Sunday, April 13, 2014

Hormesis for Setting OELs: Are you kidding me?

I have been interested in the topic of hormesis for a long time.   Even though I am not a toxicologist, some years ago I was responsible for running an inhalation toxicity laboratory in a large chemical company.   When I mentioned hormesis to my toxicologist colleagues in those days the standard response was for them to roll their eyes and dismiss it as nonsense and definitely non-science.  Their minds were closed to the ideas presented within this concept.  I am bringing it up in this blog in the hope that you will be more open to the possibilities it might present.

I am reproducing the graph I put into the blog last week for convenience.   It shows hormesis as one of 4 possible models presented for low-dose extrapolation. 

Indeed, hormesis is an old concept and is actually referred to in the famous 16th century quote from Paracelsus that has been paraphrased over the years as:  “The dose makes the poison”.   His actual quote is:

Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy. [emphasis added]

I challenge you to think of any medicine that is NOT; by definition and design, good for you at a reasonably low therapeutic dose and a poison at high dose.  A common, but very real, example in most of our medicine chests is acetaminophen (common trade name: Tylenol).  This is a ubiquitous OTC drug, which works quite well for aches and pains and fever at the recommended dose, but is deadly to our livers and lives in doses that are only a 3-5 times higher.

All micronutrients also follow the hormesis curve.  For example, consider the effect on your eyes of not having enough vitamin A in your diet or as a separate supplement.

Now consider a very common industrial chemical: ethanol.  Many of us enjoy the acute effects of ingesting ethanol (aka ethyl alcohol, drinking alcohol) as the active ingredient in beer, wine and hard liquor.  Most of us know that drinking too much can be acutely and chronically toxic resulting in alcohol poisoning and liver disease.  What some may not realize is that, in moderation (i.e., a “low-dose” of 2 drinks per day), one can enjoy the mood altering features of this chemical while also benefiting from an increase in cardiovascular health over those who do not drink any alcohol.  Most Doctors admit that this is true but have fallen short of recommending that nondrinkers start drinking for various reasons.  I will not go into the details of their reasons or the scientific evidence here but the benefits have been fairly well established to be true by research.

There have also been paper published in which low doses of very strong carcinogenic substances have results in less cancer (versus untreated controls) in animal experiments at low-dose. 

Professor Edward J. Calabrese, School of Public Health, University of Massachusetts, Amherst has devoted a considerable portion of his professional career to the study of hormesis.   He has written extensively about it and has organized workshops in which he always invites all sides to this discussion.   Most of these discussions are summarized and presented on the web site:

Dr. Calabrese once asked me to present my opinion of hormesis in low-dose extrapolation and risk assessment for a publication and one of Dr. Calabrese’s workshops:

My conclusion from almost 10 years ago remains the same today; specifically:  “… we will only be able to move forward with hormesis as a default hypothesis [for low-dose extrapolation] after the development and use of tools from the realm of molecular biology.” 

The science of the “omics” (genomics, proteomics, etc) has come a long way in the intervening years but from what I can tell it has not explicitly addressed the above issue.   Indeed, unless and until we really understand the effect of low dose at the human tissue level, we will not know which low-dose response curve is the best as either a default model or specifically applied to any substance.  

Until that happy day I believe that we need to rely on a science-informed political process to do the best we can to describe the actual risk at the OEL along with the frank admission of the uncertainty in that description.


  1. Phenol in throat spray in another good example.
    You have put some good thought provoking articles up on OEL's and I will continue to follow them to help broaden my understanding on their development.

  2. Mike. Thank you for your work. I really appreciate the time you put into your blogs.

  3. Mike: Have you ever reviewed Henry Symthe classic paper "Sufficient Challenge"?

    1. Hi Tip, No I am not familiar with it - could you send it to me?


  4. The linear extrapolation assumption (i.e., no hormesis, no threshold) is a convenient one mathematically. Perhaps convenience trumps accuracy for some folks?

    In ecology, the hormesis idea was described as a subsidy/stress pattern by Eugene Odum several decades ago. Basically, it stated that a small amount of a stress (e.g., fertilizer, pollutant, fishing) could lead to an improvement in whichever measure of ecosystem performance was being observed, and that this gave way to detrimental changes at some higher exposure.

    Seems like this process reflects changes in controlling mechanisms - which is probably what you see as potential clarifications resulting from -omics. Response results from one enzyme system/one species being "benefitted" at low exposure, but other systems/species then affected at higher exposures.