Limits calculation a true mystery, help to understand NMPA?

Limits of Nitrosamines
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Hi Everyone, I am really trying to understand the where ‘correct limits’ are been calculated by regulatory bodies.
A recent regulatory highlight article author by @AndyTeasdale, it’s raised the concern about differences in limits for NMPA (CAS 614-00-6) between FDA / EMA / Lhasa database. I am adding here ANVISA to the mix.

His paper referenced: “Limit calculated on the basis of the harmonic-mean TD50 derived from the Carcinogenic Potency Database (CPDB)”… Now please bare with me, I’m not a toxicologist (My respect to you folks).

ANVISA’s recent Nitrosamine guidance referenced: "NMPA - The acceptable intakes listed for the nitrosamines NDMA, NDEA and NMPA were calculated from the TD50 obtained from harmonic mean of the carcinogenicity studies listed in the Carcinogenicity Potency Database (CPDB) available at The Carcinogenic Potency Project (CPDB) While the website is live, when I performed a search for NMPA, it does redirect you to NIH and state “TOXNET HAS MOVED”, it does also mentioned that The CPDB was developed between 1980 and 2005

I decided to go to FDA guidance, Appendix B of Nitrosamine Guidance contains “FDA DETERMINATION OF ACCEPTABLE INTAKE LIMITS”. A sample Acceptable Intake (AI) derivation for NDMA is provided where TD50 values for NDMA are 0.0959 mg/kg/day (rat, based on Peto et al.2 52 ) and 0.189 mg/kg/day (mouse) according to the CPDB. For the AI calculation, the lower (more
54 conservative) value of the rat is used. The reference for CPBD is
Download Carcinogenic Potency Database (CPDB) Data where it states This dataset is no longer updated with new content

I hope you understand my confusion to find the data to calculate what apparently is a simple calculation. Unfortunately, I do not have access to the Lhasa database @David, but Andy already stated it’s a different value.

Any guidance is welcome, Thanks for the help…

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Naiffer, the link you provided to the toxplanet CPDB web-site does provide TD50 values, a study data summary, and literature references to their carc studies. And yes this is a static database. The FDA has determined that the CPDB carc studies for NMPA were not robust enough so that a rat TD50 value could be used. Consequently, they defaulted to the TD50 value for NDEA. NDMA is the most widely studied nitrosamine. The Nitrosamine SAR workgroup is developing monographs for NDMA as well as other popular nitrosamines. Hopefully, these will be published later this year.

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Hi @Naiffer_Host, The Lhasa database is available to everyone at carcdb.lhasalimited.org; it has both the CPDB and Lhasa values for TD50s.

As you say, neither harmonic mean is used for NMPA by the EMA and ANVISA. However, the lower value of 34.3 ng/day comes from the TD50 for the most sensitive organ in the most reliable study, rather than the harmonic mean - a better approach, speaking personally, than using a harmonic mean , and the same approach the EMA have recently used for nitrosomorpholine.

It’s the last entry on the Lhasa page, and refers to Schmahl et al (1975), Cancer Lett, 1, 215-218, where oesophageal tumours were observed in large groups of rats at multiple doses. It’s also the only study for this compound which has a Lhasa TD50, thus the overall Lhasa TD50 is the same as the study one, but the Gold one has been used in this case

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I agree with details provided by @kpcross and @David . The usual difference on selection of particular TD50 value by FDA/EMA/ICH is due to consideration of how human relevant and reliable observed effects and study data are overall by different authorities. Also, thanks to lhasa for taking lead to maintain crucial CPDB information after NIH back step.

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