In Defense of Dermal Exposure Modeling

A couple of weeks ago this blog had an Argument Against Dermal Exposure Modeling from Chris Packham which I thought made some good points.   However, being an advocate of modeling myself, I thought I would open the discussion to others for their input and publish some of the counter arguments. 

Before I get to this, one of my colleagues asked for specific clarification.  She was not sure from the discussion exactly what the purpose of estimating dermal exposure might be in our discourse.  My sense is that we are looking for quantitative estimates of systemic and local tissue exposure and dose estimation to use in comparison with dose-response information to determine or estimate the potential risk to human health from dermal exposure.  This determination of risk would be used like any other risk assessment to make decisions about potential risk management.

I had a few folks write to me defending the “no need to quantitatively model dermal exposure” approach but I also found two good examples of a cogent defense of dermal exposure modeling.    The first comes from Paul Schlosser (an Environmental Health Scientist  at the US EPA).   Paul has been working on a chemical where a significant amount of vapor uptake is via the skin. An abstract is available online :

http://link.springer.com/article/10.1007/s00204-007-0230-5#page-1 

As such, he had some very recent experience with these models.  The second set of comments comes from friend and colleague Wil tenBerge from the Netherlands who has been a thought leader in this area for many years.   Their comments are presented below:

“Something I'd said in my previous posts is that doing the experiments to quantify skin absorption will certainly be costly and time-consuming, and folding that into a PBPK model will take even more time, though simpler modeling approaches should also be useful. I would agree that if it constituted 10% or less of total absorption, that it's not important, not worth counting. But for NMP the absorption of *vapor* through the skin was measured as 40% of what's absorbed when inhalation also occurs, not insignificant, and any liquid contact increases that considerably. The fact that it's difficult doesn't mean it's not worth doing.

The EASH [European Agency for Safety and Health] statement is a bit odd. We generally don't do dose-response experiments on humans, going high enough to cause toxicity, so we typically don't have *measurements* of risk from dermal contact in humans. But the same is true for inhalation or oral ingestion of many chemicals. We *do* have scientific means of *estimating* risk in humans for all these routes of exposure, though. For systemic effects it doesn't matter how it gets into the circulation, just the concentration (peak, AUC, or perhaps other), and with the appropriate PK data we can estimate that about as well for dermal as for other routes. So the statement is simply incorrect.

Figuring or estimating the surface area of skin exposed, especially to incidental liquid contact, may be a bit subjective. But the alternative, which is to ignore the risk, seems a lot worse than a bit of subjectivity.

-Paul Schlosser “

“Dear Mike, Your blogs are always very interesting. I would like to give my opinion on the statement that modelling dermal exposure and dermal absorption is not very productive. Modelling dermal exposure and absorption is certainly not straight forward. One of the problems is to define the type of exposure. There is a need to define type and conditions of dermal exposure to: - gas, vapour - spilling liquid or solids - aerosol of liquid via air - aerosol of solid via air and further: - exposure to bare skin - exposure to skin protected by clothes and further: - exposure to pure substance - exposure to a mixture - exposure to aqueous solution and finally the fraction absorbed - which amount in mg/cm2 is deposited on the skin? - which part adheres to the skin and for what time? - which part evaporates? - which part is permeating the skin (minutes to weeks)? - which parts resides in the stratum corneum? - which part is removed by desquamation (weeks) from the stratum corneum? The IH-SkinPerm is able to quantify: - dermal absorption by whole body exposure to vapour. - dermal absorption by spill of liquid or of solid on the bare skin during a limited period of time. - dermal absorption of aerosol of liquid or of solid, deposited on the bare skin during a limited period of the working day. The deposited amount per day on the skin in relation to the type of work can be read off from so-called guidance documents for risk assessment, based on experimental observations. The real absorption of the dermal deposited dose is assessed by IH-SkinPerm. The accuracy of dermal absorption estimates by IH-SkinPerm for the few dermal exposure scenarios has been assessed by experimental exposures in volunteers. The simulated and experimentally measured absorption fractions were in fair agreement. IH-SkinPerm covers only a few but not all possible types of dermal exposure. The developed theoretical background for IH-SkinPerm is still able to simulate exposure for other exposure conditions and also for mixtures. I would highly appreciate receiving the note of Chris Packham. Best regards, Wil 

-Wil tenBerge

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This subject remains open to anyone who wants to respond to this blog or send me an email at mjayjock@gmail.com; however, I remain strong in my opinion of the positive value of Dermal Exposure Modeling for risk assessment in the context I outlined above.