Regulatory Forum Opinion Piece: Carcinogen Risk Assessment

Abstract

Throughout the last 50 years, the paradigm for carcinogenicity assessment has depended on lifetime bioassays in rodents. Since 1997, the International Conference on Harmonisation (ICH) S1B has permitted the use of a 2-year rodent bioassay (usually in the rat) and an alternative, genetically modified mouse model to support cancer risk assessment of pharmaceuticals. Since its introduction, it has become apparent that many of the stated advantages of the 6-month Tg mouse bioassay have, in actual fact, not been realized, and the concern exists that an albeit imperfect, 2-year mouse bioassay has been replaced by a similarly imperfect 6-month equivalent. This essay argues strongly that model systems, using cancer as the end point, should be discontinued, and that the recent initiatives, from the Organization for Economic Cooperation and Development and Institute of Peace and Conflict Studies, on ''mode of action,'' ''adverse outcome pathways,'' and ''human relevance framework'' should be embraced as being risk assessments based upon the available science. The recent suggested revisions to the ICH S1 guidelines, utilizing carcinogenicity assessment documents, go some way to developing a science-based risk assessment that does not depend almost entirely on a single, imperfect, cancer-based end point in nonrelevant animal species.

Pharmacological Effects and Toxicogenetic Impacts of Omeprazole: Genomic Instability and Cancer

“…There are reports of in vivo studies, in which OME had effects over increased blood flow of the gastric mucosa and PPIs: proton pump inhibitors; TNF-α: tumor necrosis factor-alpha. 6 Oxidative Medicine and Cellular Longevity expression of gastric glycoproteins [69] that is used as a precise and sensitive marker for the gastric mucosal status. Moreover, OME also plays a significant role as an antiacid, pepsin-resistant, and ulceration protector, which helps to protect the mucosal integrity [81] and reduces neutrophil infiltration [69].…”

“…OME, especially for long-term use, may induce DNA damage [6,7]. Genotoxicity assays have been shown that not only OME but all prazoles (e.g., esomeprazole, lansoprazole, pantoprazole, and rabeprazole) can induce chromosomal damages [8][9][10][11].…”

Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC

“…Differences in networks between and within human and animal populations account, in part, for interspecies differences and human variability (Meek et al 2014a). Current approaches explore the applicability of the Adverse Outcome Pathway approach (Collier et al 2016; Edwards et al 2016; Zhou 2015) as a framework for linking the initial molecular interactions with the tumour promotion though plausible key events (Becker et al 2015; Downes and Foster 2015). As the EU evaluation concluded that the incidences were due to chance and bias and the evidence does not indicate that glyphosate is an animal carcinogen, no further assessment of relevance for humans was required.…”

“…The communication of the outcome of the risk assessment is complex and controversial in the case of equivocal results (Downes and Foster 2015). The identification of a mutagenic or genotoxic mechanism plays an important role in risk assessment and requires a critical evaluation of the data as well as expert judgment (Eastmond 2012).…”

Uncertainties of testing methods: What do we (want to) know about carcinogenicity?

“…Pre-and early post-natal exposure is likely to be critical for carcinogenesis, therefore it is unlikely that the standard RCB (not covering this period) is fully predictive for real life human carcinogenesis (review conclusion in Downes and Foster, 2015).…”