Guidance Document for the Use of Data in Development of Chemical-Specific Adjustment Factors (CSAFs) for Interspecies Differences and Human

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1 Guidance Document for the Use of Data in Development of Chemical-Specific Adjustment Factors (CSAFs) for Interspecies Differences and Human Variability in Dose/Concentration Response Assessment July 2001

2 TABLE OF CONTENTS PREFACE INTRODUCTION Historical context Objectives CSAFs and the risk assessment paradigm TECHNICAL BACKGROUND Definition of terms Nature of relevant data Toxicokinetic data Physiologically based kinetic parameters Physiologically based pharmacokinetic models Toxicodynamic data Framework for development of CSAFs Traditional approach to consideration of measures of dose/concentration response for threshold toxicants Subdivision of default uncertainty factors for kinetic and dynamic aspects Composite factor (CF) GUIDANCE FOR THE USE OF DATA IN DEVELOPMENT OF CHEMICAL-SPECIFIC ADJUSTMENT FACTORS (CSAFs) FOR INTERSPECIES DIFFERENCES AND HUMAN VARIABILITY Data for the development of a chemical-specific adjustment factor for interspecies differences in toxicokinetics (AK AF ) Identification of the active chemical moiety Choice of relevant toxicokinetic parameter Experimental data Data for the development of a chemical-specific adjustment factor for interspecies differences in toxicodynamics (AD AF ) Identification of the active chemical moiety Consideration of end-point Experimental data Data for the development of a chemical-specific adjustment factor for human variability in toxicokinetics (HK AF ) Identification of the active chemical moiety Choice of relevant toxicokinetic parameter Experimental data Data for the development of a chemical-specific adjustment factor for human variability in toxicodynamics (HD AF ) Identification of the active chemical moiety Consideration of end-point

3 3.4.3 Experimental data Incorporation of chemical-specific adjustment factors for interspecies differences and human variability into a composite factor (CF) REFERENCES APPENDIX 1: CASE-STUDIES APPENDIX 2: GLOSSARY OF TERMS...76 LIST OF FIGURES Fig. 1. The relationship between external dose and toxic response for specific compounds Fig. 2. Processes in the generation of a toxic response Fig. 3. Framework for the introduction of quantitative toxicokinetic and toxicodynamic data into dose/concentration response assessment Fig. 4. Overall decision tree for development of the CF Fig. 5. Derivation of AK AF Fig. 6. Derivation of AD AF Fig. 7. Derivation of HK AF Fig. 8. Development of CSAFs for human variability for various distributions within the population (HK AF /HD AF ) Fig. 9. Derivation of HD AF

4 ACRONYMS AND ABBREVIATIONS AD AF chemical-specific adjustment factor for interspecies differences in toxicodynamics AD UF default uncertainty factor for interspecies differences in toxicodynamics ADI acceptable daily intake ADME absorption, distribution, metabolism and excretion AK AF chemical-specific adjustment factor for interspecies differences in toxicokinetics AK UF default uncertainty factor for interspecies differences in toxicokinetics ANOVA analysis of variance AUC area under the concentration time curve BMC benchmark concentration BMC 05 the concentration (or its lower confidence limit) calculated to be associated with a 5% incidence of effect BMD benchmark dose C max maximum concentration delivered to target organ CF composite factor CL clearance CSAF chemical-specific adjustment factor CYP cytochrome P-450 EC 10 10% effective concentration EHC Environmental Health Criteria monograph HD AF chemical-specific adjustment factor for human variability in toxicodynamics HD UF default uncertainty factor for human variability in toxicodynamics HK AF chemical-specific adjustment factor for human variability in toxicokinetics HK UF default uncertainty factor for human variability in toxicokinetics IPCS International Programme on Chemical Safety K m Michaelis-Menten constant LCL lower confidence limit LOAEL lowest-observed-adverse-effect level NADPH reduced nicotinamide adenine dinucleotide NOAEC no-observed-adverse-effect concentration NOAEL no-observed-adverse-effect level PBPK physiologically based pharmacokinetic PBTK physiologically based toxicokinetic PTWI provisional tolerable weekly intake RfC reference concentration RfD reference dose SD standard deviation SEM standard error of the mean TDI tolerable daily intake UCL upper confidence limit UDP uridine diphosphate maximum rate of metabolism V max 4

5 PREFACE This document was prepared through a project on Uncertainty and Variability in Risk Assessment under the auspices of the IPCS initiative on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. The members of the Planning Workgroup are: Erik Dybing, National Institute of Public Health, rway (Chair) Robin Fielder, Department of Health, UK Donald Grant, Consultant to IPCS, Canada Ursula Gundert-Remy, Federal Institute for Consumers Health Protection and Veterinary Medicine (BGVV), Germany (Liaison, Harmonization Steering Committee) Bette Meek, Health Canada Sharon Munn, Commission of the European Communities, Italy Edward Ohanian, Office of Water, USEPA, USA Andy Renwick, University of Southampton, UK Jun Sekizawa, National Institute of Hygienic Sciences, Japan Cindy Sonich-Mullin, IPCS Harmonization Project and Office of Research and Development, USEPA, USA Theo Vermeire, National Institute of Public Health and Environmental Protection (RIVM), The Netherlands Vanessa Vu, USEPA, USA Drew Wagner, Department of Human Services and Health, Australia Maged Younes, Secretariat, IPCS This Guidance Document was developed based on the discussions and output of the IPCS Workshop on Incorporating Uncertainty and Variability into Risk Assessment held in May 2000 in Berlin, Germany and through a follow-up meeting convened in August 2000 (and subsequently) in Ottawa, Ontario, Canada by the following Drafting Group consisting of several of the Planning Workgroup members and participants in the Berlin Workshop: Allan Boobis, Imperial College, London, UK Michael Dourson, Toxicology Excellence for Risk Assessment, USA Donald Grant, Consultant to IPCS, Canada Ursula Gundert-Remy, Federal Institute for Consumers Health Protection and Veterinary Medicine (BGVV), Germany (Liaison, Harmonization Steering Committee) Bette Meek, Health Canada Sharon Munn, Commission of the European Communities, Italy Edward Ohanian, Office of Water, USEPA, USA Andy Renwick, University of Southampton, UK 5

6 1. INTRODUCTION The objective of this document is to provide guidance to risk assessors on the use of quantitative toxicokinetic and toxicodynamic data to address interspecies and interindividual differences in dose/concentration response assessment. In section 1, a brief historical account of the development of this document is presented, followed by contextual reference to the relevance of this guidance in the context of the broader risk assessment paradigm and to other initiatives of the International Programme on Chemical Safety (IPCS) Project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals (Harmonization Project). Technical background material is presented in section 2, followed by generic guidance for the development of chemical-specific adjustment factors (CSAFs) in section 3 and accompanying summary figures. Illustrative case-studies are included in Appendix Historical context The IPCS Harmonization Project was initiated in 1993 following a recommendation at the United Nations Conference on Environment and Development in This project was endorsed by the Intergovernmental Forum on Chemical Safety in Its objective is to improve the understanding of the methods and practices used in various countries and organizations so as to develop confidence in, and acceptance of, risk assessments (convergence being the long-term goal). At the outset of this harmonization project, work was focused on an end-point-specific basis. In this regard, general issues in non-cancer risk assessment were identified as an activity that could benefit from harmonization. Through review of existing methodology worldwide at a Workshop on the Harmonization of Risk Assessment for n-cancer End-points held in 1996, a number of key areas for harmonization were identified. Specifically, issues of dose or concentration response extrapolation were considered a high priority. It was the recommendation of the 1996 Workshop to convene an additional workshop to delineate the choice of default values for uncertainty factors, to provide a forum for information exchange to refine default uncertainty factors for toxicokinetic and toxicodynamic interfaces and to consider the extent of data necessary to replace the current default uncertainty factors. It was with these goals in mind that a Planning Workgroup was established to work with IPCS to further identify the issues and to develop a plan of action. In May 2000, the Planning Workgroup organized a major Workshop on Human Variability and Uncertainty in Risk Assessment in Berlin, Germany, to examine specific issues related to toxicokinetics and toxicodynamics to address both interspecies and interindividual differences. To facilitate this, a series of casestudies was developed to increase common understanding of the sufficiency of different types of toxicokinetic and toxicodynamic data to replace default uncertainty factors for interspecies differences and human variability. The essential content of a draft guidance document, developed to assist risk assessors in the use of experimental data in deriving CSAFs and including some of these case-studies, was agreed to at the Berlin Workshop. The draft guidance document was subsequently revised by a drafting workgroup at a meeting held in Ottawa, Canada, in August The revised draft was circulated for review by all participants in the Berlin Workshop, review comments were incorporated, and the guidance document was finalized. 6

7 1.2 Objectives The principal objectives of the development of this guidance document are 1) to increase common understanding and to encourage the incorporation of relevant quantitative data in a context consistent with traditional approaches to development of measures of dose/concentration response, and 2) to more fully delineate appropriate avenues of research to enable more predictive estimates of risk. With respect to the latter objective, this approach necessarily requires ethically derived human data from either in vivo or in vitro studies in order to inform the selection of appropriate adjustment factors for interspecies differences or human variability. The types of data considered to be informative in this context are also often from in vitro animal studies, consistent with objectives to reduce and replace animals in toxicological testing. The approaches described in the following sections are also amenable to presentation in a probabilistic context (rather than development of single measures for dose/concentration response), where data available are sufficient to meaningfully characterize the distribution of interest. Thus, this guidance on the incorporation of quantitative data on interspecies differences or human variability in toxicokinetics and toxicodynamics into dose/concentration response assessment through the development of CSAFs is designed primarily for risk assessors. However, it is also relevant to those who commission or design relevant studies for the purposes of refining dose/concentration response relationships. Indeed, it is hoped that the guidance included herein will encourage the development of appropriate data and facilitate their incorporation in dose/concentration response assessment for regulatory purposes. It is recognized that for many substances, there are few data to serve as a basis for development of CSAFs. Indeed, currently, relevant data for consideration are often restricted to the component of uncertainty related to interspecies differences in toxicokinetics. While there are commonly fewer appropriate, relevant data at the present time to address the three other components considered here namely, interspecies (animal to human) differences in toxicodynamics, interindividual (human) variability in toxicokinetics and interindividual (human) variability in toxicodynamics it is anticipated that the availability of such information will increase with a better common understanding of its appropriate nature. Application of the approach even in the absence of data is considered to be informative, therefore, since it focuses attention on gaps in the available information that, if filled, would permit development of more appropriate measures of dose/concentration response. This guidance complements outputs of other initiatives of the IPCS harmonization project, where, for example, a framework for the transparent presentation of weight of evidence for mode of action has been developed (IPCS, 1999a). The approach described herein also presupposes that data that contribute to quantitative characterization of interspecies differences and human variability in the development of CSAFs have been critically reviewed and considered in the context of criteria for weight of evidence, such as consistency, etc. Relevant data often emanate from studies additional to those recommended routinely for toxicity testing, and multidisciplinary review of this information is encouraged. 7

8 1.3 CSAFs and the risk assessment paradigm Risk assessment has traditionally been considered to consist of four steps: 1. hazard identification the identification of the inherent capability of a substance to cause adverse effects; 2. assessment of dose/concentration response relationships the characterization of the relationship between the dose of an agent administered or received and the incidence of an adverse effect; 3. exposure assessment the qualitative and/or quantitative assessment of the chemical nature, form and concentration of a chemical to which an identified population is exposed from all sources (air, water, soil and diet); 4. risk characterization the synthesis of critically evaluated information and data from exposure assessment, hazard identification and dose response considerations into a summary that identifies clearly the strengths and weaknesses of the database, the criteria applied to the evaluation and validation of all aspects of methodology, and the conclusions reached from the review of the scientific information (IPCS, 1999b). In relation to risk characterization, a major area of recent advance has been an increasingly common understanding of the concept of mode of action and its contrast with mechanism of action. In this context, mode of action is essentially a series of events that may lead to induction of the relevant end-point of toxicity for which the weight of evidence supports plausibility, whereas mechanism of action implies a detailed molecular description of causality. In hazard characterization, a component of risk characterization, the weight of evidence on hazard and mode of action for the spectrum of various end-points is critically assimilated as a basis for defining appropriate end-points for and approaches to characterization of dose/concentration response. It is this latter component of risk assessment (i.e., assessment of dose/concentration response relationships) for which the development of CSAFs is relevant. In general, dose/concentration response assessment is often based on only two or three data points in the experimental range. Either the experimental data are assessed to determine a level without adverse effects (the no-observed-adverse-effect level or NOAEL) or a curve is modelled that best fits the central estimates of the relationship defined by these experimental points and confidence intervals calculated. There are two distinct approaches for extrapolation of risks to humans, based on the data within the experimental range those that assume a threshold and those for which it is assumed that there is no threshold. Generally, for all effects with the exception of those induced by direct interaction of the compound or its metabolites with genetic material, it is assumed that there is a threshold below which the probability of harm is negligible, and a presumed safe level of exposure is developed. This is traditionally based on an approximation of a value that would be below the threshold, through division of a NOAEL, lowest-observedadverse-effect level (LOAEL) or benchmark dose or concentration (BMD or BMC), a model-derived estimate (or its lower confidence limit) of a particular incidence level (e.g., 5%) by uncertainty factors to address principally interspecies and interindividual variation (IPCS, 1987, 1994). Alternatively, the magnitude by which the NOAEL (or LOAEL) or BMD/BMC exceeds the estimated exposure (i.e., the margin of 8

9 safety or margin of exposure ) is considered in light of various sources of uncertainty and variability. For effects involving direct interaction with genetic material (i.e., some types of carcinogenicity and germ cell mutagenicity), it is generally assumed that there is a probability of harm at any level of exposure (i.e., there is no threshold below which the probability of harm is considered to be negligible). At present, there is no clear consensus on appropriate methodology for dose/concentration response assessment in this case and options range from expression of dose/exposure response as potency in or close to the experimental range, to risks in the low-dose range estimated through linear extrapolation from an effective dose (i.e., akin to a BMD for non-cancer effects), or to predication of control measures on the basis of reduction of exposure to the extent practicable (Younes et al., 1998). In future, as relevant approaches are based increasingly on understanding of mode of action, there will be less reliance on empirical mathematical modelling and, hence, the assumptions of threshold or not. Inter- and intraspecies considerations are an essential part of extrapolation to humans for all of these approaches (IPCS, 1999b) and were described in EHC 210 as follows: a) Interspecies consideration: comparison of the data for animals with a representative healthy human. Species differences result from metabolic, functional and structural variations. b) Intraspecies or interindividual consideration: comparison of the representative healthy human with the range of variability present within the human population in relation to the relevant parameters. It is the use of quantitative toxicokinetic and toxicodynamic data to inform interspecies and interindividual extrapolations in dose/concentration response assessment (i.e., CSAFs) that is the focus of this guidance document. Previously, CSAFs were called data-derived uncertainty factors (Renwick, 1993; IPCS, 1994, 1999b). The new nomenclature of chemical-specific adjustment factors has been adopted because it better describes the nature of the refinement to the usual default approach. Also, it avoids confusion with factors that are based on an analysis of data for a group of chemicals sharing a common characteristic i.e., categorical default factors such as those based on common physical/chemical characteristics or pathways of metabolism, which are sometimes referred to as data-derived factors and that are not chemical-specific. It should be recognized that CSAFs represent part of a broader continuum of increasingly datainformed approaches to account for interspecies differences and human variability, which range from default ( presumed protective ) to more biologically based predictive (Fig. 1). The approach along this continuum adopted for any single substance is necessarily determined principally by the availability of relevant data. The extent of data available is, in turn, often a function of the economic importance of the substance. 9

10 Basic data set EXTERNAL DOSE TOXIC RESPONSE Physiologically based kinetics EXTERNAL DOSE INTERNAL DOSE TOXIC RESPONSE Physiologically based kinetic model EXTERNAL DOSE INTERNAL DOSE TARGET ORGAN DOSE Physiologically based kinetic model plus local target organ metabolism EXTERNAL DOSE INTERNAL DOSE TARGET ORGAN DOSE Biologically based dose-response model TARGET ORGAN METABOLISM TOXIC RESPONSE TOXIC RESPONSE EXTERNAL DOSE INTERNAL DOSE TARGET ORGAN DOSE TARGET ORGAN METABOLISM TARGET ORGAN RESPONSES TOXIC RESPONSE Fig. 1. The relationship between external dose and toxic response for specific compounds (from Renwick et al., 2001). The development of CSAFs may not always be possible or even necessary. For example, if the margin between the no- or lowest-effect level or BMD/BMC and anticipated human exposure is very wide, the generation of the more sophisticated data necessary to replace part of a default uncertainty factor would not warrant the necessary experimentation in animals and humans and the associated resource expenditure. However, where this margin is small, development of additional chemical-specific quantitative data may be justified to refine the dose response analyses and scientific credibility of the outputs, such as acceptable daily intakes (ADIs)/tolerable daily intakes (TDIs), margins of exposure or margins of safety. The focus of this guidance is the incorporation of quantitative data on toxicokinetics and toxicodynamics into dose/concentration response analyses for approaches that lead to the estimation of a presumed safe (subthreshold) value, such as tolerable, acceptable or reference intakes or concentrations. However, it should be noted that the methodology described herein is equally applicable to the other approaches to exposure response analyses described above (e.g., margins of exposure or linear extrapolation from estimates of potency close to the experimental range). It also lends itself to presentation of doseresponse in a probabilistic context, where data are sufficient to confidently characterize the distributions of interest. 10

11 2. TECHNICAL BACKGROUND 2.1 Definition of terms As illustrated in Figure 2, there are a large number of steps on the pathway between administration of the external dose and the final toxic effect. EXTERNAL DOSE TOXIC RESPONSE ABSORBED DOSE CONCENTRATIONS IN GENERAL CIRCULATION CLEARANCE DISTRIBUTION TO NON-TARGET TISSUES INTRACELLULAR CHANGES + - CONCENTRATIONS IN TARGET TISSUE ANY LOCAL BIOACTIVATION - the balance of local bioactivation and detoxification - not reflected by plasma kinetic measurements INTERACTION WITH INTRACELLULAR TARGET(s) + - CYTOPROTECTIVE MECHANISMS te - CONCENTRATIONS refers to the relevant active form delivered by the general circulation and may be the parent compound or an active metabolite produced in another tissue and delivered to the target tissue/organism. Fig. 2. Processes in the generation of a toxic response. Subdivision into toxicokinetics and toxicodynamics is a pragmatic division of this continuous process between external dose and response. These terms were defined in EHC 170 (IPCS, 1994) as follows: a) Toxicokinetics: the process of the uptake of potentially toxic substances by the body, the biotransformation they undergo, the distribution of the substances and their metabolites in the tissues, and their elimination from the body. Both the amounts and the concentrations of the substances and their metabolites are studied. The term has essentially the same meaning as pharmacokinetics, but the latter term should be restricted to the study of pharmaceutical substances. b) Toxicodynamics: the process of interaction of chemical substances with target sites and the subsequent reactions leading to adverse effects. In the context of this guidance document, pharmacokinetic and toxicokinetic can be considered to have the same meaning, and a physiologically based pharmacokinetic (PBPK) model is equivalent to a physiologically based toxicokinetic (PBTK) model. 11

12 2.2 Nature of relevant data Where there are adequate in vivo data in humans to characterize exposure response in the general population or the critical sensitive subgroup thereof, these data, which encompass both kinetic and dynamic aspects, would serve as the basis for development of tolerable or acceptable concentrations or doses. More often, such data are not available. However, data addressing either kinetic or dynamic aspects in animals and humans for specific compounds can be informative in quantitatively addressing interspecies and interindividual variation in a contextual framework Toxicokinetic data Data on the comparative absorption, distribution, metabolism and excretion of chemicals (ADME) are increasingly available as a basis for definition of plasma and tissue toxicokinetics. These data permit quantitation of interspecies differences (i.e., those between test species and humans) and variability among humans (i.e., those in different subsets and individuals within the population) in the internal or target organ dose. Quantitative characterization in both of these areas requires the availability of toxicokinetic data for humans. Ideally, relevant data would be derived from in vivo studies that define the kinetics of the circulating chemical, or active metabolite, under the experimental conditions in animals and in humans at the anticipated human exposure dose or concentration. Appropriate toxicokinetic data may be derived from in vivo experimentation in human volunteers given very low doses of the chemical under evaluation, from in vitro measurements of critical processes (e.g., enzyme activity) and, in some cases, from measurements related to environmental exposures. For this latter case, however, exposure has often not been adequately characterized for the individual or population as a whole. Such data may be informative, however, if the fate of the chemical is clearly understood based on studies in animals. For example, even without precise quantitation of exposure, simple urine and plasma measurements are a reflection of total clearance for a substance that is eliminated largely via the kidneys Physiologically based kinetic parameters Parameters such as clearance (CL) and the area under the plasma or tissue concentration time curve (AUC) can be derived from in vivo studies. Alternatively, such parameters can be derived from in vitro enzyme studies combined with suitable scaling to determine in vivo activity. Plasma data will reflect partitioning of the chemical between the general circulation and the body tissues, but will not give a direct measure of the concentration in the target organ. In general, partitioning between plasma and tissues is by simple passive diffusion and is not a major source of either interspecies differences or interindividual variability; however, interspecies differences in tissue:plasma ratio could occur for chemicals that are highly protein bound Physiologically based pharmacokinetic models PBPK models can be used to develop measurements of the target organ dose based on animal data with appropriate interspecies scaling, in cases where the measured kinetic parameters are not sufficiently predictive of the anticipated exposure scenario; for example, PBPK models are often helpful in extrapolations 12

13 across routes, over large dose ranges or where tissue uptake is non-linear. Partitioning of the chemical between the general circulation and target tissue is usually based on measurements of the partition coefficient using animal tissues or other in vitro models. Partitioning between human tissues and the general circulation is frequently incorporated into the PBPK model for humans using data obtained from animal tissues; in consequence, such a human PBPK model will add little to physiologically based parameters, such as AUC and CL. PBPK models may be subdivided into two types: a) those that estimate the target organ dose of the parent compound or a circulating active metabolite; and b) those that additionally incorporate local target organ bioactivation processes as part of the PBPK model. PBPK models incorporating local tissue bioactivation have been used most frequently in the context of extrapolation between species for carcinogens (e.g., dichloromethane) Toxicodynamic data Toxicodynamic data are those that address any of the whole range of steps from molecular interaction, e.g., receptor binding, up to the effect at the target site. Whereas mode of action is understood for a range of effects induced by particular chemicals, a detailed knowledge of the mechanism of action is often not available (see Section 1.3). There is usually also no detailed knowledge on how the dose/ concentration effect relationship of one step at the effect site is related to the dose/concentration effect relationship of the next step. However, CSAFs for interspecies differences and human variability may be derived from comparative response data for the toxic effect itself in the target organ (e.g., haemolysis as in Case B) or for a point in the chain of events that is considered critical to the toxic response (i.e., a relevant end-point, sometimes referred to as a biomarker of effect) based on understanding of mode of action, under experimental conditions where toxicokinetic variations have been precluded. Hence, CSAFs could be derived from in vitro studies, from in vivo studies in which the toxicokinetic component has been delineated or from ex vivo experimentation. Some of the measurements of effect relate to biological responses that develop instantaneously without a time lag after exposure. They could be reversible or irreversible. Some measures of response relate to biochemical changes (e.g., elevation of liver enzymes) that result from early histopathological changes after continuous administration of the chemical. In kinetic dynamic link models that must be externally validated, the estimated concentrations or amounts at the site of action are related to the response by an empirical mathematical link-function formula. Such models provide estimates of the concentration response relationship excluding toxicokinetic aspects. t all in vitro or in vivo measurements represent processes that are critical to the development of the in vivo toxic response. There are frequently numerous sequential steps in producing a toxic response, and biomarkers of early changes may not reflect the critical toxicodynamic process. In order to serve as a surrogate marker for toxic effect, the measurements should be representative, both qualitatively and quantitatively, of the critical toxic end-point. 13

14 Incorporation of appropriate in vitro toxicodynamic data into considerations of species differences in toxicodynamics could contribute to a reduction in in vivo animal studies. For the generation of a CSAF for interspecies differences, parallel in vitro studies would be required in both animal and human tissues (see section 3). 2.3 Framework for development of CSAFs While the text below focuses on a framework for development of CSAFs for use in estimating safe (subthreshold) values, such as tolerable, acceptable or reference intakes or concentrations, the principles of the methodology described herein are equally applicable to other approaches to exposure response analyses, all of which lend themselves to incorporation of relevant comparative toxicokinetic and toxicodynamic data to quantitatively address interspecies differences and human variability. It also lends itself to presentation of dose-response in a probabilistic context, where data are sufficient to confidently characterize the distributions of interest Traditional approach to consideration of measures of dose/concentration response for threshold toxicants The usual starting point for dose response characterization of threshold effects is the NOAEL or BMD on a body weight basis (e.g., mg/kg body weight) or the no-observed-adverse-effect concentration (NOAEC) or BMC (i.e., concentration in air) for the critical effect in animal studies. The NOAEL or NOAEC is the highest level of exposure that causes no detectable adverse alteration of morphology, functional capacity, growth development or life span of the target organism and therefore is considered to be at or below the threshold in animals. BMCs or BMDs are levels that cause specified levels of response for critical effects. NOAELs/NOAECs and BMDs/BMCs are normally divided by safety or uncertainty factors to derive levels of human exposure that will be without significant adverse effects. For ingestion, the safe human exposure is usually termed acceptable (for an additive) or tolerable (for a contaminant) together with a time base, which is related to the potential for accumulation, e.g., ADI or provisional tolerable weekly intake (PTWI) for chemicals that accumulate. For inhalation, tolerable or reference concentrations (RfCs) are generally considered to be the airborne concentration to which the general population can be exposed continuously without adverse effect. Traditionally, in relation to exposure of the general population, the NOAEL/NOAEC for the critical effect in animals has often been divided by an uncertainty factor of 100. The normal 100-fold factor can be regarded as comprising the product of two 10-fold factors, one for interspecies differences and one for interindividual variability in humans (IPCS, 1987). Thus, one 10-fold factor can be considered to estimate the NOAEL anticipated for a small group of normal human beings on the basis of the NOAEL for animals (derived from a small group of relatively homogeneous test animals). When data are available from direct experimentation in groups of human volunteers, the NOAEL has traditionally been divided by an uncertainty factor of 10 to allow for human variability. However, there is a paucity of such data, and its utility in characterization of dose/concentration response is often limited, largely due to limitations of exposure determination and control for confounding in 14

15 epidemiological studies and limited periods of exposure of small numbers of subjects in clinical studies in volunteers. Therefore, by far the majority of analyses of dose/exposure response are based on studies in experimental animals. The NOAEL for potentially sensitive individuals is estimated through application of the second 10-fold factor. Extra uncertainty factors may be incorporated to allow for database deficiencies and for the severity and irreversibility of effects; these have been considered previously (IPCS, 1994) and are not part of the extrapolation for interspecies differences and human variability considered herein Subdivision of default uncertainty factors for kinetic and dynamic aspects Procedures for characterization of dose/concentration response currently range from the pragmatic approach of taking the experimental NOAEL and dividing by a default uncertainty factor (usually 100-fold for animal studies) to a full biologically based model. In reality, the vast majority of databases upon which risk assessments are made include little information on either the delivery of the parent compound (or its circulating toxic metabolite) to the target organ or data related to the mode of action. In consequence, the pragmatic default approach of uncertainty factors has remained the cornerstone of characterization of dose/concentration response. In order for either toxicokinetic or mechanistic (i.e., toxicodynamic) data to contribute quantitatively to risk assessment, in the absence of a full biologically based dose response model, it is necessary that the current procedure of applying 10-fold factors for interspecies differences and human variability be refined. Subdivision of each 10-fold factor into toxicokinetic and toxicodynamic components would allow part of the default value to be replaced by relevant, chemical-specific data when these were available, thereby advancing the scientific basis for dose response characterization and the resulting acceptable/tolerable/reference intakes or concentrations. Renwick (1993) analysed data on interspecies differences and human variability in toxicokinetics and toxicodynamics for a limited number of compounds. The majority of these chemicals were pharmaceuticals administered orally or intravenously to human volunteers and patients, since data in humans are essential for analysis of interspecies differences and human variability. Subdivision of the 10-fold uncertainty factors was based primarily on data for pharmacokinetic parameters, such as CL and AUC, because these relate directly to the steady-state body burden during chronic administration. The dynamic data for humans were based on pharmacokinetic pharmacodynamic modelling of a range of pharmacological and therapeutic responses, in which the interindividual variability in response is corrected for any interindividual variability in kinetics by the application of the model to the individual data. Based, to the extent possible, on available data, it was therefore proposed that each of the 10-fold factors could be subdivided into a factor of (4) for toxicokinetics and (2.5) for toxicodynamics. Generally, rodents metabolize compounds at a faster rate than humans, and the subdivision is consistent with the approximately 4-fold difference between rats (the most commonly used test species) and humans in basic physiological parameters that are major determinants of clearance and elimination of chemicals, such as cardiac output and renal and liver blood flows. The limited data analysed by Renwick (1993) indicated greater potential variability within humans in kinetics than in dynamics, so that a larger factor was suggested for kinetic variability. 15

16 In a subsequent review for a World Health Organization Task Group on Environmental Health Criteria for Guidance Values for Human Exposure Limits (IPCS, 1994), it was concluded that the subdivision of the interspecies factor was appropriate. However, it was considered that the database analysed was insufficient to justify an uneven subdivision of the 10-fold factor for human variability, and therefore this factor was divided evenly into two subfactors each of (3.16 or 3.2). This equal subdivision of the human variability factor was supported by a subsequent, more extensive analysis of appropriate kinetic parameters for 60 compounds in humans and concentration effect data for 49 compound-related effects (Renwick & Lazarus, 1998) Composite factor (CF) The scheme for dose/concentration response assessment developed in the IPCS (1994) document is summarized below (Fig. 3). The scheme is based on subdivision of the 10-fold factors and collapses back to the usual 100-fold factor in the absence of appropriate data, but allows the potential for quantitative chemical-specific data to be introduced. SELECTION OF PIVOTAL STUDY AND CRITICAL EFFECT ADEQUACY OF PIVOTAL STUDY NOAEL FROM HUMAN DATA NOAEL FROM ANIMAL DATA INTERSPECIES DIFFERENCES IN TOXICODYNAMICS AD UF 2.5 ( ) INTERSPECIES DFFERENCES IN TOXICOKINETICS AK UF 4.0 ( ) HUMAN VARIABILITY IN TOXICODYNAMICS HD UF 3.2 ( ) HUMAN VARIABILITY IN TOXICOKINETICS HK UF 3.2 ( ) OTHER CONSIDERATIONS NATURE OF TOXICITY OVERALL DATABASE DATA OVERVIEW CF AD UF - Animal to human dynamic uncertainty factor AK UF - Animal to human kinetic uncertainty factor HD UF - Human variability dynamic uncertainty factor HK UF - Human variability kinetic uncertainty factor Chemical-specific data can be used to replace a default uncertainty factor (UF) by an adjustment factor (AF). In the absence of appropriate data, the subdivision of the 10-fold factors collapses back to the 100-fold factor. Fig. 3. Framework for the introduction of quantitative toxicokinetic and toxicodynamic data into dose/concentration response assessment (from IPCS, 1994). 16

17 This procedure allows the replacement of part of the usual 100-fold uncertainty factor with quantitative chemical-specific data relating to either toxicokinetics or toxicodynamics, which will thereby have a direct and quantitative impact on the risk assessment outcome. The replacement of a default subfactor for either toxicokinetics or toxicodynamics with quantitative chemical-specific data will result in a CSAF for that particular aspect for which data were available. This has the effect of replacing a default factor for an area of uncertainty with chemical-specific data, thereby reducing the overall uncertainty. The composite factor (CF) applied to the NOAEL or NOAEC is the composite of the chemicalspecific adjustment factors and any remaining default uncertainty factors for which appropriate chemicalspecific data were not available: CF = [AK AF or AK UF ] [AD AF or AD UF ] [HK AF or HK UF ] [HD AF or HD UF ] where: C A represents the animal to human extrapolation factor (based on quantitation of interspecies differences) C H represents the human variability factor (based on quantitation of interindividual differences) C K stands for toxicokinetic differences C D stands for toxicodynamic differences C AF is the adjustment factor calculated from chemical-specific data C UF is the uncertainty factor, a default value that is used in the absence of chemical-specific data. The total CF could be either greater than or less than 100, depending on the quantitative scientific data that have been introduced to replace the default uncertainty factors. It is recognized in EHC 170 (IPCS, 1994) that the result of such replacement might be a CF that is less than the normal default of 100. Under such circumstances, a different toxic effect with a higher NOAEL/NOAEC combined with a standard default 100- fold uncertainty factor could become the critical effect. In consequence, arrows go back to the outset of the process in Figure 3 to ensure that all potential adverse effects and appropriate adjustment/uncertainty factors are considered adequately. The critical effect has been defined as the first adverse effect, or its known precursor, that occurs in the increasing dose/concentration scale. When CSAFs are adopted and this results in a CF of less than the usual total default of 100, the critical effect may be that which gives the lowest outcome after the application of appropriate factors. The dose/concentration response assessment may need to be based on an effect that occurs at a higher dose or concentration but for which relevant kinetic or dynamic data are not available as a basis for replacing default (see Case A2). This aspect should be considered when CSAFs are less than the default they replace. This possibility needs also to be considered in designing studies to develop data as a basis for CSAFs In the vast majority of cases, dose/concentration response assessment will be necessary in the absence of quantitative toxicokinetic or toxicodynamic data. In consequence, the framework has been designed to be compatible with the current default procedures, which are used when such data are not available. Because of the nature of the data on which the subdivision of the 10-fold uncertainty factors is based, local tissue bioactivation represents the first step in the local tissue response to the delivery of the chemical from the general circulation and therefore, in this context, is considered the initial step in toxicodynamics. Thus, in the context of the subfactors for toxicokinetics and toxicodynamics, PBPK models that include local 17

18 tissue bioactivation will include an initial part of the factor for toxicodynamics, and this will need to be considered on a case-by-case basis. For example, in some cases, tissue uptake is a function of the first step of bioactivation at the target site. The replacement of the interspecies toxicokinetic factor by parameters from PBPK models that include target organ bioactivation will take into account an undefined part of the interspecies toxicodynamic factor; the extent of this can only be defined by a full biologically based dose/concentration response model, and this would replace both aspects, i.e., the original 10-fold factor, when it is available. 18

19 3. GUIDANCE FOR THE USE OF DATA IN DEVELOPMENT OF CHEMICAL-SPECIFIC ADJUSTMENT FACTORS (CSAFs) FOR INTERSPECIES DIFFERENCES AND HUMAN VARIABILITY In the absence of adequate data in humans to characterize exposure response in the general population or a critical sensitive subgroup thereof, chemical-specific data on kinetic and dynamic aspects can be informative in quantitatively addressing interspecies and interindividual variation in the development of tolerable or acceptable concentrations or doses. In the following sections, guidance for the application of such data is provided in the context of replacing default values with those based on more robust chemical-specific scientific data on kinetics and dynamics. Kinetic data are those considered to be related to delivery of the chemical to the target organ, and dynamic data to concentration response in the target tissue. It should be recognized that while this guidance is presented in the context of the current default framework to address interspecies and interindividual variation by two 10-fold factors, this does not imply that these values are necessarily correct, but rather permits incorporation of informative data on kinetics and dynamics, in the absence of a full biologically based dose response model. It is anticipated that with increasing information on mode of action, reliance on 10-fold factors to address these aspects will decrease. The framework also lends itself to presentation of dose-response in a probabilistic context, where data are sufficient to confidently characterize the distributions of interest. One of the first steps in implementation of this guidance is careful consideration of the relevant toxicokinetic parameter (e.g., CL, AUC), sometimes referred to as metric, or the measure of effect for quantitation of interspecies differences or human variability in toxicodynamics as a basis for CSAFs, in relation to the delivery of the chemical to the target organ. Measures of various end-points in vivo (i.e., biomarkers) may represent purely toxicokinetics or toxicokinetics and part or all of the toxicodynamic processes. CSAFs to replace the toxicokinetic default for interspecies differences or human variability can be based on measured parameters that reflect the internal dose (e.g., the concentration of a chemical in the circulation). In vivo measurements that incorporate some aspect of intracellular processing related to the mode of action, such as formation of protein adducts or enzyme activation or inhibition, will reflect the uptake and delivery (kinetics) and at least part of the dynamics. Such a measurement could be used to replace the toxicokinetic and a proportion of the toxicodynamic default for interspecies differences (see section 3.1 on AK AF ). In some cases, the pragmatic split between kinetics and dynamics in the framework may not be appropriate, and some flexibility in approach will need to be maintained. For example, local metabolism in the target site may be important in both uptake into the target tissue (nominally kinetics) and the mode of action (nominally dynamics). The basis for the subdivision of the original 10-fold default factors was human pharmacokineticpharmacodynamic (PKPD) data primarily related to systemic exposure after oral and intravenous dosage and associated systemic effects. However, the contextual framework is equally applicable for other routes of exposure, such as inhalation, though defaults for components may vary somewhat. Thus the approach is, for example, analogous to the RfC methodology developed by the US EPA for effects produced following inhalation exposure. 19

20 An important aspect of the use of experimental data in the development of CSAFs is the recognition that part of the apparent human variability may be due to experimental or other errors. In consequence, CSAFs for human variability will tend to be conservative, because they will include any variability due to experimental errors. In well designed and conducted studies, random experimental errors, but not systematic or study design errors, will not greatly influence the central tendency that is used for chemical-specific adjustment factors related to interspecies differences. The overall decision tree for the framework presented in Figure 3 is given in Figure 4. In the sections that follow ( ), guidance for the development of adjustment factors for interspecies differences and human variability is presented for each component of the framework. This guidance is also presented diagrammatically in Figures 5, 6, 7, and 9. Overall decision tree *Proceed to relevant decision tree Are there adverse effect data in humans? Select pivotal animal study(s) and critical effect(s) and define NOAEL(s)? Has the NOAEL been defined in the appropriate susceptible group? Are the data adequate to establish a NOAEL? Uncertainty or adjustment factor not necessary Are compound-specific or compound-related data available for humans? Apply the usual default uncertainty factor (e.g., 100) to NOAEL(s) from animal studies Use default AK UF of 4.0 Are data on interspecies toxicokinetic differences available? *1. Derive AK AF Use default AD UF of 2.5 Are data on interspecies toxicodynamic differences available? *2. Derive AD AF Use default HK UF of 3.2 Are data on interindividual toxicokinetic differences available? Use default HD UF of 3.2 Are data on interindividual toxicodynamic differences available? *3. Derive HK AF Undertake risk assessment for other adverse effects Derive composite factor Will composite factor be adequate for all adverse effects detected in animal and/or human studies? *4. Derive HD AF Use composite factor te: NOAEL could also be NOAEC or BMD/BMC Fig. 4. Overall decision tree for development of the CF. 20

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