Module 3 - Strategic case studies in practice

The accuracy of the TD 50 strongly depends on study quality and size. Confidence intervals of TD 50 values from studies with only one or two dose groups are higher as compared to studies with more dose groups. Studies with four or more dose groups are however exceptions. Only in the case of NDMA and NDEA are comparable studies in the same rat strain with the same number of dose groups available. The CPDB reports for each chemical species-specific harmonic means of the TD 50 using the TD 50 values of the most sensitive tumour target of each positive study. Most of the N- nitrosamine studies reported in the CPDB only have one or two dose groups, which are included in the reported harmonic mean TD 50 . On the one hand, this approach gives weight to studies with few dose groups but on the other hand includes the variable sensitivity of different rodent strains. Therefore, neither study specific TD 50 values nor harmonic mean TD 50 values provide an accurate measure for real potency. Using only the most extensive rat carcinogenicity study done for NDMA and NDEA [Peto et al. (1991)] the TD 50 for liver tumours would be 42 µg/kg/day for NDMA and 50 µg/kg/day for NDEA resembling the alkylating potency in figure 2.4.2.1-1. The harmonic mean TD 50 calculated using all rat studies in the CPDB database is 96 µg/kg/day for NDMA and 26.5 µg/kg/day for NDEA, respectively. In addition, other ranking systems like the EPA cancer slope factor also depend on data quality with respect to accuracy. The US Department of Agriculture (USDA, 2014) has calculated the oral slope factor for carcinogenic potency of some volatile and non-volatile N- nitrosamines in pork bacon (table 2.4.3-2). They ranked NDEA > NDMA > NPIP > NDBA > NPYR whereas non-volatile N- nitrosamines such as NPRO, NTCA and NTHZ where ranked as non-carcinogenic. The calculated values with 150 (mg/kg/day) -1 for NDEA and 51 (mg/kg/day) -1 for NDMA resembles the potency ranking by using the harmonic mean TD 50 of the CPDB.

Table 2.4.3-2 Oral slope factors for carcinogenicity of selected N- nitrosamines (USDA/FSIS/OPHS/RAAS 2014)

Oral slope factor (mg/kg/day) -1

Notes

Nitroso-

--dimethylamine (NDMA) --pyrrolidine(NPYR) --piperidine(NPIP) --diethylamine(NDEA) --dibutylamine(NDBA)

51

Source:EPAIRIS Source:EPAIRIS

2.1 9.4 150 5.4

Source:CaliforniaOEHHA

Source:EPAIRIS Source:EPAIRIS

IARC Group3 (“not classifiable as to its carcinogenicity to humans”) referred to as non-carcinogenic by Lijinsky (1979). Not listed by IARC. NTCA is “likely to be of little importance as far as its oncogenic properties are concerned.” (Lin and Gruenwedel1990). Not listed by IARC. Referred to as non-carcinogenic by Lijinsky(1979).

--proline(NPRO)

-

--thiazolidine-4- carboxylicacid(NTCA)

-

--thiazolidine(NTHZ)

-

The ranking of N- nitrosamines by their carcinogenic potency by using data of lifetime rodent carcinogenicity studies depends on the method used and varies. However, it seems to be relatively reliable by means of potency ranking when studies with multiple dose groups and a sufficient number of animals are available. It also seems that most non-volatile N- nitrosamines are of less concern with regard to carcinogenic potency (table 2.4.3-1).

EMA/369136/2020

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