Critical Reviews in Toxicology, 38:817–845, 2008
Copyright c ?2008 Informa UK Ltd.
ISSN: 1040-8444 print / 1547-6898 online
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
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 identi-
fied 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 de-
fault 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 assess-
ment and management is needed to ensure consideration of societal, scientific, and regulatory
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: firstname.lastname@example.org
L. L. SMITH ET AL.
toxicology community because it represents the contributions of
key scientists from around the world from government, academia,
challenges, scientific mapping, societal challenges, toxicology
HESI, product safety, regulatory challenges, scientific
Chemicals1are introduced into the environment from a vari-
nificance and consequences of these exposures are of increasing
concern to the general population. From a historical perspec-
tive, 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.”
Understanding of the toxicology of various substances has
by which chemicals can affect physiologic and metabolic pro-
cesses. Many of these scientific insights have evolved into reg-
ulatory requirements and frameworks through which the safety
and health of the public are protected.
For scientists, regulators, and society as a whole, project-
ing 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 Sci-
ences 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 gov-
ernment and academic scientists. Predicting future challenges
can be achieved via several methods. Mapping is a proven, use-
ful technique for engaging organizations in exploring the issues
facing their memberships or constituencies. Among the organi-
Institutes of Health (NIH). HESI (http://www.hesiglobal.org/)
undertook such an exercise for toxicology, and included per-
spectives on scientific, regulatory, and societal projections for
In April 2004, HESI convened an expert group of key aca-
demic, government, and industry scientists from around the
world to conduct a scientific mapping exercise. The group ex-
amined extensive information that was received, in advance of
tially significant scientific, regulatory, and societal importance
for the next 10 years. The group established a temporal prior-
ity, estimated the magnitude of each problem, and assessed the
1In 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 ex-
perts 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
from which HESI prioritized the issues that were of greatest im-
portance to its constituency. The maps that were developed as a
result of the exercise are only snapshots in time. They are, how-
ever, 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 speci-
ficity 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 recommen-
dations for future research.
The scientific mapping exercise has particular value to the
scientists from around the world from government, academia,
and industry. The various industry sectors involved in HESI ac-
tivities will be particularly interested in the issues appearing
on the HESI Combined Challenges Map. From a broader per-
spective, the series of maps provides the wider audience with
opportunities to determine the importance of the full comple-
ment of issues considered by HESI, develop different temporal
as an organization lends significance to the results of HESI’s
April 2004 ‘Scientific Mapping’ exercise, both for the organi-
zation’s constituency and for the public at large. Information
about the mapping process, the results of the exercise, and the
readers unfamiliar with HESI, a primer is offered here.
The mission of HESI, a global branch of ILSI, is to stim-
ulate and support scientific research and education programs
that contribute to the identification and resolution of health and
nity, government agencies, and industry. HESI draws its mem-
bership from the chemical, agrichemical, petrochemical, phar-
maceutical, biotechnology, and consumer-products industries.
Approximately 50 companies from the US, Europe, and Japan
for HESI programs; however, HESI also receives financial and
in-kind support from a variety of US and international govern-
ment agencies, scientific professional societies (e.g. Society of
Toxicology), and other non-profit organizations.
HESI programs bring together scientists from industry, gov-
ernment agencies, academia, and other research organizations
around the world to address both long-standing and emerg-
ing questions associated with human health and environmental
issues. This ‘tripartite’ approach (i.e. engagement of industry,
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
FIG. 1. Overview of HESI scientific mapping process.
taken 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 con-
sensus on a variety of scientific issues because of its attention
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 immuno-
toxicology, mechanisms of cancer, use of transgenic mice in
the evaluation of cancer hazards, improvements in risk assess-
ment, development of a better understanding of the application
http://www.hesiglobal.org/publications). Most of these issues
are identified and managed through early recognition of a sci-
entific dilemma or opportunity which requires analysis and/or
laboratory experiments to provide greater insight into the un-
derlying science. This process of identification and resolution
has served HESI well by permitting efficient and productive
engagement of members, academic advisors, and government
HESI held a scientific mapping exercise on April 6–7, 2004.
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
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 En-
vironmental Health Sciences.
An overview of the method used to develop the HESI Sci-
entific 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 Steward-
ship Committee, the Emerging Issues Steering Committee, and
categories and are presented in their entirety in Appendix 2. At
the mapping session, the array of scientific, regulatory, and so-
cietal issues was refined and supplemented through interactive
discussion in breakout groups, and then consolidated to reduce
duplication and combine closely related areas. To assess po-
tential impact and examine the likely timeframe for action, the
array of consolidated issues was placed on an ‘opportunity ma-
trix’ (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 de-
velopment and evolution of the organization’s scientific project
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
L. L. SMITH ET AL.
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
FIG. 3. HESI societal challenges map.
(i.e. hexagons for regulatory issues, squares for societal issues,
perimeter of each shape on the map indicates the relative prior-
ity 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
Societal Issues (Square)
HESI’s primary mission is to provide an international fo-
rum for the advancement of the understanding and resolution
of scientific issues related to human health, toxicology, risk as-
sessment, and the environment. It is generally accepted that so-
cietal 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 di-
rectly 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
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
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
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 deter-
mine outcomes and outweigh emotional or prejudicial views on
prediction of what may be concluded, with the objective, scien-
tific 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.
FIG. 6. HESI Combined Challenges Map: 2005–2015.
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
FIG. 7. HESIchallengeswereidentifiedasbeingprimarilyreg-
ulatory, societal, or scientific.
and decision-making, is that ignoring the influence of societal
pressures is at best naive and, at worst, irresponsible.
differing, and sometimes conflicting, agendas of all individu-
als 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
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 influ-
ence scientific judgments on some issues. For example, with the
introduction of the European Union (EU) legislation known as
REACH (Registration, Evaluation, and Authorisation of Chem-
icals), which is discussed later in this paper, there has arisen a
conflict between the desire to adequately test the tens of thou-
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 vali-
dated; however, the pressure to use them and thus avoid the use
of experimental animals can be considerable, even if not pub-
licly stated by regulators. Consequently, there is a danger that
the assessment of chemicals will be compromised by an unwill-
ingness 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
in vitro test systems have been valuable substitutes for animal
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
ogy (Interagency Research Animal Committee, 1985; National
Research Council, 2007).
For the HESI mapping exercise, societal challenges were se-
lected that will either have a beneficial effect on society or en-
courage scientific activity. It is not unexpected that HESI’s se-
lection 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 is-
sue 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 sci-
entific advancements creates societal issues of economic impor-
review of a toxicological challenge should include the recogni-
tion 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 trans-
lation 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
Populations and Children’s Health for related topics.)
Regardless of the toxicological endpoint, certain individu-
als 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 anesthet-
ics 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
L. L. SMITH ET AL.
been more extensively evaluated (Brown and Hartwell, 1998;
ity 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,
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 fac-
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 tech-
niques; (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 in-
dividual susceptibility, and some scientists believe this can be
achieved. With advances in sequencing the human genome and
sequences, there is the potential, yet to be proven, to evaluate
individuals for variations in sequences that are related to differ-
ences in particular susceptibilities. This approach involves an
understanding of toxicological endpoints associated with spe-
cific genes that are involved in pathways targeted by individual
drugs or chemicals. These pathways can be involved in regu-
latory 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 biomed-
ical 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 phys-
iological impact of such genetic diversity (i.e. the expressed
phenotype) can vary as a function of age and environment. Ad-
ditionally, we know very little as yet about the key role played
regions encoding micro-RNA), multiple transcription start sites
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/).
polymorphisms have become more apparent. With the se-
quencing of the human genome and the development of high-
throughput technologies, an expectation has evolved in the pub-
lic and scientific communities that the identification of all poly-
morphisms inherited by an individual could provide a means
of predicting the diseases that an individual will eventually de-
velop. 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 exam-
ple, 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
have been detected that can identify certain populations with in-
creased or decreased susceptibility. One well-studied example
is fast versus slow acetylators, in which the metabolism of cer-
tain 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 bi-
ological 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
The importance of single nucleotide polymorphisms has
greatly changed the individual-susceptibility landscape, al-
though the number of actual, documented examples is small.
The discovery of new relationships between human polymor-
phisms 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 individual-
ized 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
lishing a genomic basis for individual susceptibility is a modern
approach to an issue that has existed for some time for indi-
viduals who take drugs for clinical benefit and for populations
exposed to chemicals in the workplace.
chemical or chemicals to which they are exposed. The dilemma
has been whether to set safety limits for exposure to such chem-
icals on the basis of the most susceptible individuals in the pop-
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
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
in the workplace. The purpose of this action is to protect the
health of the individual and reduce or eliminate the company’s
involved in clinical trials. Once marketed, however, the num-
ber 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 (Pirmo-
hamed et al., 2004; Wiffen et al., 2002). The cost to society can
be considerable, both in terms of individual harm and economic
The difference in societal consequences between events in-
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 ac-
cepted 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. Expo-
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.
marketability or profitability of products), or society (e.g. better
availability and quality, and lower costs, of consumer products
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 in-
dustry, 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.
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 Nondiscrim-
ination Act (H.R. 493) became law. The legislation seeks to
ment. 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’
(e.g. children, the elderly, populations with particular genetic
polymorphisms), which are often viewed as particularly vul-
nerable to environmental toxicants, are a test case for ensur-
ing health-information privacy, which seeks to protect individ-
uals with respect to health insurance and employment. This bill
was reported in the US Senate in April 2007 (S. 358, US 110th
The scientific community at large faces an enormous chal-
lenge, 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, diag-
noses, 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 pro-
vide safe and effective medicines for the treatment of diseases.
The Institute of Medicine convened a committee of pharma-
cologists, academics, and members of the alternative medical
community to develop a report on alternative medicine (Insti-
tute of Medicine of the National Academies, 2005). Although
many recommendations were included in the report’s summary
should be approved by the US Food and Drug Administration
(FDA), nor was there any recommendation that safety and ef-
ficacy 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 sup-
plements must be resolved, because billions of dollars are being
spent on ‘medications’ consumed by the public, most with un-
uate the need, safety, and efficacy of any product which claims
or infers medical benefits.
acceptance without the requirement for safety testing. However,
natural and synthetic chemicals are handled similarly from a bi-
ological perspective (i.e. kinetics, metabolism, mechanisms of
toxicity) (National Research Council, 1996). There are several
well-documented toxicities associated with the use of alterna-
tive 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 carcinogenic-
ity resulting from the intake of natural weight-loss supplements
containing aristolochic acid (Cosyns et al., 1999), and the re-
and the intake of supplements containing ephedra (Fontanarosa
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 prod-
ucts. 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 dis-
ease. From a societal viewpoint, it can be argued that as long
as an individual benefits from an alternative therapy, the ab-
sence 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 pa-
tient’s belief that the medicine will be effective. Nevertheless,
ference to the patient’s feeling of well-being cannot and should
not be underestimated.
ticals should be based solely on the outcome of well-designed
clinical trials. The vast majority of scientists believe that evi-
dence of efficacy is an absolute requirement for the sale of sub-
stances 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 individ-
ual 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
scientists dismiss the use of alternative therapies on the basis of
general ‘scientific illiteracy’. Any therapy, traditional or alter-
native, to which the public avails itself should be beneficial and
without significant risk.
Education of the Public on the Precautionary
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 impor-
application (Commission of the European Communities, 2000;
Health and Safety Executive, 2007; Joint Nature Conservation
threats of harm to human health or the environment, precaution-
tionships are not fully established scientifically” (Raffensperger
neously as meaning that unless there is confidence that humans
(or the environment) will not be harmed by a chemical, the sub-
stance should not be used until appropriate evidence of safety is
available. However, it was also stated in the origin of the prin-
ciple 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 applica-
tion 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
vironmental or public health terms.
The most scientific approach to the prevention of injury to
humans from chemicals or substances is the use of the risk-
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 fac-
tial for human hazard posed by exposure to chemicals. It is im-
portant to ensure that the public is made aware of the substantial
efforts that scientists and regulators make (through rational risk
human health and the environment from chemical threats. Com-
fidence 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 understand-
ing and inappropriate application of the Precautionary Principle
will remain a serious challenge to the risk-assessment process,
minimal risks from everyday activities are poorly tolerated by
Obesity in the Developed World (2009)
The incidence of obesity is reaching epidemic proportions in
the developed world (Centers for Disease Control and Preven-
tion, 2007a; Mokdad et al., 1999; National Institute for Clinical
prone to obesity. Apart from the direct consequences of obesity,
there are several diseases indirectly associated with the condi-
tion 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 evolu-
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
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
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 well-
balanced 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
uals 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 in-
creasing evidence that this genetic component is a key factor in
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
are, at best, controversial. Progress in the development of phar-
maceuticals that reduce appetite has been more encouraging,
but even this success depends largely on the compliance of indi-
viduals, as well as their physiology and biochemistry. Whether
of societal choice and the continued abandonment of common
dogma to prevent or tackle the problem of obesity, it must be
versial. 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
The science of dieting is not well understood; neither is it a
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 reg-
imen, 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.
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
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.,
Aylin, 2005; Wilmoth and Longino, 2006). A higher proportion
of older patients are now manifesting, for example, obesity, dia-
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 med-
ications, bacterial resistance to antibiotics will make pharma-
ceutical therapy more complex, and drug toxicity and adverse
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 evalu-
ated for this possibility. The problem of the toxicity of mixtures
health. The very population with the greatest need for expensive
will be the population with the least ability to pay for those re-
sources. Social-servicesexpenditure will increase as people live
longer. These societal issues greatly affect how resources will
be deployed to target sub-populations for drug development, in-
vestigation of dietary supplements, and approaches for avoiding
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
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 envi-
ronment 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 (Kirk-
land 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 ap-
ply to humans increasingly requires a mechanistic understand-
ing 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
tion, 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 re-
sources (including animals) more efficiently, and that improve
istry techniques. With the development of new technologies,
particularly ‘omics’, individual variations in susceptibility can
be identified, as can variations in susceptibility at different life
Like most of the scientific community, HESI has tradition-
ally focused its attention on the risks of representative indi-
vidual chemicals or classes of chemicals. The mapping ex-
ercise 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
The HESI map includes scientific issues that, over the next
10 years, include the application of new technologies for de-
velopment 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
Cancer Testing (2005)
Numerous difficulties have been identified with the current
use of 2-year bioassays in rodents to predict carcinogenic ac-
tivity. Obvious issues are cost and time. More important, how-
ever, 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 lit-
DNA, mimicking radiation carcinogenesis. It was also assumed
that chemical carcinogens in animal models would be carcino-
gens in humans (interspecies extrapolation) at any dose (dose
ity assays in rodents are not always indicative of carcinogenic
rin (an artificial sweetener) show that cancer in rats occurs by
et al., 2003). Quantitative differences in response are illustrated
by chloroform (a contaminant in water) and melamine (an in-
dustrial chemical and pesticide) which produce cancer in rats
only at relatively high doses. Exposures to lower levels reflect-
ing actual human exposures are not carcinogenic (Meek et al.,
2003). With the development of mode of action and human rel-
evance 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 re-
sults of the carcinogenicity assays with respect to relevance of
cancer risk to humans.
Chemicals producing cancer have been divided into DNA-
trapolation to humans. Various approaches are being developed
are based on examination of mode of action using shorter-term
search Council, 2007). In addition to further modifications of
existing assays, these approaches incorporate many new tech-
nologies and further expand the use of structure-activity rela-
tionships. Incorporation of developments in genomics is being
efforts include the development of transgenic and knockout an-
imal models that incorporate information about mechanisms of
action (Gulezian et al., 2000; MacDonald et al., 2004), molecu-
application of transcriptomics, proteomics, and metabonomics
to focus on better predictive methods based on science, rather
than relying on observational testing involved with current ro-
dent assays. Advances in computerized structure-activity rela-
of various biological activities, whether they are therapeutic or
An urgent need exists to devise new approaches to cancer-
standing of carcinogenesis based on scientific, mechanistic in-
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
of such approaches should not necessarily be judged against the
2-year rodent bioassay, as this assay has been shown to be inac-
curate in predicting human carcinogenesis.
Tiered Approach to Assessing the Bioaccumulation
of Chemicals (2005)
Assessing the bioaccumulation potential of chemical sub-
stances is an important issue that will affect international chem-
ical management policies and public-health decision making.
Further advances in bioaccumulation science are needed to reli-
ably assess this substance-specific property in an efficient man-
ner. To develop effective guidance for a tiered approach to eval-
uate the bioaccumulation potential of chemicals, international
consensus and coordination is necessary.
near future for their aquatic bioaccumulation potential in North
America, Europe, and Asia. Some of these chemicals are per-
sistent, 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 as-
chemicals, there is a need to develop reliable tiered approaches
for assessing bioaccumulation potential.
Bioaccumulation is the culmination of multiple physiologi-
ing aquatic and mammalian species that focus on ADME are
being explored. New approaches under evaluation include im-
provement 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
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 genotox-
icity assays has been shown to be relatively high, demonstrating
the low specificity of these assays (Kirkland et al., 2005). Be-
cause it is generally believed that data obtained in vitro demon-
strate the intrinsic genotoxic properties of the test compounds,
ies, 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 plausi-
ble that there exists a threshold concentration or dose below
which there is little likelihood of inducing genotoxicity or
vere cytotoxicity or high concentrations of the test material that
do not reflect anticipated or known human or animal internal
the current issues in the field of in vitro genetic toxicity testing,
see Kirkland et al. (2007a, 2007b) and Thybaud et al. (2007).
toxicity tests for the purposes of accurate human-health risk
assessment needs to be improved. The range of Organisation
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 chemi-
cals. However, in the 25 years since these tests were developed,
through which drugs or chemicals may provoke a positive re-
sponse. 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 in-
centive 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 scien-
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 Weitz-
man, 2004). Suicide, homicide, and infectious diseases are also
serious problems. Although controversial, some evidence exists
in part, to the following problems: congenital malformations;
cancer; sudden infant death syndrome; respiratory disease; en-
ple autism, mental retardation, convulsive disorders, and learn-
ing 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 dis-
eases and children’s diseases, and there are many diseases or
L. L. SMITH ET AL.
medical problems that occur only in children (Table 1; Brent
et al., 2004).
prove 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 con-
duct of clinical trials for life-threatening diseases. The second
initiative was Executive Order 13045 signed by the US Presi-
Risks and Safety Risks’. The Order states that “... each Fed-
eral Agency ... shall make it a high priority to identify and
assess environmental health risks and safety risks that may dis-
proportionately 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 environmen-
tal 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 recog-
nized, 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 stud-
ies utilizing infant and juvenile animals. This deficiency is com-
pounded 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.
equacy of risk assessment for children: (a) the understanding of
pharmacokinetics in children, which is an essential cornerstone
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
These three specific areas of concern are directly applica-
ble to understanding children’s susceptibility to environmental
toxicants: exposure sensitivity; behavior and physiological dif-
ferences; and ongoing development.
Exposure Sensitivity. Are children universally more sensi-
tive 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 in-
nocuous 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
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, result-
ing 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 differ-
are deficient due to lack of rigor.
tal toxicants in the following areas (Brent et al., 2004):
• linear growth and bone maturation;
• maturation of the immunological system and immuno-
logic and allergic reactions to environmental agents;
• endocrine organ maturation and development;
• enzymatic maturation and function of the liver and
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 develop-
ing from birth through adolescence. The major factor is not that
makes them so susceptible; rather, it is children’s vulnerability
due to ongoing development.
In the context of risk assessment applied to the administra-
tion 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. In-
adequate information for this population has led to the off-label
use of a majority of all prescription medications. Developmen-
tal 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).
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
Diseases that occur primarily in infancy, childhood, and adolescence (Brent et al., 2004).
Acute lymphocytic leukemia (predominantly in children). Other malignancies of the white blood cells in
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.
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.
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.
Wilm’s tumor. Accounts for 6% of childhood cancers.
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).
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
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).
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.
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.
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 thera-
peutic 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 Pe-
diatric 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 biolog-
ics 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 supplemen-
tal 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. Child-
hood 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 im-
of adult diseases, such as cardiovascular diseases, cancer, and
neurological diseases that may have their initiation in childhood
Mixtures and Co-exposures (2006, 2009)
occur simultaneously with exposures to many different chem-
icals, sometimes of similar chemical class, but often of other
chemical classes. Moreover, human exposures to chemical mix-
tures 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 tox-
icologic manifestations, such as the effect of cigarette smok-
ing 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 com-
ponent of the mixture or a subset of components caused the
effect. Furthermore, the interactions of chemicals within a mix-
ture or with other chemicals to which an individual is exposed
are frequently unknown. The assumption is often made that in-
teractions of chemicals with known effects, especially if they
have similar toxicologic effects, are additive or possibly syn-
ergistic. 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, in-
cluding an emphasis on possible effects at realistic levels of
exposure, is of increasing importance, and requires several av-
enues 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
tems 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
realistically exposed. When similar mechanisms of actions are
known to exist, it is often appropriate to accept the default as-
sumption of additivity to evaluate the components of chemical
mixtures in their combined state. Even this assumption, how-
ever, has been called into question through the use of ‘omics’
Mixtures continue to be a major challenge for establishing
a scientific basis for performing risk assessments for environ-
mental chemicals. In nearly all such cases, default assumptions
are relied on, despite numerous examples of chemical interac-
tions 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 some-
times possible, such as in the testing of flavor extracts. In these
circumstances, a sufficiently high dose can be administered to
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
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)
Challenges Map in several locations. For a discussion of the
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
challenges associated with sensitive populations, see the Sensi-
tive Populations (2006–2010) subheading in the Societal Issues
Predicting Idiosyncratic Reactions (2008)
Adverse effects resulting from administration of drugs can
be considered predictable (high incidence, dose-related) or un-
predictable (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 con-
sidered to be idiosyncratic. Idiosyncratic toxicities by their very
nature, therefore, present both a human health risk and a chal-
lenge to the development of safe, novel pharmaceuticals.
Idiosyncratic toxicities can affect any organ system; how-
ever, hepatotoxicity is perhaps one of the most widely studied
unpredictable adverse effects, and may present as severe dis-
ease with a long latency period (up to 12 months). This pre-
sentation 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 vari-
ability or inflammatory cytokine status). Preclinical models are
generally recognized as not capable of detecting idiosyncratic
hepatotoxicity, and pre-marketing clinical trials may not be suf-
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. adap-
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. transcrip-
tomics, metabolomics, and proteomics) are particularly chal-
lenging. 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 biolog-
ical processes and pathology to understand the toxicological
significance of observed changes in an ‘omics’ parameter (Pen-
nie et al., 2004). For example, the simple observation that there
is a change in gene expression should not be equated with tox-
icity. 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.
‘Omics’ are high-throughput technologies designed to
evaluate hundreds or thousands of parameters simultaneously,
Several ‘omics’ technologies have been developed, including
gene expression, protein expression, and metabolic profiling.
Additional variations continue to be developed, such as epige-
nomics, DNA methylation status (part of epigenomics), pro-
tein phosphorylation (part of proteomics), and others. Initial
claims for these technologies have been tempered by inves-
tigations demonstrating the limitations of the methods. Issues
such as sensitivity and specificity become paramount when us-
ing these technologies for screening purposes. Other variables,
such as strain of animal, diet, time of day and feeding sched-
ule, 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 pathol-
ogy, biochemistry, genetics, and pharmacology. To avoid being
seduced by technology, adherence to basic biology and the sci-
entific method will guide their proper application. Public dis-
cussions across sectors on the application of these technologies
for risk and safety evaluation are also critical to build consen-
sus on scientifically valid approaches to interpretation of these
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 reg-
ulated industries, as well as for the toxicology community as a
whole” (Pennie et al., 2004).
Sensitive Populations (2009)
Challenges Map in several locations. For a discussion of chal-
lenges associated with sensitive populations, see the Sensitive
Populations (2006–2010) subheading in the Societal Issues sec-
Environmental Toxicology (2010)
The field of environmental toxicology is based on a founda-
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 in-
creasing number of environmental risk assessments, the devel-
L. L. SMITH ET AL.
models is on the increase. One such challenge is the definition
of appropriate test organisms. Unlike human-health risk assess-
ments, for which there is a single species of interest, environ-
species, using only a handful of toxicity tests. Additionally, the
methods currently employed to conduct environmental risk as-
sessments 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 proba-
bilistic 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
ing the methodology and developing the critical thinking that is
necessary to accurately predict the potential for environmen-
tal 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 sci-
entific challenges or advancements, usually result in policy de-
velopment, 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. Deci-
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 regu-
lation in each industry differs. For example, regulation of phar-
maceuticals is aimed at ensuring the safety, as well as efficacy,
of therapeutic agents, and thus requires a risk–benefit assess-
ment. It may be acceptable from a general societal perspective
provides sufficient justification for that risk (although, increas-
ingly, 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 Sci-
tation of large screening and data-collection programs, such as
REACH and DSL (the Canadian Domestic Substances List un-
der the Canadian Environmental Protection Act); (b) the quality
and impact of increasingly available exposure data and mod-
els 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;
gaps; and (f) concerns about fair and equitable protection of the
privacy of individual health information. These issues necessar-
ily include societal and scientific components, and some have
already entered the realm of debate, where risks, benefits, re-
sources, and politics are playing significant roles. In all cases,
HESI perceives a need for global dialogue and harmonization
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 initia-
tives. 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 objec-
tive of these programs is to screen large numbers of chemicals
for the purposes of hazard identification. Compounds of con-
cern identified from the screening process are then evaluated for
human-health and environmental risks.
REACH and DSL will require chemical companies to pro-
vide information to international government agencies on exist-
to, the EU and Canada (Environment Canada, 2006; European
tion of technical workshops with participants from government,
their methodologies in the evaluation of chemicals.
Because a limited number of validated alternatives to ani-
mal testing are available, it is impractical to retrospectively test
every chemical entity for its complete toxicological and eco-
toxicological properties in animal studies. Hence, prioritization
strategies can help to determine which chemicals need addi-
tional data gathered about them. Once high-priority chemicals
type of approach. With REACH in the EU, tier-based decisions
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
formation. The newly established European Chemicals Agency
will soon propose criteria for prioritization. Under the Canadian
must be ‘categorized’ (a priority-setting mechanism) according
to potential for exposure, persistence, bioaccumulation, or tox-
icity (Environment Canada, 1999). Prioritization of chemicals
and data collection.
Programs like REACH and DSL are designed to protect hu-
man 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
in effective communication, outreach, and dialogue. As prioriti-
zation gives way to data requirements, the need for harmonized
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 ex-
ample, 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 ver-
as inhalation or dietary intake, is needed. Confounding factors
such as toxicokinetic variability over time may result in a weak
sue dose. Health consequences may depend on developmental
stage or age, requiring exposure characterizations at multiple
time points (Albertini et al., 2006; National Research Council,
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 appro-
priate focus on toxicological study design and human exposure
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 method-
ological deficiencies must be addressed, including the lack of
practical, cost-effective measurement techniques, the lack of
validated methods for measuring relevant exposure and total
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 im-
provements to exposure analysis for risk assessment purposes,
harmonized guidance and methodologies will be forthcoming
New Technologies (2005)
New technologies (e.g. products and methodologies) can be
promise, however, public acceptance of these new technologies
is typically cautious. Regulatory and industrial perspectives on
new technologies often vary, depending on anticipated potential
Examples of promising, new technologies are identified be-
low. 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 underpin-
nings for toxic injury);
• better in vivo assays for evaluating the impact of xeno-
biotics on biological systems, such as the use of trans-
2000; MacDonald et al., 2004);
altered gene expression and the characteristics and im-
pact of human chemical exposure or pharmaceutical
• platform standardization;
• development of improved analytical measurement ca-
• novel imaging technologies for better understanding
drug distribution and in situ biomarker expression.
• high-yield, genetically modified crops;
• use of nanotechnology in commercial products, en-
ergy generation and distribution, food processing,
building construction, and environmental remediation
(Holsapple et al., 2005; Thomas and Sayre, 2005).
L. L. SMITH ET AL.
All new technologies have associated challenges. In the con-
text 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 no-
observed-effect level that is determined by new analytical tech-
using new technologies represent true toxicity, or does adapta-
tion 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 hu-
man health and environmental safety. New technologies that
represent measurable improvements to, and, where possible, re-
placements for, traditional approaches will ultimately enjoy the
Transitioning New Science into Regulations
and Guidelines (2006, 2007, 2008)
Governments have varying decision-making processes and
are often inconsistent across borders. This makes it difficult for
global industries to maintain current knowledge about and com-
pliance 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 trans-
lated 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
In reality, a lengthy process is required to determine the appro-
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 perfor-
mance with existing methods, and the publication of methods
and results in peer-reviewed journals.
as the institution that approves validated toxicity-testing proto-
cols. 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, depending on the nature of the test, involves research in-
stitutes, academia, industry, and other organizations, such as
ICCVAM (Interagency Coordinating Committee on the Valida-
tion of Alternative Methods) and ECVAM (European Centre for
the Validation of Alternative Methods).2ICCVAM defines de-
tailed 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 toxic-
ity 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 ani-
mals in toxicology tests where scientifically feasible and practi-
cal” (Interagency Coordinating Committee on the Validation of
entific and regulatory acceptance of alternative methods which
are of importance to the biosciences, through research, new test
development and validation, and the establishment of special-
ized 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 sci-
entific community should play an active role in ICCVAM and
ECVAM activities that focus on the applicability of animal test-
Even on completion of the lengthy validation process, regu-
lators must determine whether a given test can fulfill country-
specific or region-specific regulatory mandates for specific sub-
stances. The entire validation process operates within timelines
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.
ernment, industry, and academia is necessary to transition new
(a) avoiding the adoption of new test requirements without sci-
entific 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
which can act as an impediment to innovation.
2It is not the purpose of this paper to evaluate the procedures, value, or
effectiveness of ICCVAM and ECVAM.
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
Conservative Default Factors, Data Quality (2008, 2009)
ibility 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.
• 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 bet-
ter identify biomarkers of both exposure and effect in
animals, compared with humans?
• Have peer-reviewed, scientific publications been
weighted appropriately against ‘gray’3literature?
• When is the quantity of data sufficient to make an eval-
uation or an assessment?
In the absence of adequate information, the use of conser-
vative default factors is reasonable and desirable for protection
of public health. However, the available database must be eval-
uated first, followed by decisions to apply uncertainty factors
to bridge data gaps. Moreover, when new scientific information
becomes available, these uncertainty factors should be modi-
fied appropriately (Dourson et al., 1996). Among other types
of data, human data (e.g. toxicokinetics, biomarkers of expo-
sure, 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 sub-
jects 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 un-
certainty (or safety) factors is the Food Quality Protection Act
special protection for infants and children against pesticides, by
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 Clin-
ical Trials for Therapeutics in Adult Healthy Volunteers (2005)
also recommends a default safety factor of 10, to allow for vari-
in humans. Circumstances under which the safety factor should
and Drug Administration, 2005). The scientific basis for the ap-
plication and extent of such safety factors, however, has been
questioned. A concern exists that the introduction of one—or,
3Gray literature typically includes documents not published in scientific
peer-reviewed journals, such as reports, fact sheets, newsletters, theses, disser-
tations, working papers, and the like.
level of conservatism in the risk assessment that is inconsistent
High-quality data enhance science-based safety assessment.
constructive impact on policy and decision making, resulting in
the development of a rational regulatory framework that is pro-
emphasis on the tripartite approach, involving participation of
scientists from government, industry, and academia.
Sensitive Populations (2010)
Sensitive populations are represented on the HESI Com-
bined Challenges Map in several locations. For a discussion of
challenges associated with sensitive populations, see the Sensi-
tive Populations (2006–2010) subheading in the Societal Issues
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 di-
government, academia, and industry, to identify issues of gen-
lection 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 signifi-
cantly to HESI’s strategic planning, and enabled the organi-
zation 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 impor-
tance to the HESI constituency. Active committees have been
formed on cancer-hazard-identification strategies, risk assess-
ment of mixtures, safety assessment of nanomaterials (a ‘new
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.
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 orga-
Map, additional issues of societal, scientific, and regulatory im-
portance have arisen which are not captured in Appendix 1 (e.g.
food yield requirements). These and other issues would proba-
exercise was conducted today.
judgments based on extrapolations from the present and modi-
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 dif-
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. Al-
from the management of safety issues in society, it recognizes
that toxicology, in particular, is subject to the influence of so-
cietal and cultural mores. For example, societal concerns about
the use and humane treatment of animals have influenced toxi-
cologic 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 manage-
ment. More flexibility might be allowed in the regulatory ap-
plication of scientific data for a pharmaceutical developed for a
sites. Because HESI is committed to an evidence-based exam-
ination of best scientific practices, societal issues are included
to serve as a barometer for the social importance of the scien-
tific and regulatory issues on the HESI Combined Challenges
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 regula-
tory areas. For example, societal concerns inherent in consid-
ering 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 represent-
ing societal, research, and regulatory sectors can solve prob-
lems in an integrated way. Other disciplines, such as the le-
gal and ethics communities, should be included to ensure that
societal, scientific, and regulatory consequences are properly
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 chil-
dren’s health and sensitive populations, there is a clear concor-
dance 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 regu-
latory area. Examples of close integration are evident by com-
paring the issues described in Figures 3–5. Nonetheless, it can
be misleading to think of overlap among societal, scientific, and
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 acceptabil-
ity of these approaches can take several years or longer to be
of difficulties in persuading regulatory authorities of the sci-
entific appropriateness of new technologies or approaches, but
because they are a necessary precaution required by the regu-
latory process to ensure that novel approaches can be sustained
over a long period of time.
Another particularly relevant example of overlap among so-
cietal, scientific, and regulatory areas is the prediction of id-
iosyncratic toxicity associated with the use of pharmaceuticals.
Adverse drug reactions are responsible for untoward, and some-
reactions also result in considerable cost to private insurance
of sensitive populations and development of new technologies,
such as genomics and proteomics. For each issue, scientists ex-
plore new hypotheses that might explain toxic responses. The
regulatory effects. In the case of adverse drug reactions, regu-
latory 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
quences. These scientific and regulatory decisions have societal
implications in terms of the cost incurred by adverse drug re-
actions and patient attitudes toward pharmaceuticals. Although
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
society generally views the pharmaceutical industry as provid-
ing 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 de-
scribed in this paper offers an opportunity for a broad audience
important health and environmental safety issues in the future.
Any organization can conduct a similar exercise to include soci-
For representatives from government, academia, and industry,
the HESI Combined Challenges Map specifies the issues that
reflect the high-priority societal, scientific, and regulatory con-
cerns that provide a challenge for action over the next decade.
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 publi-
cation. 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
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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 Lab-
oratory, Human Studies Division)
Dr. Neil Carmichael (Bayer CropScience)
Dr. Samuel Cohen (University of Nebraska Medical Center)
Dr. Vicki Dellarco (US Environmental Protection Agency, Of-
fice 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 Toxicolog-
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
Appendix 2. ‘Surface Issues’ Identified by HESI Contacts
in Advance of the April 2004 Scientific Mapping Meeting.
? SOCIETAL CHALLENGES
1. Agri-terrorism, terrorism in general
3. Global poverty
4. Genetic modification (GM)/biotechnology—moratorium
5. Nanotechnology—extrapolating anti-GM rhetoric into
other new technologies
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
8. ‘Go east’ strategy
9. Market price of products
10. Cost of research and development (R&D)
11. Impact of changes in the cost of drugs on R&D
12. Freedom to sell—consumer attitude toward food
13. Consumer/public education (e.g. science, biology, toxicol-
versus natural—a chemical is a chemical
14. ‘Silent Spring’ that never happened
15. How to manage increase in speed of communications (e.g.
how to manage internet rumors)
16. Education of society
18. Zero risk
20. Access to clean water and food
21. Environmental contamination of ground water, soil
and air from manufacturing and chemical companies—
determining the risks and developing abatement programs
22. Impact of solid waste disposal
23. Aging world population
24. Sensitive populations and/or economic consequences
25. Children’s health
26. Sensitivity of developing organism
27. Sustainable development
28. Proving the absence of theoretical possibilities
29. NGO pressure—growing skill-base/capability—use of the
internet as equivalent to scientific peer-reviewed literature
30. Interrelationships between scientific community, regula-
tors, consumers, and NGOs
31. Regulatory harmonization—delay and impact on animal
32. Ethics of animal testing
33. Increased pressure regarding animal testing—animal ac-
tivists getting more radical—public support decreasing
34. Data sharing—reduction in animal usage
35. Risk perception
36. Risk and benefit (not just health)
38. Chronic effects of low dose exposures
39. Trust in science industry
40. Independent safety testing
41. Decrease in funding of basic research by government and
42. Independence of regulatory authorities—fear of litigation
43. 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?
44. Precautionary principle
45. Gene therapy
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE
46. Human testing
47. Satellite Disease Mapping System—Geographic Informa-
tion 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
? SCIENTIFIC CHALLENGES
1. Safety assessment of biotechnology products
2. Safety/uncertainty factors (interspecies and intraspecies,
pharmacokinetic/ pharmacodynamic, FQPA, characteriza-
tion of dose-response)
3. Use of ‘systemic dose’ versus ‘external (given) dose’ in
4. Eliminating testing of drugs and chemicals in in vivo an-
imal studies using mg/kg exposures—for toxicology and
5. Simulation and computer modeling of toxicokinetics and
6. Characterization of dose-response curves, particularly at
low doses, including hormesis; mechanistic considerations
8. Guidance and quality control in epidemiology studies
9. Improving epidemiological studies
10. Focus on mechanism, understanding pathophysiology, bi-
ological pathways, cellular interactions and responses
11. Defining adverse (as opposed to adaptive or homeostatic)
12. Defining ‘effect’ versus ‘adverse effect’ (NOEL versus
13. Distinguishing between a ‘change’ and toxicity
15. Children and the elderly
16. Infant and childhood susceptibility
17. Sensitivity of the developing organism
18. Obesity as a toxicological risk factor
21. Metabonomics (For #19, 20, and 21: Predictive tool or
potential replacement for conventional hazard evaluation
protocols. Need for evaluation/validation. Do these com-
‘omics’ markers for a specific product may be more useful
than collecting a wide range of markers.)
22. Integrating ‘panomics’ and other recent advances in
biomedical sciences into toxicology such that safety eval-
uation is improved
23. Bioinformatics approaches and toxicological databases;
develop informatics methodology to cope with mountains
24. Advances in the use of microarrays
25. Sensitivity of new endpoints (with toxicogenomics, ‘ef-
fects’ are seen at levels lower than current NOELs). What
does this mean in terms of hazard and risk?
26. Gaining acceptance of new scientific approaches to safety
approach to validation
27. Use of in silico toxicology as a predictive tool for hazard
28. Genomics and/orpharmacogenetics—‘individualized
medicine—fact or fantasy?’ (Customization of products,
drugs based on individual genetic differences, e.g. SNPs.)
29. Gene therapy—insertional mutagenesis, ethical issues,
30. Toxicology of/exposure to mixtures
31. Immunotoxicology—validation of functional tests
32. Marginalization of the discipline of toxicology
sure, design of population studies
34. Environmental monitoring—sensitivity and relevance
36. Magnitude of genetic risks from environmental drugs and
37. Natural toxins (e.g. mycotoxins, endotoxins) and human
38. Releases of pharmaceuticals into aquatic environment re-
sult in estimated predicted|exposure concentration (PEC):
predicted no-effect concentration (PNEC) ratios larger
environmental risks, development of concepts to set prior-
ities for registration and evaluation, to introduce strategies
for testing and to address aspects of human health
40. Mechanisms in genotoxicity
41. Implications of advancing molecular-biological under-
standing of cellular reactions to the insult of genotoxic
agents to (thresholded) dose response
42. Rehabilitating the term ‘threshold’
43. Proving the absence of theoretical possibilities
44. Understanding the basis for development of drug or target
45. How good are animal models in predicting effects in
humans—development of replacement methods and val-
46. Transgenic animals—models of disease states in humans
L. L. SMITH ET AL.
47. Failure to predict adverse events in populations, under-
standing drug: individual patient interactions
48. Bovine spongiform encephalopathy (BSE) and other prion
diseases in the future
49. Incorporating biology ‘systems approach’ into toxicology
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 Na-
tional Toxicology Program (NTP) two-year bioassay the
it include the NTP bioassay as conducted?
53. Evaluating/validating in vitro testing protocols for onco-
genic risk in humans
55. Nanoparticles/nanotechnology—health issue, opportunity,
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
try and regional level
2. Expansion of Proposition 65-like regulations
3. Harmonization of regulatory interpretation—streamline
process—focus on science rather than politics, trade
• importance of FDA/European Medicines Agency
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
7. Chemical assessment/inerts/REACH—increasing number
of chemical policies globally (also Canadian DSL)
8. Toxicology/risk assessment of mixtures (chemicals and
9. Consideration of impact of multi-drug therapy
10. New regulation—herbal remedies
11. Exposure-based approach to regulatory testing; chemicals
12. Safety/uncertainty factors (interspecies and intraspecies,
conservatism versus scientific relevance in human risk as-
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 sen-
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 accom-
21. Human testing and use of data
22. Theincreasing resistance
Boards (IRBs) to approve certain types of clinical
23. How good are animal models in predicting effects in hu-
24. Animal testing regulations (e.g. EU 7th amendment)
26. Transgenic animals—models of disease states in humans
27. Use of in silico toxicology as a predictive tool for hazard
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 ‘anti-
31. Labeling regulations
32. Gaining acceptance of new scientific approaches to safety
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.
demic scientists with industry ties—from participating on
government advisory committees
37. Continued resistance to address ‘lifestyle diseases’ (obe-
sity) as clinical diseases
38. Risk benefit analysis
39. Accountability of regulations—cost–benefit analysis of
40. Responding to potential biohazards
41. Burden of cancer due to environmental genotoxins; repro-
HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE EXERCISE Download full-text
42. Environmental risk assessment of pharmaceuticals
43. Gene/cell therapy
vice” for encapsulated cell factories)
cleotides [how they get validated and regulated])
46. Incorporation of mechanistic information into risk assess-
47. Re-evaluation of current linear-based approaches to can-
cer risk assessment, including genotoxic chemicals; appli-
cation of margin of exposure (MOE) and/or mechanism-
48. Establishing data quality guidelines for use of science in
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 ap-
propriately define true risks)
to include endpoints beyond body weight and pathology
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, in-
60. Impact of AgHealth Study and National Children’s Study
61. Weighting the ‘gray’ literature
63. Application of new technologies to bring new products to
market—lack of a ‘safe harbor’ mechanism (pharmaceuti-
cals); on the other hand, for the chemical industry, impact
of regulation on innovation; impact of regulation on access
to pesticides for certain applications
particulate matter); includes quantitative structure-activity
relationships (QSARs); validation
65. Transitioning new science into actual regulatory practice