“A Report of the Italian Society of Toxicology Task Force
on Endocrine Disrupting Chemicals Expert Consensus Documents”

by Emanuela Testai, Corrado L. Galli, Wolgang Dekant, Marina Marinovich, Aldert H. Piersma and Richard M. Sharpe

È stato finalizzato il position paper dal titolo “A Report of the Italian Society of Toxicology Task Force on Endocrine Disrupting Chemicals Expert Consensus Documents”. Il documento si propone di esaminare criticamente gli approcci proposti per la valutazione delle sostanze attive a livello endocrino.

In recent years, following evidence that exposure to environmental chemicals can lead to interference of endocrine function in a number of wildlife species, concern has been expressed by the scientific community that comparable effects might also affect human health.
To answer to these worries in the last years the European Commission has published the report on “State of the Art Assessment of Endocrine Disrupters” (Kortenkamp et al., 2011), and work is ongoing with the organization of a number of meetings and workshops on the issue in association with other authorities (Organisation for Economic Co-operation and Development, US EPA, WHO, etc.), also in order to clearly define what is meant by the term endocrine disruptor (ED). The document has aroused more than a concern in the scientific community both for the scientific and methodological aspects, also in anticipation of an application in the regulatory field. 
The aim of the position paper “A Report of the Italian Society of Toxicology Task Force on Endocrine Disrupting Chemicals Expert Consensus Documents” by Emanuela Testai, Corrado L. Galli, Wolgang Dekant, Marina Marinovich, Aldert H. Piersma and Richard M. Sharpe is to address the definition of a weight-of-evidence (WoE) approach as regards the risk assessment of chemicals acting on endocrine system.
The paper faces the definition of endocrine disruptor (ED) in comparison with endocrine active substance (EAS) based on the relative mode of action, the quality of the studies to support this hypothesis and the reliability of the existence of a non-monotonic curve of the dose-response for these effects.
The authors emphasize that the difference between endocrine modulation and endocrine disruption must be the basis for the distinction between EAS and ED. Indeed, many adaptive, compensatory, and physiological processes necessary for the correct functioning of an organism result in measurable endocrine changes, and it is only when these natural mechanisms are affected by endogenous and/or exogenous factors to such a degree that the organism cannot compensate, that adverse effects are induced. There are clearly specific requirements for a substance to be defined as an ED: 1) the demonstration of an adverse effect in an intact organism; 2) an endocrine disruption mode-of-action (biological plausibility); 3) a causal link between the endocrine activity and the adverse effect (strength of association). Existing regulatory toxicological tests are generally unable to show causal links between disruption of an endocrine mechanism and an adverse effect. A cause-effect relationship should be demonstrated between endocrine activity and an adverse health effect. All the available studies (either positive or negative) should be evaluated, but their quality and reliability has to be carefully assessed in order to give them the correct weight in the WoE approach.
An other crucial point afforded in the document is the potency. Environmental estrogens are often orders of magnitude weaker than the body's endogenous hormones so adversity cannot be presumed or established from the hazard alone, but a risk approach integrating information on the potency of the chemical, the exposure and the susceptibility of the exposed population should be considered.
In the case of EDs there is still a strong debate about the ‘low dose hypothesis’, according to which “low dose effects”, which are not present at higher doses may display a non-monotonic dose-response (NMDR). However, up to now no scientific consensus has been reached as to the validity of the studies supporting the low dose hypothesis.
It follows that before using a cut-off procedure concerning the identification of EDs laid down in various European regulations based on hazard identification, it is necessary to refine the analysis of the mass of data published in the current scientific literature, since often the information gathered lacks a critical methodology needed to make a robust risk assessment. In fact, the differences in endocrine response between species is often assumed which weakens any causal relevance to the estimation of risk and human health assessment. Results obtained in vitro using cell preparations that express different hormone receptors (often transfected in) and that lack any straightforward physiological relevance to the in vivo situation as far as pharmacokinetics and bioavailability are concerned, must be considered as complementary information and not the basis for formulating a hazard identification relevant to human health.