Module 3 - Strategic case studies in practice

TD 50 approach. The ‘1 in 100,000’ risk of cancer is the chance of the rodent species developing cancer, not humans. There are no adjustment factors for extrapolation from animal to humans in this calculation. This has been accepted over the years, as the linear extrapolation provides such a low number, but this should be considered when interpreting this value and performing risk evaluations. BMDL methodologies have the advantages that confidence intervals are used, whole dose response is considered, and covariate analysis can be applied. The BMDL analysis is accessible (e.g. online PROAST) and makes no assumptions about linearity or threshold. The use of this method would ensure a harmonised approach with the method used by EFSA . The use of BMDL 10 as point of departure instead of TD 50 was extensively discussed by the CHMP in the Art 31 referral on sartans and the conclusion to use TD 50 remains unchanged for the moment as there is still no internationally agreed methodology and the need for extensive multiple dose groups studies is much more essential for BMDL10 as for the TD 50 approach. The ad-hoc meeting group acknowledged that a harmonized global approach is needed before the BMDL 10 approach can be used. The ad-hoc expert group also concluded that harmonization of methodology for using BMDL 10 would be possible with manageable effort (see section 3.1.). Another possibility would be using the cancer slope factor described by US EPA. However, the problems are basically the same as those identified for the BMDL 10 approach. As a conclusion, based on all available data, the CHMP recommends using the TD 50 approach. The insufficiencies and shortcomings of human data available are described below. Several N- nitrosamines are known to be potent mutagenic carcinogens in various animal species and therefore have been classified by the International Agency for Research on Cancer (IARC) as probably carcinogenic in humans. In the following, we focus on N- nitrosamines which have been classified at least as probable carcinogens (Group 2A) by the IARC or are mentioned in EFSA (2017). The search was done in PubMed and Embase databases for articles published in English mentioning “nitrosamine” or “nitroso” in the title. Any articles published until October 2019 are considered. For inclusion in our review, an article had to meet the following additional criteria: • Mention of the term “nitrosamine”, “nitroso” or any name or synonym of N- nitrosamine in the title • At least one occurrence of “cancer”, “malignant neoplasm” or “carcinoma” in the title or abstract • Description of a “cohort” or “case-control” study design or the occurrence of the terms “population” or “epidemiology” in the title or abstract 2.4.6. Literature review of epidemiological studies

• No reference to “animal” OR “rat” OR “mouse” OR “hamster” OR “rodent” OR “cat” OR “monkey”

No mentioning of “smoking” OR “tobacco”

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EMA/369136/2020

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