ENDOCRINE DISRUPTORS

An endocrine disruptor is any chemical (including dietary) or physical agent that modulates one or several of the endocrine organs or the function of these organs. The endocrine system works primarily as a closed feedback loop that functions to maintain homeostasis. It is made up of a series of organs, the hormones these organs produce and release, and the organs and tissues affected by these hormones. Endocrine disruptors can modulate any segment of the endocrine system.

A simple example of this loop is the axis between the pituitary and the thyroid. The anterior pituitary gland secretes thyroid-stimulating hormone (TSH) in response to signals from the hypothalamus. The TSH travels to the thyroid gland via the circulatory system and activates pathways that lead to uptake of iodine and the synthesis and eventual secretion of thyroid hormone. The thyroid hormone is carried in the blood to end organs and tissues where it regulates metabolism. Thyroid hormone is eventually metabolized in the liver and excreted as a conjugated metabolite. The decreasing levels in the blood initiate a response in the hypothalamus that restarts the cycle in the pituitary gland. If the levels of thyroid hormone are chronically low (hypothyroidism) the anterior pituitary secretes increasing amounts of TSH that, if the thyroid cannot synthesize thyroid hormone (for example, in the absence of dietary iodine), leads to an enlarged thyroid and in some cases goiter. An endocrine disruptor can be any condition (chemical, diet, radiation, stress) that modulates any of these critical steps, or similar steps in any endocrine system.

Several chemical classes have been identified as endocrine disruptors. The compounds that affect the gonadal-pituitary axis are those that modify the metabolism and/or synthesis of estradiol and testosterone, such as the 5[.alpha]-reductase inhibitors that block production of dihydrotestosterone. These inhibitors are drugs, but are also found in herbs such as saw palmetto. Several chemicals are estrogen mimics that bind to the high-affinity estrogen-binding protein called the estrogen receptor (ER). These chemicals include drugs, natural products, and manufactured chemicals. The concern about estrogen mimics is that they may be involved in causing breast cancer, uterine cancer, and developmental defects. In addition, there is a large class of herbal remedies that are marketed for "female" and "male" health. These preparations are physiologically active and clearly modify the target endocrine system. The standard for determining if these compounds are endocrine modulators is to test them in laboratory systems that have been validated as reasonable surrogates for the intact endocrine system. Estrogen mimics that are widespread in the environment are the substituted phenols such as Bisphenol A, and the longer chain nonyl-and octyl-phenols. These are many times weaker than the active human hormone estradiol in classic assays. Several derivatives of the pesticides DDT and methoxychlor are active as estrogens and/or anti-androgens through mechanisms that involve the respective estrogen or androgen receptors. Natural products, such as genistein from soy, exhibit remarkable estrogenic activity.

There are many endocrine-disrupting chemicals in the environment. The question is what impact these agents have, and how they affect public health. In the occupational setting, if high levels of exposure occur, the risk of disease is very high. This was seen during the manufacturing of diethylstilbestrol (DES), the prototypical endocrine disruptor. The effects of environmental levels of estrogen modulators may be masked by dietary factors, natural hormones, or therapeutic agents. However, exposures of select populations, such as PCB exposures in China, may be of such magnitude as to be discernible in the clinical setting.

In the light of public health concern, the best policy is to minimize exposure and at the same time determine the mechanisms of action of each class of chemical involved in disrupting the function of a particular organ system. It appears that for the most part environmental levels of these pollutants may be tolerated in adults (animals and humans) but there are very few data on the effects of these agents in the developing endocrine systems of the fetus or of children.