Categorizing the characteristics of human carcinogens: a need for specificity

Abstract

The International Agency for Research on Cancer (IARC) has recently proposed employing "ten key characteristics of human carcinogens" (TKCs) to determine the potential of agents for harmful effects. The TKCs seem likely to confuse the unsatisfactory correlation from testing regimes that have ignored the differences evident when cellular changes are compared in short and long-lived species, with their very different stem cell and somatic cell phylogenies. The proposed characteristics are so broad that their use will lead to an increase in the current unacceptably high rate of false positives. It could be an informative experiment to take well-established approved therapeutics with well-known human safety profiles and test them against this new TKC paradigm. Cancers are initiated and driven by heritable and transient changes in gene expression, expand clonally, and progress via additional associated acquired mutations and epigenetic alterations that provide cells with an evolutionary advantage. The genotoxicity testing protocols currently employed and required by regulation, emphasize testing for the mutational potential of the test agent. Two-year, chronic rodent cancer bioassays are intended to test for the entire spectrum of carcinogenic transformation. The use of cytotoxic doses causing increased, sustained cell proliferation that facilitates accumulated genetic damage leads to a high false-positive rate of tumor induction. Current cancer hazard assessment protocols and weight-of-the-evidence analysis of agent-specific cancer risk align poorly with the pathogenesis of human carcinoma and so need modernization and improvement in ways suggested here. KeywordsTen key characteristics of human carcinogens • TKC • International Agency for Research on Cancer • TKC broad and lack specificity • TKCs give high rate of false positives

Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing

“…The specificity (True Negative rate) of the assay is relatively low (45% for IARC carcinogens, 23% for OncoLogic). However, the lack of specificity appears to be an overarching issue in carcinogenicity assessment by individual tests, including in vivo and in vitro methods [3,15]. This can be addressed by improved mechanistic understanding, integration into mechanism-based testing approaches and strategies combining methods covering multiple traits and pivotal events, which would allow to better translate the results from in vitro tests and increase their predictivity towards humans [7].…”

“…The initially recognized six 'hallmarks of cancer' included unlimited growth, self-sufficiency in growth signals, insensitivity to anti-growth signals, apoptosis evasion, angiogenesis, the ability for tissue invasion and metastases [11]. Subsequently, additional cancer hallmarks have been proposed and discussed [7,[12][13][14][15].…”

“…These fundamental and traditionally recognized differences have been reflected in the testing and safety assessment approaches for the two groups of carcinogens. The rodent cancer bioassay is being challenged from the perspective of the 3Rs principle and regarding its utility and (in)ability to predict carcinogenicity in humans reliably [15,[18][19][20][21]. The alternative, using in vitro testing methods and batteries, has already been established for GTxC, and some assays developed into OECD Test Guidelines [22].…”