Authors
Bigsby R, Chapin RE, Daston GP, Davis BJ, Gorski J, Gray LE, Howdeshell KL, Zoeller RT, vom Saal FS

Title
Evaluating the effects of endocrine disruptors on endocrine function during development.

Journal
Environmental Health Perspectives 107 Suppl 4:613-8. 1999.

Early development is characterized by endocrine-sensitive periods in which changes in gene activity, tissue differentiation and other physiological events are mediated by the precise coordination of endocrine signals. Endocrine disruption during these sensitive 'windows' may have many different manifestations: implantation failure or fetal death, congenital abnormalities or subtle changes in endocrine function that may not become apparent until the onset of puberty or adulthood. Critical areas of investigation include the regulation of development by three key hormone systems: estrogens, androgens and thyroid hormones. The sex steroids are essential for the normal development of the reproductive system, central nervous system and the immune system, whereas thyroid hormones mediate normal function of most tissues. Thus, disruption of any of these three systems by endocrine-active chemicals (EACs) could represent a potential risk.

Quantification of endocrine signals is essential to the understanding of the risk posed by environmental chemicals. Some chemicals may have additive effects, others may be potent at low doses and have different inhibitory effects at higher doses. Dose-response assessments of endogenous hormones are required to first characterize these responses, followed by assessment of test compounds to ascertain the potential for risk following exposure. Ideally, dose-response curves would be constructed within the range of predicted dosages that regulate endogenous endocrine receptor activity. The shape of the dose-response curve represents another area of investigation as endocrine disruptors may exhibit affinity for multiple receptors. Several key compounds (eg. diethylstilbestrol (DES), methoxychlor, bisphenol A, octylphenol, phthalates etc.) were proposed as test compounds to be used to determine the effective dosage range. These compounds were selected as much is known about their mechanisms of action and adverse effects.

Endocrine disruption during early development, unlike adulthood, can produce abnormalities that are irreversible. Many examples of irreversible errors have been characterized following changes in endogenous estrogen or androgen levels (eg., sexual differentiation, cell function). To best identify the effects of endocrine disruption, identification of biological or biochemical end points that could be measured using screening assays or tests were recommended. Hormone receptor binding and function, steroid synthesis inhibition, plasma transport and rates of metabolism and clearance are key end points that could be used to assess endocrine function. Adverse effects on organ function following endocrine disruption should also be investigated. The authors propose that endocrine disruptor screening systems should be designed to identify chemicals that elicit effects at low doses. As there are many uniquely endocrine-sensitive periods during embryo/fetal development, studies should be designed to investigate endocrine modulation during early embryo and fetal development.

In order to better understand and identify adverse effects of endocrine disruptors during embryo/fetal development the authors recommend further research into the normal regulation of embryo development by the endocrine system. While the authors emphasized the importance of investigating EAC exposure only during embryo/fetal development and not during later periods of life, it may still be difficult to extrapolate these results to humans. The use of biological end points will enable the development of screening assays and tests, and will also provide a standard so that different studies can be compared. Identifying the low dose range of EACs is a critical step in the evaluation of the risks posed by endocrine disruptors, however, the authors do not define "low dose". Indeed, what may be a low dose for one substance may be a high dose for another, depending on potency. For example, what is viewed by the authors as being low dose for chemical contaminants will almost always be much greater than currently prescribed low dose oral contraceptives. Since test compounds are much less potent than oral contraceptives and human exposure to environmental contaminants is lower that that of oral contraceptives, it may not be possible to consider the effects of EACs as low dose.

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