Categorizing the characteristics of human carcinogens: a need for specificity
by:
Smith CJ, Perfetti TA, Hayes AW, Sir Colin Berry et al.
Smith CJ, Perfetti TA, Hayes AW, Sir Colin Berry et al.
Summary:
The International Agency for Research on Cancer (IARC) has proposed using “ten key characteristics of human carcinogens” (TKCs) to assess agents' harmful potential. However, TKCs may exacerbate poor correlations in testing regimes by overlooking species-specific differences in cellular changes, stem cell, and somatic cell phylogenies between short- and long-lived species. Their broad nature risks elevating the already high false-positive rate. Testing well-established, safe therapeutics against this TKC framework could prove informative. Cancers arise from heritable and transient gene expression shifts, followed by clonal expansion and progression through mutations and epigenetic changes conferring evolutionary advantages. Regulatory genotoxicity tests prioritize mutational potential, while two-year rodent bioassays aim to capture full carcinogenic processes. Yet, employing cytotoxic doses that induce sustained proliferation and genetic damage yields excessive false positives in tumor induction. Overall, existing hazard assessment protocols and weight-of-evidence analyses misalign with human carcinoma pathogenesis, necessitating modernization as outlined herein.
The International Agency for Research on Cancer (IARC) has proposed using “ten key characteristics of human carcinogens” (TKCs) to assess agents' harmful potential. However, TKCs may exacerbate poor correlations in testing regimes by overlooking species-specific differences in cellular changes, stem cell, and somatic cell phylogenies between short- and long-lived species. Their broad nature risks elevating the already high false-positive rate. Testing well-established, safe therapeutics against this TKC framework could prove informative. Cancers arise from heritable and transient gene expression shifts, followed by clonal expansion and progression through mutations and epigenetic changes conferring evolutionary advantages. Regulatory genotoxicity tests prioritize mutational potential, while two-year rodent bioassays aim to capture full carcinogenic processes. Yet, employing cytotoxic doses that induce sustained proliferation and genetic damage yields excessive false positives in tumor induction. Overall, existing hazard assessment protocols and weight-of-evidence analyses misalign with human carcinoma pathogenesis, necessitating modernization as outlined herein.