human and environmental health challenges for the ... -...

(Received 24 March 2010; revised 15 June 2010; accepted 04 July 2010)

ISSN 1040-8444 print/ISSN 1547-6898 online © 2010 Informa Healthcare USA, Inc.DOI: 10.3109/10408444.2010.506640 http://www.informahealthcare.com/txc

R E V I E W A R T I C L E

Human and environmental health challenges for the next decade (2010–2020)

Marc S. Bonnefoi1, Scott E. Belanger2, Dennis J. Devlin3, Nancy G. Doerrer4, Michelle R. Embry4, Shoji Fukushima5, Ernest S. Harpur6, Ronald N. Hines7, Michael P. Holsapple4, James H. Kim4, James S. MacDonald8, Raegan O’Lone4, Syril D. Pettit4, James L. Stevens9, Ayako S. Takei10, Sally S. Tinkle11, and Jan Willem van der Laan12

1sanofi-aventis, Bridgewater, New Jersey, USA, 2The Procter and Gamble Company, Cincinnati, Ohio, USA, 3Exxon Mobil Corporation, Irving, Texas, USA, 4ILSI Health and Environmental Sciences Institute, Washington, DC, USA, 5Japan Bioassay Research Center, Hadano, Japan, 6sanofi-aventis, Northumberland, United Kingdom, 7Medical College of Wisconsin, Milwaukee, Wisconsin, USA, 8Chrysalis Pharma Partners, LLC, Chester, New Jersey, USA, 9Eli Lilly and Company, Greenfield, Indiana, USA, 10ICaRuS Japan Limited, Tokyo, Japan, 11National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA, and 12National Institute for Public Health and the Environment, Bilthoven,

The Netherlands

AbstractThe public health and environmental communities will face many challenges during the next decade. To identify significant issues that might be addressed as part of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) scientific portfolio, an expert group of key government, academic, and industry scientists from around the world were assembled in 2009 to map the current and future landscape of scientific and regulatory challenges. The value of the scientific mapping exercise was the development of a tool which HESI, individual companies, research institutions, government agencies, and regulatory authorities can use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future.

Keywords: Environmental health challenges; HESI; human health challenges; priority setting; risk assessment; scientific mapping; strategic planning; toxicology

Abbreviations: 3Rs, replacement, reduction, and refinement; ECVAM, European Centre for the Validation of Alternative Methods; EMA, European Medicines Agency; EPA, Environmental Protection Agency (United States); ES, embryonic stem cells; EC, European Commission; EU, European Union; FDA, Food and Drug Administration (United States); GMO, genetically modified organism; H1N1, swine influenza virus, subtype A; HESI, ILSI Health and Environmental Sciences Institute; HLA, human leukocyte antigen; HTS, high-throughput screening; ICCVAM, Interagency Coordinating Committee on the Validation of Alternative Methods (US); ILSI, International Life Sciences Institute; iPS cells, induced pluripotent stem cells; ISO, International Organization for Standardization; JaCVAM, Japanese Center for the Validation of Alternative Methods; KorVAM, Korean Center for Validation of Alternative Methods; LCA, life cycle assessment; LCIA, life cycle impact assessment; MMR, measles, mumps, and rubella; NGO, non-governmental organization; NOAEL, no observed adverse effect level; NRC, National Research Council; OECD, Organisation for Economic Co-operation and Development; PBPK, physi-ologically based pharmacokinetic; POP, persistent organic pollutants; PPCP, pharmaceutical and personal care products; QSAR, quantitative structure-activity relationship; REACH, Registration, Evaluation, Authorisation and Restriction of Chemicals (European Union); SNP, single-nucleotide polymorphism; TSCA, Toxic Substances Control Act; TTC, threshold of toxicological concern.

Critical Reviews in Toxicology, 2010; 40(10): 893–911Critical Reviews in Toxicology

2010

893

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24 March 2010

15 June 2010

04 July 2010

1040-8444

1547-6898

© 2010 Informa Healthcare USA, Inc.

10.3109/10408444.2010.506640

Address for Correspondence: Nancy G. Doerrer, ILSI Health and Environmental Sciences Institute, 1156 Fifteenth Street, NW, Suite 200, Washington, DC 20005, USA. E-mail: [email protected].

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http://informahealthcare.com/doi/abs/10.3109/10408444.2010.506640

mailto:[email protected].

894 M. S. Bonnefoi et al.

Introduction

Scientists and regulators are cognizant of the importance of trying to anticipate future health, safety, and environ-mental challenges. Early recognition of and engagement in these issues sets the stage for scientific innovation, dis-ease prevention, healthy lifestyles, protection of ecological resources, a productive and sound economic outlook, and a sustainable environment. To anticipate future scientific, regulatory, and societal issues that are likely to present themselves to the public health and environmental com-munities from 2010 to 2020, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) undertook a scientific mapping activity in July 2009. An expert group of key government, academic, and indus-try scientists from around the world were assembled to accomplish this task, which was a follow-up to an earlier HESI scientific mapping exercise conducted in 2004 (Smith et al., 2008). The results of the exercise as described in this paper reflect the perspectives of the meeting participants at that time, and provide a useful starting point for strategic planning into the future.

The purpose of the 2009 HESI scientific mapping exercise was to identify issues likely to present significant and relevant challenges during the next decade that might be addressed as part of the HESI scientific portfolio, as well as to inform the strategic agendas of individual companies, research institutions, government agencies, and regulatory authori-ties in the developed world. The mapping exercise has broad value for the scientific community because it represents the contributions and perspectives of government, academic, and industrial experts from around the world. The various stakeholders involved in HESI activities may be particularly

interested in the issues appearing on the 2010–2020 HESI Combined Challenges Map (Figure 1). Other audiences with differing missions and objectives may be interested in examining the full complement of issues considered by meeting participants or may elect to take a similar approach to predicting future challenges.

The mapping exercise was not intended to provide specifi-city on how to address, advocate, or manage the prioritized issues. Rather, the value of the exercise was the development of a tool that HESI, its partners, or any other research institu-tion could use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future.

Unbiased science is at the core of HESI and drives all that the organization strives to accomplish. Although there are many perspectives offered from its tripartite constitu-ency, the focus of the organization is on bringing the best science forward in a given area. It is not the intent of HESI to advocate any specific position on issues but rather to bring forward the best available scientific thinking. HESI’s scientific activities are intended to inform discussions that may potentially lead to regulatory and/or public policy deci-sions that are based on strong science. This approach was fundamental to the current mapping exercise. By ensuring broad cross-functional participation, the conclusions on the most important scientific challenges over the next 10 years represent a balanced and scientifically robust view. Although there are certainly other perspectives on areas in need of focus in the years ahead, the tripartite process at the core of HESI assures that what is presented here does not result from any specific individual scientific or commercial interest.

Contents

Abstract .............................................................................................................................................................................................. 893Abbreviations..................................................................................................................................................................................... 893Introduction ....................................................................................................................................................................................... 894Methodology...................................................................................................................................................................................... 895 January 2009 Japan scientific mapping meeting ........................................................................................................................ 895 July 2009 scientific mapping meeting ......................................................................................................................................... 896Results ................................................................................................................................................................................................ 896 Immediate (2010) .......................................................................................................................................................................... 897 Short term (2011–2012) ................................................................................................................................................................ 899 Medium term (2012–2015) ........................................................................................................................................................... 900 Long term (2015–2020) ................................................................................................................................................................. 902Discussion .......................................................................................................................................................................................... 903About HESI ........................................................................................................................................................................................ 904Acknowledgements ........................................................................................................................................................................... 905Declaration of interest ...................................................................................................................................................................... 905References .......................................................................................................................................................................................... 905Appendix A: Participants in the July 2009 HESI scientific mapping meeting in Reston, Virginia, USA .................................... 906Appendix B: Participants in the January 2009 HESI scientific mapping meeting in Hamamatsu, Japan ................................. 907Appendix C: Spring 2009 pre-meeting survey results .................................................................................................................... 907

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Challenges for the next decade 895

Methodology

HESI held its second scientific mapping exercise on July 28–29, 2009. Organized by the HESI Board of Trustees Program Strategy and Stewardship Committee, the exercise was designed to first identify issues of general interest to a broad audience, and ultimately determine and prioritize health and environmental issues of scientific, regulatory, and societal importance to HESI during the next decade. A group of 50 invited scientists from Australia, Europe, Japan, and the United States participated in the meeting (see Appendix A). Several of the scientists who attended an earlier Japanese mapping exercise attended this session (see description below).

Although meeting participants also examined health and environmental issues of societal importance, the focus was primarily on scientific and/or regulatory impact. It should be noted that experts in the social sciences were not present at the meeting. The results of this mapping exercise represent scientific perspectives on issues that, if addressed, might measurably benefit society at large.

January 2009 Japan scientific mapping meetingAs a prelude to the July 2009 scientific mapping meeting, HESI conducted a regional mapping exercise in Hamamatsu, Japan, in January 2009. The objective of the meeting in Japan was to identify key scientific, regulatory, and societal issues likely to be of greatest importance and concern to the Japanese scien-tific community during the next 10 years, and to incorporate these issues into the subsequent July 2009 HESI scientific mapping meeting in the United States.

The participants in the Japan scientific mapping meeting are identified in Appendix B. Twenty-five Japanese scientists from government, industry, and academia participated in the meeting (64% public sector; 36% private sector).

A pre-meeting survey (in Japanese) was distributed to approximately 140 individuals in the Japanese scientific com-munity in the fall of 2008. Of these, 40 scientists (55% public sector; 45% private sector) nominated 103 potential scientific, regulatory, and/or societal topics for consideration.

As a result of extensive discussions (held in Japanese to reduce barriers to active communication), the participating scientists in the January 2009 meeting selected two challenges

Animal use andwelfare

Vaccinedevelopment,use, and safety

Genomics

Human health:scientificevaluation of sensitive populations

Sustainability

Stem celltechnology

Food safety

Communicationand perceptionof risk versusbenefit

Improved riskassessmentthroughbiomonitoring andepidemiology

Risk / benefit:regulation ofchemicals incommerce

Translationalbiomarkers

Riskassessment ofsensitive /vulnerablepopulations

Environmentalquality

Emergingcontaminants

Safety ofgeneticallymodified organismsand foods

Regulatoryframework fornew methods

Computationaltools / toxicology

Use of science insetting publicpolicy

“Omics” in riskassessment

Risk assessment of co-exposures

Nanomaterials /nanotechnology

Paradigm shiftsin risk assessment /life cycle assessment

Stem cell therapy

Individualsusceptibility

Improved testingand assessmentstrategies

Regulatoryframework forcarcinogenicitytesting

Alternatives toanimal models

Epigenetics inrisk assessment

Exposure-basedrisk assessment

Improvedbiomonitoringthroughbiomarkers

Relativeimpact

Time: immediate (2010) to long-term (2020)

Figure 1. 2010–2020 HESI Combined Challenges Map. Each axis appearing on the 2010–2020 HESI Combined Challenges Map is a continuum. All issues on the map are of high importance/impact based on prioritization by the participants in the mapping meeting exercise. “Relative impact” is a qualitative measure of importance among high-priority topics. The location of issues along the “time” continuum is an approximation of when the topic is likely to become a major issue, with a reasonable possibility of resolution, in the time frame from 2010 to 2020.

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as having the highest overall priority in Japan during the next decade.

Stem cell research and testing (induced pluripotent stem •[iPS] cells and embryonic stem [ES] cells)Nanomaterial safety•

All challenges rated as high or medium priority in each category at the January 2009 Japan meeting are presented in Table 1. These challenges were included as key high- or medium-priority topics during the July 2009 HESI scientific mapping meeting in the United States.

July 2009 scientific mapping meetingIn the spring of 2009, HESI conducted a survey of its tripartite, international constituency in which identification of topics for consideration at the mapping meeting in July was requested. As a result of the survey, 115 scientific, regulatory, and/or societal topics were identified (Appendix C). A planning com-mittee conservatively clustered topics within the scientific, regulatory, and societal challenge areas. The purpose of this pre-meeting exercise was to reduce duplication and combine closely related topics, as appropriate.

An overview of the method used to develop the 2010–2020 HESI Combined Challenges Map is shown in Figure 2. At the July mapping meeting, participants engaged in a series of five breakout sessions. During these small-group meetings, participants confirmed the planning committee’s clustering results, and prioritized and assessed the impact of topics. Initially, a high-level, global view of priority and importance was taken. This exercise was necessarily subjective, reflect-ing the diverse background, experiences, and perspectives of each participant.

In subsequent sessions, participants assessed the highest priority issues within the scientific, regulatory, and societal

challenge areas for their importance and relevance to HESI as an organization. The results of the January 2009 HESI scientific mapping meeting in Hamamatsu, Japan, were included at this stage to ensure integration of tripartite input from HESI’s Japanese colleagues. An “opportunity matrix” was used to determine the expected impact and likely time frame for action (Figure 3). Using this tool, the matrix allowed meeting participants to postulate and view, in two dimen-sions, the potential impact of each issue from “low” to “high” against an approximation of when HESI might reasonably be able to contribute to the resolution of each issue (i.e., imme-diate, short-term [1–2 years], medium-term [2–5 years], and long-term [5–10 years]).

Opportunity matrices were prepared for scientific, regu-latory, and societal issues respectively. From these three matrices, a single 2010–2020 HESI Combined Challenges Map (Figure 1) was developed. A number of other issues considered to be of general interest were determined to be outside HESI’s capacity or strategic objectives (Table 2).

The 2010–2020 HESI Combined Challenges Map is popu-lated by four vertical columns of issues. The issues are placed strategically to indicate “relative impact” (the y-axis), which is a qualitative measure of importance among the high-priority topics, and to identify an approximate time frame (the x-axis) during which the topic is likely to become a major issue between 2010 and 2020.

Results

Brief descriptions of each issue selected for inclusion in the final 2010–2020 HESI Combined Challenges Map (Figure 1) follow. Issues are organized according to their location on the map’s time continuum. For example, all issues appear-ing in the first vertical column on the left side of the map are described first. These topics are judged as likely to be of

Table 1. Challenges of high or medium priority as defined at the January 2009 HESI Scientific Mapping Meeting in Japan.

Priority

Category High Medium

Scientific Stem cell research:

Technologies to realize efficient production of iPS cells and induction •of cell differentiationMethods for safety and toxicity evaluation with iPS/ES cells•Application of stem cells to treatment of diseases•Stem cell banking•

Nanomaterial safety evaluation methods:

Human health effects/environmental effects•Standardization/harmonization of toxicity evalua-•tion methods

GMO food safety evaluation methods:Ecological effects of genetically modified crops

Regulatory Nanomaterial public acceptance:

New regulatory scheme to ensure public acceptance•

Toxicity evaluation with ES/iPS cells

Reevaluation of carcinogenicity testing and assessment:

Genotoxicity, non-genotoxic mechanisms, threshold, methodology•

Training of regulatory staff responsible for toxicology evaluation

Societal Stem cells (iPS and ES cells):

Application, safety and societal acceptance to tailor-made medicine•

Nanomaterials:

Safety concerns and social acceptance•

Genetically modified plants:

Safety assessment and societal acceptance (particu-•larly GMO foods)

Multiple chemicals:

Human health, safety, and ecological effects•

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importance in the immediate time frame. Issues in the second vertical column, which are likely to become major concerns in the short-term (1–2 years), are discussed next, followed by issues in the third vertical column at the medium-term time frame (2–5 years), and finally, those issues appearing in the fourth vertical column at the long-term location (5–10 years). In the discussion below, the authors rely on the artificial construct of time frame categories (immediate, short-term, medium-term, and long-term) simply for ease of presenta-tion. Because the map’s axes are continuums, the location of each issue on the map should be viewed as a qualitative

estimate of impact and time frame, as judged by the expert participants in the July 2009 mapping meeting. Precision regarding impact and time frame is not implied.

The 2010–2020 HESI Combined Challenges Map (Figure 1) presented here is an accurate depiction of the results of the mapping meeting. Readers will note that some issues appearing on the map overlap with others (e.g., “ani-mal use and welfare” and “alternatives to animal testing”). HESI acknowledges this phenomenon, and embraces the complexity inherent in understanding and addressing the nuances of seemingly similar challenges. During the next decade, as HESI selects issues for action from among these challenges, an effort will be made to integrate those areas with overlapping scope and reexamine overall impact and relevance when addressing broad areas.

Immediate (2010)Animal use and welfareThe broad issue identified as “animal use and welfare” is defined by the global movement to replace, reduce, and refine (3Rs) animal use in testing (Russell and Burch, 1959). Although regulatory and societal pressure exists to reduce and/or eliminate animal testing, the realization of this goal requires the development of scientifically reliable alternatives, as well as the evolution of regulatory initia-tives to evaluate, integrate, and accept these alternatives. Unfortunately, some legislation, with the well-intentioned goal of protecting human health and the environment from the harmful effects of chemicals, will result in an increase in animal testing, at least in the near term. For example, the European Union’s (EU) REACH program (Registration, Evaluation, Authorisation and Restriction of Chemicals) (EC, 2007) requires that manufacturers and importers provide complete safety dossiers on chemicals before entering the market. Gap filling to meet minimum dossier needs is now predicted to result in a very large, unanticipated increase in animal testing (Hartung and Rovida, 2009). Therefore, to meet the combined objectives of understanding safe use of chemicals while adhering to 3R principles, regulators and industry are strongly encouraged to reduce and refine animal use in testing, and evaluate and accept alternative testing strategies and methods. Although North America and Japan are not yet subject to similarly comprehensive national programs, the EU regulations have already had a global impact.

Vaccine development, use, and safetyVaccine development, use, and safety was prioritized by meeting participants as likely to have immediate impact because of the high visibility and level of global regulatory activity mandated by the requirement for rapid develop-ment of vaccines in response to emerging disease (e.g., the H1N1 virus). The urgency associated with vaccine issues is demonstrated by the discussions and considerations of the balance between expedited approval of vaccines to counter potential pandemic influenza illness versus more extended evaluation to increase confidence in vaccine

Mapping Process

DevelopCombinedChallenges

Map

Assess Impactand Timeframe

Prioritize Clustered Issues

Cluster Survey Issues

Fifth breakout session

First breakout session

Fourth breakout session:Develop individual maps using“opportunity matrix”

Second and third breakoutsessions

“filter” approach

Figure 2. Overview of HESI scientific mapping process.

HESI Opportunity Matrix

IMPA

CT

Immediate(now)

Short-term(1-2 years)

Medium-term(2-5 years)

Long-term(5-10 years)

high

med

ium

low

Time Frame

Figure 3. HESI opportunity matrix.

Table 2. Issues included on the “opportunity matrix” but not on the 2010–2020 HESI Combined Challenges Map.

Alternative medicines

Climate change

Cumulative risk of stressors

Food sciences

Healthcare reform impact

Integration of human health and ecological risk assessment

Preventable diseases

Regulatory transparency

Scientific credibility/conflict of interest

Scientific literacy

Water availability

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safety and efficacy. Examples include concerns about the use of the MMR (measles, mumps, and rubella) vaccine; claims of a link between vaccines and autism; uncertainty about adjuvants and an association with autoimmunity; and concern that adjuvanted whole-virion pandemic influenza vaccines, when given to naïve populations (e.g., infants, young children), might predispose some subjects to more serious influenza disease during a pandemic). Variations in approaches to regulatory approval of some vaccines, for example in approval of the use of adjuvants that are acceptable in Europe but not in the United States, further complicate this issue.

The safe use of vaccines, particularly in potentially sen-sitive populations such as children and pregnant women, their timely availability, the use of new adjuvants, and the communication of risks and benefits of vaccines in a social context are concerns shared by scientists, regulators, and the general public.

GenomicsGenomics is a growing field in which new technologies continue to emerge. Among the issues for immediate con-sideration by the scientific and regulatory communities are the following:

Research on the mechanism of cellular response to •genotoxicity.Elucidation of the effects of chemical exposure on •microRNA expression, as well as the role of microRNA in the modulation of toxic responses and as biomark-ers to establish a better mechanistic basis for risk assessment.Application of pathway analysis to interpret genomic •or genetic changes in the context of physiology and biochemistry. In addition, systems biology approaches are essential to reduce large volumes of “omics” data to interpretable data sets that assist with understand-ing mechanisms of action, facilitate data-mining, and enhance decision-making.Application of genomics in risk assessment. Genomics •technologies are being developed to assess genotoxic and carcinogenic potential. Other important areas for exploration are the application of genomics tech-nologies to determine points of departure, e.g., the no observed adverse effect level (NOAEL), and the devel-opment of better exposure-based, physiologically based pharmacokinetic (PBPK)-biodynamic models.

Human health: scientific evaluation of sensitive populationsThis challenge area, although broad, is focused on those issues that can be addressed immediately from a scien-tific perspective. Sensitive populations are exposed to both pharmaceutical and non-pharmaceutical substances (e.g., drugs, environmental contaminants, airborne pol-lutants), and strategies for identifying and assessing risks are varied. Among the high-priority issues identified by

meeting participants for immediate consideration are the following:

Adverse drug reactions and hypersensitivity. Emerging •data suggest that human leukocyte antigen (HLA) vari-ants may predict idiosyncratic adverse reactions and define sensitive populations exposed to certain drugs such as abacavir, sulfamethoxazole, or carbamazepine (Gatanaga et al., 2008).Genetic polymorphisms in susceptibility genes. For •example, the stratification of individuals into high/medium/low metabolizers based on known cytochrome P450 single-nucleotide polymorphism (SNP) variants is being used to predict biological/pharmacological response.Socioeconomic factors. Some socioeconomic factors •(e.g., micronutrient status, maternal education, eco-nomic status, and asthma incidence) may increase the probability of adverse responses.Gene-environment interactions. The complex interac-•tion of environmental exposures (e.g.. to arsenic and airborne particulates) and genetic influences can affect sensitivity.Carcinogenic risks. Emerging data support the impor-•tance of assessing possible carcinogenic risks in popula-tions or individuals with genetic predispositions or other susceptibilities/vulnerabilities.

SustainabilitySustainability has evolved from a concept to a reality, although technical barriers still exist. Initiatives are under-way to expand the role of green chemistry in sustainability, objectively quantify sustainability outcomes, develop rel-evant metrics that can be used to inform the consuming public, and integrate sustainability concepts within the supply chain. Other areas in need of future action include the following:

Assessment of product life cycles, along with greater •integration of green chemistry concepts and new energy efficiency goals.Due to an increased awareness that these issues tran-•scend national borders, there is a growing need to establish a clear, measurable, actionable, and universally accessible definition of sustainability (Satterfield et al., 2009). An important first step in meeting this objective is to better understand and establish international stand-ard metrics to assess sustainability. Currently, carbon and water footprints are being developed as metrics to inform consumers about environmental attributes of products and to contribute information to life cycle assessment (LCA) and life cycle impact assessment (LCIA).LCA is a resource intensive tool, and results are generally •accepted if they conform to appropriate International Organization for Standardization (ISO) standards (e.g., ISO, 2006). This approach can limit the potential utility of

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the tool. A need exists for screening or tiered approaches in LCA.Climate change is critical to current and future LCAs. •Greenhouse gas emissions (CO

2 equivalents) are an

important metric, and carbon labeling has become a significant issue in the consumer product sector (food and non-food). There is intense debate regarding the relevance of product versus natural emissions and the possible role of global warming in upsetting global car-bon balances (emissions from the sea as a consequence of pH and temperature shifts, etc.).In addition to water availability, raw material availability •is a critical component of sustainability. Perhaps equally important is waste management, including electronic consumables.

Stem cell technologyThe prospect of creating induced pluripotent stem (iPS) cells that can be differentiated into different cell populations cre-ates the possibility of improving the use of human cells in in vitro testing. It also opens the door to applying population genetic approaches to in vitro test systems. Broadly, potential advantages of using iPS cells include the production of large numbers of cells, control of genetic variability, reproduc-ibility, testing at different stages of cellular maturation, and, in the long term, personalized tests using iPS cells of single individuals. The potential for this technology to improve the accuracy of human health risk assessment and to reduce or replace the use of animals in toxicity testing (e.g., in reproduc-tive toxicity and carcinogenicity testing) is significant (Chapin and Stedman, 2009). (See also “Stem Cell Therapy” below for concerns associated with the use of ES cells in research and testing.)

Food safetyFood safety is of immediate concern based on awareness and perceived issues with genetically modified foods (particularly in Japan), the use of cloned animals as food sources and the risk for new dietary allergens, and microbial contamination of foods. Other issues viewed as falling within this broad topic are the reevaluation of food additives and other chemicals (of particular concern in Europe), food quantity and sources in the developing world, patterns of food consumption and the global distribution of food, the regulation of botanical prod-ucts, the adulteration of food ingredients, possible chemical contamination of and leaching from plastic food contain-ers, and the association of the use of antibiotics in the food industry with the risk of antibiotic resistance.

Communication and perception of risk versus benefitA global need exists for effective communication of hazard and risk assessment data to user populations and to the gen-eral public. The proliferation of information sources via the internet and other electronic media poses unprecedented challenges to decision makers responsible for developing public policy and communicating technical information to lay audiences. Public perception about controversial and/ or

highly complex scientific issues is often based on limited information without weighing societal benefits against risks or determining whether the risks are real or perceived.

Short-term (2011–2012)Improved risk assessment through biomonitoring and epidemiologyA critical component of risk assessment and regulatory decision-making is the need for reliable exposure metrics. Biomonitoring and epidemiology are among the tools that can provide such data. However, interpretation of epidemio-logical studies is often difficult due to uncertainty associated with exposure estimates (e.g., if exposure is based on resi-dues) or if exposure estimates are based on recall. Similarly, it is unclear how decisions will be made when biomonitoring data show some evidence of increased exposure but are not statistically significant. Significant improvements to human health risk assessments that use biomonitoring and/or epi-demiological data are anticipated if these data are collected and interpreted using reliable methodologies for assessing exposure and effect.

Risk/benefit: regulation of chemicals in commerceFor a given chemical or drug in commerce, the regulatory community is charged with assessing the adverse effects, estimating the costs associated with regulatory action, and, at the same time, quantifying environmental and/or human health improvements or benefits. One example is the evalua-tion of brominated flame retardants. These chemicals, which are persistent organic pollutants (POPs), can be environ-mentally hazardous; yet, their use has clear societal benefit (i.e., in reducing risk of fire). Weighing risks and benefits is a complex, but necessary, action for local, regional, national, and international decision makers.

Quantification or estimation of the potential impact on benefits should be assessed when considering restriction or elimination of substances from commerce. For example, if an agricultural chemical currently on the market poses a potential environmental hazard, the benefits of using the chemical (i.e., fewer plant diseases, higher yield, etc.) should be taken into account in making a decision whether or not to restrict or prohibit its use. Currently, little agreement exists on the method(s) by which benefits are measured or on how to compare them with risks.

Translational biomarkersHESI has had a long-standing interest in the science of char-acterizing novel biomarkers. Recent efforts in the preclinical evaluation of a urinary biomarker panel for drug-induced renal injury by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were sup-ported by significant data contributions from HESI scientific programs. Future data submissions to support preclinical application of these markers are anticipated, and suggest that the focus on novel biomarker development will continue. Consensus on the translation of these markers (singularly or as a panel) to clinical application remains outstanding.

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Clinical validation can be challenged by interpretive, financial, and logistical hurdles. However, international ini-tiatives for translational marker evaluation are underway and hold significant promise for the future.

Risk assessment of sensitive/vulnerable populationsThis challenge area includes consideration of risks to popu-lations that are sensitive and vulnerable (Hines et al., 2010). Sensitivity is the capacity for higher risk due to the combined effect of susceptibility (innate biological factors) and differ-ences in exposure. Vulnerability incorporates the concepts of susceptibility and sensitivity, as well as additional factors that include social and cultural parameters (e.g., socioeco-nomic status and location of residence) that can contribute to an increased health risk. Obvious examples of potentially vulnerable populations include children, pregnant women, and obese individuals, but other vulnerable populations may exist as well. Legislative bodies and regulatory agencies have focused considerable attention on children as a sensitive population, as evidenced by the formation of the Pediatric Committee within the EMA, the passage in the US of the Best Pharmaceuticals for Children Act (2002) and the proposed Kid-Safe Chemicals Act (2008).

In some cases, evaluation of vulnerable populations has resulted in clinical adoption of targeted therapies. This trend toward “personalized medicine” is anticipated to increase over the next few years. From a population perspective, risk assessment for environmental exposures in subpopulations with differing susceptibilities represents a greater challenge due to the difficulty in measuring and interpreting exposure data and in developing approaches to manage and control exposure.

Environmental qualityEnvironmental quality is a broad issue, exemplified by the ongoing development of frameworks to assess risks to ecosystems from chemicals and effluents released into the environment. These paradigms will likely involve regulatory consideration of data from in situ biomonitoring, effluent toxicity testing, environmental chemistry, assessment of habitat quality, and laboratory ecotoxicity testing of chemi-cals as they relate to verification and prediction of risk to the environment from chemicals (De Zwart et al., 2006). One such example is water quality assessment under the EU Water Framework Directive (Tueros et al., 2009). In the United States, similar discussions are envisioned as part of reauthorization of the Toxic Substances Control Act (TSCA), as well as within state regulatory programs.

Emerging contaminantsThis issue was chosen for inclusion on the 2010–2020 HESI Combined Challenges Map largely due to widespread attention being given to pharmaceuticals and personal care products (PPCPs) in the environment by the media, regulatory agencies, and some non-governmental organi-zations (NGOs). Other emerging contaminants included as part of this issue are nanomaterials, biofuels, and other new

and/or alternative energy sources. One of the key challenges in addressing this issue will be the need to differentiate between what is “science” and what is “policy.”

Safety of genetically modified organisms and foodsAs noted above in the section on “food safety,” a key soci-etal concern in the developing world is food quantity and sources. Global food shortages are a serious problem in developing regions, and are likely to present challenges to developed countries as well. One solution to this problem is the use of genetically modified organisms (GMOs) and plants. Although the scientific basis for the safety of most GM foods is strong, societal acceptance remains a hurdle.

Medium-term (2012–2015)Regulatory framework for new methodsThis topic addresses the need for frameworks that guide the process of gaining regulatory acceptance and/or consideration of new methods as part of a safety evalua-tion data package to support marketing authorization of a new product. Currently, the absence of such overarching frameworks contributes to delays in the integration of novel approaches into safety assessments. A focus on developing frameworks would facilitate definition of both data needs and the logistics of building consensus around new meth-ods and approaches. Frameworks could be constructed for regulatory consideration of novel techniques (e.g., imaging), markers (e.g., novel protein biomarkers), test systems (e.g., stem cells), or data integration approaches (e.g., systems biology).

Computational tools/toxicologyCurrent risk assessment paradigms, particularly in regu-latory submissions for drugs and chemicals, generally depend on standardized methodologies. There is potential for computational tools to refine, improve, and, in some cases, even replace existing tests. Computational tools are essential for increasing throughput, reducing the burden of animal testing, and generating novel hypotheses for risk assessment.

Computational tools are useful not only in making predic-tions, but also in refining existing risk assessment paradigms. For example, quantitative structure-activity relationship (QSAR) approaches to assessing risk may facilitate place-ment of chemicals with incomplete data sets in appropriate risk categories. Computational modeling includes PBPK models, as well as modeling dose-response.

Use of science in setting public policyAs noted above in the section on “Emerging Contaminants,” a critical need exists to differentiate the boundaries of sci-ence and policy. The use of science in setting public policy was viewed by meeting participants as an important topic for action within the next few years. A particular need exists for consistency and harmonization in the use of sci-ence. There was strong consensus on promoting the value of using evidence-based outcomes, rather than intuition

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and/or the precautionary principle, in setting public policy. Equally important are the needs to address the misuse of science and/or the use of “pseudoscience” to inform policy and to establish guidelines for the use of different scientific approaches by policy makers.

“Omics” in risk assessmentThis topic incorporates many suggestions related to the development, application, and interpretation of “omics” data received during the initial scoping survey. For example, the topic includes concerns with the evolving use of toxi-cogenomics and proteomics as a means to define adverse events or elucidate mechanism(s) of action.

Meeting participants discussed whether “omics” data will remain as supplementary information or whether such data could evolve sufficiently to replace some traditional tests within a model system. Currently, “omics” data are accepted as confirmatory data in some regulatory contexts, but they are rarely used as stand-alone data. The future regu-latory impact of these data was judged to be highly depend-ent upon the progression of both scientific and regulatory acceptance.

Risk assessment of co-exposuresRisk assessment of co-exposures emerged as an important issue for evaluation. The topic includes exposures to multiple chemicals and chemical mixtures, cumulative exposures, and the potential effects of various matrices. Several approaches to cumulative risk assessment have been proposed and utilized in various regulatory applications, but there are dif-fering opinions on approaches. As of this writing, HESI has two initiatives dedicated to examining risk assessment of co-exposures: (1) the Mixtures Project Committee and (2) a cumulative risk subteam within the Risk Assessment in the 21st Century project.

Nanomaterials/nanotechnologyThe number of nanotechnology products in development and on the market is on the rise. Because of widespread commercial application, this technology presents unique exposure and risk assessment challenges. Both exposure and environmental fate of metal and carbon-based nano-particles need to be assessed, for example. Nanomaterials are included in consumer products and food; consequently, a better understanding of risk assessment on nanotechnol-ogy products remains an important developing area. The use of nanotechnology in medicine (e.g., in drugs and medi-cal devices) requires a better assessment of the associated potential safety risks.

Paradigm shifts in risk assessment/life cycle assessment (LCA)Although risk assessment is a component of virtually all issues represented on the 2010–2020 HESI Combined Challenges Map, meeting participants determined that a focus on the science of risk assessment and LCA is war-ranted. In particular, translating new science and technology

into paradigm shifts in best practices for risk assessment is a critical goal.

Among the multiple issues that are included in this broad challenge area are the following:

Assessing the risks of mixtures and other stressors is •an area that requires additional focus. Environmental risk assessment often involves assessment of mixtures because attribution of initial sources is not possible once chemicals leave the point of first use. More dia-logue between the environmental and human safety sciences is needed in this area. Standardized methods for assessing the risk of exposure to multiple genotoxic and/or non-genotoxic contaminants are also important issues (e.g., Bercu et al., 2008).The relevance of low exposure situations, as well as •establishing thresholds of toxicological concern (TTC) for exposure to genotoxic and non-genotoxic con-taminants, remains at the core of some of the most challenging areas of risk assessment. Risk assessment scientists continue to struggle with establishing whether thresholds exist and, if so, how to establish reasonable approximations of thresholds below which negligible effects on human health or environmental quality may occur.Clear connections exist between data needs for risk •assessment (e.g., weight of evidence, mode of action, thresholds) and translation of genomics data into risk assessment practice. An important translational impera-tive may be the National Research Council’s (NRC) “Toxicity Testing in the 21st Century” initiative (NRC, 2007), which has been and will continue to be integrated into new testing strategies, particularly in the United States.LCA is an effective means of quantifying numerous •attributes of products and services as they relate to human and environmental quality. Key to its effective use in the future are the following:

Adequate and up-to-date information on energy, •water, and material inputs into relevant phases of a product life cycle is needed. As new technologies emerge, new inputs are needed. Examples include nanomaterials, biofuels, and biologically based raw materials used in the potential replacement of syn-thetic or petrochemically based chemicals. Existing LCA axes (e.g., eutrophication, smog potential, human toxicity, environmental toxicity, greenhouse gas pro-duction) may require reevaluation or innovation.Interactive evaluations are needed to assess the risk of •contamination throughout the life cycle of chemical production, including use and disposal.Consistent LCA and LCIA practices across geographic •boundaries are needed to promote understanding and comparison of results across regions, particu-larly with regard to chemicals that are used globally or contaminants that have global dispersion potential (i.e., those that have long-range transport potential).

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Mapping of cause and effect chains for water-related •indicators is an important gap that needs to be filled to begin the process of estimating the impact of water use on different ecosystems.

Stem cell therapyThe therapeutic use of stem cells poses ethical challenges. For example, the procurement of stem cells from human embryos is hotly debated. The advent of iPS cell technology is a mechanism to avoid the use of human embryos. iPS cells can differentiate into any type of human tissue (endodermal, mesodermal, and ectodermal), and are thought to provide an ideal testing platform, distinct from the traditional in vitro testing using immortalized cell lines and primary cultured cells. iPS cells can be prepared from healthy volunteers of different races and sexes, as well as from patients with vari-ous diseases. The use of iPS cells is likely to have a significant impact on patient-specific cell therapy, and may hold great promise as a research tool to improve the predictive power of toxicology testing.

However, there are many hurdles to validating iPS cell testing systems. Detailed mechanisms for reprogramming, as well as how closely iPS cells resemble conventional ES cells, are not yet known. The efficiency of derivation of human somatic cells remains low. Many stem cell–derived systems have a relatively immature phenotype. Hence, the relevance and applicability of stem cell-based systems will need to be carefully evaluated.

Individual susceptibilityIndividual susceptibility to disease and chemical toxicity has received increasing public attention. As a result, some companies now offer genome-wide screens for genetic vari-ation that might impact disease susceptibility, although the current value of this is questionable (Hall and Gartner, 2009). In addition, the availability of electronic information about individual genetic variation is on the rise (e.g., a public wiki, SNPedia, is available that describes the functional impact of specific single-nucleotide polymorphisms; the program Promethease builds reports based on SNPedia and a file of genotype data). This broad issue includes challenges associated with the application of personalized medicine, the potential misuse of such information, as well as con-cerns regarding exclusion policies resulting from individual genotype analysis.

Long-term (2015–2020)Improved testing and assessment strategiesThis challenge area covers a broad range of issues, many of which are related to large-scale and ambitious new testing paradigms laid out in the National Research Council (NRC) report on “Toxicology Testing in the 21st Century” (NRC, 2007) and the EU REACH program (EC, 2007).

At the core of this topic are regulatory implications of programs designed to integrate large quantities of toxicol-ogy data to provide broad contexts for interpreting safety and risk. Among the many challenges posed by such programs

is the introduction of potentially unmanageable levels of complexity and testing burdens. Novel testing and assess-ment strategies should emphasize simplified and stream-lined approaches. Other possible improvements to testing and assessment strategies include the development and use of translational biomarkers, assessment of chronic low-dose exposures, tiered testing strategies, and integration of high-throughput data in risk assessment.

Regulatory framework for carcinogenicity testingMeeting participants predicted that the 2-year rodent car-cinogenicity bioassay could undergo significant revision or replacement within the next decade. Advancements in sci-ence justify a critical reevaluation of the need for the cancer bioassay and whether these tests can be replaced by a more systematic, mechanistically based approach. Currently, use of the 2-year rodent carcinogenicity bioassay results in risk communication problems, incurs significant development costs, and is a difficult system in which to apply advances in biomedical science (Boobis et al., 2009). Cohen et al. (2004) proposed that a prospective approach be developed to define and understand key carcinogenic events with a well-defined dose-response relationship. This information should then be used to determine human relevance in association with human exposure risk assessment. Recently, Boobis et al. (2009) conducted a retrospective analysis of chemicals show-ing tumors in rodent cancer bioassays. For non-genotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in 2-year studies after 13 weeks utilizing conventional endpoints. Additional end-points may be needed to identify some signals not detected with routine evaluation. Efforts such as that undertaken by Boobis et al. (2009) to find alternatives to the 2-year rodent cancer bioassay will ultimately improve the predictivity of human carcinogenic risk.

Alternatives to animal modelsThis important challenge area includes the development of improved test systems that reduce the use of animals and increase throughput in testing capacity for chemicals. A con-current theme is the validation of newer test systems (e.g., stem cells and their relevance to both reduction of animal use and more accurate prediction of human risk).

The use of 3R approaches in toxicity testing must be •counterbalanced by the introduction of alternatives that are at least as, if not more, predictive and repeat-able than standard tests. These approaches must be validated for risk assessment use in decision-making and regulatory implementation (Hartung and Daston, 2009). National and international efforts, such as the EU REACH and the US “Toxicology Testing in the 21st Century” programs, are rapidly moving forward to test a broad range of chemicals and formulate risk assess-ments using in vitro and surrogate testing strategies. For example, the US Environmental Protection Agency’s

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(EPA) ToxCast™ program (www.epa.gov/ncct/toxcast) is using state-of-the-art high-throughput screening (HTS) bioassays to help build computational models to f orecast the potential human toxicity of chemicals.There is continuing interest in the use of QSAR and •other read-across approaches in risk assessment. A need exists to ensure that the domains of applicability of such approaches are adequately characterized and recognized.The 2-year rodent carcinogenicity bioassay is among •the existing testing strategies that could benefit from an improved, alternative testing system(s), as discussed above.

Coordinated discussion and international agreements are needed to assure harmonization of alternatives to ani-mal testing. For example, the Organisation for Economic Co-operation and Development (OECD) has taken a step forward with its Mutual Acceptance of Data (OECD, 1981). Among the organizations involved in validation efforts are the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) in the United States, the European Centre for the Validation of Alternative Methods (ECVAM), the Japanese Center for the Validation of Alternative Methods (JaCVAM), and the Korean Center for Validation of Alternative Methods (KorVAM).

Within the scientific community, the value of animal alternatives is the subject of much research and debate. For example, although alternative testing clearly can, and fre-quently does, lead to increased throughput and decreased costs, can in vitro tests and in silico models provide safety information equivalent to animal tests? A clear understand-ing of the advantages and limitations of alternatives to animal testing is needed, particularly when attempting to demon-strate human relevancy. In addition, there is no robust and globally consistent framework for the regulatory acceptance of new methods.

Epigenetics in risk assessmentThe role of epigenetic changes in mechanisms of toxic action is an active area of scientific exploration. To date, epigenetics has been shown to play a role in some cancers, in endocrine disruption, and in other disease processes. Yet, toxicologi-cal relevance for some epigenetic changes, such as histone modification, has not been fully established. A greater under-standing of epigenetic mechanisms is needed for inclusion of these data in risk assessment and subsequent application in regulation.

Exposure-based risk assessmentIncorporating adequate exposure information into risk assessments is critical. Information is needed on exposure methods, measurements, sources, and pathways. Low-dose exposures represent a particular challenge. According to Hubal (2009), a transformational change in exposure science is underway that contributes significantly to the goals of the NRC vision for “Toxicity Testing in the 21st Century” (NRC,

2007). A new generation of scientific tools has emerged to rapidly measure signals from cells, tissues, and organisms following exposure to chemicals. Methods for monitoring, modeling, and analysis of exposure continue to evolve.

Improved biomonitoring through biomarkersBiomonitoring (i.e., measurement of environmental chemi-cals, their metabolites, or specific reaction products in human biological specimens) is used to assess internal exposure (i.e., body burden). Biomarkers are any substances, structures, or processes that are measured to indicate an exposure or sus-ceptibility or that predict the incidence or outcome of disease. The measurement of biomarkers, in combination with other data, plays an integral role in identifying exposure (sources, trends, etc.), potential human health effects, and/or the effectiveness of public health measures introduced to control exposures. Selection and validation of biomarkers of exposure are critical factors in interpreting biomonitoring data.

Discussion

A comparison of the 2004 and 2009 HESI Combined Challenges Maps (Figures 4 and 1, respectively) is instruc-tive. Readers will note that some issues included on the 2004 map are missing from the 2009 map. In certain cases, issues appearing on the 2004 map, but not on the 2009 map, already are under investigation, and progress toward resolution is underway (e.g., a tiered approach to assess-ing bioaccumulation of chemicals). Some issues appearing on the 2004 map have been reframed such that they are represented differently on the 2009 map (e.g., co-exposure assessment). Indeed, very few of the 2004 challenges were completely dropped from the 2009 map. For example, 2004 issues identified as Sensitive Populations, Children’s Health, and Aging are now incorporated into the 2009 map in the topics on Individual Susceptibility, Human Health: Scientific Evaluation of Sensitive Populations and Risk Assessment of Sensitive/Vulnerable Populations. The 2004 issue on Education of the Public Regarding the Precautionary Principle is now part of the 2009 issue on Communication and Perception of Risk versus Benefit. Conservative Default Factors (2004) is now part of the 2009 issue on Paradigm Shifts in Risk Assessment/Life Cycle Assessment. In fact, this latter 2009 issue represents an overarching theme that cap-tures a number of challenges identified in 2004 and antici-pates bold, new approaches in the future. The incorporation of certain aspects of 2004 issues in the 2009 map demon-strates a trend towards maturation of the challenges, chang-ing perceptions, and evolving expectations for resolution within the next decade.

Some issues are new to the 2009 map, such as Animal Use and Welfare and Alternatives to Animal Models. The inclusion of these new issues demonstrates their critical importance in biomedical research and risk assessment, and highlights the need for collaborative partnerships between scientists in gov-ernment, industry, and academia. Stem Cell Technology and Stem Cell Therapy offer promising alternative test models and

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therapeutic avenues while at the same time pose significant ethical challenges for regulatory and societal acceptance.

Various approaches exist for organizations to build their scientific project portfolios. These approaches often are based on requesting input from stakeholders and constituents, and agreeing on the consolidated input to determine the best fit with current, expected needs. Such processes carry the risk of potentially missing new, overarching issues that may become important in the future. HESI’s 2004 and 2009 mapping exer-cises represent an attempt to capture these overarching human health and environmental issues of scientific, regulatory, and societal importance that are, or are likely to become, highly relevant over the next decade. The 2009 map is not intended to be definitive or comprehensive. Rather, the map is intended as a guide to stimulate discussion and debate across the spectrum of interested stakeholders and committed scientists.

About HESI

For readers unfamiliar with HESI, the organization’s mis-sion is to stimulate and support scientific research and

educational programs that contribute to the identification and resolution of health and environmental issues of concern to the public, scientific community, government agencies, and industry (www.hesiglobal.org). HESI’s programs bring together scientists from these sectors to address and reach consensus on scientific questions that have the potential to be resolved through creative application of intellectual and financial resources. A “tripartite” (academia, government, industry) approach forms the core of every HESI scientific endeavor. As a nonprofit organization, HESI provides a unique, objective forum for in-depth dialogue among sci-entists with different perspectives and expertise. Industry members provide primary financial support for HESI pro-grams, but HESI also receives financial and in-kind support from a variety of US and international government agencies and other scientific organizations.

HESI was established in 1989 as a global branch of ILSI to provide an international forum to advance the understand-ing of scientific issues related to human health, toxicology, risk assessment, and the environment. In 2002, HESI was recognized by the United States government as a publicly

Updated Spring 2007

HESI Combined Challenges Map: 2005–2015

2015

2010

2009

2008

2007

2006

2005 2005

2006

2007

2008

2009

2010

2015

Societal Issues Scientific Issues Regulatory Issues The thickness of the perimeter of each shape indicates the relative priority, i.e., the thickerthe shape, the higher the priority.

Environ-mental

Toxicology

Obesity

ConservativeDefaultFactors

Data quality

PredicitingIdiosyn-craticReactions

“Omics”/Bioinfor-matics

Children’sHealth:Late-LifeOutcomes

Children’sHealth:PK, MOA

AlternativeTherapies

TieredApproach to

Bioaccumulation ofChemicals

CancerTesting

NewTechnologies

Exposure Inputs to Risk Assessment/ Regulation:Data qualityand Collection

PositiveResultsin in vitroGenetoxTesting

SensitivePopulations:SNPs

Toxicologyof Mixtures

Mixtures and Co- Exposures: Empiricism,Hypothesis-Testing

Transitioning New Science into Regulationsand Guidelines:Scientific Flexibility

Sensitive Populations: Safety Factors/Predictive Models

Educationof the Publicon thePrecautionaryPrinciple

Transitioning New Science into Regulationsand Guidelines:Validation

Transitioning New Science in to Regula-tions and Guidelines:Intl. Decision-MakingProcess

Sensitivepopulations:EvaluativeDatabases

Mixtures and Co- Exposures: Theoretical,Proof of Principle

SensitivePopulations:HealthInformationPrivacy

Aging WorldPopulations

REACHand DSL:

Tier-BasedDecisions,

Prioritizations

REACH andDSL:Communica-tion andEducation

Exposure Input to Risk

Assessment/ Regulation: Prioritization and Tox Testing Desig

Figure 4. HESI Combined Challenges Map: 2005–2015 (developed at 2004 HESI Scientific Mapping Meeting, and updated in spring 2007) (Smith et al., 2008).

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supported, tax-exempt organization, independently chartered from ILSI. HESI draws its membership from the chemical, agrochemical, petrochemical, pharmaceutical, biotechnol-ogy, consumer products, communications, energy and trans-portation industries, and providers of scientific or technical services used in safety testing of products by these industries. Member companies are based in the United States, Europe, and Japan.

The scientific quality and credibility of all work conducted by HESI is of utmost importance to the organization. By ensuring its scientific credibility, HESI provides a trusted forum through which experts in various scientific disciplines affiliated with regulatory, academic, and industrial institu-tions can discuss mutually important issues affecting public health and the environment.

All HESI initiatives are subject to rigorous scientific evalu-ation, and all project proceedings are transparent, undergo strenuous peer review, are presented at public forums, and are published in the scientific literature. The only form of advocacy in which HESI engages is the promotion of the use of evidence-based science as an aid in decision-making. HESI does not conduct lobbying activities.

HESI works to achieve consensus on a variety of scien-tific issues through attention and commitment to informed and inclusive dialogue. Participants in HESI activities must represent a balance of perspectives in an open forum, and every attempt is made to minimize the impact of bias and to eliminate potential conflicts of interest.

Acknowledgements

The authors extend their sincere appreciation to the fol-lowing members of the HESI Scientific Mapping Meeting Planning Committee for their insight and leadership dur-ing the planning and conduct of the July 2009 meeting: Prof. Alan Boobis (Imperial College London), Dr. Henry Chin (The Coca-Cola Company), Dr. Samuel Cohen (University of Nebraska Medical Center), Dr. Jay Goodman (Michigan State University), Dr. Lewis Smith (Syngenta Ltd.), Dr. Kendall Wallace (University of Minnesota Medical School), and Dr. Harold Zenick (US Environmental Protection Agency).

Declaration of interest

The authors have sole responsibility for the writing and content of the paper. Affiliations are shown on the first page. HESI provided funding and resources for the July 2009 scien-tific mapping meeting, as well as for the preparation of this paper. Although industry members provide primary finan-cial support for HESI programs, HESI also receives financial and in-kind support from a variety of US and international government agencies.

The views expressed in this paper are those of the authors and do not necessarily reflect the opinions or policies of the US EPA, US FDA, US NIEHS, or the participants in the July 2009 HESI Scientific Mapping meeting (see Appendix A).

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http://www.govtrack.us/congress/bill.xpd?bill=s110-3040

http://www.oecd.org/document/41/0,3343,en_2649_34365_1890473_1_1_1_1,00.html

http://www.oecd.org/document/41/0,3343,en_2649_34365_1890473_1_1_1_1,00.html


Appendix A: Participants in the July 2009 HESI scientific mapping meeting in Reston, Virginia, USA

Prof. Herman Autrup (University of Aarhus)Dr. Scott Belanger (The Procter & Gamble Company)Dr. Karen Blackburn (The Procter & Gamble Company)Dr. P. Michael Bolger (US Food and Drug Administration)Dr. Marc Bonnefoi (sanofi-aventis)Prof. James Bridges (University of Surrey)Dr. Neil Carmichael (Bayer CropScience)Dr. Henry Chin (The Coca-Cola Company)Dr. Samuel Cohen (University of Nebraska Medical Center)Dr. Jack Dean (University of Arizona)Dr. Dennis Devlin (Exxon Mobil Corporation)Ms. Nancy Doerrer (ILSI Health and Environmental Sciences Institute)Dr. Michelle Embry (ILSI Health and Environmental Sciences Institute)Dr. Bruce Fowler (Centers for Disease Control and Prevention/ATSDR)Dr. Shoji Fukushima (Japan Bioassay Research Center)Dr. B. Bhaskar Gollapudi (The Dow Chemical Company)Dr. Jay Goodman (Michigan State University)Prof. Dr. med Helmut Greim (Technical University of Munich)Dr. Laurie Hanson (Pfizer Inc.)Dr. Ernie Harpur (sanofi-aventis)Dr. Suzanne Harris (International Life Sciences Institute)Dr. Ronald Hines (Medical College of Wisconsin)Dr. Michael Holsapple (ILSI Health and Environmental Sciences Institute)Dr. David Jacobson-Kram (US Food and Drug Administration)Dr. Norbert Kaminski (Michigan State University)Dr. James Kim (ILSI Health and Environmental Sciences Institute)Dr. James Klaunig (Indiana University School of Medicine)Dr. Serrine Lau (University of Arizona)Dr. Lois Lehman-McKeeman (Bristol-Myers Squibb Company)Dr. Germaine Buck Louis (Eunice Kennedy Shriver National Institute of Child Health and Human Development)Dr. James MacDonald (Chrysalis Pharma Partners, LLC)Dr. Charlene McQueen (Auburn University)Dr. Peter Moldéus (AstraZeneca R&D)Dr. Michael Ritchie Moore (Water Quality Research Australia)Dr. Raegan O’Lone (ILSI Health and Environmental Sciences Institute)Dr. Klaus Olejniczak (Federal Institute for Drugs and Medical Devices, Germany)Ms. Syril Pettit (ILSI Health and Environmental Sciences Institute)Dr. Christopher Portier (National Institute of Environmental Health Sciences)Prof. Ivonne Rietjens (Wageningen University)Dr. Stephen Safe (Texas A&M University)Dr. Josef Schlatter (Swiss Federal Office of Public Health)Dr. A. Robert Schnatter (ExxonMobil Biomedical Sciences)Dr. Lewis Smith (Syngenta, Ltd.)Dr. James Stevens (Eli Lilly and Company)Dr. Wataru Takasaki (Daiichi Sankyo Pharma Development)Ms. Ayako Takei (ICaRuS Japan Limited)Dr. Sally Tinkle (National Institute of Environmental Health Sciences)Dr. Hiroyuki Tsuda (Nagoya City University Graduate School of Medical Sciences)Dr. Jan Willem van der Laan (Netherlands National Institute for Public Health and the Environment—RIVM)Dr. Kees van Leeuwen (TNO Quality of Life)Dr. Jean-Marc Vidal (European Medicines Agency)Dr. Kendall Wallace (University of Minnesota Medical School)Dr. Gary Williams (New York Medical College)Dr. Harold Zenick (US Environmental Protection Agency)Dr. Donald Zink (US Food and Drug Administration)

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Appendix B: Participants in the January 2009 HESI scientific mapping meeting in Hamamatsu, Japan

Dr. Toyohiko Aoki (Eisai Company Limited)Dr. Samuel M. Cohen (University of Nebraska Medical Center)Ms. Nancy G. Doerrer (ILSI Health and Environmental Sciences Institute)Dr. Makoto Ema (National Institute of Advanced Industrial Science and Technology)Dr. Shoji Fukushima (Japan Bioassay Research Center)Dr. Masao Hirose (Food Safety Commission)Dr. Kiyoshi Imai (Biosafety Research Center)Prof. Katsumi Imaida (Kagawa University Medical School)Prof. Toshihisa Ishikawa (RIKEN Omics Science Center)Dr. Satoshi Kawamura (Sumitomo Chemical Company Limited)Prof. Yoichi Konishi (Nara Medical University)Dr. Sunao Manabe (Daiichi Sankyo Company Limited)Dr. Mutai, Mamoru (Mitsubishi Tanabe Pharma Corporation)Dr. Dai Nakae (Tokyo Metropolitan Institute of Public Health)Dr. Yuji Oishi (Astellas Pharma Inc.)Prof. Jun Sekizawa (Tokushima University)Prof. Tomoyuki Shirai (Nagoya City University Medical School)Dr. Atsushi Sugiyama (University of Yamanashi Graduate School of Medicine and Engineering)Prof. Katsushi Suzuki (Nippon Veterinary and Life Science University)Dr. Michihito Takahashi (Pathology Peer Review Center)Ms. Ayako Takei (ICaRuS Japan Limited)Prof. Hiroyuki Tsuda (Nagoya City University Graduate School of Medical Sciences)Dr. Takashi Umemura (National Institute of Health Sciences)Prof. Hideki Wanibuchi (Osaka City University Medical School)Dr. Masahiko Wasaki (Mitsubishi Tanabe Pharma Corporation)Dr. Masaki Yamamoto (Takeda Pharmaceutical Company Limited)Prof. Tsuyoshi Yokoi (Kanazawa University Graduate School of Medical Science)

Appendix C: Spring 2009 pre-meeting survey results1. Evaluate current state of the use of embryonic stem cells in treating chronic diseases.2. Need for improved (interdisciplinary) education of biologists, noting the importance of understanding and applying

mathematics and engineering principles.3. Construction of artificial organs to reduce the reliance on animal models in the long term. Draw on efforts and

investments already made in the artificial organ industry.4. Use of induced pluripotent stem (iPS) cells.5. Preventable diseases, e.g., contribution of diet, lifestyle, with consequent obesity, to metabolic, cardiovascular

disease, and cancer. Also vaccine development and vaccination programs for diseases such as HIV, malaria, and tuberculosis.

6. Significant number of rodents is used in single-dose acute toxicity studies on intermediates of synthesis (for worker safety and labeling purposes). As such, acute toxicity studies are now seen to be a poor predictor for human toxicity. There is a need to institute a reduction and replacement policy to reduce the number of animals used in such tests.

7. Development of probabilistic risk assessment methods consistent with recommendations of the National Academies of Sciences Report on Science and Risk Assessment.

8. Issues of non-threshold models applied to non-cancer endpoints as suggested in recent National Academies of Sciences Report on Science and Risk Assessment.

9. Validation that assumed climatological changes—at the magnitudes predicted—are capable of influencing human public health.

10. Development of “best practice guidelines” for benefits estimation in environmental benefit-cost analysis.11. Carbon and water footprints of products are two metrics being used to provide sustainability information to con-

sumers. Platforms for consistent use and international standards are sorely needed.12. Environmental fate and effects of nanoparticles is hampered by the void of fundamental environmental chemistry

knowledge (state, form, and concentration once released to the environment).13. Relevance of low exposure concentrations of pharmaceuticals and personal care products in environmental matrices.

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14. Frameworks to use eco-epidemiology (in situ biomonitoring, effluent toxicity, chemistry) studies for verifications and predictions of environmental risk of chemicals.

15. Identification of common mechanism groups for cumulative risk assessment.16. Use of pathway analysis in mode/mechanism of action studies.17. Alternatives to the 2-year rodent cancer bioassay.18. Improving exposure assessment in epidemiology studies.19. Assessment of risk when epidemiology data are not statistically significant.20. Development of exposure information and screening tools to place “omics” data into context. Typical exposure tools

estimate exposure at the point of contact, with some higher tier tools assessing absorbed dose or even higher tier PBPK type models. Improved understanding of (a) contact and (b) how contact translates to target tissue concentra-tions will be needed to better understand the significance of the results of laboratory tests to real-world exposures.

21. Improved understanding of exposure sources to better respond to the increasing amount of biomonitoring data. Biomonitoring data represent integrated exposure from all sources. In cases where biomonitoring data suggest exposure should be minimized, it will be important to understand the relative contribution of individual sources to total exposure.

22. Life cycle assessment. Increasing interest in all life cycle aspects combined with improvements in LCA tools will result in greater application of these tools in the future. Further tool improvement and input data availability are needed, as are consistent approaches and boundary domains to enable relative comparisons of results, so that tool application can be used for impactful decision-making.

23. Sensitive subpopulations. This area will continue to grow in importance as our understanding increases. Improved data will allow a better focus on determinants of most importance.

24. Water availability. As global demand increases for products and services that require water, availability will become an issue of increasing importance. Societal expectations may need to be adjusted and/or more efficient technolo-gies for water use and recycling will need to be developed.

25. Effectively communicating risks to user populations/general public.26. Toxicology of mixtures.27. Development of more effective/rapid methods for predictive toxicology.28. Prediction of long-term consequences of toxicant exposure.29. Consumer-based risk assessment, wherein retail businesses assess risks for their customers, e.g., the elimination of

China-derived infant paraphernalia because of lead concerns. In this way, retail businesses could have broad influ-ence on the pharma, agchem, and other industries, in terms of products they choose to stock. Science could take a back-seat to media-driven consumer risk perception.

30. Interpreting genomic technologies into risk assessment practices. Defining whether a transcriptional response is an adverse event that should be considered and weighed in risk regulation.

31. Carcinogenicity of growth factors, hormones, etc. With irregular intervals, there is a discussion on the “promoter” activity of endogenous growth factors, such as insulin-like growth factor and growth hormone.

32. Developmental and reproductive toxicity of vaccines. Clinically, use of vaccines during pregnancy.33. Adjuvants and adverse effects. In Europe, several new adjuvants are included in vaccines, whereas the United States

is hesitating. What are the possible risks for autoimmunity adverse effects? How to detect these effects?34. Behavioral training of experimental animals in toxicology may lower animal activist criticism to animal

experiments.35. In vitro only testing as a final stage in testing safety. Is it possible? Yes or no.36. Environmental reproductive health problems associated with chemical exposures, lifestyle, and genetic back-

ground. The contributions from food-borne toxicants is increasingly in focus. More information bridging the chemi-cals in food and actual exposures by biomonitoring.

37. Risk assessment should move away from a labor-intensive and animal-consuming approach to intelligent and pragmatic testing by combining exposure and hazard data effectively and trying to group chemicals (category approaches). The focus should be on reducing the overall uncertainties of 100,000 chemicals while acknowledging the existence of the uncertainty paradox: reducing uncertainty in the assessment of individual chemicals following the classical chemical-by-chemical approach as we have in previous decades will result in a prolongation of uncer-tainty for the entire group of 100,000 chemicals as a whole. With the first REACH registration deadline (2010) rapidly approaching, a mindset change is urgently needed. We can speed up the regulatory acceptance process, starting with the maximum use of currently available exposure and hazard data, tools, and models. Optimal use should also be made of experimental exposure and hazard data generated under REACH. Only such an approach will make it possible to obtain a sufficient level of information within the time frame of REACH. A much more intensive dialogue between stakeholders is necessary.

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38. Relationship between nanoparticle characteristics and biological interactions. This fundamental knowledge is criti-cal for future biomedical applications research, as well as quantifying the environmental, health, and safety con-cerns for these nanoparticles.

39. Toxic effects of recently developed nanomaterials, such as metals, fullerenes, and carbon nanotubes. Metals cover-ing carbon black surface are used as toners. Fullerenes are to be used for drug delivery carriers. Carbon nanotubes are used to strengthen plastics.

40. Toxicogenomics (and other omics, as well as bioinformatics): application to risk assessment, reduced animal use, discovery toxicology. Also, testing protocols for regulatory submissions and use of data in determining adverse effect levels.

41. Development and validation of in vitro alternatives to animal testing,42. Development, refinement, and validation of in silico models and their application to discovery, development, and

regulatory toxicology.43. Hazard and risk assessment of multiple chemical exposures and/or exposure to mixtures.44. Risk communication: communication of hazard and risk assessment data to the lay public.45. Support for animal research. NRC report on toxicology testing in the 21st century, other regulatory pressure, and

pressure from NGOs is threatening our ability to perform necessary safety testing. The utility of animal research needs continued advocacy.

46. Need to clarify the utility of genomics and other methods in establishing NOAELs necessary for risk assessment. NOELs and NOAELs are quite different, but there is regulatory pressure to use them interchangeably.

47. Further characterization and utility of biomarkers to detect specific organ toxicity in preclinical species. Current biomarkers that have been evaluated within consortia (PSTC, etc.) will need further experiments in preclinical spe-cies using drugs that produce more subtle pathologies or no histopathology, but changes in the physiology of the target organ. This will be particularly important in organs such as the kidney. Consideration should also be given to whether these biomarkers could be tested in animal models of spontaneous disease, to better understand how they perform in tissues affected only by spontaneous disease (diabetic nephropathy). Collaborations with veterinary schools might yield a rich source of material for spontaneous liver and kidney disease in dogs, and access to the “veterinary community” is often overlooked by toxicologists.

48. Understanding mechanisms of genotoxicity associated with positive chromosomal aberration findings in vitro and associated human risk.

49. Early in vivo gene expression changes associated with genotoxic and non-genotoxic rodent carcinogenicity.50. Recently, FDA and EMEA have approved seven urinary biomarkers for drug-induced renal injury whose utility is

based upon changes observed in rats treated with renal toxicants. The normal ranges of urinary excretion of these markers are not established with regard to physiological changes in renal function. Suggest that the significance of urinary biomarker changes be studied both in the rat and in the dog.

51. Drug safety evaluation paradigm that provides higher throughput and more reliable predictive performance.52. Increased emphasis on in vitro studies without adequate appreciation for the need to use these as hypothesis-gen-

erating activities that require confirmation in vivo.53. Role of toxicology in regulation of exposure to agents (chemical, biological, and physical).54. Replacement of dose response and threshold with the concept of minimal to some concern.55. Alternatives to animal testing. There is increasing pressure from regulatory authorities (in EU mostly), animal rights

organizations, and the general public to reduce the numbers of animals used in research. Additional tools as well as evaluations of human relevance are needed in order to advance in this area, and to gain acceptance. Alternative methods show promise of being more human relevant, less costly, and more humane, but considerable work needs to be done in this area.

56. Criteria for new assay validation. The EPA, under the Endocrine Disruption Screening Program, is about to issue Tier I test orders requiring testing with several scientifically non-validated assays. Criteria for evaluating results from such assays have not been provided or suitably validated by EPA. Tier II assays under the Endocrine Disruptor Screening Program (EDSP) have not been published and, therefore, companies with Tier I test orders will not know whether there are sufficient higher-tier studies already conducted, avoiding the need to generate the questionable Tier I data.

57. Role of microRNA species in the modulation of response to toxicity, as biomarkers, and in mechanistically based risk assessment.

58. Role of altered DNA methylation in the transgenerational transmission of the effects of chemical exposure.59. Effects of chemical exposure on microRNA expression in the male gamete and its possible effects in transmitting

paramutagenic effects leading to a phenotype independent of polymorphism.

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60. Use of toxicogenomics database to develop genetic toxicity signatures. This can be extended to metabolomics and proteomics levels as well.

61. Application of in vitro models to risk assessment.62. Surrogate animal models in risk assessment.63. Food and feed production from cloned animals.64. The effect of climate change on environment pollution.65. Monitoring adulteration of food ingredients.66. Validation of key measures of sustainability.67. Nanotechnology.68. Development and utilization of mammalian embryonic and somatic stem cells, including human cells, as in vitro

surrogates for use in toxicogenomic studies as well as for other toxicological endpoints.69. Develop an understanding of the contribution of autophagy to the process of induced cell death. Autophagy is a

catabolic process that is critical in the maintenance of cellular homeostasis, and understanding the effects of toxins on this process provides a greater understanding of programmed cell death.

70. Animal welfare, alternative toxicity testing, 3Rs.71. Respiratory sensitization and allergy. There have been reports of increases in the incidence of allergy and asthma in

most of the industrialized countries. Currently, there are no validated methods for identifying chemicals or agents that are capable of inducing asthma or respiratory hypersensitivity. This field of research warrants immediate atten-tion from a public health perspective.

72. Epigenome and the environment. There will be an explosion of research in the coming years into the understanding of the control of gene expression through changes in the epigenome. Lines will become blurred between mutations and heritable epigenetic modification. Environmental and dietary influences on the epigenome will likely attract significant attention in the scientific community.

73. Credibility of science. There has been an increasing trend to judge the science not on its quality, but rather based on the source of funding. Key stakeholders and scientists with relevant expertise are often excluded from scientific discourse simply based upon perception of conflict of interest stemming from the funding source for their research. This is not a healthy situation for the protection of both public health and the environment.

74. Identification of “danger signals” that are associated with immune-mediated adverse drug reactions as well as other forms of allergy. This is the “missing link” in understanding risk for drug allergy: genomics has identified, and continues to identify, heritable risk factors, but these alone do not account for development of allergies. A more systematic approach to identifying the environmental factors to complete understanding of pathogenesis would be valuable.

75. Sustainability.76. Climate change—its impact on operations, product development, etc.77. Best practices for causal inference. (Follow-up to weight of evidence activities.)78. Evaluating the safety of nanoparticles.79. Overcoming the hurdle of toxicity observed in animals that cannot be detected or monitored in humans.80. Evaluating the safety of combination products, including drug/drug, drug/device, drug/biologic, biologic/device,

and drug/device/biologic.81. How to promote the acceptability of new approaches, such as omics, systems biology, signaling pathway effects,

etc., in regulatory human safety evaluations.82. Risk assessment of food and consumer products manufactured by nanotechnology.83. Pathophysiology of hypersensitivity reactions to drugs and in vitro diagnostic strategies.84. Qualification of clinical biomarkers for both kidney and liver.85. In silico toxicology and structure-activity relationships become more prevalent and need to be validated. Accuracy

needs to be explored.86. While risk assessment of food chemicals is a well-developed scientific process, an equivalent for benefit assessment

is currently under development, as is a quantitative comparison between the two (benefit-risk analysis for foods or BRAFO). Such a framework once developed needs to be implemented in the regulatory process, and its practicabil-ity needs to be tested.

87. To analyze experimental toxicity data, mathematical modeling is increasingly used. Guidance is needed for uncon-ventional approaches (such as benchmark dose analysis), as well as for complex techniques (heat map analyses in genomics), in relation to application and interpretation.

88. Effects of climate change on emerging infectious disease.89. Updated and simplified scientific development of regulatory safety packages.

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90. Integration of human health and ecological risk assessment.91. Application of high-throughput methods in quantitative risk assessment.92. MicroRNA biomarkers for carcinogen exposure.93. Risk assessment of genetic toxicants.94. Human genetic polymorphisms and individual susceptibility to disease and toxic effects. Knowledge of individual

polymorphisms that modify susceptibility to disease and toxic effects has increased dramatically, and will impact both risk assessment and the practice of medicine dramatically.

95. Emerging use of biomonitoring data in public policy.96. Epigenetic changes as a mechanism of toxicant action and incorporation of this mode of action into risk assessment.97. Quantitative assessment of mixtures.98. Harmonization of protocols for assessing sensitive populations and incorporation into risk assessment.99. Chronic, low-dose exposures and their role in toxicity and risk assessment.100. Real-world applications and challenges with personalized medicine.101. Increasing focus on risk assessment for the individual, considering their unique susceptibilities (e.g., SNPs, etc).102. Ensuring that assessments of risk based on biomonitoring of chemical exposure have a solid, scientific basis.103. Accessibility of raw data to the general public and tools to ensure appropriate use; avoiding misuse.104. Implementation of NRC “Toxicity Testing in the 21st Century.”105. Emerging/evolving risk assessment methodologies (e.g., recent National Academy of Sciences report “Science and

Decisions”).106. The role of pathway mapping in providing mechanistic insight into toxicological effects.107. The evidence base that the dose-response curve for the carcinogenic effects of (some) DNA reactive genotoxicants

exhibits a threshold.108. The increasing use of the precautionary principle in the face of negative epidemiology (no significant risk; no sig-

nificant trend with exposure).109. Epigenetics and the consequences for toxicity testing and risk assessment.110. Nanomaterial safety assessment.111. Nanotoxicology.112. Toxicology testing.113. Non-animal testing.114. Testing for carcinogenicity.115. Induced pluripotential stem cells.

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