Is the current product safety assessment paradigm protective for epigenetic mechanisms?

The emerging field of epigenetics has revealed a new layer of gene regulation that is only now being fully explored. Concomitant with the increase in our understanding of epigenetic regulation are questions as to the role environmental factors may play in altering the epigenome. As these correlations between epigenetic changes and toxicity are made, the natural next question is if the current safety assessment paradigm utilizing a no-observed-adverse-effect level (NOAEL) is protective of public health for an epigenetic mechanism.

To begin to answer this question, several case studies were examined where apical end point dose response curves were compared to dose response data on epigenetic end points for 1,3-butadiene, arsenic, and diethylstilbesterol.

This limited examination of the available literature for these three molecules revealed that epigenetic alterations largely fell within the dose response curve for apical effects. Perhaps more importantly, this analysis also revealed some key data gaps that should be addressed such as incongruent study designs and limited epigenetic dose response data for only a small subset of known epigenetic marks. Taken together, the answer to the question of whether the current product safety assessment paradigm is protective of epigenetic alterations is "yes, based on our current understanding of epigenetics". That is, this paradigm would be protective of any mechanism that resulted in adverse effects typically observed in guideline studies, because product safety assessment is based upon observed apical effects to drive an overall NOAEL that is the basis to set reference doses for a risk assessment.

These adverse apical effects are the culmination of all molecular events, regardless of mechanism and may include alterations in the epigenome secondary to the actions of those mechanism(s). The epigenome is in a constant state of flux throughout cellular growth and development, and this dynamic variability is not completely characterized. Thus given the state of our current scientific understanding, a change in itself cannot be contextualized as adverse in the absence of a phenotypic anchor. Clearly, more research is needed in this area to perform additional epigenetic studies that include apical end points with full dose response curves in order to gain a more comprehensive understanding of adverse health outcomes that could be causally linked to epigenetic changes.