An Analysis of Pharmaceutical Experience with Decades of Rat Carcinogenicity Testing

Abstract

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.

Lack of human tissue-specific correlations for rodent pancreatic and colorectal carcinogens

“…The results of these studies have typically been used in risk assessments as the basis for predicting human cancer risk and for deriving safe limits for human exposure to chemicals of potential concern. As outlined in Section 1.0 and elsewhere, however, there are limitations to these assays that may render their usefulness unclear with regard to the evaluation of cancer risk due to low level chemical exposure in the general population, and various alternative approaches have been suggested (Trosko and Upham, 2005;Knight et al, 2006a;Billington et al, 2010;Jacobson-Kram, 2010;Sistare et al, 2011).…”

International regulatory needs for development ofan IATA for non-genotoxic carcinogenic chemical substances

“…However, taken together with other, more mechanistically based data and in a WoE approach, this information may be useful and increase the relevance in the evaluation of carcinogenicity. For data rich pharmaceuticals, the absence of histopathological data combined with information on mutagenicity and hormonal activity has been shown to correlate well with non-carcinogens (Sistare et al, 2011), and this could also be the case for chemicals.…”

Reassessing the two-year rodent carcinogenicity bioassay: A review of the applicability to human risk and current perspectives

“…Based on the ability of a chemical to produce a ''positive'' concordant tumor result where 9 of 10 known human carcinogens tested are positive, the rodent bioassay would identify a low, even implausible, 22% positive, while half of all human carcinogens would not be detected, and considered false negative (Ennever and Lave, 2003;Long 2007). Further, certain lesions may be rodentspecific or progress through processes unique to the rodent: nephropathic and urinary diseases of alpha 2u globulin (renal tumorigenic), calcium phosphate urinary precipitate (urinary bladder cytotoxic), and endocrine differences involving the pituitary, as well as adrenal feedback and thyroid stimulating hormonal loops all having no human counterpart (Alden, 1996;Alden et al, 2011;Cohen, 2004;Cohen et al, 2000;Monro, 1996;Sistare et al, 2011). It is now well known that rodent-specific mechanisms associated with chronic trophic hormonal stimulation at the target site can promote endocrine tumors at sites distal to the primary site of action (Alison et al, 1994).…”