route-specific MOA.

3.2.2. Theme 2: Fit-for-purpose MOA analysis for dose response Most dose–response assessments are based on effect levels identified in animal or human dose–response studies designed principally to identify defined hazard response levels, (e.g., NOAEL, LOAEL, etc.), followed by application of default extrapolation approaches (e.g., division by uncertainty factors or linear extrapolation). Only rarely are MOA data used directly

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in the dose–response analysis and risk characterization. Lack of integration of data on MOA limits predictivity, since results then cannot be easily extrapolated to other chemicals and/or conditions. Early focus on patterns of effects, taking into account MOA data on toxicokinetics and dynamics, can be informative in considering appropriate approaches for extrapolations addressing interspecies differences and human variability. Thus MOA analysis can be applied throughout an assessment, informing many aspects flagged as important in NRC (2009), including but not limited to the approach for low-dose extrapolation. For example, MOA is critical in identifying likely susceptible populations and the potential range of variability in response in both the general and susceptible populations. Work to develop a database of accepted MOAs as noted by Carmichael et al. (2011) will additionally facilitate incorporation of MOA in risk assessment to address issues raised within the NRC Science and Decisions report. The NRC (2009) noted that there is a need for increased understanding in the risk assessment community of the basis for defaults and their underlying assumptions, so that assessors can evaluate if and when other approaches may be appropriate. The NRC committee stressed that clear criteria and guidance should be available for judging whether, in specific cases, data are adequate to support inference in place of default, and what level of evidence is needed to justify use of agent-specific data instead of a default. An important contribution of the workshops and framework relates to increasing familiarity in an accessible and structured format, with international and existing relevant US EPA guidance and illustrative case studies, addressing specifically the objective above cited by the NRC committee (see, for example IPCS, 2005, 2006; U.S. EPA, 1994, 2011). Depending on the needs identified in the problem formulation, there is a range of approaches incorporating increasingly biologically informed and chemical specific knowledge on MOA, into dose–response assessment (see Fig. 1 and associated guidance). These approaches as considered here reflect a continuum of increasing degrees of understanding of how (the) chemical(s) induce(s) critical adverse effect(s) and the implications of that information for understanding dose response. Thus, problem formulation should include consideration of the appropriate extent of analysis of MOA in any assessment, depending on the expected importance to potential risk management decisions. Transparency in problem formulation regarding the expected value of the MOA analysis also serve to provide ‘‘up front’’ incentives for valuing collection of information on MOA. Case Study Box #3 illustrates the potential of information on MOA to inform more predictive and accurate quantification of dose–response in humans, including potentially sensitive populations; see also the case study on chemical-induced ovarian effects (Kirman and Grant, 2012). Implications of the mode of action analysis for this case study are relevant to other compounds that act through cholinesterase inhibition, but for which fewer data are available; the case study also illustrates how MOA can be helpful in addressing one of the more generic methodological issues raised in the NRC report (i.e., addition to background). In relation to the latter, the NRC (2009) report stated that ‘‘effects of exposures that add to background processes and background endogenous and exogenous exposures can lack a threshold if a baseline level of dysfunction occurs without the toxicant and the toxicant adds to or augments the background process,’’ an idea initially raised by Crump et al. (1976). However, Case Study #3 provides an example of using a data-based, computational modeling approach to inform the low-dose response in the face of background biological activity,

rather than being constrained to either of two alternative default approaches. Case Study Box #3

Quantitative Assessment of Sensitivity and Variability in Humans Key points: This study addresses MOA, human kinetic and dynamic variability, background response variability, and interaction with background exposures and predisposing disease processes. Method: A source-to-outcome model provided a quantitative description of the relationship. between the amount of dietary residues of chlorpyrifos (CPF) in food, and the impact of the exposures on inhibition of cholinesterase in exposed populations (Price et al., 2011; Hinderliter et al., 2011). Longitudinal dietary exposure was modeled and combined with a physiologically – based pharmacokinetic/ pharmacodynamic (PBPK/PD) model of response. The resulting model quantitatively predicts changes in the activity levels of cholinesterase that occur as a result of an oral (i.e., dietary) dose of CPF. Variability in dose and response was addressed through Monte Carlo analysis. Conclusions: The approach illustrates the use of chemicalspecific MOA data to characterize the dose–response for a chemical at environmentally relevant exposures, including consideration of variations in background biological activity. It allows for identification of a dose that does not cause a biologically meaningful change in a critical precursor MOA key event (cholinesterase inhibition), and by inference, one where increases in apical effects are not expected, even for individuals who are at increased susceptibility due to other stressors. This approach is an example of how MOA can inform a population threshold as defined by NRC (Conceptual model 2 as described by NRC, 2009, page 141).

3.2.3. Theme 3: Endogenous and background exposures The Science Panel identified several issues relevant to the dose– response implications of exogenous exposures that had similar impact as an endogenous process. In such scenarios, population variability in endogenous levels and associated response needs to be considered, but high variability alone is an inadequate basis to conclude that exogenous exposure may be a trivial contributor to risk. Of critical importance is the quantitative difference between the magnitude of response associated with endogenous exposures compared to that induced by exogenous exposures. In particular, a key issue in this comparison is how close the biological response to endogenous levels is to an adverse effect level (i.e., how much of a margin exists between the level of exposure for the biological response and the level of exposure for the adverse effect). It would be helpful to understand, for example, the relative contribution to total dose of both endogenous and exogenous sources, and any kinetic differences between the two sources in the formation or disposition of the chemical that may affect its toxic potential. This sort of information can better inform selection of dose response models appropriate for assessing risks associated with low-dose exogenous exposures, as a basis for informing risk management options (see also the case study on background/ endogenous damage at http://www.allianceforrisk.org/Workshop/ WS3/CaseStudies WS3.html). As an example, DNA damage originating from some exogenous chemical exposures may be identical to that resulting from

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Fig. 1. Increasingly biologically-informed and chemical-specific approaches.

endogenous biological processes. For other chemicals, these two sources of DNA damage may be differentiated, but only by complex laboratory testing. For example, Swenberg et al. (2011) showed that low-level exogenous chemical exposures result in DNA adducts, the nature of which are indistinguishable from those resulting from endogenous background, and those resulting from exogenous exposure only exceed endogenous levels at higher doses. These cases can provide key generic insights into the potential shape of the dose response curve and the risk associated with low-level exposures to some DNA-reactive substances.

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transparent consideration of available scientific support) from science policy, (i.e., selection of options motivated by the desire for increased public health protection). Subsequent revisions of the ARA framework are intended to better enable interested risk assessment scientists to consider a broad range of dose response methods in the context of recommendations made in the NAS report and perhaps more importantly, may facilitate selection by risk managers of an appropriate dose response method through a review of problem formulations offered in different case studies. The ARA is facilitating an ongoing process to expand the repository of fit-for-purpose methods for dose–response analysis. New methods and revisions will be incorporated to keep the ARA methods Framework and materials ‘‘evergreen.’’ This approach includes Science Panel review of methods on a regular basis, allowing for updates to additionally illustrate the ARA risk assessment methods framework. Additional enhancements could also include expansion of the framework from the current focus on dose–response methods to include other components of risk assessment.

Conflict of interest The authors declare that they have no conflicts of interest.

Funding sources 3.3. Additional methods needed The Science Panel identified the following priorities for future addition to illustrate and populate the framework:  Risk assessment for combined, multiple, exposures including aggregate and cumulative exposures.  Case studies on value of information.  Case studies that illustrate an entire risk assessment, from problem formulation to conclusion.  Case studies that illustrate in vitro to in vivo extrapolation. The Science Panel also recommended investigating the potential utility of linking the ARA methods Framework to case studies and examples that illustrate methods that have not undergone ARA Science Panel review. 4. Conclusions and future work There is a wide range of decision contexts, necessitating different approaches to dose–response analysis. Incorporation of increasingly biologically informed and chemical specific knowledge in MOA-based approaches has the potential to additionally refine estimates of hazard based on issues identified by the NRC (2009) committee, including, for example, consideration of susceptible subgroups, though this must necessarily be balanced against resource and time constraints for completion of assessments to inform risk management. Sharing and communicating in structured fashion (the developed framework to consider potential contribution of these methodologies in a problem formulation context) is considered important as a basis to increase understanding of the availability of various methodologies incorporating increasingly biologically informed and chemical specific knowledge. The ARA methods framework is expected to contribute to increasing transparency in the basis for selection of fit-for-purpose approaches to dose–response assessment as well as to promote continuing advancements in that practice, as a basis to increase predictivity and efficiency. Such transparency is anticipated to aid in distinguishing and communicating science judgments (i.e., weighting of options based on

The workshop series described in this paper was supported by over 50 sponsors and collaborators, including government agencies, industry groups, scientific societies, non-profit organizations/consortia, and consulting groups. These groups are listed at http:// www.allianceforrisk.org/ARA_Dose-Response_Sponsors.htm. Some government employees received travel reimbursement for their participation, but no other compensation.

Disclaimer The information in this document has been funded in part by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. This paper reflects the views of the authors and does not necessarily represent views or policies of the employers of the non-Agency authors. These views should also not be construed to represent those of science panel members who are not listed as contributing authors. Nor should these views be construed to represent those of the project’s 55 sponsors. Acknowledgments The authors thank the almost 50 sponsors and collaborators including government agencies, industry groups, scientific societies, non-profit organizations/consortia, and consulting groups (http:// www.allianceforrisk.org/ARA_Dose-Response_Sponsors.htm). The workshop series built upon the consideration of the evolution of risk assessment of the authors of Science and Decisions (NRC, 2009). Results of the workshop series are available at http:// www.allianceforrisk.org/ARA_Dose-Response.htm. The authors wish to thank all of the workshop participants for their contributions, particularly the case study authors, science panel members who declined or were otherwise unavailable for authorship and Oliver Kroner for his work in organizing the workshops.

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