Sunday, July 1, 2007

The Critical Period

The International Conference on Fetal Programming and Developmental Toxicity was held from May 20 - 24, 2007 in Torshavn, Faroe Islands, where researchers in the fields of environmental health, environmental chemistry, developmental biology, toxicology, epidemiology, nutrition, and pediatrics met to discuss the human health effects of developmental exposure to environmental toxicants. The focus of the meeting conference was to review the effects of prenatal and infant exposure to toxicants and to examine the lifelong impact of exposure.

As summarized by Christensen (2007), it is already well know that the developing fetus is highly susceptible to the intrauterine environment. As a result, the many physiological processes underway during development are highly vulnerable to toxic effects of environmental contaminants. Upon meeting, the researchers were already aware that toxic exposures to chemical pollutants during times of increased susceptibility can cause disease, functional deficits, and disability in infants and children that may stretch across their lifetime. Congenital malformations are well recognized and documented to occur with environmental exposures to contaminants, such as pesticide exposure. during gestation. The researchers believe that discovering the critical windows of susceptibility is a crucial factor in protecting infants from harm.

"Chemical exposures during prenatal and early postnatal life can bring about important effects on gene expression, which determines normal development" and predisposition to disease risks during adolescence and adult life (Christensen, 2007). "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, amounting to 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" (Christensen, 2007).

The researchers discussed prenatal exposure to diethylstilbestrol, an estrogenic drug no longer used on pregnant women, and its link to an increased risk of vaginal, uterine, and breast cancer. Bisphenol A was noted to result in an increased susceptibility to breast cancer or prostate cancer in very low doses. Vinclozoline, a fungicide, was also noted to promote development of cancer. These substances, and many others are much more carcinogenic to infants and children than adults, mainly due to susceptible periods children go through and their smaller size. The same exposure would be more diluted in an adults larger body than a child's.

The brain is also more susceptible to toxic exposures during development, which may result in social implications and economic difficulties in the absence of any apparent mental or physical disease. Though each exposure may be minor, what has not been studied enough is the total body burden, or the combination of many toxicant exposures which may enhance neurotoxic effects. Add other adverse factors, and the damage from seemingly innocuous substances could indeed be quite severe.

Moving on to the reproductive system, the researchers conferred regarding the vulnerability of the intrauterine hormonal environment to changes, including testicular cancer and poor semen count/quality, both of which have been linked to developmental exposures to maternal smoking and endocrine disrupting chemicals. Also noted were phthalate exposure and pesticide exposure to many common substances, including polychlorinated biphenyl, polybrominated biphenyl, endosulfan, and DDT.

Lastly, the immune system may also be affected by immunotoxic chemicals, which include polychlorinated biphenyls, vaccines, and atrazine among others. These immunotoxic chemicals increase the risk of infections and development of allergy in the child.

In conclusion, the key points discussed were:

  • The mother's chemical body burden is shared with her fetus, exposing the fetus to larger doses relative to body weight.
  • Susceptibility to adverse effects is increased during critical periods of development.
  • Developmental exposures to toxicants can lead to life-long functional deficits and increased disease risk.
  • There is a new paradigm of toxicologic understanding. The old paradigm, developed by Paracelsus, was that "the dose makes the poison". The new paradigm is that "the timing makes the poison".
  • Adverse effects have been linked to chemical pollutants at realistic human exposure levels similar to those occurring from environmental sources.
  • Changes in gene expression as a result of altered epigenetic marking is of concern as it may lead to increased susceptibility to diseases and may be passed on to subsequent generations.
  • Finally, understanding chronic disease processes requires a holistic approach where multiple causalities are examined.

The researchers concluding recommendations are to:

  • Incorporate studies on the etiology of human disease in early development through longitudinal studies with planned birth cohorts, as they may affect subsequent disease risks.
  • Promote cross-disciplinary approaches and translation of animal data on exposure biomarkers and disease susceptibility in studies of human disease.
  • Emphasize the time period of early development in environmental chemical exposure assessment.
  • Consider mixed exposures (body burden).
  • Explore intake of essential nutrients and societal environment in relation to the impact of genetic variation and genetic predisposition to disease.
  • Take into account the susceptibility in early development in toxicological tests and risk assessment of environmental chemicals .
Increase the use of available test protocols to assess reproductive toxicity or developmental neurotoxicity.

In a final statement by the International Scientific Committee of the Conference, "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" (Christensen, 2007).

Sounds like good advice!

-LS

Reference

Chiristensen, TS. PPTOX. The International Conference on Fetal Programming and Developmental Toxicity. Torshavn, Faroe Islands. May 20—24, 2007.
http://www.pptox.dk/Consensus/tabid/72/Default.aspx

Blog Archive