Hormones are natural messenger chemicals that control growth, development and normal health functions in organisms. For example, fertility and reproductive health is dependent on many different hormones. These compounds have in common, that they exert their regulatory functions via hormone receptors. These receptors are proteins that can associate with their specific binding hormone and subsequently trigger a molecular process (like gene transcription). The ability to associate with a receptor is however not limited to natural hormones. Exogenous synthetic and natural chemicals that are not produced inside the body can also bind hormone receptors. Such compounds are commonly known as Endocrine Disrupting Chemicals (EDCs), and scientifically speaking this term applies to any exogenous substances that interfere with any aspect of hormone signalling (like resulting in changes to hormone levels etc.) (Zoller et al. 2012; Diamanti-Kandarakis et al. 2009). Endocrine Disrupting Chemicals can either trigger hormone action, or they can block receptors, making them unavailable for natural hormones; they can also interfere with hormone-synthesizing enzymes or alter natural hormone levels by affecting the way natural hormones are metabolized, and other mechanisms.
What is special about hormones and EDCs alike is that they do not follow the toxicological principle of “the dose makes the poison”. Instead, they can cause an effect at a low concentration, but have a different or even the opposite effect if the dose increases. Such nonmonotonic dose responses are common for hormones, and they have also been observed for several EDCs (Vandenberg et al. 2012). Nonmonotonicity can be due to several causes, for example because of a positive feedback between receptor occupancy and receptor concentration. This occurs when all available receptors in a cell are bound by hormone (or EDC) molecules and therefore are saturated. The subsequent reaction of the cell is to stop producing new receptors, which will lead to a reduced number of receptors, reduced sensitivity of the cell to the hormone, and a reduced effect, even if the hormone or EDC concentration increase. Another possibility is that effects overlap and cancel each other out, for example when low doses of EDC lead to cell growth, but higher concentrations trigger cell death (Jenkins et al. 2011).
The concepts of hormone action, nonmonotonicity and low dose effects are scientifically undisputed. However, their translation to regulatory toxicology of industrial chemicals is controversial and a source of on-going debate, like discussed at several scientific meetings in 2012 (see Low dose, EFSA; Why are we concerned about EDCs, KEMI; Low dose workshop, Berlin)
What is low dose?
There are several commonly used definitions. Essentially, it depends on the chemical which definition applies.
- “Low dose” reflects the estimated range of all known human exposures to a chemical. This definition implies that all uses of a given chemical and all exposure routes are know and requires high quality data.
- “Low dose” means a dose that reflects the no observed adverse effect level (NOAEL) or below. This definition implies that toxicological data (from animal experiments) are available.
- “Low dose” implies concentrations below the lowest observed adverse effect level (LOAEL), i.e. the dose at which toxicological effects have been observed in previous animal studies.
- “Low dose” reflects levels that are measured in people. This definition implies that biomonitoring data are available for the compound of interest. Low dose studies in animals will consequently administer the necessary dose to reach same blood levels like are common for humans.
More on testing for endocrine disruption in the chemical design process