Predicting Future Human and Environmental Health Challenges: The ...

Critical Reviews in Toxicology, 38:817–845, 2008 c 2008 Informa UK Ltd. Copyright ISSN: 1040-8444 print / 1547-6898 online DOI: 10.1080/10408440802486378

Predicting Future Human and Environmental Health Challenges: The Health and Environmental Sciences Institute’s Scientific Mapping Exercise Lewis L. Smith Syngenta Crop Protection AG, Basel, Switzerland

Robert L. Brent Alfred I. duPont Hospital for Children, Wilmington, Delaware, USA

Samuel M. Cohen University of Nebraska Medical Center, Omaha, Nebraska, USA

Nancy G. Doerrer ILSI Health and Environmental Sciences Institute, Washington, DC, USA

Jay I. Goodman Michigan State University, East Lansing, Michigan, USA

Helmut Greim Technical University of Munich, Germany

Michael P. Holsapple ILSI Health and Environmental Sciences Institute, Washington, DC, USA

Ruth M. Lightfoot Amgen Inc., Thousand Oaks, California, USA

To predict important strategic issues in product safety during the next 10 years, the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute initiated a mapping exercise to evaluate which issues are likely to be of societal, scientific, and regulatory importance to regulatory authorities, the HESI membership, and the scientific community at large. Scientists representing government, academia, and industry participated in the exercise. Societal issues identified include sensitive populations, alternative therapies, public education on the precautionary principle, obesity, and aging world populations. Scientific issues identified include cancer testing, children’s health, mixtures and co-exposures, sensitive populations, idiosyncratic reactions, “omics” or bioinformatics, and environmental toxicology. Regulatory issues identified include national and regional legislation on chemical safety, exposure inputs, new technologies, transitioning new science into regulations and guidelines, conservative default factors, data quality, and sensitive populations. Because some issues were identified as important in all three areas (e.g. sensitive populations), a comprehensive approach to assessment and management is needed to ensure consideration of societal, scientific, and regulatory implications. The resulting HESI Combined Challenges Map is not intended to offer a universal description of challenges in safety assessment, nor is it intended to address, advocate, or manage the prioritized issues. Rather, the map focuses on and predicts issues likely to be central to the strategic agendas of individual companies and regulatory authorities in the developed world. Many of these issues will become increasingly important in the future in rapidly developing economies, such as India and China. The scientific mapping exercise has particular value to the Address correspondence to Nancy G. Doerrer, ILSI Health and Environmental Sciences Institute, 1156 Fifteenth Street, NW, Second Floor, Washington, DC 20005, USA. E-mail: [email protected]

817

818

L. L. SMITH ET AL.

toxicology community because it represents the contributions of key scientists from around the world from government, academia, and industry.

Keywords HESI, product safety, regulatory challenges, scientific challenges, scientific mapping, societal challenges, toxicology INTRODUCTION Chemicals1 are introduced into the environment from a variety of sources, both natural and synthetic. The toxicological significance and consequences of these exposures are of increasing concern to the general population. From a historical perspective, the science of toxicology dates to the 16th century, when Paracelsus, a physician-alchemist, stated that: “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” (Gallo, 2001.) Understanding of the toxicology of various substances has evolved significantly since then, and over the past five decades in particular, a greater insight has been gained into the mechanisms by which chemicals can affect physiologic and metabolic processes. Many of these scientific insights have evolved into regulatory requirements and frameworks through which the safety and health of the public are protected. For scientists, regulators, and society as a whole, projecting the future directions of toxicology is an important means of predicting health and safety challenges. A critical supplement to and component of the scientific strategy of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) is the prediction of issues that are likely to face the scientific community and HESI as an organization in the long-term. The magnitude of such an undertaking is large, particularly given the broad interest base of HESI’s member companies and the organization’s broad constituency of government and academic scientists. Predicting future challenges can be achieved via several methods. Mapping is a proven, useful technique for engaging organizations in exploring the issues facing their memberships or constituencies. Among the organizations that have used the scientific mapping tool is the National Institutes of Health (NIH). HESI (http://www.hesiglobal.org/) undertook such an exercise for toxicology, and included perspectives on scientific, regulatory, and societal projections for the future. In April 2004, HESI convened an expert group of key academic, government, and industry scientists from around the world to conduct a scientific mapping exercise. The group examined extensive information that was received, in advance of the meeting, from HESI’s broad constituency on issues of potentially significant scientific, regulatory, and societal importance for the next 10 years. The group established a temporal priority, estimated the magnitude of each problem, and assessed the 1 In

the context of this paper, the term ‘chemicals’ includes agrichemicals, pharmaceuticals, industrial chemicals, consumer products, and physical agents.

occurrence and seriousness of each issue. At the start, the experts assumed that all the issues presented had some validity. After much discussion and debate, a series of maps (societal, regulatory, and scientific) was created on which all suggestions were represented, either specifically or in categories. Finally, a ‘Combined Challenges Map’ of scientific issues was developed, from which HESI prioritized the issues that were of greatest importance to its constituency. The maps that were developed as a result of the exercise are only snapshots in time. They are, however, a useful starting point for periodic updates when scientific issues are reconsidered in light of changing times. The mapping exercise was not intended to provide specificity on how to address, advocate, or manage the prioritized issues. Rather, the value of the exercise was the development of a creative tool that HESI could use to predict important issues, and thus refine and expand its scientific project portfolio in the coming years. For some issues, HESI offers general recommendations for future research. The scientific mapping exercise has particular value to the toxicology community because it represents the contributions of scientists from around the world from government, academia, and industry. The various industry sectors involved in HESI activities will be particularly interested in the issues appearing on the HESI Combined Challenges Map. From a broader perspective, the series of maps provides the wider audience with opportunities to determine the importance of the full complement of issues considered by HESI, develop different temporal priorities, or conduct similar mapping exercises to predict future challenges. The scientific reputation and international credibility of HESI as an organization lends significance to the results of HESI’s April 2004 ‘Scientific Mapping’ exercise, both for the organization’s constituency and for the public at large. Information about the mapping process, the results of the exercise, and the implications of those results are presented later in this paper. For readers unfamiliar with HESI, a primer is offered here. The mission of HESI, a global branch of ILSI, is to stimulate and support scientific research and education programs that contribute to the identification and resolution of health and environmental issues of concern to the public, scientific community, government agencies, and industry. HESI draws its membership from the chemical, agrichemical, petrochemical, pharmaceutical, biotechnology, and consumer-products industries. Approximately 50 companies from the US, Europe, and Japan are HESI members. Industry members provide financial support for HESI programs; however, HESI also receives financial and in-kind support from a variety of US and international government agencies, scientific professional societies (e.g. Society of Toxicology), and other non-profit organizations. HESI programs bring together scientists from industry, government agencies, academia, and other research organizations around the world to address both long-standing and emerging questions associated with human health and environmental issues. This ‘tripartite’ approach (i.e. engagement of industry,

HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE

819

FIG. 1. Overview of HESI scientific mapping process. government, and academia), which is part of every project undertaken by HESI, ensures an objective forum for dialogue among scientists with different perspectives and expertise. As with any organization that works with a diverse constituency, it is rare for complete agreement to be reached on every issue. Nonetheless, HESI has proven to be unusually successful in achieving consensus on a variety of scientific issues because of its attention and commitment to informed and inclusive dialogue. All project proceedings are transparent, undergo strenuous peer review, and are presented at public forums, and the products are published in the scientific literature. Over the last two decades, HESI has contributed to a greater understanding of complex scientific issues, including immunotoxicology, mechanisms of cancer, use of transgenic mice in the evaluation of cancer hazards, improvements in risk assessment, development of a better understanding of the application of genomics to toxicology, and many others (HESI publications: http://www.hesiglobal.org/publications). Most of these issues are identified and managed through early recognition of a scientific dilemma or opportunity which requires analysis and/or laboratory experiments to provide greater insight into the underlying science. This process of identification and resolution has served HESI well by permitting efficient and productive engagement of members, academic advisors, and government contacts. METHODOLOGY HESI held a scientific mapping exercise on April 6–7, 2004. Organized by the HESI Board of Trustees Program Strategy and Stewardship Committee and the HESI Emerging Issues Steering Committee, the exercise was designed to identify and prioritize potential scientific, regulatory, and societal issues that present opportunities for HESI activities over the next 10 years. Invited

scientists from European and US government agencies joined corporate and academic members of the two committees at the meeting (see Appendix 1). Guests included representatives of the European Commission, the European Medicines Agency, the US Environmental Protection Agency, the US Food and Drug Administration’s National Center for Toxicological Research, the National Cancer Institute, and the National Institute of Environmental Health Sciences. An overview of the method used to develop the HESI Scientific Map is given in Figure 1. Well in advance of the April 2004 meeting, HESI solicited broad input on issues of potential concern and interest from the Program Strategy and Stewardship Committee, the Emerging Issues Steering Committee, and HESI’s extensive list of key contacts. These 182 ‘surface issues’ were organized into scientific, regulatory, and societal challenge categories and are presented in their entirety in Appendix 2. At the mapping session, the array of scientific, regulatory, and societal issues was refined and supplemented through interactive discussion in breakout groups, and then consolidated to reduce duplication and combine closely related areas. To assess potential impact and examine the likely timeframe for action, the array of consolidated issues was placed on an ‘opportunity matrix’ (Figure 2). Using this tool, the matrix allowed meeting participants to view, in two dimensions, the potential impact on a 1–10 scale, and an approximation of time during which HESI might focus on each issue (e.g. in 1–2 years, 3–4 years, or over 5 years). Finally, based on this analysis, sets of high-priority scientific, regulatory, and societal challenges were identified to enhance HESI’s emerging-issues process, which drives the development and evolution of the organization’s scientific project portfolio. Maps were prepared for societal, scientific, and regulatory issues respectively (Figures 3–5). The issues included on each map were classified according to the approximate year during

820

L. L. SMITH ET AL.

(i.e. hexagons for regulatory issues, squares for societal issues, and triangles for scientific issues; Figure 7). The thickness of the perimeter of each shape on the map indicates the relative priority assigned to the issue at the 2004 HESI Scientific Mapping session; that is, the thicker the shape, the higher the priority. RESULTS AND DISCUSSION The issues represented on the HESI Combined Challenges Map (Figure 6) are described and discussed in further detail below.

FIG. 2. HESI opportunity matrix. which the issue might be of highest importance, and as low, medium, or high priority. As a summary step, a HESI Combined Challenges Map was prepared (Figure 6), which consists of a mix of high-priority scientific, regulatory, and societal issues of relevance to HESI, as identified by meeting participants. Many other issues were considered to be of general interest, but were determined to be outside HESI’s capacity or strategic objectives. The Combined Challenges Map begins with the year 2005, at the bottom of the chart, and ends with the year 2015, at the top of the chart. Each issue represented on the map is marked with a geometric symbol

Societal Issues (Square) HESI’s primary mission is to provide an international forum for the advancement of the understanding and resolution of scientific issues related to human health, toxicology, risk assessment, and the environment. It is generally accepted that societal pressures can directly or indirectly influence the issues that HESI and other organizations prioritize to meet the needs of their stakeholders. Societal pressures also play a role in directly or indirectly influencing regulatory policy, such that the manufacturers of pharmaceuticals, pesticides, or chemicals find it necessary to defend their activities. Generally speaking, the regulatory process relies on evidence-based arguments that can and are challenged by technical experts in regulating agencies or through scientific advisory panels appointed to give counsel on particular issues. However, because societal pressures partially influence which issues are considered to be of concern, they can also create an expectation of regulatory decision-making

FIG. 3. HESI societal challenges map.


821

FIG. 4. HESI scientific challenges map.

without due regard for scientific evidence. In an ideal world, it might be possible to argue that scientific evidence should determine outcomes and outweigh emotional or prejudicial views on a given subject. In reality, societal concerns are influenced by the

prediction of what may be concluded, with the objective, scientific truth often skewed to accommodate the expected outcome. From this experience, the important lesson for an organization such as HESI, which is committed to evidence-based analysis

FIG. 5. HESI regulatory challenges map.

822 FIG. 6. HESI Combined Challenges Map: 2005–2015.


FIG. 7. HESI challenges were identified as being primarily regulatory, societal, or scientific.

and decision-making, is that ignoring the influence of societal pressures is at best naive and, at worst, irresponsible. The term ‘societal pressures’ does not adequately capture the differing, and sometimes conflicting, agendas of all individuals and organizations. The composition and power of societal pressure is greatly determined by media attention, which can be generated by individuals or groups who, through their tenacity, financial resources, and commitment, can deliver issues to the media in a form that attracts attention and provides good copy for newspapers, television, or radio. Often, these groups form non-governmental organizations (NGOs). The vast majority of NGOs legitimately pursue their stated goals; some, however, adhere to a particular viewpoint to the exclusion of evidence to the contrary. For example, those who believe pesticides are universally harmful will argue that there is no safe level of exposure, and that a movement toward organic agriculture is the only means by which society will avoid the perceived dangers posed by crop protection chemicals. Likewise, businesses, industries, and government agencies and officials are influenced by their constituencies, resulting in actions that may not be in the best interest of science. It is not the purpose of this paper to argue the merits for and against these societal pressures, but rather to point out their existence and potential to significantly influence scientific judgments on some issues. For example, with the introduction of the European Union (EU) legislation known as REACH (Registration, Evaluation, and Authorisation of Chemicals), which is discussed later in this paper, there has arisen a conflict between the desire to adequately test the tens of thousands of chemicals to which humans are exposed and the concern over the increased use of experimental animals in tests normally associated with safety evaluation. This conflict can lead, and indeed has led, to strategies that attempt to significantly reduce the number of animals used in studies or that promote the use of in vitro tests for the assessment of human safety. Many in vitro tests have not been fully or adequately validated; however, the pressure to use them and thus avoid the use of experimental animals can be considerable, even if not publicly stated by regulators. Consequently, there is a danger that the assessment of chemicals will be compromised by an unwillingness to use the most appropriate biological test systems to evaluate the chemicals in question. This dilemma has spawned an industry supporting the aspiration to provide sufficient in vitro test systems to substitute for animal studies. In some cases,

823

in vitro test systems have been valuable substitutes for animal studies (Zurlo et al., 1994; European Centre for the Validation of Alternative Methods, 2007). Nevertheless, for many endpoints, there is no substitute for the use of experimental animals that provides an integration of cells into organs and organs into a functional entity, thus more closely reflecting actual human biology (Interagency Research Animal Committee, 1985; National Research Council, 2007). For the HESI mapping exercise, societal challenges were selected that will either have a beneficial effect on society or encourage scientific activity. It is not unexpected that HESI’s selection of societal issues overlaps with its selection of scientific challenges. In some instances, the societal challenge actually precedes the scientific challenge, and in others, the societal issue will be a consequence of the scientific development. An example of the latter instance is the development of testing for the presence of genetic disease and other predictors of health or disease in the human population. For the individual, knowing of impending disease may influence his or her personal attitude toward life and, perhaps more importantly, generate concerns about employment issues, insurance candidacy, or inclusion in health care systems. The application of new technology and scientific advancements creates societal issues of economic importance and, eventually, political significance. In short, any holistic review of a toxicological challenge should include the recognition that apart from and beyond the scientific challenges that are selected for investigation lie the influence of society. Therefore, funding of research, interpretation of its meaning, and/or translation of its consequences should be considered in the context of other factors that may influence the direction and outcome of the scientific process.

Sensitive Populations (2006–2010) The issue of sensitive populations was recognized as one of significant societal, scientific, and regulatory importance, and is found at several locations on the HESI Combined Challenges Map. Challenges associated with sensitive populations will be discussed in this section only. Sensitive populations can be identified on the basis of age, ethnicity, gender, or genetic polymorphisms. This discussion addresses the latter group. (See also the sections on Aging World Populations and Children’s Health for related topics.) Regardless of the toxicological endpoint, certain individuals are at greater risk than others. The data suggest that the phenomenon of sensitive populations may be genetically based (Blumenthal, 2000; Corsini and Kimber, 2007). Examples of genetically-based differences of clinical significance include susceptibility to malignant hyperthermia (Gronert et al., 1988) secondary to sensitivities in the metabolism of certain anesthetics or succinyl choline, and susceptibility to isoniazid-induced liver toxicity due to differences in rates of detoxification by acetylation (Weber et al., 1983). Such toxicological differences are analogous to individual susceptibility to disease, which has

824

L. L. SMITH ET AL.

been more extensively evaluated (Brown and Hartwell, 1998; Redmond, 1981). Genetic polymorphisms can contribute to human susceptibility to environmental toxicants on the basis of several factors: (a) the frequency of the genotype in the population; (b) the type of genetic abnormality or variation (chromosomal, point mutation, recessive homozygous, recessive carrier, sex-linked, dominant); and (c) whether or not the genetic polymorphism results in a disease state and an increased susceptibility to toxicants. It is likely that the extent of genetic polymorphisms in the general population is much greater than is currently accepted. To better understand genetic polymorphisms, the following factors should be assessed: (a) the severity of the toxic effect; (b) the proportion of the population that is sufficiently highly exposed and thereby potentially susceptible; (c) the ability to diagnose the genetic defect with or without invasive interventional techniques; (d) the pervasiveness of the environmental toxicant; and (e) the ability to control or prevent population exposure. Attempts to identify which individuals are at greatest risk from exposure to drugs or chemicals are on the rise. Members of the general population increasingly want to know their individual susceptibility, and some scientists believe this can be achieved. With advances in sequencing the human genome and the development of rapid, high-throughput screening of genomic sequences, there is the potential, yet to be proven, to evaluate individuals for variations in sequences that are related to differences in particular susceptibilities. This approach involves an understanding of toxicological endpoints associated with specific genes that are involved in pathways targeted by individual drugs or chemicals. These pathways can be involved in regulatory processes, enzyme activation and de-activation, transport mechanisms, and a variety of other biological processes. The completed human genome sequence and its public availability is being used to make significant strides in biomedical research and the translation of that research into improved healthcare and standards of living. Investigators are beginning to catalogue genetic diversity through such sequencing efforts as the International HapMap Project (http://www.hapmap.org/), the PharmGKB (Pharmacogenetics and Pharmacogenomics Knowledge Base) Network (http://www.pharmgkb.org), and a host of individual efforts reported in the literature in databases such as NCBI dbSNP (Sherry et al., 2001). Further, the physiological impact of such genetic diversity (i.e. the expressed phenotype) can vary as a function of age and environment. Additionally, we know very little as yet about the key role played by regions of DNA previously thought not to be transcribed (e.g. regions encoding micro-RNA), multiple transcription start sites within a gene (indeed, the evolving notions as to what constitutes a gene), and heritable epigenetic modifications of DNA that are beginning to be cataloged in a variety of databases, such as the Human Epigenome Project (http://www.epigenome.org/). The complexities of evaluating the possible effects of genetic polymorphisms have become more apparent. With the sequencing of the human genome and the development of high-

throughput technologies, an expectation has evolved in the public and scientific communities that the identification of all polymorphisms inherited by an individual could provide a means of predicting the diseases that an individual will eventually develop. This presumption has turned out to be extraordinarily na¨ıve, and ignores the role of environmental influences, levels of exposure, the issue of concordant and sequential exposure, and the interaction of effects on different pathways. For example, in a study of tumor concordance in twins by organ site, the highest concordance was about 30% (Lichtenstein et al., 2000). For most tissues, the concordance was only 5% or less. There are also difficulties arising from the redundancy of metabolic pathways, multiple isozymes, and multiple steps available that can produce the same metabolic result for a chemical. Enzyme induction or inhibition can greatly alter the consequences of a specific polymorphism. Despite the difficulties, some specific genetic polymorphisms have been detected that can identify certain populations with increased or decreased susceptibility. One well-studied example is fast versus slow acetylators, in which the metabolism of certain drugs is affected (e.g. isoniazid and liver toxicity, certain carcinogens such as 4-aminobiphenyl in cigarette smoke and its relationship to bladder cancer; Cohen et al., 2006). Even for these examples, the influence of specific polymorphisms on biological effects is extremely difficult to identify and verify in epidemiologic studies. Furthermore, high exposure levels can overwhelm subtle differences in metabolic rates due to genetic polymorphisms. The importance of single nucleotide polymorphisms has greatly changed the individual-susceptibility landscape, although the number of actual, documented examples is small. The discovery of new relationships between human polymorphisms and response to toxicants requires the use of clinical assessment, genomic technology, and epidemiology (Burchiel, 2001; Olden, 2004; Patel et al., 2005). The goal of individualized toxicity profiles provides an opportunity to identify those chemicals or drugs that have a specific effect on an individual or group of individuals within the population. To the individual affected, however, the issue is more personal. Will the cessation of exposure to the chemical or drug lead to an amelioration of symptoms and a return to normal, or near normal, health? Establishing a genomic basis for individual susceptibility is a modern approach to an issue that has existed for some time for individuals who take drugs for clinical benefit and for populations exposed to chemicals in the workplace. Some individuals in the workplace can become sensitized to a chemical or chemicals to which they are exposed. The dilemma has been whether to set safety limits for exposure to such chemicals on the basis of the most susceptible individuals in the population or on the basis of how the vast majority of the population responds. In some cases, the individual who develops an adverse response to a chemical in the workplace is moved from the job function to another part of the organization. In other cases, steps are taken to lower the acceptable exposure level of the chemical


in the workplace. The purpose of this action is to protect the health of the individual and reduce or eliminate the company’s liability. Idiosyncratic reactions to pharmaceuticals are rare and generally impossible to identify, given the small number of individuals involved in clinical trials. Once marketed, however, the number of individuals affected, in absolute terms, can be large. For example, approximately 6% of patients occupying beds in the National Health Service in the UK or other European countries were hospitalized because of an adverse drug reaction (Pirmohamed et al., 2004; Wiffen et al., 2002). The cost to society can be considerable, both in terms of individual harm and economic consequence. The difference in societal consequences between events involving chemicals and those involving pharmaceuticals can vary dramatically. Both chemical types provide benefits to society— one through the generation of economic resources and indirect health benefits, and the other through direct improvements in the health of individuals, which in turn can have huge economic benefits to individuals and society. The benefits realized by the large percentage of people taking medicines are generally accepted as outweighing the risks of adverse effects in a very small percentage of the population. With industrial chemicals and pesticides, however, society judges risk differently. Exposure to chemicals in the environment or in the workplace is often perceived as involuntary, compared with voluntary exposure to pharmaceuticals. Clear benefits are not necessarily apparent for the individual at risk. The benefits may be to the employer (e.g. improved yield or productivity), the manufacturer (e.g. increased marketability or profitability of products), or society (e.g. better availability and quality, and lower costs, of consumer products and pharmaceuticals). This difference in societal attitudes is vitally important in the way that chemicals and drugs are regulated. If decision-makers were to move toward absolute safety in the pharmaceutical industry, then a sharp decline in available drugs would result. Fortunately, there is an intuitive, societal recognition that some adverse affects can be tolerated to reap the benefits that drugs provide to the population at large. Similarly, modern society enjoys many benefits that may not otherwise exist if absolute safety of chemicals was required. Some significant issue regarding individual susceptibilities is the potential use or abuse of such information. Although some protection is already provided by law (e.g. Health Insurance Portability and Accountability Act Privacy Rule, Public Law 104–191). In May 2008, the Genetic Information Nondiscrimination Act (H.R. 493) became law. The legislation seeks to protect individuals with respect to health insurance and employment. Nonetheless it is unclear how health-information privacy will be protected as scientific advancements are made. Policies and regulations that protect against insurer discrimination of individuals or populations, as well as provisions for continued access to health insurance when a ‘sensitivity’ or ‘vulnerability’ is detected, are needed. Populations presumed to be ‘sensitive’

825

(e.g. children, the elderly, populations with particular genetic polymorphisms), which are often viewed as particularly vulnerable to environmental toxicants, are a test case for ensuring health-information privacy, which seeks to protect individuals with respect to health insurance and employment. This bill was reported in the US Senate in April 2007 (S. 358, US 110th Congress). The scientific community at large faces an enormous challenge, and will need the help of regulators and legislators to devise fair and equitable mechanisms to protect the privacy of individuals in terms of their genetic make-up, exposures, diagnoses, diseases, and treatment.

Alternative Therapies (2006) The commercial importance of alternative-therapy medical products is growing rapidly. Sales of these products will soon exceed the entire budget of the NIH in the US. The notion that dietary supplements can be introduced and sold to the public without having to demonstrate their safety and efficacy may be considered a major retrograde step in attempts by the US to provide safe and effective medicines for the treatment of diseases. The Institute of Medicine convened a committee of pharmacologists, academics, and members of the alternative medical community to develop a report on alternative medicine (Institute of Medicine of the National Academies, 2005). Although many recommendations were included in the report’s summary statement, there was no recommendation that these supplements should be approved by the US Food and Drug Administration (FDA), nor was there any recommendation that safety and efficacy must be demonstrated. Current US law does not require such an evaluation for supplements, in striking contrast to the strict requirements and regulations for pharmaceuticals, food additives, and many consumer products. In the next 10 years, the controversy over the use of alternative medical dietary supplements must be resolved, because billions of dollars are being spent on ‘medications’ consumed by the public, most with unproven efficacy. More resources are needed to scientifically evaluate the need, safety, and efficacy of any product which claims or infers medical benefits. There is a perception by the general public that all natural substances, such as dietary supplements, are safe, giving rise to their acceptance without the requirement for safety testing. However, natural and synthetic chemicals are handled similarly from a biological perspective (i.e. kinetics, metabolism, mechanisms of toxicity) (National Research Council, 1996). There are several well-documented toxicities associated with the use of alternative therapies (Colson and De Broe, 2005; Duleba et al., 2006; Fraunfelder, 2005; Niggemann and Gruber, 2003; Woodward, 2005), such as severe renal urothelial toxicity and carcinogenicity resulting from the intake of natural weight-loss supplements containing aristolochic acid (Cosyns et al., 1999), and the recently demonstrated association between cardiovascular toxicity and the intake of supplements containing ephedra (Fontanarosa

826

L. L. SMITH ET AL.

et al., 2003). Furthermore, alternative therapies can influence the pharmacokinetics of pharmaceuticals that are also taken by the patient, possibly decreasing the desired pharmacologic and therapeutic effect or increasing the risk of an adverse effect. Nevertheless, given the large number of individuals who make use of alternative medicine, it is surprising that the number of reported adverse affects is relatively small compared with the numbers associated with proven, ethical pharmaceutical products. Of course, the placebo effect for both pharmaceuticals and alternative medicines can be impressive, especially for illnesses or symptoms not based, or not entirely based, on organic disease. From a societal viewpoint, it can be argued that as long as an individual benefits from an alternative therapy, the absence of a pharmacological affect does not matter. However, the problem for the individual (and, eventually, society) becomes significant when the disease to be treated with an alternative medicine has an organic basis, with the likelihood of a serious detrimental outcome. While the psychological benefit from the belief in medicines is real, in the vast majority of cases, organic disease is rarely effectively treated solely on the basis of a patient’s belief that the medicine will be effective. Nevertheless, from a patient’s viewpoint, a placebo effect that makes a real difference to the patient’s feeling of well-being cannot and should not be underestimated. The issue for society is whether the regulation of pharmaceuticals should be based solely on the outcome of well-designed clinical trials. The vast majority of scientists believe that evidence of efficacy is an absolute requirement for the sale of substances that claim medical benefit. This is not just to ensure that there is a real, rather than perceived, benefit, but also to enable a proper risk–benefit analysis to be carried out, on both individual and societal terms. Because the science of medicine is an uncertain process, it is easy to understand why the absence of certainty in medical benefit provides an opportunity for some groups or individuals to claim that alternative therapies provide just as much benefit with fewer adverse reactions. Neither should scientists dismiss the use of alternative therapies on the basis of general ‘scientific illiteracy’. Any therapy, traditional or alternative, to which the public avails itself should be beneficial and without significant risk.

Education of the Public on the Precautionary Principle (2007) There is still considerable misunderstanding on the part of the public and many scientists about the meaning and application of the Precautionary Principle. In part, this is due to the various interpretations of the Precautionary Principle and, more importantly, to differing views about the value and consequences of its application (Commission of the European Communities, 2000; Health and Safety Executive, 2007; Joint Nature Conservation Committee, 2007; Tickner et al., 1998). In 1998, the Precautionary Principle was expressed as follows: “When an activity raises threats of harm to human health or the environment, precaution-

ary measures should be taken even if some cause and effect relationships are not fully established scientifically” (Raffensperger and Tickner, 1999). This principle is sometimes interpreted erroneously as meaning that unless there is confidence that humans (or the environment) will not be harmed by a chemical, the substance should not be used until appropriate evidence of safety is available. However, it was also stated in the origin of the principle that the action to deal with the suspected adverse effect of a chemical should be proportionate to the likely hazard posed by the chemical or substance. This addendum has become the essence of the problem in reaching a consensus on the application of the Precautionary Principle. The Precautionary Principle is a response by policy makers to a perceived threat, when it is deemed that the outcome of a risk assessment is uncertain and the worst-case scenario is considered unacceptable, in either environmental or public health terms. The most scientific approach to the prevention of injury to humans from chemicals or substances is the use of the riskassessment paradigm. Risk assessment considers hazard and the extent of exposure, and has a built-in ‘precautionary’ element in the application of safety factors and the use of worst-case assumptions. Safety factors (sometimes called ‘uncertainty factors’) are used when relying on animal testing to assess the potential for human hazard posed by exposure to chemicals. It is important to ensure that the public is made aware of the substantial efforts that scientists and regulators make (through rational risk assessments) to provide reasonable and meaningful protection of human health and the environment from chemical threats. Communication strategies need to be developed to restore public confidence and promote the view that the scientific process remains by far the most effective way to provide protection and benefit in society. However, it can be expected that poor understanding and inappropriate application of the Precautionary Principle will remain a serious challenge to the risk-assessment process, especially in developed countries, where the acceptance of some minimal risks from everyday activities are poorly tolerated by the public while, at the same time, some serious risks are ignored.

Obesity in the Developed World (2009) The incidence of obesity is reaching epidemic proportions in the developed world (Centers for Disease Control and Prevention, 2007a; Mokdad et al., 1999; National Institute for Clinical Health and Excellence, 2003; World Health Organization, 1998, 2006). In the developing world, the ‘urban poor’ are particularly prone to obesity. Apart from the direct consequences of obesity, there are several diseases indirectly associated with the condition that increase both morbidity and mortality (e.g. diabetes; Manson and Bassuk, 2003; Mokdad et al., 2001, 2003). The causes of obesity are biological and cultural. In evolutionary terms, individuals who could sustain vital functions with minimal food intake would have an advantage. However, this selection process has become counterproductive as high-calorie diets, rich in sugar and fats, became prevalent. Some refer to


these foods as ‘toxic foods’ when they dominate the diet. The other major cause of obesity is insufficient physical activity. In relative terms, the convenient availability of high-calorie foodstuffs is a new phenomenon. Educational programs have not greatly influenced behavior, and the need to select a wellbalanced diet is difficult to convey. Also, there is often a cost associated with ‘healthy diets’ compared with readily available ‘fast foods’. For example, purchasing whole foods or spending greater time in food preparation may be viewed by some individuals as burdensome or even prohibitive. Even when knowledge of a healthy diet is well understood and its rationale is accepted, a change in behavior is not necessarily the consequence. In part, such barriers are cultural, but they are also driven by differences in the genetic expression of recognition of satiety. There is increasing evidence that this genetic component is a key factor in some individuals who are morbidly obese. Attempting to control access to certain foods raises serious questions about the nature and purpose of government in this regard. Disincentives, such as taxation or restriction of access to certain foodstuffs, are an anathema in some cultures. The challenge to medical professionals is also complex. The development of drugs and substances in developed countries that allow the excessive intake of food without the penalty of obesity are, at best, controversial. Progress in the development of pharmaceuticals that reduce appetite has been more encouraging, but even this success depends largely on the compliance of individuals, as well as their physiology and biochemistry. Whether the use of pharmaceuticals or, more rarely, surgical intervention, will become a global phenomenon depends, in part, on a mixture of societal choice and the continued abandonment of common sense. Although eating less and exercising more might be the simple dogma to prevent or tackle the problem of obesity, it must be recognized that the phenomenon of dieting has also been controversial. The range of diets claiming to facilitate the reduction of body weight is enormous. In one sense, diets are almost certain to fail, because without sustained, long-term lifestyle changes, the benefits of dieting are quickly eroded by the return of the psychological and cultural drives that led to obesity in the first place. The science of dieting is not well understood; neither is it a process that is easy to investigate in an entirely objective manner. Consumer-sponsored organizations often test the hypothesis that particular combinations of food may lead to less weight gain, or even weight loss. There is an enormous incentive for consumer companies to demonstrate the efficacy of their products in this process. Even without the intention to promote a particular regimen, there is inevitably some bias in the selection of the diets and their controls, which have the potential to compromise the results. Furthermore, any solution in terms of dietary change must be consistent with societal food-consumption practices. This has particular relevance for those in the developed world where ‘eating out’ or consuming ‘take-away’ pre-cooked food is a culturally accepted practice.

827

A major driver to reduce the prevalence of obesity is likely to be the cost to society. Already, in some countries, clinicians deny treatment to patients who are significantly obese until they demonstrate an active commitment to reducing their weight. The treatment of many associated diseases and their recovery from the treatment is compromised by continuing obesity. In the developed world, it is generally accepted that those who sustain injury from accident and disease through no fault of their own can expect some degree of societal protection. However, attitudes toward obesity are still controversial. Often, there is a clash between personal freedom of expression and the need for the proper use of limited resources in the treatment of disease and ill health. It seems improbable that the problem of obesity can be solved without some change in societal pressure, and the consequent change will have other ramifications in the culture of the societies that introduce it.

Aging World Population (2010) Major changes in the prevalence of diseases in the aging population are occurring over time (Boyle et al., 2001; Centers for Disease Control and Prevention, 2003, 2007b; Cowie et al., 2006; Crimmins and Saito, 2000; Flegal et al., 2002; Majeed and Aylin, 2005; Wilmoth and Longino, 2006). A higher proportion of older patients are now manifesting, for example, obesity, diabetes, and dementia. Degeneration of the central nervous system is also more prevalent, partly as a result of increases in the rates of cure and palliation of cardiovascular disease and cancer. The elderly will continue to be exposed to a larger array of medications, bacterial resistance to antibiotics will make pharmaceutical therapy more complex, and drug toxicity and adverse drug reactions will become more prevalent. An older population with several complex medical problems will result in different susceptibilities to adverse effects from specific environmental chemicals, and each chemical will have to be separately evaluated for this possibility. The problem of the toxicity of mixtures of drugs and chemicals will be important in this population. Society will need to balance the importance of the health and welfare of its senior citizens versus the cost of maintaining them in good health. The very population with the greatest need for expensive medicine and nursing care (with its associated clinical resources) will be the population with the least ability to pay for those resources. Social-services expenditure will increase as people live longer. These societal issues greatly affect how resources will be deployed to target sub-populations for drug development, investigation of dietary supplements, and approaches for avoiding exposure to harmful chemicals. On a global scale, this is an issue that many societies have not yet begun to develop strategies or solutions for, or even faced in most cases.

Scientific Issues (Triangle) The scientific issues ultimately selected for placement on the HESI Combined Challenges Map (Figure 6) were those that

828

L. L. SMITH ET AL.

could potentially be addressed by HESI to some degree over the next 10 years. For each scientific issue on the HESI map, a need exists for mechanisms to address potential risks to humans or the environment on the basis of data from several sources, including epidemiology, animal models, in vitro testing, systems biology evaluations, or in silico investigations. For example, much of toxicology on new and existing chemicals involves screening in a variety of in vivo (MacDonald et al., 2004), in vitro (Kirkland et al., 2007a, 2007b), and in silico (Kollmann and Sourjik, 2007) model systems. This screening approach is generally the basis for hazard identification. Extrapolating conclusions to apply to humans increasingly requires a mechanistic understanding of the observation in the model systems, ultimately leading to a qualitative and quantitative (dose response) assessment of the concordance between the model and humans (Boobis et al., 2006; Meek et al., 2003). Because of the central role of dose response in the assessment of risk, increasing emphasis is being placed on sophisticated exposure analysis. Absorption, distribution, metabolism, and excretion (ADME) and other physiologic factors provide the basis for moving away from administered dose to an assessment of target tissue dose. Development of new testing and assessment frameworks is needed for several toxicological endpoints, including cancer. Emphasis is placed on developing new procedures that can be timelier, that use resources (including animals) more efficiently, and that improve the predictability of effects in humans. There is a focus on possible applications of new technologies, such as the various ‘omics’ approaches, new imaging systems, and improved analytic chemistry techniques. With the development of new technologies, particularly ‘omics’, individual variations in susceptibility can be identified, as can variations in susceptibility at different life stages. Like most of the scientific community, HESI has traditionally focused its attention on the risks of representative individual chemicals or classes of chemicals. The mapping exercise identified several additional types of agents that need to be addressed, some of which require new approaches, such as mixtures, and some that arise from new technologies, such as biologics (monoclonal antibodies, gene therapy) and nanomaterials. The HESI map includes scientific issues that, over the next 10 years, include the application of new technologies for development of better approaches to hazard identification, better predictive ability for assessing human and environmental risk, an improved ability to address variations in susceptibility of the human population, and evaluation of differences in environmental settings. Cancer Testing (2005) Numerous difficulties have been identified with the current use of 2-year bioassays in rodents to predict carcinogenic activity. Obvious issues are cost and time. More important, however, is the concern that such assays are not predictive of car-

cinogenic activity in humans (Cohen, 2004). Long-term rodent bioassays are empirically based, and were developed when little was known about carcinogenesis or the carcinogenic process. Chemical carcinogens were assumed to act by directly damaging DNA, mimicking radiation carcinogenesis. It was also assumed that chemical carcinogens in animal models would be carcinogens in humans (interspecies extrapolation) at any dose (dose extrapolation). Extensive research demonstrates that chemical carcinogenicity assays in rodents are not always indicative of carcinogenic risks to humans. For example, studies in d-limonene (a naturally occurring substance in citrus fruits and other plants) and saccharin (an artificial sweetener) show that cancer in rats occurs by mechanisms qualitatively different from those of humans (Meek et al., 2003). Quantitative differences in response are illustrated by chloroform (a contaminant in water) and melamine (an industrial chemical and pesticide) which produce cancer in rats only at relatively high doses. Exposures to lower levels reflecting actual human exposures are not carcinogenic (Meek et al., 2003). With the development of mode of action and human relevance frameworks by the ILSI Risk Science Institute (Meek et al., 2003) and the World Health Organization’s International Programme on Chemical Safety (WHO/IPCS) (Boobis et al., 2006), a defined process is now available for evaluating the results of the carcinogenicity assays with respect to relevance of cancer risk to humans. Chemicals producing cancer have been divided into DNAreactive and non-DNA-reactive (proliferative and/or epigenetic) modes of action, with significantly different implications for extrapolation to humans. Various approaches are being developed to improve prediction of potential carcinogenic activity, focusing specifically on risk to humans. Fundamentally, these approaches are based on examination of mode of action using shorter-term assays than the standard lifetime rodent bioassays (National Research Council, 2007). In addition to further modifications of existing assays, these approaches incorporate many new technologies and further expand the use of structure-activity relationships. Incorporation of developments in genomics is being intensively investigated for potential application in testing. Such efforts include the development of transgenic and knockout animal models that incorporate information about mechanisms of action (Gulezian et al., 2000; MacDonald et al., 2004), molecularly engineered cell systems for in vitro and in vivo analysis, and application of transcriptomics, proteomics, and metabonomics to focus on better predictive methods based on science, rather than relying on observational testing involved with current rodent assays. Advances in computerized structure-activity relationship analysis are providing rapid and economical predictions of various biological activities, whether they are therapeutic or toxicologic. An urgent need exists to devise new approaches to cancerhazard identification that incorporate developments in the understanding of carcinogenesis based on scientific, mechanistic information rather than on empirically based screening. Validation


of such approaches should not necessarily be judged against the 2-year rodent bioassay, as this assay has been shown to be inaccurate in predicting human carcinogenesis. Tiered Approach to Assessing the Bioaccumulation of Chemicals (2005) Assessing the bioaccumulation potential of chemical substances is an important issue that will affect international chemical management policies and public-health decision making. Further advances in bioaccumulation science are needed to reliably assess this substance-specific property in an efficient manner. To develop effective guidance for a tiered approach to evaluate the bioaccumulation potential of chemicals, international consensus and coordination is necessary. Thousands of commercial chemicals will be prioritized in the near future for their aquatic bioaccumulation potential in North America, Europe, and Asia. Some of these chemicals are persistent, bioaccumulative, and toxic substances. However, only limited bioaccumulation data are available for many chemicals, and the generation of new data using traditional test protocols is time consuming, costly, and requires considerable animal use (Weisbrod et al., 2007). To address the scientific challenges associated with conducting bioaccumulation assessments for these chemicals, there is a need to develop reliable tiered approaches for assessing bioaccumulation potential. Bioaccumulation is the culmination of multiple physiological and physico-chemical processes. Consequently, methods using aquatic and mammalian species that focus on ADME are being explored. New approaches under evaluation include improvement of existing bioaccumulation models; re-application of pharmaceutical models; development of in vitro systems; in vivo invertebrate and vertebrate tests; passive sampling devices; and population-level monitoring of wildlife, humans, and food. Significance of Positive Results in In Vitro Genotoxicity Testing (2005) The number of compounds producing positive responses in in vitro genetic toxicity tests is known to be high, especially in in vitro chromosome-damage tests. Moreover, the proportion of noncarcinogens eliciting a positive response in in vitro genotoxicity assays has been shown to be relatively high, demonstrating the low specificity of these assays (Kirkland et al., 2005). Because it is generally believed that data obtained in vitro demonstrate the intrinsic genotoxic properties of the test compounds, other data, such as results from in vivo tests or mechanistic studies, are needed to help determine the biological significance of in vitro positive results. It is recognized that some compounds are genotoxic via indirect mechanisms (e.g. impairment of the mitotic spindle, interference with protein and DNA synthesis, or imbalance of the nucleotide pool). For these compounds, it is plausible that there exists a threshold concentration or dose below which there is little likelihood of inducing genotoxicity or mutagenicity.

829

Another area of debate is the relevance of positive in vitro test results obtained under extreme experimental conditions (e.g. severe cytotoxicity or high concentrations of the test material that do not reflect anticipated or known human or animal internal dosimetry). There is currently no conclusive threshold or weight of evidence approach, however, that could form a basis for regulatory risk assessment for genotoxic compounds. For a review of the current issues in the field of in vitro genetic toxicity testing, see Kirkland et al. (2007a, 2007b) and Thybaud et al. (2007). The scientific basis for interpreting results from in vitro genotoxicity tests for the purposes of accurate human-health risk assessment needs to be improved. The range of Organisation for Economic Cooperation and Development (OECD) approved genotoxicity tests that is currently used was developed in the 1970s and early 1980s. These tests have become the testing paradigm for determining the genotoxicity of drugs and chemicals. However, in the 25 years since these tests were developed, there has been relatively little development or innovation to provide a better understanding of the precise biological mechanisms through which drugs or chemicals may provoke a positive response. This may, in part, reflect a degree of comfort on the part of regulators and industry with the way in which the results of these tests are handled. This comfort does not provide an incentive to employ new ‘omics’ technologies to the current test systems to generate knowledge or hypotheses about how these tests may or may not be altered to improve their relevance to humans. Follow-up strategies should be developed by the scientific community to determine the relevance of in vitro test results for human health, and a framework should be proposed for the integration of in vitro test results into a risk-based assessment of the effects of chemical exposures on human health.

Children’s Health (2006, 2007) Every society is concerned about the health and survival of its children. From birth to 19 years of age, accidents are the major cause of death and disability (Brent and Weitzman, 2004). Suicide, homicide, and infectious diseases are also serious problems. Although controversial, some evidence exists to indicate that environmental toxicants may be causally related, in part, to the following problems: congenital malformations; cancer; sudden infant death syndrome; respiratory disease; endocrine dysfunction; immunological diseases; growth problems; infections; and diseases of the central nervous system, for example autism, mental retardation, convulsive disorders, and learning disabilities (Bates, 1995; Centers for Disease Control and Prevention, 1997; David et al., 1993; Devesa et al., 1995; Etzel, 1999; Gold et al., 1979; Goldman and Koduru, 2000; Guzelian et al., 1992; Hoet et al., 2000; Holladay and Smialowicz, 2000; Miller, 1995; National Cancer Institute, 1999; Needleman et al., 1990; National Research Council, 1993; Olshan et al., 1993; US Environmental Protection Agency 2004, 2005, 2006, 2007). There is clearly a difference between the spectrum of adult diseases and children’s diseases, and there are many diseases or

830

L. L. SMITH ET AL.

medical problems that occur only in children (Table 1; Brent et al., 2004). To address concerns about the adequacy of risk assessment for children, two initiatives were introduced in the US in 1997 to improve risk assessment in this special population. First, Congress enacted the Food and Drug Administration Modernization Act of 1997 (Public Law 105–115). An important component of the Act is the requirement for drug testing in children and the conduct of clinical trials for life-threatening diseases. The second initiative was Executive Order 13045 signed by the US President entitled ‘Protection of Children from Environmental Health Risks and Safety Risks’. The Order states that “. . . each Federal Agency . . . shall make it a high priority to identify and assess environmental health risks and safety risks that may disproportionately affect children . . . ” In 2000, a third initiative was enacted with the passing of the Children’s Health Act of 2000 (Public Law 106–310) to support The National Children’s Study, which is a national longitudinal study of environmental influences on children’s health and development. The Best Pharmaceuticals for Children’s Act (Public Law 107–109) was enacted in 2002, followed by the Pediatric Research Equity Act (PREA, Public Law 108–155) in 2003. Although certain human teratogenic agents are well recognized, in general, the evaluation of health risks in children from environmental and therapeutic exposure is problematic. Many chemicals are tested in toxicology studies in pregnant and adult animals; however, there is still a relative paucity of animal studies utilizing infant and juvenile animals. This deficiency is compounded by the fact that very few clinical studies are conducted in children (Children’s Health Act of 2000, Public Law 106– 310), due in part to ethical concerns. Three specific areas of concern exist when considering the adequacy of risk assessment for children: (a) the understanding of pharmacokinetics in children, which is an essential cornerstone of risk assessment, may be lacking and is often extrapolated from adult exposures; (b) the understanding of mechanisms of action in children may be poor and also inappropriately derived from adult risk assessments; and (c), perhaps of primary concern, the understanding of the potential for adult disease consequent to childhood exposure to environmental and therapeutic agents is lacking. These three specific areas of concern are directly applicable to understanding children’s susceptibility to environmental toxicants: exposure sensitivity; behavior and physiological differences; and ongoing development. Exposure Sensitivity. Are children universally more sensitive to environmental toxicants than adults when exposures are equivalent (US Environmental Protection Agency, 2004)? Data exist to support the conclusion that exposure that may be innocuous to an adult may have a deleterious effect on an infant or child. However, while many studies reveal that the infant and developing animal are more vulnerable to the toxic effects of certain environmental chemicals, other studies indicate that the infant and developing animal may be less vulnerable and more

resilient to other chemicals on a toxicokinetic basis (Brent et al., 2004). Behavior and Physiological Differences. Does the behavior and physiology of children increase their risks from exposures to environmental toxicants (Etzel, 1999; Guzelian et al., 1992; National Research Council, 1993)? •

Infants may be exposed to environmental toxicants to a greater extent because they put items in their mouth and crawl on the floor. • Adolescents are risk-takers and act impulsively, resulting in accidental injuries and death. Adolescents may also take up smoking and drug experimentation. • Physiologic differences and deficiencies in kidney function, respiration, metabolism, and liver function have been assumed to indicate that children are more vulnerable from toxicant exposures. Actual scientific studies to determine whether the physiologic differences increase or decrease the vulnerability of children are deficient due to lack of rigor. Ongoing Development. The ongoing development of organs and tissues increases children’s risks from exposures to developmental toxicants in the following areas (Brent et al., 2004): •

linear growth and bone maturation; maturation of the immunological system and immunologic and allergic reactions to environmental agents; • endocrine organ maturation and development; • maturation and development of the central nervous system; and • enzymatic maturation and function of the liver and other organs. •

There is no doubt that the most important explanation for why children may be preferentially at risk from exposure to environmental toxicants is that organs and systems are developing from birth through adolescence. The major factor is not that children’s increased sensitivity to environmental toxicants per se makes them so susceptible; rather, it is children’s vulnerability due to ongoing development. In the context of risk assessment applied to the administration of therapeutic agents to children, pediatric patients may not be classified arbitrarily as a universally susceptible population, but, certainly, as a population that is different from adults. Inadequate information for this population has led to the off-label use of a majority of all prescription medications. Developmental differences in all components of drug disposition, including absorption, distribution, metabolism, and excretion, have been characterized. Of the various ADME studies, the ontogeny of metabolism, particularly tissue-specific metabolism, is the most complex (Ginsberg et al., 2004; McCarver, 2004). For some drugs, developmental differences result in increased toxicity or failed efficacy; however, in others, decreased toxicity has been demonstrated (Brent, 2004; Brent et al., 2004; Done, 1964).


831

TABLE 1 Diseases that occur primarily in infancy, childhood, and adolescence (Brent et al., 2004). Tumors (malignant Acute lymphocytic leukemia (predominantly in children). Other malignancies of the white blood cells in and non-malignant) children and adults. Accounts for 30% of all childhood cancers. Adenocarcinoma of the vagina from prenatal exposure to diethylstilbestrol (DES). Cancer occurs primarily in adolescence. There is a 1:1,000 to 1:10,000 risk of exposures in pregnancy. Astrocytoma (brain tumor). Ependymoma and choroid plexus tumors (brain tumor). Ewing’s sarcoma (bone tumor). Accounts for 1% of childhood cancers. Glioma. Hemangioma (benign congenital vascular tumors). Accounts for 2% of cancers in infants and children. Lymphangioma (benign lymphatic growths)—rarely invasive. Medulloblastoma (brain tumor). Brain tumors account for 22% of childhood cancers. Neuroblastoma. Accounts for 7% of childhood cancers. Non-Hodgkin lymphoma and Hodgkin lymphoma. Occurs in adults and children, but more common in young adults and those over 55. Accounts for 4% of childhood tumors. Burkitt lymphoma. Osteogenic sarcoma. Rarely occurs in the aged with Paget’s disease. Accounts for 2% of childhood cancers. Pontine glioma (very rare). Rhabdomyosarcoma. Accounts for 3% of childhood cancers. Retinoblastoma. Genetically transmitted and due to new mutations. Accounts for 3% of childhood cancers. Sacrococcygeal teratoma and other teratomas. Risk of malignant degeneration. Thymoma. Wilm’s tumor. Accounts for 6% of childhood cancers. Infections E. coli urinary tract infections, septicemia, or meningitis (newborn or infancy). Bronchiolitis (viral infections; a disease of young infants). Croup (inflammation of the epiglottis due to infection, allergy, or trauma). Group B streptococcus septicemia, pneumonia, meningitis, and osteomyelitis (risk of neonatal death; vaccine has been prepared). H. influenza type B epiglottis or meningitis (almost eliminated by vaccine). Other diseases Caloric insufficiency due to ‘failure to thrive’ resulting in neurocognitive impairment. Congenital malformations that are not diagnosed at birth and are not recognized until infancy or childhood (e.g. craniosynostosis). Colic. Cow’s milk allergy (genetic susceptibility). Disuse amblyopia (disease of early childhood) Febrile seizures (multiple causes). Henoch Sch¨onlein Purpura (autoimmune disease). Idiopathic intussusception in young children (multiple etiologies). Impaired language development due to deafness. Increased susceptibility to caries due to exposure to environmental tobacco smoke (ETS). Infant botulism in early infancy because of low acid stomach secretion (spores not destroyed). Kernicterus (hyperbilirubinemia with staining of the basal ganglia)—cerebral palsy, deafness. Mental retardation due to hypothyroidism. Necrotizing enterocolitis (prematurity). Pyloric stenosis (genetic and environmental). Respiratory distress syndrome (increased risk in diabetic mothers; Caesarean section). Retinopathy of prematurity (high oxygen exposure). Salter Harris fracture. Sudden Infant Death Syndrome (unknown etiology). Transient tachypnea of the newborn. Note: There are many diseases that occur exclusively or predominantly in infancy or childhood. Some of these diseases could be caused by environmental exposures (e.g. DES exposure during pregnancy or high levels of oxygen in premature babies necessitating respiratory support). The largest group of diseases includes malignant or benign tumors of infancy and childhood. Some of these malignancies are due to an inherited mutation or chromosome abnormality. If a second mutation is necessary for the tumor to develop in childhood, it is not understood why these malignancies stop occurring in late adolescence. The etiology of many of these diseases has not been definitively determined.

832

L. L. SMITH ET AL.

Pediatric populations may also experience ineffective dosing with therapeutics known to be effective in adults because of the lack of pharmacokinetic or mechanistic data in this population. A lack of formulations suited to pediatric administration has also restricted the use of some therapeutic agents in this population. Many knowledge gaps in developmental pharmacology and toxicology persist; however, recent FDA regulatory action is likely to assure the continued accumulation of pediatric therapeutic data. Through the Best Pharmaceuticals for Children’s Act, these data gaps are being addressed via exclusivity and patent protections, as well as via a mandate for an Office of Pediatric Therapeutics. As a result, pediatric labeling now exists for a substantial number of therapeutics. The PREA provided additional impetus by requiring the study of off-patent biologics and drugs in children except in defined situations and by creating a Pediatric Advisory Committee. The PREA allows for extrapolation from adult data with appropriate supplemental pharmacokinetic, pharmacodynamic and safety data, and for extrapolation from one age group to another. In summary, the effect of therapeutic or toxicant exposures during childhood may have an impact on the occurrence, onset, and severity of adult diseases. The most important perturbations that can affect health are effects that will compromise growth or the immune, endocrine, respiratory, or nervous systems. Childhood exposures could have effects that last or are delayed into adulthood; however, the magnitude of such effects is unknown. These theoretical risks necessitate studies to determine the impact of childhood exposures on the incidence, onset, and severity of adult diseases, such as cardiovascular diseases, cancer, and neurological diseases that may have their initiation in childhood exposures.

Mixtures and Co-exposures (2006, 2009) Toxicology has traditionally focused on evaluation of individual chemical exposures. However, exposures to one chemical can occur simultaneously with exposures to many different chemicals, sometimes of similar chemical class, but often of other chemical classes. Moreover, human exposures to chemical mixtures occur through a variety of routes (i.e. dietary, dermal, and inhalation) and to thousands of naturally occurring chemicals. Exposures to certain mixtures are well known to cause toxicologic manifestations, such as the effect of cigarette smoking on inflammatory, functional, and neoplastic changes in the lung. Frequently, it is not clear, however, whether a mixture caused the toxicologic effect, or whether an individual component of the mixture or a subset of components caused the effect. Furthermore, the interactions of chemicals within a mixture or with other chemicals to which an individual is exposed are frequently unknown. The assumption is often made that interactions of chemicals with known effects, especially if they have similar toxicologic effects, are additive or possibly synergistic. However, numerous examples have been identified in which chemicals with known toxicities behave quite differently

within a mixture or, in co-exposures, act antagonistically, rather than in complement with each other. The need for better toxicologic evaluation of mixtures, including an emphasis on possible effects at realistic levels of exposure, is of increasing importance, and requires several avenues of investigation to enhance the prediction of toxicologic manifestations of mixtures. An obvious first step is to improve the chemical analysis of mixtures. Sophisticated technologies, particularly focusing on mass spectrometry and various types of chromatography, provide extremely sensitive techniques for identifying components of mixtures. In vitro and in vivo test systems are needed that can evaluate mixtures or co-exposures in their entirety, as well as the interactions of specific components. Unlike the evaluation of most environmental chemicals, which are tested at high doses, the evaluation of potential interactions of various components of a mixture should include doses at the no-observed-effect level, no-observed-adverse-effect level, and the lowest-observed-effect level, and an emphasis on the effects, if any, at doses that might result from levels to which humans are realistically exposed. When similar mechanisms of actions are known to exist, it is often appropriate to accept the default assumption of additivity to evaluate the components of chemical mixtures in their combined state. Even this assumption, however, has been called into question through the use of ‘omics’ technology. Mixtures continue to be a major challenge for establishing a scientific basis for performing risk assessments for environmental chemicals. In nearly all such cases, default assumptions are relied on, despite numerous examples of chemical interactions producing different effects than would be expected from the toxicology of the individual components. Drug interactions, on the other hand, are probably the best known and studied, with one drug affecting the metabolism, kinetics, or even the pharmacological effect of another drug. Default assumptions are not typically needed due to the routine collection of ADME data. Evaluation of a mixture in toxicological tests is sometimes possible, such as in the testing of flavor extracts. In these circumstances, a sufficiently high dose can be administered to adequately establish a substantial margin of safety. Furthermore, the composition of such a mixture can be analyzed in detail, thus gaining an understanding of the toxicology of the components as well as the entire mixture. Such possibilities, however, are seldom realistic. Complicating risk assessments of mixtures is the difficulty of establishing the relevance of in vitro and in vivo models to the prediction of actual risk for humans. The potential for chemical interactions also considerably influences the design and interpretation of epidemiologic investigations. The need for scientific investigations of mixtures is viewed by HESI as one of the major challenges of the next 10 years.

Sensitive Populations (2007) Sensitive populations are represented on the HESI Combined Challenges Map in several locations. For a discussion of the


challenges associated with sensitive populations, see the Sensitive Populations (2006–2010) subheading in the Societal Issues section.

Predicting Idiosyncratic Reactions (2008) Adverse effects resulting from administration of drugs can be considered predictable (high incidence, dose-related) or unpredictable (low incidence, may or may not be dose-related). Unpredictable adverse effects may be further categorized into those that are clearly immune-mediated and those that are considered to be idiosyncratic. Idiosyncratic toxicities by their very nature, therefore, present both a human health risk and a challenge to the development of safe, novel pharmaceuticals. Idiosyncratic toxicities can affect any organ system; however, hepatotoxicity is perhaps one of the most widely studied unpredictable adverse effects, and may present as severe disease with a long latency period (up to 12 months). This presentation is generally considered to represent a manifestation of specific characteristics of the drug (such as the capacity to form reactive metabolites and deplete glutathione reserves) and an individual’s response to the drug (such as metabolic variability or inflammatory cytokine status). Preclinical models are generally recognized as not capable of detecting idiosyncratic hepatotoxicity, and pre-marketing clinical trials may not be sufficiently powerful to detect such low-incidence effects. Progress has been made in identifying assays or endpoints that provide insight into characteristics of pharmaceuticals that may contribute to idiosyncratic toxicity, and in predicting individual variability in ADME characteristics, but an extensive, coordinated effort between preclinical and clinical sciences is required to provide additional insight into idiosyncratic responses in patients.

‘Omics’ and Bioinformatics (2008) The ability to differentiate a physiological change (i.e. adaptation) from a toxic effect is one of the most important questions faced in toxicology. Indeed, the ability to answer this question when dealing with results of standard toxicity evaluations in whole animals is often less than satisfactory. Attempts to make this distinction when dealing with ‘omics’ data (e.g. transcriptomics, metabolomics, and proteomics) are particularly challenging. To achieve this goal, a substantial amount of work lies ahead. In particular, a concerted research effort needs to be focused on linking ‘omics’ changes to fundamental biological processes and pathology to understand the toxicological significance of observed changes in an ‘omics’ parameter (Pennie et al., 2004). For example, the simple observation that there is a change in gene expression should not be equated with toxicity. The importance of performing experiments that employ realistic doses, rather than high doses aimed solely at producing an effect, cannot be overemphasized. Performing exploratory research involving a partnership of government, industry, and academia will maximize chances for success.

833

‘Omics’ are high-throughput technologies designed to evaluate hundreds or thousands of parameters simultaneously, producing an enormous amount of data that can frequently be unwieldy and difficult to manage, statistically evaluate, or interpret. Several ‘omics’ technologies have been developed, including gene expression, protein expression, and metabolic profiling. Additional variations continue to be developed, such as epigenomics, DNA methylation status (part of epigenomics), protein phosphorylation (part of proteomics), and others. Initial claims for these technologies have been tempered by investigations demonstrating the limitations of the methods. Issues such as sensitivity and specificity become paramount when using these technologies for screening purposes. Other variables, such as strain of animal, diet, time of day and feeding schedule, have been identified that can greatly influence results and, consequently, interpretation. Undoubtedly, these technologies have much to offer in terms of mechanistic understanding and potential identification of useful biomarkers. Regardless of the application, however, grounding in basic biology is essential for the proper use of these technologies, specifically when used in combination with more traditional disciplines such as pathology, biochemistry, genetics, and pharmacology. To avoid being seduced by technology, adherence to basic biology and the scientific method will guide their proper application. Public discussions across sectors on the application of these technologies for risk and safety evaluation are also critical to build consensus on scientifically valid approaches to interpretation of these data. As an example, HESI activities in the genomics arena have produced novel, publicly available data sets that have provided “a unique opportunity for the integration and distillation of this collective experience for the benefit of the regulators and regulated industries, as well as for the toxicology community as a whole” (Pennie et al., 2004).

Sensitive Populations (2009) Sensitive populations are represented on the HESI Combined Challenges Map in several locations. For a discussion of challenges associated with sensitive populations, see the Sensitive Populations (2006–2010) subheading in the Societal Issues section.

Environmental Toxicology (2010) The field of environmental toxicology is based on a foundation of basic principles of toxicology and environmental fate and transport. A key focus is on the potential effects of environmental pollutants on ecosystems, populations, and communities, rather than on individuals. Several scientific challenges are unique to environmental risk assessment and its goal of protecting these highly diverse and variable systems. With the passing of new regulatory legislation (such as REACH), which requires an increasing number of environmental risk assessments, the development of novel and sometimes complex scientific methods and

834

L. L. SMITH ET AL.

models is on the increase. One such challenge is the definition of appropriate test organisms. Unlike human-health risk assessments, for which there is a single species of interest, environmental risk assessments aim to estimate the risk to a multitude of species, using only a handful of toxicity tests. Additionally, the methods currently employed to conduct environmental risk assessments do not take into consideration a particular chemical’s mechanism or mode of action. The development of revised or additional testing guidelines and strategies, in conjunction with more advanced methods for data interpretation (such as probabilistic modeling), would improve such assessments. The recent discovery of previously unidentified potential stressors (such as human and veterinary pharmaceuticals) at very low levels in the environment demonstrates the need for further work in establishing the methodology and developing the critical thinking that is necessary to accurately predict the potential for environmental risks (Daz-Cruz et al., 2003; Dorne et al., 2007; European Medicines Agency, 2005). Regulatory Issues (Hexagon) In the developed world, societal pressure, coupled with scientific challenges or advancements, usually result in policy development, regulation, or legislation. Decision-making may be driven by knowledge from past experience, societal demand, presence or absence of scientific knowledge, political pressure, economic considerations, foresight, and even fear. No matter how or why the issue arises, regulation, once set in place, is not quickly modified or revoked. Consequently, it is imperative that decisions regarding human health and the environment are made in the context of all available scientific information. Decisions (e.g. guidance, policy, regulations, or legislation) should be structured to accommodate dynamic populations, environments, and economies, and should incorporate flexibility to allow for modifications based on new scientific information. Although much of what is discussed in this section generally holds true for the regulation of pharmaceuticals, environmental chemicals, pesticides, and other agents, the foundation for regulation in each industry differs. For example, regulation of pharmaceuticals is aimed at ensuring the safety, as well as efficacy, of therapeutic agents, and thus requires a risk–benefit assessment. It may be acceptable from a general societal perspective to assume a certain degree of risk from drug intake, if the benefit provides sufficient justification for that risk (although, increasingly, this perspective is challenged from the viewpoint of the individual). However, for environmental chemicals, the focus of regulation is largely on risk alone because benefits are not readily apparent. Low levels of chemicals in the environment are often regulated because of powerful societal expectations of little to no risk. (See the introduction to the Societal Issues section for a discussion about the influence of societal pressures on science and regulation.) Before HESI embarked on its mapping exercise, it solicited broad input on issues of concern (Appendix 2). At the 2004 Scientific Mapping meeting, participants filtered the initial, compre-

hensive list to arrive at a core group of critical ‘regulatory issues’ for HESI consideration over the next 10 years: (a) the implementation of large screening and data-collection programs, such as REACH and DSL (the Canadian Domestic Substances List under the Canadian Environmental Protection Act); (b) the quality and impact of increasingly available exposure data and models for risk assessment of chemicals and regulatory purposes; (c) incorporation of new technologies into safety-assessment strategies; (d) the challenge of transitioning new science into national, regional, and international regulations and guidelines; (e) the need for high-quality data to support risk assessment, and, when not available, reasonable uncertainty factors to bridge data gaps; and (f) concerns about fair and equitable protection of the privacy of individual health information. These issues necessarily include societal and scientific components, and some have already entered the realm of debate, where risks, benefits, resources, and politics are playing significant roles. In all cases, HESI perceives a need for global dialogue and harmonization among scientists, decision-makers, and the public. By taking this approach, decisions can be made that are scientifically sound and that provide profound benefits to society.

REACH and DSL (2005, 2010) The global use of chemicals has prompted the development of national, regional, and international safety-assessment initiatives. Two such programs are the EU’s chemicals policy, known as REACH, and Canada’s DSL (Environment Canada, 2006; European Commission, 2006; Greim et al., 2006). The objective of these programs is to screen large numbers of chemicals for the purposes of hazard identification. Compounds of concern identified from the screening process are then evaluated for human-health and environmental risks. REACH and DSL will require chemical companies to provide information to international government agencies on existing chemicals that are manufactured or processed in, or exported to, the EU and Canada (Environment Canada, 2006; European Commission, 2006). To meet this challenge, communication and education about the requirements of these regulations are necessary. One mechanism for achieving this objective is the organization of technical workshops with participants from government, academia, and industry from affected regions and countries. This approach will help to harmonize chemical assessments for global use and bridge the gap between different assessment cultures and their methodologies in the evaluation of chemicals. Because a limited number of validated alternatives to animal testing are available, it is impractical to retrospectively test every chemical entity for its complete toxicological and ecotoxicological properties in animal studies. Hence, prioritization strategies can help to determine which chemicals need additional data gathered about them. Once high-priority chemicals have been identified, a tier-based approach to gathering data can be implemented. REACH and DSL incorporate examples of this type of approach. With REACH in the EU, tier-based decisions


will be made on the basis of production volume and exposure information. The newly established European Chemicals Agency will soon propose criteria for prioritization. Under the Canadian Environmental Protection Act, all 23,000 substances on the DSL must be ‘categorized’ (a priority-setting mechanism) according to potential for exposure, persistence, bioaccumulation, or toxicity (Environment Canada, 1999). Prioritization of chemicals under both REACH and DSL is followed by additional screening and data collection. Programs like REACH and DSL are designed to protect human health and the environment by identifying and prioritizing potential hazards. These approaches, nonetheless, will require significant investment of resources to ensure compliance and harmonization across international boundaries. To implement these programs successfully, the global community must engage in effective communication, outreach, and dialogue. As prioritization gives way to data requirements, the need for harmonized approaches to tiered testing schemes and testing alternatives will become important.

Exposure Inputs to Risk Assessment and Regulation (2005, 2010) Imprecise estimates of exposure are a major limitation in the risk assessment of chemicals (Nieuwenhuijsen et al., 2006; Ritter and Arbuckle, 2007). Useful information on individual exposure and the actual (background) exposure of the general population can be obtained via biomonitoring measurements. However, several limitations need to be considered. For example, in biologic samples, it may be difficult to characterize exposure to chemicals with short residence times in the body. Moreover, a distinction between contributions from natural versus man-made sources and the different routes of exposure, such as inhalation or dietary intake, is needed. Confounding factors such as toxicokinetic variability over time may result in a weak association between environmental measurements and target tissue dose. Health consequences may depend on developmental stage or age, requiring exposure characterizations at multiple time points (Albertini et al., 2006; National Research Council, 2006). Exposure to a compound, particularly at low levels, does not necessarily result in toxicity. Toxicity testing that is prioritized on the basis of high-quality exposure data results in an appropriate focus on toxicological study design and human exposure durations that are relevant for risk assessment, thus avoiding unnecessary testing and reducing the number of animals needed for testing. Pharmacokinetic modeling based on exposure and dose information from human biomonitoring programs, as well as dosimetry data from animal studies, are useful tools to improve exposure and risk assessment. To improve the quality of exposure data, serious methodological deficiencies must be addressed, including the lack of practical, cost-effective measurement techniques, the lack of validated methods for measuring relevant exposure and total dose data directly from biological samples, and the lack of suffi-

835

ciently precise exposure assessment in epidemiologic studies. If a high priority is placed on engagement of international experts in multidisciplinary, multi-sector scientific discussions on improvements to exposure analysis for risk assessment purposes, harmonized guidance and methodologies will be forthcoming (Doerrer, 2007).

New Technologies (2005) New technologies (e.g. products and methodologies) can be catalysts for improved risk-assessment approaches, and can lead to enhanced products that pose fewer intrinsic risks. Despite their promise, however, public acceptance of these new technologies is typically cautious. Regulatory and industrial perspectives on new technologies often vary, depending on anticipated potential and past experience. Challenges begin in the research and development phase, and continue as new technologies are introduced. Examples of promising, new technologies are identified below. Although not comprehensive, this list demonstrates the wide range of research areas and practical applications in which new technologies are emerging. Improved testing procedures: •

•

•

•

• • •

bioinformatics and in silico tools (Kollmann and Sourjik, 2007; Loging et al., 2007; Mayne et al., 2006; Schuster et al., 2006); toxicokinetic and pharmacodynamic modeling used to extrapolate data from animals to humans (improved methods for understanding the mechanistic underpinnings for toxic injury); better in vivo assays for evaluating the impact of xenobiotics on biological systems, such as the use of transgenic laboratory animals for assessing the carcinogenic potential of human chemical exposures (Gulezian et al., 2000; MacDonald et al., 2004); the use of genomics to explore the relationship between altered gene expression and the characteristics and impact of human chemical exposure or pharmaceutical exposure; platform standardization; development of improved analytical measurement capabilities; and novel imaging technologies for better understanding drug distribution and in situ biomarker expression.

New technologies: • •

high-yield, genetically modified crops; crops that do not rely on commercial herbicides or pesticides; and • use of nanotechnology in commercial products, energy generation and distribution, food processing, building construction, and environmental remediation (Holsapple et al., 2005; Thomas and Sayre, 2005).

836

L. L. SMITH ET AL.

All new technologies have associated challenges. In the context of risk assessment, many new technologies are not easily included in standard test paradigms, nor are the results of some new technologies easily interpreted. For example, does a noobserved-effect level that is determined by new analytical technology qualify for regulatory purposes? Do the effects identified using new technologies represent true toxicity, or does adaptation exist? What is the relevance to human health of sensitive or novel endpoints identified using these approaches? With foresight and cooperation among all interested parties, new technologies could have profound benefits. To achieve this objective, regulatory acceptance of test strategies using novel endpoints identified via new technologies should be preceded by validation, communication, and education to improve human health and environmental safety. New technologies that represent measurable improvements to, and, where possible, replacements for, traditional approaches will ultimately enjoy the greatest success.

Transitioning New Science into Regulations and Guidelines (2006, 2007, 2008) Governments have varying decision-making processes and requirements for human and environmental health and safety that are often inconsistent across borders. This makes it difficult for global industries to maintain current knowledge about and compliance with national, regional, and international requirements for chemical and pharmaceutical toxicity evaluation. Posing an even greater conundrum is the advent of new technologies and alternative approaches to traditional methods. To date, it is not clear how a company or government can reasonably keep pace with scientific advances, neither is it clear when new science should become incorporated into, or rejected for inclusion in, regulations and guidelines. In an ideal world, new scientific advances would be translated into formalized test protocols that become internationally accepted, adopted by regulators, and used by industry and other research institutions. The rationale for rejecting new scientific advances would be made transparent via formal communication. In reality, a lengthy process is required to determine the appropriate use of and specific need for a novel test method or endpoint before it can be used in the regulatory decision-making process. The process of validation involves demonstrating that a novel test method or endpoint meets stringent criteria for test method performance, the use of reference agents, the identification of limitations of the test method, comparisons of method performance with existing methods, and the publication of methods and results in peer-reviewed journals. Internationally, the OECD is generally accepted by regulators as the institution that approves validated toxicity-testing protocols. However, for a specific test to be accepted by OECD, it must meet validation requirements that include a demonstration of its overall reliability in predicting very few false negatives

and relatively few false positives. This process takes many years and, depending on the nature of the test, involves research institutes, academia, industry, and other organizations, such as ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods) and ECVAM (European Centre for the Validation of Alternative Methods).2 ICCVAM defines detailed criteria, in addition to criteria for regulatory acceptance, and seeks to encourage the development of new and revised test methods that will “improve assessment of the potential toxicity of various agents to human health and other organisms in the environment”, and to “reduce animal use, refine procedures involving animals to make them less stressful, and replace animals in toxicology tests where scientifically feasible and practical” (Interagency Coordinating Committee on the Validation of Alternative Methods, 2007). ECVAM seeks to “promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences, through research, new test development and validation, and the establishment of specialized databases, with the aim of contributing to the replacement, reduction and refinement of laboratory animal procedures” (see the ECVAM website, http://ecvam.jrc.it). The international scientific community should play an active role in ICCVAM and ECVAM activities that focus on the applicability of animal testing alternatives. Even on completion of the lengthy validation process, regulators must determine whether a given test can fulfill countryspecific or region-specific regulatory mandates for specific substances. The entire validation process operates within timelines that are quite independent of advancements in science, and often cannot accommodate the inevitable modifications of technology and test methodology. Successful efforts to transition science into regulations and guidelines will have profound scientific and economic impact. Improvements to the speed and effectiveness of acceptance of new test methods and risk assessment will remove disincentives to innovation. More importantly, a flexible, scientific approach to acceptance of novel test methods will enhance protection of human health and the environment. An enhanced emphasis on a tripartite approach involving government, industry, and academia is necessary to transition new science into regulations and guidelines. Challenges will include: (a) avoiding the adoption of new test requirements without scientific review and validation; (b) focusing on replacing current tests with approaches that can provide more useful data; (c) juxtaposing current test requirements with current science and removing tests which no longer appear to be appropriate; and (d) dealing effectively with the issues of validation, particularly the current lengthy process of validating a proposed toxicity test which can act as an impediment to innovation.

2 It

is not the purpose of this paper to evaluate the procedures, value, or effectiveness of ICCVAM and ECVAM.


Conservative Default Factors, Data Quality (2008, 2009) Data quality is viewed as the scientific confidence in and credibility of a set of empirical data. Information to be considered as part of a data quality evaluation includes, but is not limited to, the following points. • •

Was the chemical subject to prioritization or screening? Are mechanistic or mode-of-action data available, and have these data been incorporated into the evaluation? • How can animal and human data be ‘bridged’ to better identify biomarkers of both exposure and effect in animals, compared with humans? • Have peer-reviewed, scientific publications been weighted appropriately against ‘gray’3 literature? • When is the quantity of data sufficient to make an evaluation or an assessment? In the absence of adequate information, the use of conservative default factors is reasonable and desirable for protection of public health. However, the available database must be evaluated first, followed by decisions to apply uncertainty factors to bridge data gaps. Moreover, when new scientific information becomes available, these uncertainty factors should be modified appropriately (Dourson et al., 1996). Among other types of data, human data (e.g. toxicokinetics, biomarkers of exposure, and cross-species mechanism-of-action data) provide the ability to test the validity of conservative default factors and to modify them, if appropriate. Clearly, all testing in humans must be accomplished under well-controlled conditions, pursuant to a scrupulous review by a committee on the use of human subjects in research. In addition, valuable human data (e.g. blood levels) may be obtained from individuals who are exposed to compounds of interest during the course of normal, everyday life. These studies also require review by a committee on the use of human subjects in research prior to being initiated. Among the legislative mandates that require the use of uncertainty (or safety) factors is the Food Quality Protection Act (Public Law 104–170) of 1996. The goal of this Act is to provide special protection for infants and children against pesticides, by introducing a 10-fold safety factor in the risk assessment. Safety factors are also used in other areas to account for interspecies and intraspecies differences. For example, the FDA’s guidance on Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (2005) also recommends a default safety factor of 10, to allow for variability when extrapolating from animal toxicity studies to studies in humans. Circumstances under which the safety factor should be increased or could be decreased are also considered (US Food and Drug Administration, 2005). The scientific basis for the application and extent of such safety factors, however, has been questioned. A concern exists that the introduction of one—or, 3 Gray literature typically includes documents not published in scientific peer-reviewed journals, such as reports, fact sheets, newsletters, theses, dissertations, working papers, and the like.

837

particularly, more than one—safety factor can result in an undue level of conservatism in the risk assessment that is inconsistent with knowledge about the scientific relevance of the toxicity data for humans. High-quality data enhance science-based safety assessment. When good data are available, it becomes clear that science has a constructive impact on policy and decision making, resulting in the development of a rational regulatory framework that is protective of human health. Achieving this goal will require a strong emphasis on the tripartite approach, involving participation of scientists from government, industry, and academia. Sensitive Populations (2010) Sensitive populations are represented on the HESI Combined Challenges Map in several locations. For a discussion of challenges associated with sensitive populations, see the Sensitive Populations (2006–2010) subheading in the Societal Issues section. GENERAL DISCUSSION Scientific mapping is a useful tool for identifying issues that are, or are likely to become, highly relevant for an organization seeking to understand its existing and future landscape. HESI recognized that its mapping exercise would result in a reflection of its own interests, as well as the scientific and cultural mores of the organization and its membership. To broaden the array of issues to be considered, HESI sought input from a large and diverse group of scientists representing multiple sectors, including government, academia, and industry, to identify issues of general importance for the future of health and environmental safety assessment (Appendix 1). Subsequent to this comprehensive collection of issues, a smaller group of invited representatives from government, academia, and industry made the selections that appear on the HESI Combined Challenges Map (Figure 6). Since 2004, the mapping exercise has contributed significantly to HESI’s strategic planning, and enabled the organization to apply its limited resources to high-priority scientific issues in a relevant and timely way. Several issues that were identified during the 2004 mapping exercise have been added to the HESI scientific portfolio in recognition of their importance to the HESI constituency. Active committees have been formed on cancer-hazard-identification strategies, risk assessment of mixtures, safety assessment of nanomaterials (a ‘new technology’), and risk assessment of sensitive populations, all of which are represented on the HESI Combined Challenges Map. In 2007, the HESI Combined Challenges Map was updated and supplemented by key groups involved in strategic planning for HESI. New issues (e.g. bioaccumulation of chemicals and the significance of positive results in in vitro genotoxicity testing) were added to the map and undertaken as new project initiatives by HESI. Integration of the HESI Combined Challenges Map and stewardship of the HESI scientific portfolio remains a work in progress for the organization.

838

L. L. SMITH ET AL.

Appendix 1 is likely to be most useful to readers with an interest in the breadth of insights collected in the early phases of mapping. Each of these diverse issues is important to health public health or the environment; however, for HESI as an organization, many issues were not ranked as high-priority concerns. Since the 2004 meeting to create the HESI Combined Challenges Map, additional issues of societal, scientific, and regulatory importance have arisen which are not captured in Appendix 1 (e.g. Asian flu, climate change, water shortage, biofuels, and feed and food yield requirements). These and other issues would probably appear on a comprehensive list of issues if a similar mapping exercise was conducted today. The identification and prioritization of issues that may be important in the future is always problematic. HESI’s selections are judgments based on extrapolations from the present and modified by the experience of those involved in the mapping exercise. HESI characterized the issues in terms of societal, scientific, or regulatory relevance and importance. Although some issues fit into all three categories, most appear in only one category. The division of issues into societal, scientific, and regulatory categories is a useful tool for understanding the functional differences among the three areas. As discussed in the introduction to this paper, the inclusion of societal issues in this scientific mapping exercise is intended to reflect the reality and context in which scientific and regulatory activities are conducted. Although HESI believes that science-based and evidence-based decision making, to the highest extent possible, should be separated from the management of safety issues in society, it recognizes that toxicology, in particular, is subject to the influence of societal and cultural mores. For example, societal concerns about the use and humane treatment of animals have influenced toxicologic method development. The very nature of a substance— whether it be a pharmaceutical, chemical, pesticide, or other agent—and its importance to society can directly or indirectly influence the interpretation of data and its use in risk management. More flexibility might be allowed in the regulatory application of scientific data for a pharmaceutical developed for a life-threatening human disease than might be allowed for the risk management of an environmental contaminant found at disposal sites. Because HESI is committed to an evidence-based examination of best scientific practices, societal issues are included to serve as a barometer for the social importance of the scientific and regulatory issues on the HESI Combined Challenges Map. In this paper, the authors considered addressing each issue according to the combined implications of societal, scientific, and regulatory importance. Such an approach, however, would have proved cumbersome due to the differences between and among the diverse range of issues. A few issues, nevertheless, do demonstrate overlap across societal, scientific, and regulatory areas. For example, societal concerns inherent in considering sensitive populations may affect the scientific approaches by which children’s health and mixtures or co-exposures are assessed. These assessments, in turn, affect policy, regulation,

and legislation. The sensitive-populations issue illustrates the benefit of a holistic approach, whereby stakeholders representing societal, research, and regulatory sectors can solve problems in an integrated way. Other disciplines, such as the legal and ethics communities, should be included to ensure that societal, scientific, and regulatory consequences are properly judged. In some cases, the integrated nature of certain scientific and regulatory issues demonstrates the relative ease of identifying issues of importance in the medium term (2–5 years). For children’s health and sensitive populations, there is a clear concordance among societal, scientific, and regulatory areas, as noted above. Similarly, cancer testing, as a scientific issue, resonates with new technologies and other issues identified in the regulatory area. Examples of close integration are evident by comparing the issues described in Figures 3–5. Nonetheless, it can be misleading to think of overlap among societal, scientific, and regulatory areas in a simultaneous temporal sense. For example, new scientific insights in cancer testing, sensitive populations, or ‘omics’ technology are at different stages of development and need to be converted into testing protocols for application in regulatory processes. Furthermore, even when the scientific landscape changes with a greater understanding of mechanism of action of drugs or chemicals, the application or acceptability of these approaches can take several years or longer to be adopted by regulatory authorities. Delays occur not just because of difficulties in persuading regulatory authorities of the scientific appropriateness of new technologies or approaches, but because they are a necessary precaution required by the regulatory process to ensure that novel approaches can be sustained over a long period of time. Another particularly relevant example of overlap among societal, scientific, and regulatory areas is the prediction of idiosyncratic toxicity associated with the use of pharmaceuticals. Adverse drug reactions are responsible for untoward, and sometimes serious, consequences to individual patients. Adverse drug reactions also result in considerable cost to private insurance companies and government health plans in the developed world. From a scientific perspective, investigation into potential mechanisms for adverse drug reactions complements the identification of sensitive populations and development of new technologies, such as genomics and proteomics. For each issue, scientists explore new hypotheses that might explain toxic responses. The development of these scientific technologies can have immediate regulatory effects. In the case of adverse drug reactions, regulatory authorities must be prepared to act promptly in the event that a drug causes an unacceptable degree of harm to a target population relative to its potential benefits. An understanding of scientific approaches to predicting adverse drug reactions should be developed jointly between scientists committed to improving public health and regulators responsible for managing the consequences. These scientific and regulatory decisions have societal implications in terms of the cost incurred by adverse drug reactions and patient attitudes toward pharmaceuticals. Although


society generally views the pharmaceutical industry as providing beneficial solutions to problems of ill health and expects regulators to protect the public, increasing concerns about the safety, availability, and cost of pharmaceuticals have a major impact on patient attitudes. In conclusion, the HESI scientific mapping exercise described in this paper offers an opportunity for a broad audience to use the information in Appendix 2 as a template for potentially important health and environmental safety issues in the future. Any organization can conduct a similar exercise to include societal, scientific, or regulatory issues, or other areas of key interest. For representatives from government, academia, and industry, the HESI Combined Challenges Map specifies the issues that reflect the high-priority societal, scientific, and regulatory concerns that provide a challenge for action over the next decade. ACKNOWLEDGMENTS The views expressed in this article are those of the authors and do not necessarily reflect the views of participants in the April 6–7, 2004, HESI Scientific Mapping meeting (see Appendix 1). The authors acknowledge the contributions of Dr. Michelle Embry (HESI) and Dr. Ronald Hines (Medical College of Wisconsin) to this paper. Professor Alan R. Boobis (Imperial College London) is recognized for his leadership in conducting the HESI peer-review process before its submission for publication. Appreciation is extended to all participants in the April 2004 HESI mapping session (listed in Appendix 1) and to Mr. Tim Fallon (TSI Consulting Partners, Inc.) for facilitating the session. REFERENCES Albertini, R., Bird, M.G. et al. (2006). The use of biomonitoring data in exposure and human health risk assessment. Environ. Health Perspect. 114:1755–1762. Bates, D.V. (1995). The effects of air pollution on children. Environ. Health Perspect. 103(Suppl. B):49–53. Blumenthal, M.N. (2000). Genetics of asthma and allergy. Allergy Asthma Proc. 21(1):55–59. Boobis, A.R., Cohen, S.M. et al. (2006). IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit. Rev. Toxicol. 36:781–792. Boyle, J.P., Honeycutt, A.A. et al. (2001). Projection of diabetes burden through 2050: Impact of changing demography and disease prevalence in the U.S. Diabetes Care 24:1936–1940. Brent, R.L. (2004). Environmental causes of human congenital malformations: The pediatrician’s role in dealing with these complex clinical problems caused by a multiplicity of environmental and genetic factors. Pediatrics Supplement 113(4):957–968. Brent, R.L., and Weitzman, M. (2004). The current state of knowledge about the effects, risks and science of children’s environmental exposures: Concluding remarks. Pediatrics Supplement 113(4):1158– 1166. Brent, R.L., Tanski, S. et al. (2004). A pediatric perspective on the unique vulnerability and resilience of the embryo and child to environmental toxicants: The importance of rigorous research concerning age and agent. Pediatrics Supplement 113(4):935–944.

839

Brown, P.O., and Hartwell, L. (1998). Genomics and human disease— Variations on variation. Nature Genetics 18:91–93. Burchiel, S.W., Knall, C.M. et al. (2001). Analysis of genetic and epigenetic mechanisms of toxicity: potential roles of toxicogenomics and proteomics in toxicology. Toxicol. Sci. 59:193–195. Centers for Disease Control and Prevention. (1997). Update: Blood lead levels—United States, 1991–1994. MMWR Morb. Mortal. Wkly. Rep. 46(7):141–145. Centers for Disease Control and Prevention. (2003). Public health and aging: trends in aging—United States and worldwide. National Center for Chronic Disease Prevention and Health Promotion. MMWR Morb. Mortal. Wkly. Rep. 52(06):101–106. Centers for Disease Control and Prevention. (2007a). US obesity trends. Available at http://www.cdc.gov/nccdphp/dnpa /obesity/trend/maps/index.htm (accessed 22 September 2008). Centers for Disease Control and Prevention. (2007b). Chronic disease notes and reports: special focus. National Center for Chronic Disease Prevention and Health Promotion. Healthy Aging 18:2. Cohen, S.M. (2004). Human carcinogenesis risk evaluation: an alternative approach to the two-year rodent bioassay. Toxicol. Sci. 8:225– 229 Cohen, S.M., Boobis, A.R. et al. (2006). 4-Aminobiphenyl and DNA reactivity: Case study within the context of the 2006 IPCS human relevance framework for analysis of a cancer mode of action for humans. Crit. Rev. Toxicol. 36:803–820. Colson, C.R.D., and De Broe, M.E. (2005). Kidney injury from alternative medicines. Adv. Chronic Kidney Dis. 12(3):261–275. Commission of the European Communities. (2000). Communication from the Commission on the precautionary principle. Available at: http://ec.europa.eu/food/food/foodlaw/precautionary/index en.htm (accessed 22 September 2008). Corsini, E., and Kimber, I. (2007). Factors governing susceptibility to chemical allergy. Toxicol. Lett. 168(3):255–259. Cosyns, J.-P., Jadoul, M. et al. (1999). Urothelial lesions in Chineseherb nephropathy. Am. J. Kidney Dis. 33:1011–1017. Cowie, C.C., Rust, K.F. et al. (2006). Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population—National Health and Nutrition Examination Survey 1999–2002. Diabetes Care 29:1263–1268. Crimmins, E.M., and Saito, Y. (2000). Change in the prevalence of diseases among older Americans: 1984–1994. Demographic Res. 3: Article 9. Available at: http://www.demographic-research.org /Volumes/Vol3/9/3-9.pdf (accessed 22 September 2008). David, J.R., Browonson, R.C. et al. (1993). Family pesticide use and childhood brain cancer. Arch. Environ. Contam. Toxicol. 24:87– 92. Daz-Cruz, M.S., Lopez de Alda, M.J. et al. (2003). Environmental behaviour and analysis of veterinary and human drugs in soils, sediments and sludge. TrAC Trends Anal. Chem. 22(6):340–351. Devesa, S.S., Blot, W.J. et al. (1995). Recent cancer trends in the United States. J. Natl. Cancer Inst. 87:175–182. Doerrer, N.G. (2007). Integration of human biomonitoring exposure data into risk assessment: HESI initiatives and perspectives. Int. J. Hyg. Environ. Health 210:247–251. Done, A.K. (1964). Developmental pharmacology. Clin. Pharmacol. Ther. 5(4):432–479. Dorne, J., Skinner, L. et al. (2007). Human and environmental risk assessment of pharmaceuticals: differences, similarities, lessons from toxicology. Anal. Bioanal. Chem. 387(4):1259–1268.

840

L. L. SMITH ET AL.

Dourson, M.L., Felter, S.P. et al. (1996). Evolution of science-based uncertainty factors in noncancer risk assessment. Reg. Toxicol. Pharmacol. 24:108–120. Duleba, K., Wysocki, M. et al. (2006). Complementary and alternative medicine in children with cancer—facts and myths. Adv. Clin. Exper. Med. 15(4):695–703. Environment Canada. (1999). Canadian Environmental Protection Act 1999. Available at: http://www.ec.gc.ca/CEPARegistry /the act/default.cfm (accessed 22 September 2008). Environment Canada. (2006). Domestic substances list. Available at: http://www.ec.gc.ca/CEPARegistry/subs list/Domestic.cfm (accessed 22 September 2008). Etzel, R., ed. (1999). Handbook of Pediatric Environmental Health. American Academy of Pediatrics, Elk Grove, IL. European Commission. (2006). Registration, Evaluation, and Authorisation of Chemicals (REACH). Available at: http://ec.europa.eu/ environment/chemicals/reach/reach intro.htm (accessed 22 September 2008). European Medicines Agency. (2005). EMEA Conference on Environmental Risk Assessment for Human and Veterinary Medicinal Products. 27–28 October 2005. Available at: http://www.emea.europa.eu /pdfs/general/direct/pr/35994505.pdf (accessed 22 September 2008). Interagency Research Animal Committee. (1985). U.S. government principles for the utilization and care of vertebrate animals used in testing, research, and training. Available at: http://grants.nih.gov /grants/olaw/references/phspol.htm#USGovPrinciples (accessed 22 September 2008). Flegal, K.M., Carroll, M.D. et al. (2002). Prevalence and trends in obesity among U.S. adults, 1999–2000. J. Am. Med. Assoc. 288(14):1723–1727. Fontanarosa, P.B., Rennie, D. et al. (2003). The need for regulation of dieting supplements—lessons from ephedra. J. Am. Med. Assoc. 289:1568–1570. Fraunfelder, F.W. (2005). Ocular side effects associated with dietary supplements and herbal medicines. Drugs of Today 41(8):537– 545. Gallo, M. (2001). History and scope of toxicology. In: Casarett and Doull’s Toxicology: The Basic Science of Poisons, 5th ed, C.D. Klaassen, ed., pp. 3–10, McGraw–Hill, New York. Ginsberg, G., Hattis, D. et al. (2004). Pediatric pharmacokinetic data: Implications for environmental risk assessment for children. Pediatrics Supplement 113(4):973–983. Gold, E.L., Gordis, J. et al. (1979). Risk factors for brain tumors in children. Am. J. Epidemiol. 109:309–319. Goldman, L.R., and Koduru, S. (2000). Chemicals in the environment and developmental toxicity to children: A public health and policy perspective. Environ. Health Perspect. 108(Suppl. 3):443– 448. Greim, H., Arand, M. et al. (2006). Toxicological comments to the discussion about REACH. Arch. Toxicol. 80:121–124. Gronert, G.A., Mott, J. et al. (1988). Aetiology of malignant hyperthermia. Br. J. Anaesth. 60:253–267. Gulezian, D., Jacobson-Kram, D. et al. (2000). Use of transgenic animals for carcinogenicity testing: Consideration and implications for risk assessment. Toxicol. Pathol. 28(3):482–499. Guzelian, P., Henry, C. et al., eds. (1992). Similarities and differences between children and adults: Implications for risk assessment. ILSI Press, Washington, DC. Health and Safety Executive. (2007). The precautionary princi-

ple: Policy and application. Available at: http://www.hse.gov.uk /aboutus/meetings/committees/ilgra/pppa.htm (accessed 22 September 2008). Hoet, J.J., Ozanne, S. et al. (2000). Influences of pre- and postnatal nutritional exposures on vascular/endocrine systems in animals. Environ. Health Perspect. 108(Suppl. 3):563–568. Holladay, S., and Smialowicz, R.J. (2000). Development of the murine and human immune system: Differential effects of immunotoxicants depend on time of exposure. Environ. Health Perspect. 108(Suppl. 3):463–473. Holsapple, M.P., Farland, W.H. et al. (2005). Research strategies for safety evaluation of nanomaterials, part II: Toxicological and safety evaluation of nanomaterials, current challenges and data needs. Toxicol. Sci. 88(1):12–17. Institute of Medicine of the National Academies. (2005). Complementary and alternative medicine in the United States. Board on Health Promotion and Disease Prevention. The National Academies Press, Washington, DC. Interagency Coordinating Committee on the Validation of Alternative Methods. (2007). The NICEATM-ICCVAM Five-Year Plan (2008– 2012). Draft: May 4, 2007. Available at: http://iccvam.niehs.nih.gov /docs/about docs/5YRPlan04May07FD.pdf (accessed 22 September 2008). Joint Nature Conservation Committee. (2007). The precautionary principle and approach. Available at: http://www.jncc.gov.uk /default.aspx?page=2519 (accessed 22 September 2008). Kirkland, D., Aardema, M. et al. (2005). Evaluation of the ability of a battery of three genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. 1. Sensitivity, specificity and relative predictivity. Mutat. Res. 584:1–256. Kirkland, D.J., Hayashi, M. et al. (2007a). The International Workshops on Genotoxicity Testing (IWGT): History and achievements. Mutat. Res. 627:1–4. Kirkland, D.J., Hayashi, M. et al. (2007b). Summary of major conclusions from the 4th IWGT, San Francisco, 9–10 September, 2005. Mutat. Res. 627:5–9. Kollmann, M., and Sourjik, V. (2007). In silico biology: From simulation to understanding. Curr. Biol. 17:R132–R134. Lichtenstein, P., Holm, N.V. et al. (2000). Environmental and heritable factors in the causation of cancer. New Engl. J. Med. 343:78– 85. Loging, W., Harland, L. et al. (2007). High-throughput electronic biology: Mining information for drug discovery. Nat. Rev. Drug Discov. 6:220–230. MacDonald, J., French, J.E. et al. (2004). The utility of transgenic assays for risk assessment. Toxicol. Sci. 77:188–194. Majeed, A., and Aylin, P. (2005). The ageing population of the United Kingdom and cardiovascular disease. Brit. Med. J. 331:1362. Manson, J.E., and Bassuk, S.S. (2003). Obesity in the United States. A fresh look at its high toll. J. Am. Med. Assoc. 289:229–230. Mayne, J.T., Ku, W.W. et al. (2006). Informed toxicity assessment in drug discovery: Systems-based toxicology. Curr. Opin. Drug Discov. Devel. 9:75–83. McCarver, G. (2004). Applicability of the principles of developmental pharmacology to the study of environmental toxicants. Pediatrics Supplement 113(4):969–972. Meek, M.E., Bucher, J.R. et al. (2003). A framework for human relevance analysis of information on carcinogenic modes of action. Crit. Rev. Toxicol. 33: 591–596.

HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE Miller, R.W. (1995). Special susceptibility of the child to certain radiation-induced cancers. Environ. Health Perspect. 103(Suppl. 6):41–44. Mokdad, A.H., Serdula, M.K. et al. (1999). The spread of the obesity epidemic in the United States, 1991–1998. J. Am. Med. Assoc. 282:1519–1522. Mokdad, A.H., Bowman, B.A. et al. (2001). The continuing epidemics of obesity and diabetes in the United States. J. Am. Med. Assoc. 286:1195–1200. Mokdad, A.H., Ford, E.S. et al. (2003). Prevalence of obesity related health risk factors. J. Am. Med. Assoc. 289:76–79. National Cancer Institute. (1999). Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. NIH Publication Number 99–4649. National Institute for Clinical Health and Excellence. (2003). Management of obesity and overweight (evidence briefing summary). Available at: http://www.nice.org.uk/page.aspx?o=502625 (accessed 22 September 2008). National Research Council. (1993). Pesticides in the diets of infants and children. National Academy Press, Washington, DC. National Research Council. (1996). Carcinogens and anticarcinogens in the human diet. The National Academies Press, Washington, DC. National Research Council. (2006). Human biomonitoring for environmental chemicals. The National Academies Press, Washington, DC. National Research Council. (2007). Toxicity testing in the twentyfirst century: A vision and a strategy. National Academies Press: Washington, DC. Needleman, H.L., Schell, A. et al. (1990). The long-term effects of exposure to low doses of lead in childhood. An 11-year follow-up report. N. Engl. J. Med. 322:83–88. Nieuwenhuijsen, M., Paustenbach, D. et al. (2006). New developments in exposure assessment: The impact on the practice of health risk assessment and epidemiological studies. Environ. Int. 32:996–1009. Niggemann, B., and Gruber, C. (2003). Side-effects of complementary and alternative medicine. Allergy 58(8):707–716. Olden, K. (2004). Genomics in environmental health research— Opportunities and challenges. Toxicology 198:19–24. Olshan, A.F., Breslow, N.E. et al. (1993.) Risk factors for Wilm’s Tumor: Report from the National Wilm’s Tumor Study. Cancer 72:938– 944. Patel, S., Parmar, D. et al. (2005). Contribution of genomics, proteomics and single-nucleotide polymorphism in toxicology research and Indian scenario. Indian J. Hum. Genet. 11:61–75. Pennie, W., Pettit, S.D. et al. (2004). Toxicogenomics in risk assessment: an overview of an ILSI HESI collaborative research program. Environ. Health Perspect. Toxicogenomics 112:417– 419. Pirmohamed, M.P., James, S. et al. (2004). Adverse drug reactions as cause of admission to hospital: prospective analysis of 18,820 patients. Brit. Med. J. 329:15–19. Raffensperger C., and Tickner J., eds. (1999). Protecting public health and the environment: Implementing the precautionary principle. Island Press, Washington, DC. Redmond, C.K. (1981). Sensitive population subsets in relation to effects of low doses. Environ. Health Perspect. 42:137–140. Ritter, L., and Arbuckle, T.E. (2007). Can exposure characterization explain concurrence or discordance between toxicology and epidemiology? Toxicol. Sci. 97(2):241–252.

841

Schuster, D., Steindl, T.M. et al. (2006). Predicting drug metabolism induction in silico. Curr. Top. Med. Chem. 6:1627–1640. Sherry, S.T., Ward, M.-H. et al. (2001). dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29:308–311. Shirkey, H.C., ed. (1980). Pediatric therapy, pp. 17–20, CV Mosby, St. Louis. Thomas, K.V., and Sayre, P. (2005). Research strategies for safety evaluation of nanomaterials, Part 1: Evaluating the human health implications of exposure to nanoscale materials. Toxicol. Sci. 87(2):316– 321. Thybaud, V., Aardema, M. et al. (2007). Relevance and follow-up of positive results in in vitro genetic toxicity assays: an ILSI-HESI initiative. Mutat. Res. (in press.) Tickner, J., Raffensperger, C. et al. (1998). The precautionary principle in action. A handbook. Available at: http://www.biotechinfo.net/handbook.pdf (accessed 22 September 2008). US Environmental Protection Agency. (2004). The children’s environmental health yearbook supplement. Office of Children’s Health Protection. EPA-100-R-00-0018. Washington, DC. US Environmental Protection Agency (2005). Toxicity and exposure assessment for children’s health. (TEACH: A database of toxicity information). Available at: http://www.epa.gov/TEACH/ (accessed October 1, 2008). US Environmental Protection Agency. (2006). A framework for assessing health risks of environmental exposures to children. Publication Number EPA/600/R-05/093A. US Environmental Protection Agency. (2007). Guide to considering children’s health when ceveloping EPA actions: Implementing executive order 13045. Washington, DC. US Food and Drug Administration. (2005). Guidance for industry: Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Available at: http://www.fda.gov/cder/guidance/5541fnl.htm (accessed 22 September 2008). Weber, W.W., Hein, D.W. et al. (1983). Relationship of acetylators status to isoniazid toxicity, lupus erythematosus, and bladder cancer. FASEB J. 42:3086–3097. Weisbrod, A.V., Burkhard, L.P. et al. (2007). Workgroup report: Review of fish bioaccumulation databases used to identify persistent, bioaccumulative, toxic substances. Environ. Health Perspect.115:255– 261. Wiffen, P., Gill, M. et al. (2002). Adverse drug reactions in hospital patients: A systematic review of the prospective and retrospective studies. Bandolier Extra—Evidence-Based Healthcare. Wilmoth, J., and Longino, C.F. (2006). Demographic trends that will shape U.S. policy in the twenty-first century. Res. Aging 28(3):269– 288. Woodward, K.N. (2005). The potential impact of the use of homeopathic and herbal remedies on monitoring the safety of prescription products. Hum. Exper. Toxicol. 24(5):219–233. World Health Organization. (1998). Obesity: Preventing and managing the global epidemic. Report of a WHO consultation on obesity. WHO/NUT/NCD/981, WHO, Geneva, Switzerland. World Health Organization. (2006). Obesity and overweight. Fact sheet number 311. Available at: http://www.who.int /mediacentre/factsheets/fs311/en/ (accessed 22 September 2008). Zurlo, J., Rudacille, D. et al. (1994). Animals and alternatives in testing: History, science, and ethics. Mary Ann Liebert, Inc., New York.

842

L. L. SMITH ET AL.

Appendix 1. Participants in the HESI Scientific Mapping meeting on April 6–7, 2004. Dr. Michael Bird (ExxonMobil Biomedical Sciences, Inc.) Prof. Alan Boobis (Imperial College London) Dr. Robert Brent (Alfred I. duPont Hospital for Children) Dr. James Bus (The Dow Chemical Company) Dr. Rebecca Calderon (US Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Human Studies Division) Dr. Neil Carmichael (Bayer CropScience) Dr. Samuel Cohen (University of Nebraska Medical Center) Dr. Vicki Dellarco (US Environmental Protection Agency, Office of Pesticide Programs, Health Effects Division) Ms. Nancy Doerrer (HESI) Mr. Tim Fallon (Facilitator; TSI Consulting Partners, Inc.) Dr. James Gibson (East Carolina State University) Dr. Jay Goodman (Michigan State University) Prof. Dr. Helmut Greim (Technical University of Munich) Dr. Ronald Hines (Medical College of Wisconsin) Dr. Michael Holsapple (HESI) Dr. Amy Lavin (HESI)∗ Dr. Ruth Lightfoot-Dunn (GlaxoSmithKline)∗ Dr. Robert Lindenschmidt (The Procter & Gamble Company) Dr. James MacDonald (Schering-Plough Research Institute) Dr. James MacGregor (US FDA National Center for Toxicological Research)∗ Dr. Canice Nolan (European Commission) Dr. Klaus Olejniczak (European Medicines Agency)∗ Dr. James Sanders (Aventis Pharmaceuticals) Mr. David Sandler (HESI)∗ Dr. Lewis Smith (Chair; Syngenta Ltd.) Mr. Karluss Thomas (HESI)∗ Dr. Jean-Marc Vidal (European Medicines Agency) Dr. Douglas Weed (US National Cancer Institute)∗ Dr. Samuel Wilson (US National Institute of Environmental Health Sciences) Appendix 2. ‘Surface Issues’ Identified by HESI Contacts in Advance of the April 2004 Scientific Mapping Meeting.

SOCIETAL CHALLENGES 1. 2. 3. 4. 5.

Agri-terrorism, terrorism in general Agri-disaster Global poverty Genetic modification (GM)/biotechnology—moratorium Nanotechnology—extrapolating anti-GM rhetoric into other new technologies 6. Anti-technology

7. 8. 9. 10. 11. 12. 13.

14. 15. 16. 17. 18. 19. 20. 21.

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.

∗ Indicates affiliation in April 2004. Affiliation has since changed. The views

expressed in this article are those of the authors and do not necessarily reflect the views of the participants in the April 6–7, 2004, HESI Scientific Mapping meeting.

44. 45.

Anti-globalization ‘Go east’ strategy Market price of products Cost of research and development (R&D) Impact of changes in the cost of drugs on R&D Freedom to sell—consumer attitude toward food Consumer/public education (e.g. science, biology, toxicology, chemical safety information, risk, exposure). Synthetic versus natural—a chemical is a chemical ‘Silent Spring’ that never happened How to manage increase in speed of communications (e.g. how to manage internet rumors) Education of society Obesity Zero risk Growing world population versus efficient use of resources Access to clean water and food Environmental contamination of ground water, soil and air from manufacturing and chemical companies— determining the risks and developing abatement programs Impact of solid waste disposal Aging world population Sensitive populations and/or economic consequences thereof Children’s health Sensitivity of developing organism Sustainable development Proving the absence of theoretical possibilities NGO pressure—growing skill-base/capability—use of the internet as equivalent to scientific peer-reviewed literature Interrelationships between scientific community, regulators, consumers, and NGOs Regulatory harmonization—delay and impact on animal usage Ethics of animal testing Increased pressure regarding animal testing—animal activists getting more radical—public support decreasing Data sharing—reduction in animal usage Risk perception Risk and benefit (not just health) Risk communication—confidence in regulatory authorities Chronic effects of low dose exposures Trust in science industry Independent safety testing Decrease in funding of basic research by government and industry Independence of regulatory authorities—fear of litigation Increase in litigation, lawsuits—evaluating the economic burden, the mis-education of the public, and the impact of litigation involving ‘medial monitoring’ and class action lawsuits. Can anything be done to reduce non-meritorious litigation in these areas? Precautionary principle Gene therapy


46. Human testing 47. Satellite Disease Mapping System—Geographic Information System (GIS) maps 48. Identity cards—gene mapping 49. Biomonitoring—sensitivity and significance 50. Environmental monitoring—sensitivity and significance 51. Alternative therapies 52. Ethics of pharmacogenetics and the need for education— should industry be part of this or solely the public sector? 53. Access to therapy 54. Infectious disease epidemics 55. Vaccines safety 56. Cost/benefit of regulations 57. Cost of health care 58. Health information privacy 59. Globalization of communications

22.

23.

24. 25.

26.

27.

SCIENTIFIC CHALLENGES 1. Safety assessment of biotechnology products 2. Safety/uncertainty factors (interspecies and intraspecies, pharmacokinetic/ pharmacodynamic, FQPA, characterization of dose-response) 3. Use of ‘systemic dose’ versus ‘external (given) dose’ in risk assessment 4. Eliminating testing of drugs and chemicals in in vivo animal studies using mg/kg exposures—for toxicology and reproductive studies 5. Simulation and computer modeling of toxicokinetics and toxicodynamics 6. Characterization of dose-response curves, particularly at low doses, including hormesis; mechanistic considerations 7. Hormesis 8. Guidance and quality control in epidemiology studies 9. Improving epidemiological studies 10. Focus on mechanism, understanding pathophysiology, biological pathways, cellular interactions and responses 11. Defining adverse (as opposed to adaptive or homeostatic) adjustment 12. Defining ‘effect’ versus ‘adverse effect’ (NOEL versus NOAEL) 13. Distinguishing between a ‘change’ and toxicity 14. Sensitive populations—use of pharmacogenetics in risk assessment 15. Children and the elderly 16. Infant and childhood susceptibility 17. Sensitivity of the developing organism 18. Obesity as a toxicological risk factor 19. Genomics 20. Proteomics 21. Metabonomics (For #19, 20, and 21: Predictive tool or potential replacement for conventional hazard evaluation protocols. Need for evaluation/validation. Do these complement ‘classical’ preclinical studies? Selection of critical

28.

29. 30. 31. 32. 33. 34. 35. 36. 37. 38.

39.

40. 41.

42. 43. 44. 45.

46.

843

‘omics’ markers for a specific product may be more useful than collecting a wide range of markers.) Integrating ‘panomics’ and other recent advances in biomedical sciences into toxicology such that safety evaluation is improved Bioinformatics approaches and toxicological databases; develop informatics methodology to cope with mountains of data Advances in the use of microarrays Sensitivity of new endpoints (with toxicogenomics, ‘effects’ are seen at levels lower than current NOELs). What does this mean in terms of hazard and risk? Gaining acceptance of new scientific approaches to safety assessment in an era when the half-life of a new approach is likely to be shorter than the time required for the traditional approach to validation Use of in silico toxicology as a predictive tool for hazard evaluation Genomics and/or pharmacogenetics—‘individualized medicine—fact or fantasy?’ (Customization of products, drugs based on individual genetic differences, e.g. SNPs.) Gene therapy—insertional mutagenesis, ethical issues, vector-related issues Toxicology of/exposure to mixtures Immunotoxicology—validation of functional tests Marginalization of the discipline of toxicology Biomonitoring—sensitivity and relevance, assessing exposure, design of population studies Environmental monitoring—sensitivity and relevance Environmental factors and allergic lung disease (especially asthma) Magnitude of genetic risks from environmental drugs and chemicals Natural toxins (e.g. mycotoxins, endotoxins) and human health Releases of pharmaceuticals into aquatic environment result in estimated predicted|exposure concentration (PEC): predicted no-effect concentration (PNEC) ratios larger than 1 REACH system—opportunity to contribute to evaluation of environmental risks, development of concepts to set priorities for registration and evaluation, to introduce strategies for testing and to address aspects of human health Mechanisms in genotoxicity Implications of advancing molecular-biological understanding of cellular reactions to the insult of genotoxic agents to (thresholded) dose response Rehabilitating the term ‘threshold’ Proving the absence of theoretical possibilities Understanding the basis for development of drug or target organism resistance How good are animal models in predicting effects in humans—development of replacement methods and validation Transgenic animals—models of disease states in humans

844

L. L. SMITH ET AL.

47. Failure to predict adverse events in populations, understanding drug: individual patient interactions 48. Bovine spongiform encephalopathy (BSE) and other prion diseases in the future 49. Incorporating biology ‘systems approach’ into toxicology 50. Train quality scientists with foundation in biology, not only technology 51. Methods for rapid screening of existing chemicals (i.e. not product development)—contribution of in vivo methods 52. Cancer risk assessment—How to improve?—Is the National Toxicology Program (NTP) two-year bioassay the best approach?—If the strategy were designed today, would it include the NTP bioassay as conducted? 53. Evaluating/validating in vitro testing protocols for oncogenic risk in humans 54. Stem cell utilization for treating disease and replacing vital tissues 55. Nanoparticles/nanotechnology—health issue, opportunity, or both 56. Societal determinants as explanations for expression of disease—influence of race, income, access to care 57. RNA interference technology–predictive tool? 58. Development, application and validation of efficacy/safety biomarkers REGULATORY CHALLENGES 1. Regulatory harmonization: ongoing challenges at the country and regional level 2. Expansion of Proposition 65-like regulations 3. Harmonization of regulatory interpretation—streamline process—focus on science rather than politics, trade barriers • importance of FDA/European Medicines Agency (EMEA) confidentiality agreement signed in 2003 4. Harmonization of risk assessment across different sectors (e.g. pesticides, drugs) and different types of substances (e.g. low molecular weight compounds, whole foods) 5. Data sharing—consideration of intellectual property 6. Potential issues/impact from accession countries joining the EU 7. Chemical assessment/inerts/REACH—increasing number of chemical policies globally (also Canadian DSL) 8. Toxicology/risk assessment of mixtures (chemicals and pharmaceuticals) 9. Consideration of impact of multi-drug therapy 10. New regulation—herbal remedies 11. Exposure-based approach to regulatory testing; chemicals and pharmaceuticals 12. Safety/uncertainty factors (interspecies and intraspecies, pharmacokinetic/pharmacodynamic, FQPA)—compound conservatism versus scientific relevance in human risk assessment 13. Precautionary principle–science-based decision-making; grow in scale

14. Use of ‘systemic dose’ versus ‘external (given) dose’ in risk assessment—chemical and pharmaceutical 15. Cumulative risk assessment 16. Risk assessment in the home 17. The move to regulate based on ‘hazard’ versus ‘risk’ 18. Sensitive populations—use of pharmacogenetics in risk assessment—use of genomics and SNPs to identify sensitive populations 19. Children’s health (chemicals and pharmaceuticals); include other life stages (e.g. elderly) 20. Determination of environmental risks in pregnant women and children. Will advances be made or will the little progress already achieved be the extent of what is accomplished? 21. Human testing and use of data 22. The increasing resistance of Institutional Review Boards (IRBs) to approve certain types of clinical research 23. How good are animal models in predicting effects in humans 24. Animal testing regulations (e.g. EU 7th amendment) 25. Increasing pressure to reduce or even eliminate animal testing 26. Transgenic animals—models of disease states in humans 27. Use of in silico toxicology as a predictive tool for hazard evaluation 28. Biopharma—containment and public perception 29. Pharmaceutical use of agrichemicals and vice versa 30. Regulations on new technologies, often based on ‘fear of the unknown’ (e.g. biotechnology [genetically modified organisms GMOs], nanotechnology)—overcoming ‘antitechnology’ 31. Labeling regulations 32. Gaining acceptance of new scientific approaches to safety assessment in an era when the half-life of a new approach is likely to be shorter than the time required for the traditional approach to validation 33. Data handling in the ‘omics’ world 34. Attracting expert scientists to work in regulatory agencies—mass retirement from FDA Center for Drug Evaluation and Research (CDER) in next 5 years—need to train generation of reviewers in whole-animal biology, not only technology. Competitive salaries. 35. Counteracting the trend to keep industry scientists—or academic scientists with industry ties—from participating on government advisory committees 36. Expression patterns as a fingerprint of disease and causation 37. Continued resistance to address ‘lifestyle diseases’ (obesity) as clinical diseases 38. Risk benefit analysis 39. Accountability of regulations—cost–benefit analysis of regulations 40. Responding to potential biohazards 41. Burden of cancer due to environmental genotoxins; reproductive toxicants


42. Environmental risk assessment of pharmaceuticals 43. Gene/cell therapy 44. Hybrid byproducts: biological devices (e.g. membrane “device” for encapsulated cell factories) 45. Nucleic acid products (e.g. small interfering RNA, oligonucleotides [how they get validated and regulated]) 46. Incorporation of mechanistic information into risk assessments 47. Re-evaluation of current linear-based approaches to cancer risk assessment, including genotoxic chemicals; application of margin of exposure (MOE) and/or mechanismbased inputs 48. Establishing data quality guidelines for use of science in regulation development 49. Consolidation of hazard evaluation protocols (i.e. multiple endpoints from single protocols) 50. Rationalization of natural chemical evaluations in current regulatory approaches (i.e. do current regulatory hazard testing approaches and risk assessment requirements appropriately define true risks) 51. Re-evaluate definitions of maximum tolerated dose (MTD) to include endpoints beyond body weight and pathology changes

845

52. Dietary supplements, in particular nutriceuticals and botanicals 53. Idiosyncratic reactions 54. Vaccines safety 55. New therapeutic compounds 56. Non-cancer endpoints 57. Regulating of ‘omics’ 58. Validating biomarkers 59. Role of epidemiology in risk assessment (role, weight, interpretation) 60. Impact of AgHealth Study and National Children’s Study on regulation 61. Weighting the ‘gray’ literature 62. Weight of evidence (when is enough enough?); use of MOA 63. Application of new technologies to bring new products to market—lack of a ‘safe harbor’ mechanism (pharmaceuticals); on the other hand, for the chemical industry, impact of regulation on innovation; impact of regulation on access to pesticides for certain applications 64. Use of exposure/statistical models for risk assessment (e.g. particulate matter); includes quantitative structure-activity relationships (QSARs); validation 65. Transitioning new science into actual regulatory practice