Michael H. Dong MPH, DrPA, PhD

Environmental Endocrine Disruptors Part I: Toxicity Pineal gland Hypothalamus Michael H. Dong MPH, DrPA, PhD Pituitary gland Thyroid Parathyroid gland gland Adrenal Pancreas glands Ovaries Testicles (women) (men) Readings

05/30/2004, Elk Grove, California, USA

Course Objectives • Be familiar with the terms used, especially those pertaining to environmental endocrine disruption. • Undertake a brief review of the human endocrine system, which regulates our body’s day-to-day function and development. • Understand the basic modes of endocrine disruption. • Appreciate the potential, yet at times even dreadful, effects of endocrine disruption.

Endocrine Disruption • Endocrine disruption can be defined as one or more biochemical actions disrupting the endocrine system, or as the resultant effects. • Its impact on health is not a new concept, as evident from the epidemic linking a rare form of vaginal cancer to the maternal use of the estrogen DES (diethylstilbestrol). • A good number of laboratory assays also have shown successfully that some pesticides and industrial chemicals can induce similar hormonal disruption.

Endocrine System (I) • Cells, organs, and functions in the human or animal body are regulated practically every day by the endocrine system. • Structurally, the endocrine system is a collection of ductless glands that secrete chemical messages known as hormones. • Main function of the endocrine network is to maintain homeostasis of and long-term control in the body by means of chemical signals. It works in parallel with the nervous system to control many body functions.

Endocrine System (II) • The glands that make up the (human’s) endocrine system are hypothalamus, pituitary, thyroid, parathyroid, adrenals, pineal body, pancreas, ovaries, and testicles. • The primary function of these glands is to synthesize and secrete hormones. • Acting as body’s messengers, hormones transfer information and instructions from one set of cells to another; the shape of each hormone molecule is specific and can bind to certain cellular receptors only.

Types of Hormones • Hormones are typically grouped into three classes: steroids, amines, and peptides. • Nearly all the steroid hormones are lipids synthesized from cholesterol; they are responsible for the development of many male and female sex characteristics. • Amine hormones are (all) derived from the amino acid tyrosine secreted by the thyroid. • Most hormones are peptides, thus each with only a short chain of amino acids; they are synthesized largely as proteins first.

Hypothalamus, Pituitary • The hypothalamus is located below the thalamus, in the lower center part of the brain; beneath this gland is the pituitary, which has the size of a pea. Together, these two glands control many other endocrine functions. • Hormones from the two glands are crucial to pregnancy, birth, lactation, and a woman’s menstrual cycle, including ovulation. • Growth hormone and antidiuretic hormone are also crucial hormones secreted by the anterior and posterior pituitary, respectively.

(Para)Thyroid, Adrenals • Thyroid is located in the front and middle of the lower neck; thyroxine and T3 are two important hormones from this gland. • Located within each of the thyroid lobes are a pair of tiny oval-shaped glands called parathyroid; hormones from this gland are the most important regulator of serum calcium. • The two adrenals are each situated atop of each kidney; their corticosteroid and catechol-amine hormones play an important role in metabolism, the immune system, and stress.

Pineal, Pancreas • The pineal body is located near the center of the brain, having the shape of a tiny clone; its hormone melatonin has significant effects on reproduction and daily physiologic cycles, most notably the circadian rhythms. • Pancreas has both exocrine and endocrine functions; its bulk is a ducted gland secreting digestive enzymes into the small intestine. Its endocrine function is by means of its many small clusters of endocrine cells, from which the hormones glucagons and insulin play an important role in regulating blood sugar level.

Ovaries, Testicles • The female ovaries and the male testicles, responsible for many sex characteristics, are referred to as the gonad glands or sex organs. • Female ovaries synthesize the hormones estrogen and progesterone in varying amounts depending on where in her cycle a woman is. • Testicular production of the sex hormone testosterone (a principle androgen) begins during fetal development, continues for a short time after birth, nearly ceases during childhood, and then resumes at puberty.

Modes of Disruption (I) • There are two basic avenues of endocrine disruption, each of which involves primarily two modes of biochemical reactions. One avenue is on the function or the structure of the glands or the target cells, directly or not. • The other avenue is on the metabolism and the function of hormones that the endocrine glands secrete or that the target cells bind to. • In all cases, the disruption can lead to either an excessive activation or an excessive inhibition of a hormone’s normal function.

Modes of Disruption (II) • The endocrine glands as a target organ can be impaired or affected directly or indirectly through certain toxicologic disruptions. • For example, their hormone secretion can be impaired by an intruder’s ability to inhibit the biosynthesis or the secretion process. • Other examples include the secondary endocrine toxicity of DES on the ovary and of testosterone secretion, and the primary toxicity of nicotine on the adrenal, nitrogen on the ovary, and estrogens on the pituitary.

Modes of Disruption (III) • Many foreign substances can mimic certain hormones and hence can bind to those target cellular sites receptive of natural hormones. • Some others can modulate the metabolic pathway of certain (sex) hormones; still some others can speed up the metabolism. • In short, the modes of endocrine disruption include agonistic and antagonistic receptor binding, and those actions that affect the biosynthesis, storage, release, transport, and clearance of hormones.

Pesticides as EEDs (I) • Many pesticides have been identified as environmental endocrine disruptors (EEDs). • More pesticides appear to have an adverse effect on the thyroid hormones than on others. • Some pesticides that are prominent thyroid hormone disruptors are: acetochlor, alachlor, ethylene thiourea, fipronil, heptachlor, maneb, methomyl, and zineb. • Mercury, pentachlorophenol, and PCBs are some of the thyroid hormone disruptors that are not or no longer used as pesticides.

Pesticides as EEDs (II) • Pesticides identified as environmental endocrine disruptors (EEDs) with estrogenic effects include: DDT, dieldrin, endosulfan, fenvalerate, kepone, lindane, methoxychlor, permethrin, triadimefon, and triadimenol. • Pesticide EEDs considered as androgenic or antiandrogenic are: atrazine, p,p’-DDE, lindane, procymidone, vinclozolin, etc. • Those affecting the reproductive system are fewer, including: ketoconazole, oxy-chlordane, tributyltin, and trifluraline.

Literature Evidence (I) • Many in vitro assays are currently used in U.S. EPA’s mandated Endocrine Disruptor Screening Program; these assays are used as the first tiered test to identify and confirm the potential of hundreds (or perhaps thousands) of chemicals as endocrine disruptors. • There are also sufficient in vivo studies showing that many chemicals are capable of inducing endocrine disruption, even at very low doses comparable to background levels in people living in many places.

Literature Evidence (II) • Field observations in wildlife over the years reveal a worrying trend of endocrine disruption affecting their population growth. • From 1970s to 1980s, a great number of herring gulls and other fish-eating birds were noted to have deformities caused by exposure to dioxin released into the Great Lakes. • More astounding is the observation in the 1980s that male alligators in Lake Apopka had testosterone levels as low as a female’s and penises 25% smaller than the normal males’.

Literature Evidence (III) • Although epidemiologic evidence is harder to come by, intriguing observations from epidemiology studies continue to emerge. • For example, two epidemiology studies had linked atrazine to ovarian tumors in Italian women; this antiandrogenic herbicide is known to be capable of affecting steroid metabolism and ovarian functions. • A more recent study showed that perinatal exposure to PCBs is linked to children’s play behavior.

Impacts of Toxicity Data • Evidence shown thus far represents only a small fraction of the vast amount of toxicity data on endocrine disruption; yet it appears to have carried the collective weight of evidence for biologic plausibility and consistency. • A disruptor’s toxicity is critical, but the lesser of the two components of a health risk. • The other component tends to offer more preventive measures and hence appears to play a greater role, in that it counts on the disruptor’s availability for exposure.

Michael H. Dong MPH, DrPA, PhD