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Faroes statement on developmental exposure FYI - The statement below was drafted at the International Conference on
Prenatal Programming and Toxicity held this month in Tórshavn, Faroe
Islands. The conference was organized jointly with and sponsored by among others,
NIH, CDC, WHO and the European Environment Agency. The Faroes statement: Human health effects of developmental exposure to
environmental toxicants Background
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 recognized 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 pediatrics 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 remodeling.
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 child. 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. Conclusions
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. Recommendations
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. -----------------------------------------------------------------------
LaVonne Love Switzer
U.S. Environmental Protection Agency
Children and Aging Health Protection Division
1200 Pennsylvania Avenue, NW
Ariel Rios North - Room 2512
Washington, DC 20460
Telephone: 202-564-2711
Fax: 202-564-2733
Email:
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