NEW: The PPTOX International Scientific Committee has updated the conference conclusions, and the outcome has now been published as an “OnLineEarly” open-access article in Basic & Clinical Pharmacology & Toxicology:
The print version will be published with the conference proceedings in the first 2008 issue of BCPT.
Tórshavn, Faroe Islands, Thursday, 24 May 2007
The Faroes statement:
Human health effects of developmental exposure to environmental toxicants
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 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.
- 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 proceedings.