an integrated evaluation strategy for making regulatory ...vision by the u. s. national academy of...

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An Integrated Evaluation Strategy for Making Regulatory Decisions:

Moving From Data Requirements to Knowledge Requirements.

Douglas C. Wolf, D.V.M., Ph.D., Fellow IATP, ATSOffice of Research and Development

U. S. [email protected]

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Overview of Presentation

Proposals that Stimulated the Change

Issues that have to be Addressed

Examples of Legislative Context

Problem Formulation for Regulatory Decisions

Approaches to Establish Necessary Knowledge and Supporting Activities

What the Future Will Look Like and How to Make It Happen

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The Future of Toxicology…the application of mathematical and computer models and molecular biological approaches to improve…prioritization of data requirements and risk assessments.

To support the evolution of toxicology from a predominantly observational science at the level of disease-specific models to a predominantly predictive science focused upon a broad inclusion of target specific, mechanism-based, biological observations.

…a new toxicity-testing system that evaluates biologically significant perturbations in key toxicity pathways by using new methods in computational biology and a comprehensive array of in vitro tests based on human biology.

2003 2004 2007http://ntp.niehs.nih.govwww.epa.gov/ncct

http://dels.nas.edu/Report/Toxicity-Testing-Twenty-first/11970

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NAS Vision for the Future

“Work towards transition to new integrative and predictive molecular and computational techniques to enhance efficiency and accuracy and to reduce reliance on animal testing.”

Vision by the U. S. National Academy of Sciences National Research Council 2007 report, Toxicity Testing in 21st Century: A Vision and a Strategy

“The difficulty lies, not in the new ideas, but in escaping from the old ones”John Maynard Keynes (1883–1946), British economist

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Toxicity Testing in 21st Century: A Vision and a Strategy

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Goal

Integrated evaluation strategy that provides the necessary scientific knowledge to make a regulatory determination of the potential for an adverse impact, from the use of a chemical, on public health and the environment with speed, efficiency and accuracy.

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Problem StatementWhat is needed is a conceptual breakthrough which would

enable tailored risk assessments for a variety of risk management contexts; using in vitro, in silico and other new technology based on an integrated evaluation strategy.

Allowing significantly more chemicals to be assessed without increasing the amount of resources needed for testing or evaluation;

Allowing new methods to be incorporated as they develop;

Improve relevance and accuracy while reducing the reliance on whole animal testing;

Taking exposure and modes of action into consideration.

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Why do we order a buffet when we need a simple balanced meal?

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I’LL HAVE A RAT AND MOUSE 2 YEAR STUDY, A MULTIGEN..... OH AND AN IN VITRO ASSAY, I’VE GOT TO WATCH MY ANIMAL USAGE!

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We need something like this.

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Toxic Substances Control Act of 1976adequate data should be developedinformation relating to chemical characteristicstest data to determine an unreasonable riskperiodic review of the standards for data developmentmethods for prioritization of data needsSAR methodspredictive modelsestablish screening methods and the scientific basis for these methods

Safe Chemicals Act of 2010develop minimum data setinformation on chemical characteristicsinformation on use and exposuredevelop alternative (non animal based) test methodsdevelop a strategic plan for implementing alternative test methodsuse test methods that eliminate or reduce animal useencourage submission of data using new methodssupport the scientific basis for new method development

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Safe Drinking Water Act (SDWA)as amended 1996SEC. 1442. (A) improved methods(i) to identify and measure the existence of contaminants in drinking water,(ii) to identify the source of such contaminants;(B) improved methods to identify and measure the health effects of contaminants in drinking water;

Clean Water Act (CWA)as amended 1987SEC. 104. (1) …conduct and promote the coordination and acceleration of, research, investigations, experiments, training, demonstrations, surveys, and studies relating to the causes, effects, extent, prevention, reduction, and elimination of pollution;

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Source-Exposure-Dose-Effects Continuum

TRANSPORT / TRANSFORMATION

ALTERED STRUCTURE / FUNCTION

ENVIRONMENTAL CHARACTERIZATION

SOURCE / STRESSOR FORMATION

DOSE

EXPOSURE

EARLY KEY BIOLOGICAL EVENTS

DISEASE

Toxicity Pathway

ChemicalPhysicalMicrobial

MagnitudeDurationTiming

DispersionKineticsThemodynamicsDistributionsMeteorology

AirWaterDietSoil & dust

PathwayRouteDurationFrequencyMagnitude

Statistical ProfileReference PopulationSusceptible Individual

Susceptible SubpopulationsPopulation Distributions

AbsorbedTargetInternal

Biologically Effective

MolecularBiochemicalCellularOrganOrganism

EdemaArrhythmiaNecrosisetc.

CancerAsthmaInfertilityetc.

Community

ActivityPatterns

PBPKModels

Transport,Transformation &

Fate Models

ExposureModels

BBDRModels

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Chemical

RELEASE FATE / TRANSPORT CONCENTRATION ACTIVITY EXPOSURE

Intermediates

Degradates

PR

OD

UC

T n

PR

OD

UC

T …

PR

OD

UC

T 8

PR

OD

UC

T 7P

RO

DU

CT 6

PR

OD

UC

T 5P

RO

DU

CT 4

PR

OD

UC

T 3P

RO

DU

CT 2

PRO

DU

CT 1

Release

Reaction

ProductUse

Disposal

LocationFrequencyTiming

PopulationMarket Share

Water

OutdoorAir

SurfaceDust

A C

T I V

I T I E

S

Soil

IndoorAir

Food

ChemicalManufacture

ChemicalTransportation

Production/Formulation

WorkplaceExposure

EnvironmentalRelease

EnvironmentalDisposal

Air

Water

Incineration

Recycling SewageTreatment

Food

A C

T I V

I T I E

S

Land

Transport

EnvironmentalExposure

EnvironmentalRelease

Food

Water

Land

ProductDisposal

Air

A C

T I V

I T I E

S



Lifecycle Analysis

Consistant with NAS Science and Decisions and TSCA 2010

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National Academy of ScienceExposure Project

Human and Environmental Exposure Science in the 21st Century

Develop a long-range vision for exposure science and a strategy with goals and objectives for implementing the vision over the next twenty years.

It will include development of a unifying conceptual framework for advancement of exposure science to study and assess human and ecological contact with chemical, biological, and physical stressors in their environments.

http://dels.nas.edu/Study-In-Progress/Human-Environmental-Exposure-Science/DELS-BEST-09-02

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Threshold of Toxicological ConcernRisk assessment tool based on the establishment of a human exposure threshold value for chemicals, below which there is a very low probability of adverse effects to human health.

A safe level of exposure can be identified for many chemicals based on their chemical structure and the known toxicity of chemicals which share similar structural characteristics.

Information on human exposure is crucial.

Use of the Threshold of Toxicological Concern (TTC) Approach forthe Safety Assessment of Chemical SubstancesSCCP/1171/08, 19.11.08 European Commission 2008

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Class I:Simple chemical structure and efficient metabolism that would suggest a low order of oral toxicity.

Class II:Less knowledge of metabolism and toxicology, but there is no clear indication of toxicity. Most substances in this class have functional groups similar to Class I but somewhat more reactive; more complex structures than substances in Class I

Class III:Chemical structure that permit no strong initial presumption of safety.May suggest significant toxicity.

Structural information based on a "decision tree" algorithm and grouped into three structural classes reflecting a presumed low, moderate and significant toxicity.

Cramer GM, Ford RA, Hall RA (1978). Estimation of toxic hazard – a decision tree approach. Food Cosmet Toxicol, 16: 255-276.

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International Life Sciences Instituteilsi.org

ILSI North AmericaRefining TTC as tool for prioritization of food contaminants

ILSI Research FoundationExtending TTC to support risk assessment of biocides

ILSI Health and Environmental Sciences InstituteTTC as a tool in mixtures risk assessment

ILSI EuropeTTC Task Force

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Classification based on inherent properties

For a chemical: Inherency relates to those chemical-specific properties associated with its impact on humans and the environment. (EPA perspective)

The physico-chemical and material properties, atomic composition, structure, size, surface area, solubility, surface charge, aspect ratio, etc.

The ability to interact with biological processes.

How it is made, used, degraded and disposed of.

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Initial Screening will Require Relational Integrated and Interactive Knowledgebases

Development and expansion of knowledgebases that describe inherent properties of chemicals based on their known molecular structure, and chemical and biological interactions.

Ashby's poly-carcinogen

Represents a hypothetical chemical made of many of the known structural alerts for mutagenicity.

Benigni et al, J Environ Sci Health C 25:53-97Modified fromAshby, J. (1985) Environ.Mutagen 7 , pp. 919-921.

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Metabolism and Degradate Pathway Analysis

Systematic compilation of information on observed metabolites, biotransformation reaction types, and relative biotransformationrates into a structure-searchable database.

Structure-based identification of metabolites and transformations

Identification of differences in metabolism based on gender, exposure dose, species, and methods

Identification of similar metabolites arising from different parent chemicals.

Identification of metabolites as residues in the food web.

Develop a metabolism simulator.

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Clustering Using Inherent Properties

Chemistry-based Characteristics

356

21

27

100

350 429

6

Biological Responses

Use and Exposure Considerations

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Design for the Environment

Clustering by inherent properties will enable identification of negative chemical features such as toxicity, persistence, and bioaccumulation.

Clustering by inherent properties will ALSO enable identification of positive chemical features such as minimal toxicity, no persistence, and lack of bioaccumulation.

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Tiered Testing

Most tiered testing discussions have been focused on developing approaches that are geared toward limiting or eliminating whole animal testing.

Specifically decreasing or eliminating use of mammalian experiments using primates, canines, rodents, and related species.

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Research: Learn & Refine

Screening and

Prioritizationand

Evaluation of knowledge sufficiency

Evaluation for Relevant Effects

Risk C

haracterization, Evaluation, and D

ecision

C2Cl3

ClClC

C2Cl3

ClClC

Cl

ClClCl

Cl

Cl

ClClCl

Cl

Cl

Cl

Cl

OHOH OH

Cl

Cl

OH

Cl

ClClCl

Cl

Cl

ClClCl

Cl

Cl

C2Cl3

ClClC

C2Cl3

ClClC

Cl

ClClCl

Cl

Cl

ClClCl

Cl

Cl

Cl

Cl

OHOH OH

Cl

Cl

OH

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ClClCl

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ClClCl

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ClChemical Inventories

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l

Cl O

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In Vitro Profiling: Molecular

interactions, Cellular Responses

QBAR

Existing Knowledge, exposure, use,

toxicity data, SAR, metabolism

prediction, degradateanalysis, QSAR

Efficient Focused In

Vivo Testing

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EPA has a lot of experience with Hazard prediction and Chemical databases – a few examples

Analog Identification Methodology (AIM)identifies close structural analogs that have measured data and points to sources where those data can be found

Ecological Structure Activity Relationships (ECOSAR) estimates the aquatic toxicity of industrial chemicals

ECOTOX chemical toxicity data for aquatic life, terrestrial plants and wildlife

EPI Suite™estimates physical / chemical properties and environmental fate

High Production Volume Information System (HPVIS) health and environmental effects information

OncoLogicTM

evaluates the likelihood that a chemical may cause cancer

Use Cluster Scoring System (UCSS)risk-screening system into which chemicals are grouped by common use

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Moving beyond data warehouses to integrated knowledgebases

A knowledge-based system uses artificial intelligence techniques in problem-solving processes to support human decision-making, learning, and action.

ACToR: Aggregated Computational Toxicology ResourceAggregates data from over 500 public sources on over 500,000 environmental chemicals searchable by chemical name, structure, and other identifiers. Data includes chemical structure, physico-chemical values, in vitro assay data and in vivo toxicology data.

Distributed Structure-Searchable Toxicity (DSSTox) Database NetworkStructure-activity and predictive toxicology using structure searchable standardized chemical structure files associated with toxicity data.

ToxRefDB: Toxicity Reference DatabaseDetailed chemical toxicity data in an accessible and searchable format. Links to other public hazard, exposure and risk resources.

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Taking advantage of the development of knowledgebases and moving beyond just focusing on decreasing animal use.

An evaluation strategy that results in confidence that regulatory decisions are adequately protective of public health and the environment.

Increasing levels of certainty based on the risk context of the regulatory decision.

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Increa

sing

certa

inty

Exposure, Dose and Route, Mode of Action/Relevance, in vitro assays, in vivo assays, in silico evaluation, level of acceptance, integration of informationExposure, Dose and Route,

Mode of Action/Relevance, in vitro assays, in vivo assays, in silicoevaluation, level of acceptance, integration of information

Exposure, Dose and Route, Mode of Action/Relevance, in vitro assays, in vivo assays, in silico evaluation, level of acceptance, integration of information

An Integrated Evaluation Strategy


32Modified from NRC, 2007

Source

Fate/Transport

Exposure

Tissue Dose

Biologic Interaction

Perturbation

BiologicInputs

NormalBiologicFunction

Morbidityand

Mortality

Cell Injury

Adaptive StressResponses

Early CellularChanges

• Quantitative Dose-Response• PK / PD• Toxicity Pathway Identification• in silico models •Targeted Testing

Toxicity Pathways: Cellular response pathways that, when sufficiently perturbed, are expected to result in adverse health effects.

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Toxicity Pathway

Cellular response pathways that, when sufficiently perturbed, are expected to result in adverse health effects are termed toxicity pathways.

NRC (2007). Toxicity Testing in the Twenty-first Century: A Vision and a Strategy. Washington, DC, National Academy of Sciences. 216 p.

Source

EnvironmentalContaminant

Exposure

Molecular Initiating Event Cellular Effects Individual Population Community

Application to Levels of Organization Based on

Source to Outcome

Toxicity Pathway

Mode of Action

Adverse Outcome Pathway

Source to Outcome Pathway34

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Molecular Initiating EventThe initial point of chemical-biological interaction within the organism that starts the pathway is a molecular initiating event.

Mode of ActionKey events and processes, starting with the interaction of an agent with the target cell, through functional and anatomical changes, resulting in cancer or other adverse health effects. Biological responses along the pathway that lead to, and are experimentally or toxicologically associated with, the adverse outcome are referred to as “key events”. All of these are empirically observable precursor steps that are a necessary element of the mode-of-action or are a biological marker for such an element.

USEPA (2005). Guidelines for Carcinogen Risk Assessment (Final). R. A. Forum, U.S. Environmental Protection Agency. EPA/630/P-03/001F. p 166. Boobis, A.R., et al. (2008). "IPCS framework for analyzing the relevance of a noncancer mode of action for humans." Crit Rev Toxicol 38(2): 87-96.

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Adverse Outcome PathwayAn adverse outcome pathway (AOP) represents existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome relevant to risk assessment at the individual or population levels thus spanning multiple levels ofbiological organization.

Ankley, G.T., et al. (2010). "Adverse Outcome Pathways: A Conceptual Framework to Support Ecotoxicology Research and Risk Assessment." Environmental Toxicology and Chemistry 29(3): 730-741.

Source to OutcomeThe continuum or cascade of measurable events starting from release into the environment and ending at an adverse outcome.

USEPA (2003). A Framework for a Computational Toxicology Research Program. PA/600/R-03/065. p 5.

Application to Levels of Organization Based on Source

to Outcome Source

EnvironmentalContaminant

Cellular Effects

Individual

Population

Community

Exposure

Molecular Initiating Event

Mode of Action

Adverse Outcome Pathway

Source to Outcome Pathway

Toxicity Pathway

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38


Modified from NRC, 2007

Source

Fate/Transport

Exposure

Tissue Dose


Perturbation

BiologicInputs


Morbidityand

Mortality

Cell Injury





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Sustained Stress Environment

Cellular adaptation to its environment so that it can survive and proliferate.A basic tenet of evolutionary biology.

In the case of exposure to a chemical stressor, the changes in a cell or tissue that allow the tissue, organ, and organism to continue to function and survive.

Karpinets and Foy: Journal of Theoretical Biology 227 (2004) 253–264Karpinets and Foy: Carcinogenesis vol.26 no.8 pp.1323--1334, 2005

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Modified from NRC, 2007

Source

Fate/Transport

Exposure

Tissue Dose


Perturbation

BiologicInputs


Morbidityand

Mortality

Cell Injury





New Normal State of Biological Function

Potential change in susceptibility

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ILSI Health and Environmental Sciences Institutewww.hesiglobal.org

Distinguishing Adverse from Adaptive, Non-functional and Pharmacological Changes in Toxicity Studies Subcommittee

Develop an approach for evaluating the range from benign to adverse and use it for safety assessment of chemicals/pharmaceuticals.

Develop criteria to facilitate the determination of adverse from other types of changes.

Develop an evaluation framework that integrates and prioritizes information that characterizes changes biological systems.

Draft definitions:Adverse Effect: A change in morphology, physiology, growth, development, reproduction, or life span of a cell or organism, system, or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences.

Adaptive Effect: In the context of toxicology, adaptability is the process whereby a cell or organism responds to a xenobiotic so that the cell or organism will survive in the new environment that contains the xenobiotic without impairment of function.

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Adverse Outcome PathwayER-Mediated Reproductive Impairment

Chemical effects across levels of biological organization

Greater Toxicological Understanding Greater Risk RelevanceAdverse Outcome Pathway

QSAR focus area

Chemicals

ReceptorBinding

ER Binding

Liver CellProtein

Expression

Vitellogenin (egg protein

transported to ovary)

LiverAltered

proteins(Vtg)& hormones;

GonadOva-testis;Complete

ovary in male

Sex reversal;

Altered behavior;

Repro.

In vivo

MOLECULARTarget

CELLULARResponse

TISSUE/ORGAN INDIVIDUAL

Skewed Sex

Ratios;

Yr Class

POPULATION

Toxicity Pathway

In vitro Assayfocus area

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Associating Bioactivity in vitro with Pathways and Diseases

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Chemical Space

C2Cl3

ClClC

C2Cl3

ClClC

Cl

ClClCl

Cl

Cl

ClClCl

Cl

Cl

Cl

ClOH

OH OH

Cl

ClOH

Cl

ClClCl

Cl

Cl

ClClCl

Cl

ClC2Cl3

ClClC

C2Cl3

ClClC

Cl

ClClCl

Cl

Cl

ClClCl

Cl

Cl

Cl

ClOH

OH OH

Cl

ClOH

Cl

ClClCl

Cl

Cl

ClClCl

Cl

ClC2Cl

3

Cl C

lC

C2Cl3

Cl C

lC

C2Cl3

Cl C

lC

C2Cl3

Cl C

lC

Cl

Cl

Cl

Cl C

l

ClC

l

Cl

Cl C

l

Cl

Cl

Cl

Cl

Cl C

l

ClC

lCl

Cl C

l

Cl

Cl C

l

OH

OH

OH

Cl C

l

OH

Cl

Cl

Cl

Cl C

l

ClC

lCl

Cl C

l

Cl

OH

C2Cl3

Cl C

lC

Cl C

l

OH

Cl C

l

OH C

l

Cl

Cl

Cl C

l

ClC

lCl

Cl C

l

Cl

OH

Cl

Cl

Cl

Cl C

l

ClC

l

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Cl C

l

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Cl C

l

OH

Cl C

l

OH

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Cl C

l

ClC

lCl

Cl C

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OH

Cl C

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l

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Cl C

l

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OH

Cl C

l

OHC

l Cl

OH C

l

Cl

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Cl C

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ClC

lCl

Cl C

l

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OH

Cl

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Cl C

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ClC

l

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l

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Cl C

l

OH

Cl C

l

OH

Cl

Cl

Cl

Cl C

l

ClC

l

Cl

Cl C

l

Cl

OH

Cl C

l

OH

Quantitative Structure Activity Relationships

Quantitative Biological Activity Response

Adverse Outcome Space

Biological Activity Space

Developmental Defects

Endocrine Disruption

Respiratory Disease

Neurologic Effects

Cancer

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Clustering Using Inherent Properties for Cumulative Risk Evaluation

Chemistry-based Characteristics

356

21

27

100

350 429

6

Biological Responses

Use and Exposure Considerations

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ILSI Health and Environmental Sciences Institutewww.hesiglobal.org

Emergence of Animal Alternative Needs in Environmental Risk AssessmentDevelopment of a sound technical basis for alternative tests as a means to reduce, refine, or replace standard fish toxicity test procedures.

Risk Assessment for the 21st Century: a Vision and a Plan (Risk21)

Bring applicable, accurate, and resource-appropriate approaches to the evolving field of human health risk assessment.

Center for Alternatives to Animal Testing Johns Hopkins Bloomberg School of Public Health

http://caat.jhsph.edu

Ongoing workshops in support of implementation of NAS vision.

Increa

sing

certa

inty

Exposure, Dose and Route, Mode of Action/Relevance, in

vitro assays, in vivo assays, in silico evaluation, level of

acceptance, integration of information

Exposure, Dose and Route, Mode of Action/Relevance,

in vitro assays, in vivo assays, in silico evaluation,

level of acceptance, integration of information

Exposure, Dose and Route, Mode of Action/Relevance, in vitro assays, in vivo assays, in silicoevaluation, level of acceptance, integration of information

We equate more extensive evaluation with moreanimal testing.

This is the current model, the future will be different.

It may not necessarily require more animal testing

It may mean more detailed in vitro assays, enhanced exposure assessment, greater specificity of in silico models.

47Greater certainty necessitates increased understanding, quantitative data, and greater integration at each level.

48

Modeling Toxicity From Pathways to Virtual Tissues

chemicals tissue functionpathways networks cell states

Quantitative Dose-Response

Models

Quantitative Dose-Response

Models Future

Risk assessmentsFuture

Risk assessments

Identify Key Targets and Pathways Identify Key Targets and Pathways

Moving beyond empirical models, to multi-scale computer models of complex biological systems.

49

Situational and Toxicity Pathway Based Assessments

Identify relevant adverse response in humans and wildlife

Describe Modes of Action

Identify Key Events

Develop and apply in vitro assays Tissue and cellular dose

High-throughput screens

Additional targeted testing as needed based on results

Assessment of Risk

Risk Context/Lifecycle Assessment/Exposure Context

Chemical Structure and Physical Chemical Properties/TTC Enhanced interpretation of data

50

What Is Needed To Achieve The Goal Of An Integrated Evaluation Strategy That Provides The Necessary Knowledge For Chemical Risk Assessment.

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In support of a paradigm shift from the use of experimental animals and apical end points to more efficient in vitro and computational techniques.

Shift in orientation and perceptionchampions of new approach

Change in expertise and experiencetraining and staffing

Supportive policies and incentivesreward use of new technologiesuse data in assessment processescongressional implementationsupport conducting new toxicity testinguse for regulationre-examine testing programs and guidance's

Interpretation of adverse effects through perturbations of pathwaysCommunication

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http://www.epa.gov/pesticides/science/testing-assessment.html

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Council of Canadian AcademiesThe Council supports independent, science-based, expert assessments (studies) that inform public policy development in Canada.

The Integrated Testing of Pesticides

The Minister of Health asked the Canadian Council of Academies to assess the scientific status of integrated testing strategies in assessing and regulating the risks of pesticides to both humans and environments.

What is the scientific status of the use of integrated testing strategies in the human and environmental regulatory risk assessment of pesticides?

http://www.scienceadvice.ca/en/assessments/in-progress/pesticides.aspx

54

General Concept to Move to Toxicity Pathway-Based Assessment of Potential Risk

Identify relevant human disease or rodent adverse responseWhat are the human diseases that have a significant environmental component?What are the primary rodent responses that drive our regulatory decisions?

Describe Modes of Action for these human diseases and rodent responses

Identify Key Events that describe the modes of action

Develop assays that predict or determine the activation or enhancement of key event(s)

Establish toxicokinetics – tissue and cellular dose – that initiate key event

Develop high-throughput screens for identifying activation of key events and their dose-response

Use high-throughput screens to determine the need for targeted testing

55

NAS Activities

Toxicity Pathway-Based Risk Assessment: Preparing for Paradigm Change: A Symposium Summary (2010) Highlights from a May 2009 symposium, convened at the request the U.S. Environmental Protection Agency to stimulate discussion on the application of these approaches and data in risk assessment.

Science and Decisions: Advancing Risk Assessment (2009)The report concludes that EPA's overall concept of risk assessment, which is based on the National Research Council's 1983, Red Book, should be retained but that a number of significant improvements are needed to advance the use of risk assessment in decision making.

56

The U.S. Environmental Protection Agency’s Strategic Plan for Evaluating the Toxicity of Chemicals

www.epa.gov/spc/toxicitytesting

Process of moving from research to regulatory acceptance.

Institutional Transition

Operational transition –use new types of data and models for toxicity testing and risk assessment

Organizational transition –implement new toxicity testing paradigm hiring and training of scientists with needed scientific expertise

Outreach – educate stakeholders and improve risk communication.

EPA 100/K-09/001 March 2009

57

“One of the greatest pains to human nature is the pain of a new idea.”Walter Bagehot (1826–1877), British economist.

“To innovate is not to reform”Edmund Burke (1729–1797), Irish philosopher, statesman.

an integrated evaluation strategy for making regulatory ...vision by the u. s. national academy of...

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