Hello nitrosamine community!
Does anybody have experience in calculating AI limits for pediatric populations?
Does it make sense to apply EPA’s factors for mutagenic carcinogens (EPA, 2005) to AI limits: 10× for ages 0–2 and 3× for ages 2–16?
Is extrapolation from adults based on body surface area or weight appropriate?
Do we need to consider additional safety factors?
Thank you for all comments/suggestions/contributions.
I would not mix US EPA guidance and ICH M7 guidance since they have fundamental differences. Under EPA’s guidance, they assume a (potentially) 10x higher potency for ages 0-2, but then also modify the exposure by a factor of 2 yr/70 yr to account for the short duration.
Thanks @SSimon and @SusanFelter for clarifying, it is a recurrent question in forums when discussing AI adjustment.
My understanding is that FDA does not allow AI adjustment based on population, route of administration, nor body-weight corrections for nitrosamine impurities.
For non-nitrosamines, I believe ICH M7 does not recommend such adjustments as the TTC limits are consider very conservatives.. is my understanding accurate, Susan?
I don’t believe we should be adjusting AIs based on the language in M7, per Section 7.5: The above risk approaches described in Section 7 are applicable to all routes of administration and no corrections to acceptable intakes are generally warranted. Exceptions to consider may include situations where data justify route-specific concerns that should be evaluated case-by- case. **These approaches are also applicable to all patient populations based upon the conservative nature of the risk approaches being applied.
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Also in Section 4.3 “…expansion into patient populations that include pregnant women and/or pediatrics will not warrant a reevaluation, assuming no increases in daily dose or duration of treatment.”
Dear Matthew, thank you so much for your response! These are exactly the two paragraphs I would use for the argumentation that no adjustments are required. 