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Sunday, July 13, 2014

Low Dose Response Modeling of Contact Allergy

Some folks think that, once you are sensitized, that there is really no level of exposure to an allergen that is safe.  You must simply eliminate your exposure to it.   For quite a few years, the company I worked for sold a Type IV contact allergen that was used in both industrial (e.g., Metal working fluids) and consumer products (e.g., cosmetics and house paint).   Let’s call it product A.   I was asked to do a risk assessment in which it was determined that the typical dose encountered during Product A's use when compared to the anticipated dose-response would result in a risk that was not unacceptable to the dermatological community. 

It is a fine but important distinction that “not unacceptable” is not the same as acceptable.  It is like the statistical test for differences.  We do not accept the “null hypothesis” we simply fail to reject it. 

For those of you who are unfamiliar with allergic response, it starts with a period of induction in which the body learns to “recognize” the allergen and then marshals its immunological agents to respond to it on subsequent exposures or challenges.   Thus, the first time you contacted “poison ivy” (another Type IV contact allergen) you probably did not get the characteristic rash; however, if you became induced, as about 80% of us in North America are, then you responded with a rash on subsequent exposures to this shiny 3-leaf weed. 

I started this analysis with the following assumptions:        
  •  Everyone who comes in repeated contact with Product A in normal use would become induced; that is, they would be sensitized.    This may not be true but it would be worst case.
  •  That there was no threshold of allergic response to sensitized individuals.  Again, probably not true but worst case. 
  •  That the dose-response of sensitized individuals was described by the standard log-probit dose-response curve.
  •  Guinea Pigs are a good model for human response.   That is, we can use the dose-response from these animals as a reasonable surrogate for human response.
  • That a risk of getting a skin rash from exposure to Product A of 1 in 1,000,000 would be considered de minimus or at least not unacceptable.
A final assumption is that the appropriate dose metric for contact allergy is the maximum amount of allergen applied to any particular square centimeter of skin.   Indeed, dermatologists have shown us for many years that they can both induce dermal sensitization and elicit an allergic skin rash through relatively small patches on the skin of about a square cm or so of area.   Exposing the skin over larger areas for the most part did not result in significantly different responses.


Well, it turns out that the model did a pretty good job of predicting human response for both induction and elicitation of an active skin rash.   The work was presented to the dermatolgical community and published in a peer-reviewed journal of this group.   Anyone wishing a copy of the original paper should ask me at mjayjock@gmail.com and I will send it to them.

This blog gets posted mostly to LinkedIn Discussion Groups.   As their name implies, these groups are set up to foster discussion.  I have promised to try and make this blog more interactive.  Thus, I will be asking some questions at the end of every blog from now on to encourage some discourse within the various groups or directly to the blog as you wish.

This question this week:  In general, how do you view low-dose extrapolation of dose-response models for the purpose of risk assessment?

8 comments:

  1. First, I discovered this blog through a linked-in message, maybe the first useful result of a relationship on linked in. Second, I find these posts to be excellent at defining important issues rarely addressed by the IH community.

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    1. Thanks Frank - that is high praise from someone I admire.

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  2. Back to your specific question on dose (exposure) response models. I agree that risk rates should be extrapolated from the POD, which is about 10%, down to lower risk levels. This is more useful in the OSHA context than the NOAEL(BD)/UF approach. This doesn't solve the problems of acceptable risk for endpoints other than cancer, or accounting for sub acute to working lifetime exposure, or for deriving the NOAEL(BD) from studies in people.

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  3. Mike - interesting blog. How do you address different time scales? Patch test is an instantaneous skin loading while for some consumer uses the skin loading builds up over time (e.g. vapor adsorption to skin)? Thanks for blogging. Mick

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  4. You pose a very interesting question. The assumption is that the amount going on the the highest exposed cm2 of skin per day is the dose. As far as I can tell no one has studied a dose metered evenly over 24 hours versus one that is applied all at once in a patch. It is well know, however, that there is a considerable lag time as the chemical goes through the stratum cornium to the biologically active regions of the skin.

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  5. Mike - I believe patch test checks skin after 24 hr exposure. I suppose worst case would be to compare the calculated dose over 24 hours to the patch test using an appropriate assessment factor. What is your opinion? thanks mick

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  6. Hi Mick,

    My sense is that you can compare the concentration in the patch (mg/cm2) to a daily exposure directly. Best Regards, Mike

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  7. read many article, but this is really worth. thanks for sharing.
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