Endocrine modulation versus Endocrine Disruption

Whilst the term endocrine disruption (ED) has become synonymous with endocrine modulation within the EU Hazard based regulatory environment, scientifically they relate to two separate phenomena.

Endocrine modulation can be defined as the adjustment and balance of the hormone system within normal biological processes. It can refer to chemicals or non-chemical stressors (e.g. radiation or temperature) that interact with endocrine pathways or alter hormonal action without ‘disrupting them’ i.e. without causing adversity. This would typically be considered as normal hormonal homeostatic controli. An example would be when exposure to heat can cause the sympathetic nervous system to release catecholamines (e.g. adrenaline) to trigger vasoconstriction and increase cardiac output. Examples can also include essential elements at physiologically normal concentrations, and many are integral to the regulation and functioning of multiple pathways within the mammalian endocrine system. Copper is a good example since it is critical for normal thyroid function being a key component of Superoxide Dismutase (SOD) which is an antioxidant enzyme helping regulate against oxidative damage in the thyroidii, but also intracellularly, copper, along with other essential metals such as Iron, act as co-factors facilitating the regulation of thyroid peroxidase expression which is critical for tyroxine (T4 hormone) productioniii. Copper is also required for neurotransmitter synthesis since it is an essential co-factor for dopamine β-hydroxylase which converts dopamine to noradrenaline and there are further neuroendocrine functions for which copper is necessary, including adrenergic regulation and cortisol release via the hypothalamic-pituitary axisiv.

Endocrine disruption is defined as ‘the alteration of one or more functions of the endocrine system by an endocrine disruptor’.

An endocrine disruptor, is defined by the WHO as ‘an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations’v. In the EU CLP definition, there is slightly different language, but it has essentially the same meaning ‘a substance or a mixture that alters one or more functions of the endocrine system and consequently causes adverse effects in an intact organism, its progeny, populations or subpopulations’vi.

Endocrine disrupting chemicals (EDC) can interfere with hormone biosynthesis, metabolism or action, resulting in deviation from normal homeostatic control. EDC’s can exert their action by antagonising or agonising various mechanisms. Some chemicals mimic a natural hormone, altering regulatory feedback loops or disrupting the timing of their hormonal action. Others can block the effects of a hormone from certain receptors or directly stimulate or inhibit the endocrine system and cause overproduction or underproduction of hormones. Copper is another example demonstrating that both deficiencies or excess can be associated with adversity to the thyroid or stress responses, but there are also further widespread changes in energy balance too. Ultimately, normal homeostatic process can be significantly disrupted resulting in multiple associated adversities. Mechanistically, both modulation and disruption can involve the same upstream endocrine biology however the key difference between endocrine disruption vs modulation is the progression of the endocrine change which results in an adverse outcome. Therefore, the distinction does not lie simply in whether an endocrine pathway is affected; it lies in whether the effect is adverse and causally meaningful. Within the EU regulatory framework for identifying endocrine disrupting chemicalsvii, there is no direct reference to term ‘endocrine modulation’ and instead, it is broadly encapsulated within the three critical aspects needed to meet the definition of an endocrine disruptor. There must be 1) endocrine activity (i.e. an endocrine mode of action); 2) endocrine adversity (i.e. hazardous effect); 3) biological plausibility meaning the adversity is caused by the activity. In this context, endocrine modulators would have endocrine activity, but there should not be evidence of adversity and thus, within the EU CLP framework for defining endocrine disruption, the consideration of what is an adverse change becomes critical to distinguish modulation from disruption. Within the CLP framework, ED adversity is defined as ‘a change in morphology, physiology, growth, development, reproduction or lifespan of an organism, system, population or subpopulation that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influen