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Journal compilation 2008 Nordic Pharmacological Society. Basic & Clinical Pharmacology & Toxicology, 102, 94–99
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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 [1]. 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 [2]. 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 [3].
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 [3], 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 [5]. 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 [6].
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, [email protected]).
the research, and only in 2003 was it internationally MiniReview
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 [7] 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 [8] 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. [9], 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 [16].
this type of language ‘hedging’ [10]. 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 [11], many past reports of ageing, as suggested by animal models [19].
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 [20].
was first described in case series in 1968 [12], 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 [13]. Arsenic poisoning in infants in girls, whose mothers had used diethylstilboestrol during from contaminated milk powder was found to cause permanent pregnancy [21]. Although a prescription drug, this substance brain damage in adolescent survivors in the 1970s [14].
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.) [22]. Skakkebæk biphenyls, the first report on cognitive deficits in children reported in 1987 [23] that carcinoma in situ could be found exposed from contaminated Great Lakes fish came in 1985 in foetal testicular gonocytes, thus suggesting that this [15]. 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
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Saal et al. [24] 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 [29], 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 [1] 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 [31].
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 [26]. 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 [27]. 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 [2]. 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
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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’) [32], 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 [33]. 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
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