Table 2.

Endocrine Principles Applied to EDC Research

Recommendations for the future Basic scientists actively engaged in the development of new knowledge in relevant disciplines should be involved in evaluating the weight-of-evidence of EDC studies, as well as in the design and interpretation of studies that inform the regulation of EDC. Endocrinologists and specialists in other relevant disciplines should be involved in these processes as applicable (i.e. neurologists should be involved if the affected biological process involves the brain). Endocrine principles, such as those outlined in this document, should be incorporated into programs by the EPA and other agencies charged with evaluating chemicals for endocrine-disrupting potential. State-of-the-art molecular and cellular techniques, and highly sensitive model systems, need to be built into current testing, in consultation with the appropriate system experts. The design and interpretation of tests must incorporate the biological principle that EDC act through multiple mechanisms in physiological systems. Testing needs to include models of developmental exposure during critical life periods when organisms may be most vulnerable to even very low-dose exposures.

Endocrine Principles Applied to EDC Research An ED is an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action.

Principles of the biology of endocrine systems Hormones play direct and essential roles in many aspects of development and in adult physiology. Hormones represent the means by which development progresses in an orderly and coordinated manner and by which major physiological processes are coordinated. Environmental chemicals that interfere with any aspect of hormone action should be presumed to produce adverse effects.

Principles of hormone action Hormones act on receptors, and as a consequence, hormone receptor distribution and abundance represent important characteristics defining hormone action. An EDC can interfere with hormone action on the receptor by affecting any number of steps in the biochemical pathway. This includes affecting the amount of hormones produced and interfering with the ability of a hormone to reach the right receptor at the right time and right location. Hormone-receptor systems are “tuned” such that very low doses of hormones effectively alter development and adult physiology. Accordingly, chemicals can interfere with hormone action in very low doses, producing irreversible effects on development and critical physiological systems. Some hormones exert their actions through more than one receptor. Therefore, different elements of the spectrum of effects produced by those hormones are attributable to the different individual receptors. Likewise, chemicals that interact with only a subset of the endogenous hormone's receptors will produce a mosaic of effects that does not reproduce an endocrine disease but may be detrimental nonetheless. EDC exposures during development can have effects on hormone action that cannot be corrected, leaving permanent adverse impacts on cognitive function and other health parameters. People are exposed to multiple EDC at the same time, and these mixtures can have a greater effect on the hormone system than any single EDC alone.

Tier 1 EDSP As a battery of tests, the Tier 1 of the EDSP will only identify a subset of EDC.

The route of exposure and dosing strategy are not optimized to identify EDC. Moreover, the timing of exposure does not include development. The weight-of-evidence guidance developed by the EPA must be strengthened by adhering to principles of endocrinology outlined here, including low-dose effects and nonlinear or nonmonotonic dose-response curves.