Introduction to Lhasa Carcinogenicity Database

For many years the Carcinogenic Potency Database (CPDB)¹, created by Lois Gold and her team, was an important source of long-term carcinogenicity study data. However, as the database had stopped being updated from 2007, Lhasa moved to safeguard the data by providing ongoing access through a freely available interface; the Lhasa Carcinogenicity Database (LCDB)². The LCDB was released in 2016 and has since been updated with additional data from the National Toxicology Program (NTP)³, increasing the data set to 7,745 studies covering 1,726 chemical substances. A recent update has also facilitated greater ease of access by enabling substructure and similarity-based structure queries.

TD50 values

As a measure of carcinogenic potency, the CPDB contained TD₅₀ values, indicating the lifetime dose at which tumours would be observed in 50% of animals which would have remained tumour free at 0 dose. These have been reproduced for the LCDB⁴, which now displays both the Lhasa and CPDB TD₅₀ values. This has enabled validation of the calculation method by comparison with the pre-existing CPDB values, as well as expansion of the data set by the calculation of new TD₅₀s from the newly added NTP data.

Discrepancies between Lhasa and CPDB TD50 values

While there is a high correlation between the two sets of TD₅₀ values, there are a number of instances where a CPDB TD₅₀ is available but a Lhasa calculated value has not been supplied. There are several circumstances which may contribute to this:

• The CPDB used two calculation methods to produce TD₅₀s; one using tumour incidence data from intercurrent mortality (lifetable method), and one using only the terminal sacrifice tumour incidence (summary method). When calculating the Lhasa TD₅₀s, only the terminal sacrifice data was available (obtained from the CPDB site). Therefore, Lhasa TD₅₀s have only been provided where the CPDB used the summary calculation method. While it would be possible to use the summary method to calculate TD₅₀s for the remaining studies which originally used lifetable data, the resultant values are likely to be less accurate.
• Lhasa TD₅₀s were not calculated for studies where the original author concluded treatment-related tumourigenesis was not observed.
• The CPDB assigned a notation based on the shape of the tumour incidence dose-response curve for each tumour. Lhasa TD₅₀s were not calculated where this notation indicated the lack of a dose-response relationship.
• Lhasa TD₅₀s were not calculated where only a single concentration of the test substance was used.

Case study- N-nitrosodimethylamine (NDMA)

NDMA is a member of the nitrosamine class of compounds which are of current interest due to their detection in samples of some marketed pharmaceuticals⁵. It is a potent carcinogen which has been well studied. However, there is a difference in the overall TD₅₀s in the rat between the CPDB value (0.096 mg/kg/day) and the Lhasa value (0.177 mg/kg/day). To account for this, we must first understand how these per species values are generated. There may be multiple studies conducted for the same compound in the same species. The CPDB produced a per species TD₅₀ by taking the most potent individual tumour TD₅₀ from each study and calculating the harmonic mean; a process which has been reproduced using the Lhasa TD₅₀s. However, as the Lhasa TD₅₀s were not calculated for all tumours which had CPDB TD₅₀s, there are fewer data points available when calculating the per species Lhasa TD₅₀s.

Looking first at the tumours which have both a CPDB and Lhasa TD50, there is a high correlation between the two sets of values (Fig. 1). Species level TD₅₀s derived from these values alone would be very similar.

Figure 1: Tumours with both Lhasa and CPDB TD₅₀ values 

However, NDMA has additional tumours for which the CPDB TD₅₀s are available but the LCDB TD₅₀s are not. A number of tumours were observed in studies where only a single concentration of the test substance was used (Fig. 2). While this data was not considered appropriate for TD₅₀ calculation by Lhasa, there are CPDB TD₅₀s available, which will therefore contribute to the overall species TD₅₀.

Figure 2: Tumours where only a single concentration was tested

Finally, there are several tumours where the CPDB used the lifetable method to calculate TD₅₀ values. While terminal sacrifice data was available for these, enabling the Lhasa summary method to be used, the two sets of values show a greater divergence (Fig. 3). The lifetable method consistently produced lower, more conservative, TD₅₀s compared to those calculated using the summary method. As such, the summary method-based Lhasa TD₅₀s were not included in the LCDB and so not used in determining the species level TD₅₀s.

Figure 3: Tumours where CPDB used the Lifetable calculation method

With the removal of inappropriate, or less accurate data points it is possible to see how the different summary TD₅₀s ascribed to NDMA have come about. Both sets of values have been maintained in the LCDB to enable both continued access to the CPDB data and allow for transparency in how the data has been derived.

References

[1] Carcinogenic Potency Project (CPDB). https://toxnet.nlm.nih.gov/cpdb/

[2] Lhasa Limited. Carcinogenicity Database. https://carcdb.lhasalimited.org/

[3] National Toxicology Program. https://manticore.niehs.nih.gov/cebssearch/

[4] Thresher A., Gosling J.P., Williams R., Toxicology Research (2019) 8, 696-703. https://doi.org/10.1039/c9tx00118b

[5] European Medicines Agency (EMA), 2020. Nitrosamine Impurities in Human Medicinal Products. EMA/369136/2020. https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf