Generation of TD50 values for carcinogenicity study data

Abstract

Carcinogenic potency is a key factor in the understanding of chemical risk assessment. Measures of carcinogenic potency, for example TD50, are instrumental in the determination of metrics such as the threshold of toxicological concern (TTC), acceptable intake (AI) and permitted daily exposure (PDE), which in turn impact on human exposure. The Carcinogenic Potency Data Base (CPDB) has provided a source of study information, complete with calculated TD50 values. However, this is no longer actively updated. An understanding of carcinogenic potency, which can be derived from dose–response data, can be used as part of human risk assessments to generate safety thresholds under which cancer risk is judged to be minimal. The aim of this paper is to produce a transparent methodology for calculating TD50 values from experimental data in a manner consistent with the CPDB. This was then applied across the same data as used in the CPDB and analysis done on the correlation with the CPDB TD50 values. While the two sets of values showed a high level of correlation overall, there were some significant discrepancies. These were predominantly due to a lack of clarity in the CPDB methodology and inappropriate use of a linear model in TD50 calculation where the data was not suitable for such an approach.

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities

“…In addition, Lhasa Limited independently calculated TD 50 values (herein referred to as Lhasa TD 50 ) based on the same data used for the Gold TD 50 and using Lhasa’s published methodology. 28 The LCDB was searched for available TD 50 values for carcinogenic N -nitrosamines of interest and the most robust available study identified according to criteria noted in ICH M7(R1). 3 Briefly, ideal studies for AI derivation contained 3 dose groups, at least 50 animals per group, with animals treated for a lifetime, with dosing at least 5 days per week; however, studies that did not meet all of these criteria were also considered for AI derivation in our evaluation, particularly when there was a robust tumor response.…”

“…When both Lhasa and Gold TD 50 values existed for a given N -nitrosamine, Lhasa values were utilized since the Lhasa database is current and calculations of TD 50 values are transparent. 28 Additionally, the studies with Lhasa TD 50 values are generally more robust than those with only Gold TD 50 values since Lhasa requires more than one treatment group for the derivation of a TD 50 . In instances where a compound was not reported in the LCDB, tumor incidence data were collected from literature references and a TD 50 calculated using R code was adapted from Lhasa.…”

“…In instances where a compound was not reported in the LCDB, tumor incidence data were collected from literature references and a TD 50 calculated using R code was adapted from Lhasa. 28 In short, a model, based on binomial likelihood and optimized using the Broyden–Fletcher–Goldfarb–Shanno algorithm within the optim function used a linear model to capture the effect of dose on the probability of tumor occurrence and to ultimately estimate the TD 50 . For every N -nitrosamine evaluated, the TD 50 value selected to represent its carcinogenic potency was taken (in a conservative approach) from the most robust study (if more than one study was reported) and, within that study, the most sensitive species, sex, and target organ.…”

Deriving Compound-Specific Exposure Limits for Chemicals Used in Pharmaceutical Synthesis: Challenges in Expert Decision-Making Exemplified Through a Case Study-Based Workshop

“…The CPDB, however, is no longer being updated. As a result, Lhasa Limited is now providing TD 50 values through the Lhasa Carcinogenicity Database using methodology described in Thresher et al 10 The main difference between the Lhasa Carcinogenicity Database and CPDB is that Lhasa excludes the calculation of a TD 50 in certain cases where the carcinogenicity data were deemed not robust, such as when a single dose group is used in the study.…”

Identification, isolation, structural characterization, in silico toxicity prediction and in vitro cytotoxicity assay of simeprevir acidic and oxidative degradation products

“…35 (ii) Carcinogenic potency (TD 50 ) which predicts the median tumorigenic dose (the dose required to produce a tumorigenic effect in 50% of rats) of a chemical in a chronic exposure toxicity test. 35 TD 50 has been used historically as a metric to determine carcinogenic potency and was included in the Carcinogenic Potency Data Base (CPDB) 36 and (iii) developmental toxicity potential which predicts whether a chemical compound is likely to be toxic in a developmental toxicity potential assessment. The developmental toxicity is any functional or structural change, either reversible or irreversible, that interferes and alter homeostasis, normal growth, differentiation, development or behaviour.…”