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: email@example.com
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.