Critical analysis of carcinogenicity study outcomes. Relationship with pharmacological properties

Abstract

Predicting the outcome of life-time carcinogenicity studies in rats based on chronic (6-month) toxicity studies in this species is possible in some instances. This should reduce the number of such studies and hence have a significant impact on the total number of animals used in safety assessment of new medicines. From a regulatory perspective, this should be sufficient to grant a waiver for a carcinogenicity study in those cases where there is confidence in the outcome of the prediction. Pharmacological properties are a frequent key factor for the carcinogenic mode of action of some pharmaceuticals, but data-analysis on a large dataset has never been formally conducted. We have conducted an analysis of a dataset based on the perspective of the pharmacology of 255 compounds from industrial and regulatory sources. It is proposed that a pharmacological, class-specific, model may consist of an overall causal relationship between the pharmacological class and the histopathology findings in rats after 6 months treatment, leading to carcinogenicity outcome after 2 years. Knowledge of the intended drug target and pathway pharmacology should enhance the prediction of either positive or negative outcomes of rat carcinogenicity studies. The goal of this analysis is to review the pharmacological properties of compounds together with the histopathology findings from the chronic toxicity study in rodents in order to introduce an integrated approach to estimate the risk of human carcinogenicity of pharmaceuticals. This approach would allow scientists to define conditions under which 2-year rat carcinogenicity studies will or will not add value to such an assessment. We have demonstrated the possibility of a regulatory waiver for a carcinogenicity study in rats, as currently discussed in the International Council for Harmonization (ICH) - formerly known as the International Conference on Harmonization (ICH), by applying the proposed prediction approach in a number of case studies.

Progress in identifying epigenetic mechanisms of xenobiotic-induced non-genotoxic carcinogenesis

“…Whilst substantial progress has been made in identifying epigenetic mechanisms and biomarkers of xenobiotic-induced non-genotoxic carcinogenesis in animal models, determining the human relevance of structurally and functionally distinct non-genotoxic carcinogenic compounds that induce a diverse range of tissue-, gender-, strain-and speciesspecific tumors in animals still remains a major challenge for toxicologists, although several rodent NGC modes of action are generally accepted as not being relevant for humans [4,5,10] A number of human cellular models and humanised rodent genetic models have been deployed for NGC hazard identification but these are unlikely to fully recapitulate human tissue responses to xenobiotic exposure. Given the likely importance of epigenetic mechanisms during NGC it is particularly noteworthy that the DNA methylation profiles of mammalian cells differ from those of the primary tissues from which they were derived due to rapid reprogramming of epigenetic and transcriptional profiles following adaptation of primary cells to culture [67].…”

“…If xenobiotic exposure in animals is found to be associated with either tumor induction or early indicators of neoplastic hazard, then a weight of evidence-based cancer risk assessment is generally recommended. A key contributing factor to the weight of evidence approach for xenobioticinduced non-genotoxic carcinogenesis (NGC) is the determination of a mechanism or mode of action since this provides an entry point for subsequent assessments of potential human relevance [4,5] [Meek 2014]. A molecular basis for species-specific non-genotoxic carcinogenesis has been proposed for a number of compounds [4,5,10] Cohen and Arnold 2016].…”

“…A key contributing factor to the weight of evidence approach for xenobioticinduced non-genotoxic carcinogenesis (NGC) is the determination of a mechanism or mode of action since this provides an entry point for subsequent assessments of potential human relevance [4,5] [Meek 2014]. A molecular basis for species-specific non-genotoxic carcinogenesis has been proposed for a number of compounds [4,5,10] Cohen and Arnold 2016]. However, the diverse range of xenobioticinduced tumor types that are typically observed in animal carcinogenicity studies, often exhibiting tissue-, gender-, strain-and/or species-specificities, make the determination of mechanism and assessment of potential relevance to humans very challenging.…”

Regulatory Aspect of Pre-clinical Studies for Regenerative Medicine

“…Carcinogenicity studies of chemical compounds are to be conducted if (1) the results of genotoxicity studies suggest a concern about carcinogenic potential, (2) a possible risk of cancer in humans has previously been indicated, (3) the structure-activity relationship suggests genotoxic and/or carcinogenic potential, (4) repeated-dose toxicity studies provide evidence of paraneoplastic changes, and/or (5) the parent compound or its metabolite(s) remain in the tissue for a long time, possibly resulting in local histological or pathological changes. Carcinogenicity studies are also required for chemical compounds intended to be used for at least 6 months [13]. The required observation period is 24 to 30 months for rats and 18 to 24 months for mice and hamsters [13].…”

“…Carcinogenicity studies are also required for chemical compounds intended to be used for at least 6 months [13]. The required observation period is 24 to 30 months for rats and 18 to 24 months for mice and hamsters [13]. Antigenicity studies are intended to evaluate antigenic potential of guinea pigs that are challenged repeatedly with the test compound or a compound-protein conjugate, followed by boosting 2 to 3 weeks after challenge.…”