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Monday, July 7, 2014

Evaluation of IHSkinPerm with In vitro Data


It is always exciting to meet a new (to me) colleague and come across a piece of work that materially adds to our understanding of dermal exposure assessment.  This happened for me at the recent AIHce in San Antonio.   I had the good fortune of hearing a presentation by Dr. Deborah Lander entitled:  Are Dermal Absorption Models Effective in Refining Dermal Exposure Assessment for Product Stewardship and Regulatory Risk Assessments?   

Debbie and her colleague William Fasano from DuPont’s Haskell Labs posed this question and set about to answer it.    Some of the salient points listed in Debbie slides include:

       Regulatory requirements increasingly require assessment of     dermal exposure
       There are ways to estimate the loading to the external skin      surface (measurement, and increasingly models)
       Old conservative rule is use 100% dermal absorption unless      MW greater than 500 and Log Kow is greater than -1 and less than 4, then 10% is conservative (De Heer 1999).

She then asked “What is Plan B”?   Which is listed below:

Assuming there is no animal dermal toxicity testing for the substance of interest or similar analog we:

       Could use steady-state permeability (Kp) from an aqueous        solution of infinite volume if applicable
       Could perform in vitro testing on human skin
       Could perform bioavailability studies such as sweat                   extraction (reasonable if water soluble)
       Could use a model to predict dermal absorption

Ah ha!  They looked at the last bullet and considered AIHA IH SkinPerm with the question:  How do the predictions from this model differ from the results of well conducted in vitro studies of 15 neat organic chemicals for 60 minute flux time?   She reports a total range for the ratio of predicted to measured  values of 0.03 to 8.95.    In Dr. ten Berge's work he reports a ratio of 0.1 to 30 for 26 chemicals.   This data set shows that 27% of the model predictions were within a factor of 2,  73% where within a factor of 10 and all of them were within a factor of 30 fold.   Dr. Lander calls these MUs or model uncertainty factors.

Dr. Lander’s results were for VOCs with MW well below 500 and LogKow less than 5.5.   She then examines the situation for neat lipophilic compounds with LogKow greater than 5.5.    Her data indicated that IH SkinPerm is conservative for these compounds and one could probably exclude the application of any model MU.

Clearly an MU of 30 is a relatively large factor but my sense is that it can be brought down by future experimental data in which the consistency of the quality of the experimental data are carefully monitored and assured.   Another approach would be to assign MUs based on the grouping of compound families related to empirical factors such structure.  However, all of this requires more data and good data which is something for the future and because it will need funding it could be the distant future.   What about today?

One might think that the application of an MU of 10 for 73% inclusion or 30 for 100% inclusion would not be very useful but the reality is that in many situations multiplying the model predicted value by 30 will still provide a significantly lower estimate of dermal absorption that the assumption that all of the material contacting the surface of the skin penetrates to the circulatory system of the body.    Also we now have some analysis that indicates IH SkinPerm is conservative for lipophilic (LogKow greater than 5.5) compounds.

The above is what I found most interesting and informative about Debbie’s presentation; however, she has given me permission to send the slides to whomever asks me for them at mjayock@gmail.com.   They cover evaluation of the NIOSH dermal model and some other issues and they have all of the references.   She is also planning on submitting this work for publication.









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