PPTOX 2007  [Printer-friendly version]
May 24, 2007


[Editor's introduction: In this powerful consensus statement, more
than 200 scientists from five continents call for a precautionary
approach to toxic chemicals, to protect fetuses and children from
chemical exposures that may cause serious disease later in life, and
which may also afflict their children and grandchildren. The Faroes
Statement defines a "new paradigm of understanding in toxicology."]

[Introduction: This consensus statement was issued March 24, 2007, by
the International Conference on Fetal Programming and Developmental
Toxicity held May 20-24, 2007, at Torshavn, Faroe Islands, which was
attended by more than 200 biologists, toxicologists, epidemiologists,
nutrion researchers, and pediatricians. The conference was organized
jointly with, and sponsored by, BCPT (the journal, Basic & Clinical
Pharmacology and Toxicology); the World Health Organization; the
European Environment Agency; the Centers for Disease Control and
Prevention; National Institute of Environmental Health Sciences and
National Institute of Child Health and Human Development, National
Institutes of Health. The conference was co-chaired by Philippe
Grandjean (University of Southern Denmark and Harvard School of Public
Health) and Pal Weihe (The Faroese Hospital System).]


Fetal life and early infancy are periods of remarkable susceptibility
to environmental hazards. Toxic exposures to chemical pollutants
during these windows of increased susceptibility can cause disease and
disability in infants, children, and across the entire span of human
life. Among the effects of toxic exposures recognised in the past have
been congenital malformations and other adverse pregnancy outcomes.
These outcomes may be readily apparent and have been linked to
toxicant exposures during or prior to pregnancy. Even subtle effects
caused by chemical exposures during early development may lead to
important functional deficits and increased risks of disease later in
life. The notion of developmental plasticity of organ functions and
disease risks has gained much support from both experimental and
epidemiological studies. The timing of exposure -- with an emphasis on
critical windows of susceptibility -- has therefore become a crucial
factor to be considered in toxicological assessments.

During May 20-24, 2007, researchers in the fields of environmental
health, environmental chemistry, developmental biology, toxicology,
epidemiology, nutrition, and paediatrics gathered at the International
Conference on Fetal Programming and Developmental Toxicity, in
Torshavn, Faroe Islands. The conference goal was to highlight new
insights into the effects of prenatal and early postnatal exposure to
toxicants, and their sustained effects on the individual throughout
their lifespan. The Conference brought together, for the first time,
key researchers to focus on human data and translation of laboratory
results to elucidate the environmental risks to human health.

Research state of the art

The developing fetus is extraordinarily susceptible to perturbation of
the intrauterine environment. Fetal development is adjusted to the
intrauterine environment of nutrients and energy supply to fit the
anticipated postnatal environmental conditions. If a disparity arises
between prenatal and postnatal environments, it can cause
abnormalities in energy metabolism, endocrine functions, and organ
development. Evolution seems to have favoured a "thrifty" phenotype
that optimizes the energy use, but which, in an environment with ample
food and limited energy expenditure, can increase the likelihood of
developing obesity, metabolic syndrome, and associated diseases.

The physiological mechanisms involved in the development of energy and
nutrient metabolism are also highly vulnerable to toxic effects of
environmental chemicals. Chemical exposures during prenatal and early
postnatal life can bring about important effects on gene expression,
which determines normal development and also predisposes to disease
risks during adolescence and adult life. Many environmental chemicals
can alter gene expression by DNA methylation and chromatin
remodelling. These epigenetic changes can cause lasting functional
changes in specific organs and tissues and increased susceptibility to
disease that may even affect successive generations.

New research on rodent models shows that developmental exposures to
toxic chemicals, such as the hormonally active substances,
diethylstilbestrol, tributyl tin, bisphenol A, genistein, can increase
the incidence of reproductive abnormalities, metabolic disorders,
including obesity and diabetes, and cancer, presumably through
epigenetic mechanisms that do not involve changes to DNA sequences but
may be heritable.

Prenatal exposure to diethylstilbestrol, an estrogenic drug no longer
used on pregnant women, causes an increased risk of vaginal, uterine,
and breast cancer. Low-level developmental exposure to a plastics
ingredient, bisphenol A, can result in increased susceptibility to
breast cancer or prostate cancer, and prenatal exposure to
vinclozoline, a common fungicide, also promotes later development of
cancer. These substances are only weak carcinogens, if at all, in the
adult organism but are nonetheless hazardous to the growing fetus. In
addition, when exposure to a carcinogenic substance occurs during
early development, the expected life-span will exceed the normal
latency period for development of the disease.

Functioning of the human reproductive system is highly vulnerable to
changes in the intrauterine hormonal environment. In men, increasing
occurrence of testicular cancer, poor semen quality, and
cryptorchidism have all been linked to developmental exposures to
maternal smoking and endocrine disrupting chemicals, such as
diethylstilbestrol. Additional risk factors include fertility
treatment of the mother, phthalate exposure, and occupational exposure
to pesticides with suspected estrogenic and antiandrogenic activity.
Perinatal exposure to endocrine disrupting chemicals, such as
polychlorinated or polybrominated biphenyls, endosulfan, or DDT
compounds, may affect puberty development and sexual maturation at
adolescence. Expression of some of these effects may be promoted by
predisposing genetic traits.

The brain is particularly sensitive to toxic exposures during
development, which involves a complex series of steps that must be
completed in the right sequence and at the right time. Slight
decrements in brain function may have serious implications for social
functioning and economic activities, even in the absence of mental
retardation or obvious disease. Each neurotoxic contaminant may
perhaps cause only a negligible effect, but the combination of several
toxic chemicals, along with other adverse factors, such as maternal
stress or decreased thyroid function, may trigger substantial
decrements in brain function and may predispose to the development of
serious degenerative disease.

The immune system also undergoes important development both before and
after birth. New evidence suggests that exposure to some immunotoxic
chemicals, such as polychlorinated biphenyls and atrazine, and
maternal stress may cause aberrant reactions of the immune system to
foreign proteins, including vaccines. Such effects may be related to a
shift in immune system balance, with an increased susceptibility to
infections and an increased risk of development of allergy in the

While the research on developmental toxic effects has to date
emphasised maternal exposures and the neonatal environment, the
possibility exists that paternal exposures may also affect the child's
development. Experimental studies suggest that ionizing radiation,
smoking, and certain chemicals may be of importance, and some
exposures may also affect the sex ratio of the children.


Three aspects of children's health are important in conjunction with
developmental toxicity risks. First, the mother's chemical body burden
will be shared with her fetus or neonate, and the child is then likely
to be exposed to larger doses relative to the body weight. Second,
susceptibility to adverse effects is increased during development,
from preconception through adolescence. Third, developmental exposures
to toxicants can lead to life-long functional deficits and
manifestations of increased disease risks.

Research into the environmental influence on developmental programming
of health and disease has therefore led to a new paradigm of
toxicologic understanding. The old paradigm, developed over four
centuries ago by Paracelsus, was that "the dose makes the poison".
However, for exposures sustained during early development, the most
important issue is that "the timing makes the poison". This extended
paradigm deserves wide attention to protect the fetus and child
against preventable hazards.

Part of the new insight derives from numerous animal studies on fetal
programming being responsible for reproductive, immunological,
neurobehavioural, cardiovascular, and endocrine dysfunctions and
diseases, as well as certain cancers and obesity. These adverse
effects have been linked to chemical pollutants at realistic human
exposure levels similar to those occurring from environmental sources.
Among the mechanisms involved, particular concern is raised about
changes in gene expression due to altered epigenetic marking, which
may not only lead to increased susceptibility to diseases later in
life, but the effects may also be passed on to subsequent generations.
Most chronic disease processes are characterised by multi-causality
and complexity. Understanding such processes requires a more holistic
approach that focuses on systems and tissue biology.


** Studies on the etiology of human disease therefore need to
incorporate early development and characterise appropriately the
factors that determine organ functions and subsequent disease risks.
Such associations can best be examined in long-term prospective
studies, and existing and planned birth cohorts should be utilized for
this purpose.

** Cross-disciplinary approaches and translation of animal data on
exposure biomarkers and disease susceptibility need to be promoted for
application in studies of the etiology of human disease. Communication
and clarification of key concepts and terms needs to be stimulated
between the scientific disciplines involved and between these
scientists and policymakers.

Environmental chemical exposure assessment should emphasise the time
period of early development. Exposure data already routinely collected
need to be optimised for application in epidemiological studies. Cord
blood, cord tissue, human milk and other biological samples can be
applied for assessment of exposure biomarkers and for determination of
gene expression changes.

Since humans are exposed to numerous chemicals during development and
throughout life, mixed exposures need to be considered in a life-
course approach to disease. Further, the interaction due to other
life-style factors, such as intake of essential nutrients and societal
environment, needs to be explored. This research should also involve
the impact of genetic variation and genetic predisposition to disease.

** Toxicological tests and risk assessment of environmental chemicals
need to take into account the susceptibility of early development and
the long-term implications of adverse programming effects. Although
test protocols exist to assess reproductive toxicity or developmental
neurotoxicity, such tests are not routinely used, and the potential
for such effects is therefore not necessarily considered in decisions
on safety levels of environmental exposures.

The accumulated research evidence suggests that prevention efforts
against toxic exposures to environmental chemicals should focus on
protecting the fetus and small child as highly vulnerable populations.
Given the ubiquitous exposure to many environmental toxicants, there
needs to be renewed efforts to prevent harm. Such prevention should
not await detailed evidence on individual hazards to be produced,
because the delays in decision-making would then lead to propagation
of toxic exposures and their long-term consequences. Current
procedures therefore need to be revised to address the need to protect
the most vulnerable life stages through greater use of precautionary
approaches to exposure reduction.

Note: This statement has been developed by the International
Scientific Committee of the conference, taking into account comments
and suggestions from the conference participants. The statement
(pending minor editorial revision) will be included in the conference

Members of the International Scientific Committee

David Barker (UK)
David Bellinger (USA)
Ake Bergman (Sweden)
Roberto Bertollini (WHO)
Sylvaine Cordier (France)
Terri Damstra (WHO)
George Davey-Smith (UK)
Erik Dybing (BCPT)
Brenda Eskenazi (USA)
David Gee (EEA)
Kimberly Gray (NIEHS)
Mark Hanson (UK)
Peter van den Hazel (The Netherlands)
Jerry Heindel (NIEHS)
Birger Heinzow (Germany)
Irva Hertz-Picciotto (USA)
Howard Hu (USA)
Terry Huang (NICHD)
Tina Kold Jensen (Denmark)
Philip J Landrigan (USA)
Caroline McMillen (Australia)
Katsuyuki Murata (Japan)
Larry L Needham (USA)
Sjśršur Olsen (Denmark)
Beate Ritz (IARC)
Greet Schoeters (Belgium)
Niels E Skakkebęk (Denmark)
Staffan Skerfving (Sweden)

Copyright 2006 by Thomas Steen Christensen