Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 94–99 MiniReview Late Insights into Early Origins of Disease Philippe Grandjean
Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark, and Department of Environmental Health,
Harvard School of Public Health, Boston, MA, USA
(Received August 2, 2007; Accepted August 25, 2007)
Abstract: Burgeoning research into early functional programming has opened a new perspective of developmental originsof disease and organ dysfunction. In examining the roots of this emerging paradigm, it appears that crucial observationswere made already 25 years ago. Clear examples include the discoveries of foetal alcohol syndrome, cancer in daughterswhose mothers had used diethylstilboestrol during pregnancy, and neurotoxicity of lead and methyl mercury. However, thisresearch was often considered controversial, scientific conclusions were cautiously hedged, and stakeholders demandedreplication in excess. Recognition of the new paradigm was therefore delayed, preventive interventions even further so. Inhindsight, and in light of the precautionary principle, the adverse effects incurred on public health and the environmentwould call for responsible judgment to balance reasonable scientific scepticism against the risks associated with inaction. The traditional scientific scrutiny whether confidence limits include the possibility of no effect must be modified to allowconsideration of the likelihood of worst-case scenarios. Additional emphasis should be placed on the question: what couldbe known, given our study opportunities and methodologies? Our late insights into the early disease origins may thenbenefit science and prevention.
The recognition of developmental origins of diseases and
1972. I saw victims from Minamata, Japan, who had travelled
functional deficits constitutes a paradigm shift in toxicology
to Scandinavia to demonstrate the neurological consequences
and public health . This new insight supersedes the past
of developmental exposure to mercury pollution. Their
belief that development was generally a homogeneous and
suffering made a lasting impression on me, and I think, on
invariant sequence of developmental stages and instead
many viewers worldwide, that a mother could be fairly
stresses plasticity, continuity and multicausality . It will
unharmed by the pollution, but would give birth to a child with
likely have tremendous impact on prevention and pollution
serious poisoning, as reported by Japanese physicians .
abatement in the future, and this conference is testimonyof the growing cross-disciplinary attention to this topic
The early origins of a paradigm
worldwide. However, when exploring the origins of the newconcept, a paradox becomes obvious, namely, that very early
The serious consequences of methyl mercury exposures
research discoveries clearly foretold the new understanding,
during early development constituted a warning signal that
but their implications were largely ignored and, therefore,
adverse effects of toxicants depend on the developmental
failed to cause a wider impact on research and prevention.
stage. This epidemic of a new neurological disease started
One may appropriately ask why the paradigm of develop-
in the 1950s in a Japanese fishing village; methyl mercury
mental programming surfaced so late. In order to consider
accumulated in seafood was recognized as the cause of
this question, we need to ascertain the early origins of the
Minamata disease by 1960. However, the official approval of
early origins hypothesis. I will focus on the last 25 years,
this conclusion by government took many more years to
that is, the time since I became professor and chair of envi-
appear , even though developmental neurotoxicity due to
ronmental medicine in Odense, Denmark.
methyl mercury had been reported elsewhere years before
My own interest in environmental health was triggered
[3,4]. While evidence of the vulnerability of the developing
by a TV news programme from the first United Nations
brain was growing, expert groups went no further than to
Environment Conference held in Stockholm, Sweden, in
conclude that the foetus may be more susceptible to methylmercury toxicity than the adult . More recent studies (e.g. from the Faroes and New Zealand) suggested that methylmercury from seafood even far from point sources of pollution
Author for correspondence: Philippe Grandjean, Department of
could also impact negatively on brain development .
Environmental Health, Harvard School of Public Health, P.O. Box
Again, reviews by expert panels emphasized weaknesses in
15697, Boston, MA 02215, USA (fax 617 384-8994, firstname.lastname@example.org).
the research, and only in 2003 was it internationally
accepted that a decreased methyl mercury exposure limitwas needed to protect against developmental toxicity.
Lead provides a parallel and even more compelling example.
Lead poisoning was initially thought to be an acute diseasethat eventually cleared and left no sequelae. The pioneeringstudy by Byers and Lord  showed that lasting brain damageoccurred in lead-poisoned children, but the study had littleimmediate consequence. However, increased concerns aboutenvironmental lead exposure were raised when Patterson in1965  reported from geochemical studies that current leadexposures were 100-fold above ‘natural’ levels. This reportinspired virtually hundreds of epidemiological studies toexamine adverse health effects in children exposed tolead from petrol additives and other sources. Some studieswere non-informative, mainly because of imprecise exposure
Fig. 1. Delayed recognition of developmental effects in human
assessment and deficient design. Highly convincing evidence
beings caused by environmental chemicals. The scientific insight
was published in 1979 by Needleman et al. , who used the
has developed over many years, starting with the first discoveries of
amount of lead retained in deciduous teeth as exposure
occupational poisonings and other intoxications. Later studies of
marker to document that mental deficits in children were
populations with environmental exposures have identified greater
dose-related. Still, regulatory agencies and expert committees
effects in individuals exposed during development, and at lowerexposure levels, to which larger population groups are exposed.
found reasons to raise doubt, and those concerns were of
Lead, methyl mercury and several other substances have followed
course highlighted by industry groups with an interest in
this sequence of events towards the upper right, but available
information on most other environmental chemicals currently is
A contentious atmosphere at scientific meetings stirred
limited to the bottom left of the figure. Redrawn from Grandjean
sharp debates, where alleged or real methodological flaws
were used to raise doubt about scientific conclusions. Inorder to protect themselves against critique, scientists wereparticularly careful about mentioning relevant caveats and
recent report suggests that even lower-level current-day
downplaying the significance of their findings. Linguists call
exposures may not be free of developmental neurotoxicity .
this type of language ‘hedging’ . The lay reader not
These studies focused on neurobehavioural effects in
familiar with this custom may erroneously believe that the
childhood or adolescence, but cumulated subclinical damage
results are more uncertain that they really are. When re-
could potentially trigger or facilitate subsequent development
reading our own 1980s publications on lead neurotoxicity in
of degenerative nervous system disease. Combined with the
children, I discover with dismay that we too frequently used
concept of reserve capacity [17,18], developmental program-
double negations and words like may, maybe and perhaps.
ming could involve a decreased resistance against the effects
In light of current evidence on lead , many past reports
of ageing, as suggested by animal models .
were unnecessarily hedged and underestimated the impact
The experience from the studies of neurotoxicants is
of environmental lead exposure on brain development. As a
summed up in fig. 1. The very first discoveries of clinical
result of the apparent uncertainties, the phase-out of lead
toxicity often occurred under occupational circumstances,
additives in petrol, the most important global source of lead
later on followed by case reports involving children or pregnant
pollution, proceeded only slowly and has not yet been
women. As better studies were carried out, pollutant-induced
toxicity was documented in children exposed to lower levels
The cases of methyl mercury and lead are not unique.
during early development. Deficits were thus observed at
Other impacts of neurotoxicity during development were
widespread and low exposures, thereby contributing to a
discovered 25 or more years ago. The foetal alcohol syndrome
silent epidemic of developmental neurotoxicity .
was first described in case series in 1968 , and, during
The new insights were not limited to brain development.
the subsequent years, dose–response relationships were
One of the most remarkable findings of developmental origins
observed for neurobehavioural delays associated with
of disease was the discovery in 1971 of clear cell carcinoma
maternal alcohol intake . Arsenic poisoning in infants
in girls, whose mothers had used diethylstilboestrol during
from contaminated milk powder was found to cause permanent
pregnancy . Although a prescription drug, this substance
brain damage in adolescent survivors in the 1970s .
was later used as a standard oestrogen for comparison with
Although this experience was later forgotten, evidence is
other industrial compounds. During the following years,
now emerging that developmental exposure to environmental
long-term consequences of perinatal exposure to hormones
arsenic may cause neurotoxicity. In regard to polychlorinated
began to be unravelled (e.g. by Bern et al.) . Skakkebæk
biphenyls, the first report on cognitive deficits in children
reported in 1987  that carcinoma in situ could be found
exposed from contaminated Great Lakes fish came in 1985
in foetal testicular gonocytes, thus suggesting that this
. While polychlorinated biphenyls were later banned, a
cancer could be of intrauterine origin. Ten years later, vom
Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 94–99 MiniReview
Saal et al.  happened upon adverse effects on reproductive
various species, and developmental processes may continue
system development in mice exposed to minute amounts on
to be vulnerable to adverse effects also after birth. As
bisphenol A, a plastics component. Endocrine disruption
suggested by Lucas , a preferred term would therefore
due to industrial chemicals has now become a major concern
be developmental programming, or developmental origin of
human disease and dysfunction. The most recent years have
The roots of developmental vulnerability can be traced
provided a wealth of experimental data in support of this
back even further. Measles infection during early pregnancy
concept  and epigenetic mechanisms, which may be
was first linked to congenital defects by an Australian
heritable, have been firmly supported as a possible mode of
ophthalmologist in 1941. After the advent of modern
immunological techniques in the 1960s, the substantial riskof congenital defects from foetal measles infection was
Challenges to research
finally appreciated. The placenta had been thought to providean excellent barrier against foreign compounds, including
From this brief overview, it is clear that the current shift in
drugs, but an epidemic of congenital malformations
paradigm has roots that extend back in time at least 25
occurred in the early 1960s and was found to be associated
years (table 1). However, because of the dramatic implica-
with the use of thalidomide against morning sickness in
tions of the developmental origins paradigm for both
pregnancy. The idealized placental barrier – thought to be
research and public health, the new concept challenged the
impenetrable by foreign compounds – was then realized to
balance in science between two conflicting obligations .
Good science is characterized by proper scepticism, although
Early insights in related fields of epidemiology also
not to an extent so that no new ideas will be generated.
include Forsdahl’s report in 1977 that infant mortality
Gullibility should not be so generous that it prevents the
geographically was linked to subsequent adult mortality.
distinction between useful and worthless ideas. In regard to
Studies by Barker et al. during the following years showed
our research field, it seems that scientific scepticism in the
that birth weight was a risk indicator for heart disease, obesity
past took precedence and that absence of evidence erroneously
and type 2 diabetes . Important support for early origin
was thought to speak against the early origins hypothesis.
of adult disease came from observations on a cohort born
Indeed, evidence has been only slowly emerging due to
during the Dutch Hunger Winter 1944 –1945 . These
complexities of research. The first warning signs appeared
experiences inspired further epidemiology research empha-
from clinical research, but population studies are time-
sising a life-course approach, where early events were linked
consuming, and animal models must be scrutinized in light of
to subsequent disease development . Birth weight alone is
species differences in developmental stages.
no longer considered the key factor, as it poorly reflects
In addition to the long-time interval between the causative
intrauterine events and depends on several factors unrelated
exposure and the outcomes, epidemiologic research was
to developmental programming. As a recent addition,
severely hampered by common problems with sensitivity,
researchers have begun more systematically to address the
specificity, precision and statistical power. Further com-
toxic impacts on programming (e.g. due to maternal smoking
plicating this research, the exact time of exposure during
development could affect the type of outcome. The lack of
The initial focus of this research was on the foetal origin
specificity meant that confounding could be present, and
of certain diseases in adulthood. However, the foetal period
multifactorial causality would need to be considered. Due
is completed at birth, which occurs at different stages in
to all of these obstacles, studies undertaken in this field ran
Examples of early information on toxicants already available 20–25 years ago on the developmental origins of disease and organ dysfunction.
Foetal alcohol syndrome first described in a case series
Formal recognition that methyl mercury caused Minamata disease
Clear cell carcinoma discovered in girls whose mothers used diethylstilboestrol during pregnancy
Permanent damage found in survivors of infancy arsenic poisoning from milk powder
Infant mortality and low birth-weight first linked to adult mortality
Dose-related mental deficits reported in children with past lead exposure at ‘background’ levels
Cognitive deficits in children prenatally exposed to polychlorinated biphenyls from maternal intake of Great Lakes fish
Adverse effects observed in children exposed to ‘background’ methyl mercury from maternal fish intake during pregnancy
Carcinoma in situ documented in foetal testicular tissue
Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 94–99 MiniReview
the risk of being both expensive and non-informative. As a
routinely labelled ‘negative’, instead of ‘non-informative’.
further hurdle, such studies often take too long for academic
Lead, mercury and other environmental hazards did not
achievement purposes, not to mention short-term grant support.
become more toxic with time, but better science began to
Epidemiology has sometimes been criticized for showing
document effects at lower exposure levels; thresholds for
irrelevant associations (‘black-box epidemiology’) , and
toxicity may be very low, if they exist. After some latency,
almost unachievable goals for optimal epidemiology
consensus was reached, and exposure limits were eventually
research have been promoted, with inspiration from vested
revised downwards. Unfortunately, the delay in preventing
industrial interests that could use such criteria to disqualify
hazardous exposures put large population groups at risk of
unwelcome research . Because virtually all research is
developmental toxicity, and likely continues to do so today.
less than optimal in some way, hedging is a necessary
This experience therefore challenges the traditional ideal of
rhetorical means of projecting due caution and modesty,
the sceptical ivory-tower scientist, who profusely hedges all
when concluding from a study. In seeking the balance
between the innovative but risky, and the correct but trivial,
The developmental origins paradigm suggests the need
the researcher attempts to make the strongest claim for
for a different emphasis in research, perhaps a new paradigm
which there appears to be epistemic authority. In a contentious
of science. A revised perspective could enjoy inspiration
environment, the risks from making strong statements
from the precautionary principle, which has triggered much
increase, thereby pushing inference towards the trivial with
new thinking on prevention in environmental health,
emphasis on caveats and needs for replication.
but not yet influenced the practice and interpretation of
Epidemiology often seems an insensitive instrument to
environmental health science [34,36]. One consequence is
reveal links between hazardous environments and human
that science needs to shed the traditional and monocular
disease. Evidence that, at first, appears to show no adverse
emphasis whether confidence limits include the possibility
effects of an environmental hazard may later on turn out to
of no effect. This is far from being the only interest,
be a false negative when larger and more decisive studies are
although oftentimes this issue is considered the main
carried out. Although the opposite may also occur, false
success criterion. We need to scrutinize one or more worst-
positive assertions in environmental epidemiology appear to
case scenarios: how serious could the adverse effects be, and
be comparatively rare. In general, epidemiology is inherently
how large an effect can be reasonably ruled out?
biased towards the null hypothesis due to such problems as
Another major consideration is of paramount importance.
low statistical power, overemphasis on a 5% probability level,
In interpreting research results, we must recognize that a
imprecise exposure data, and short-term or incomplete
phenomenon may well exist, even if we cannot see it. We
must ask ourselves: what could be known, given our study
Further compounding this bias, scientific tradition
opportunities and methodologies? Only then will we be able
demands less uncertainty by more research. When expert
to properly judge new ideas and allow a promising paradigm
groups of scientists develop evaluations of environmental
to grow. As a related charge, we should critically consider
risks, they often recommend further research with emphasis
the scientific tradition of replication and identify new ways
on ideal practices of epidemiology, although unlikely to be
to inspire innovative hypothesis testing.
feasible within a reasonable time span. Partially as a result
Had these issues been considered 25 years ago, perhaps
of this desire for further information before reaching a firm
the paradigm shift that we are now witnessing would today
conclusion, replication has been hailed as a mainstay in
have been a matter of history, from which prevention would
science, thereby augmenting the inertia. A review of published
already have benefited tremendously. Figure 2 illustrates
papers in environmental health journals will reveal that they
how early research and precautionary action may be logically
primarily deal with a limited, rather stable list of pollutants.
linked to subsequent risk assessment and evidence-based
Lead is one of them, and PubMed now lists thousands of
action. The experience from developmental programming
scientific publications on the human health effects of
indicates that a better and earlier connection between research
environmental lead exposure. Other important toxicants are
and prevention is crucial, and that prudent intervention
poorly studied in comparison. Thus, both research attention
may be warranted in the absence of convincing evidence.
and funding are directed away from new and emergingproblems. Conclusions
With early foundations already laid at least 25 years ago, the
Late science lessons
paradigm of developmental origins of human disease and
Now that the notion of early origins is taking shape, it
organ dysfunction has been slow to develop. The delayed
becomes easier to identify its roots and how the strengths
recognition undoubtedly resulted in major costs to society
and weaknesses of this field of research were misread,
due to the lack of intervention that could have been reasonably
thereby delaying recognition of paradigm change. Scientific
justified long ago. Now that this paradigm is gaining
rigor has often been misunderstood as the unrealistic
ground, its full prevention implications must be recognized.
requirement for controlled studies that could furnish virtual
In addition, this experience suggests that undue scepticism
statistical certainty. Likewise, inconclusive studies have been
and demands for endless replication should be countered by
Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 94–99 MiniReview
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Journal of Medical Microbiology (2006), 55, 127–131Detection of mixed infections with Mycobacteriumlentiflavum and Mycobacterium avium by moleculargenotyping methodsPhilip Suffys,1 Adalgiza da Silva Rocha,1 Adeilton Branda˜o,2Bart Vanderborght,3 Wouter Mijs,4 Geert Jannes,4 Fernanda C. Q. Mello,3Heloisa da Silveira Paro Pedro,5 Leila de Souza Fonseca,6Rosaˆngela Siqueira de Oliveira,7 Sylvia
The following table is only meant as guidance. Under normal domistic conditions an acceptable life span can beexpected, if those in the table indicated polymered medicaments are used. Character explanation: A : good, suitable for continuous usage. B : satisfactory, suitable for periodic usage. F : above average, suitable for periodic or seldom usage. O : no information available at this mo