The numerical probability of carcinogenicity to humans of some antimicrobials: Nitro-monoaromatics (including 5-nitroimidazoles), quinoxaline-1,4-dioxides (including carbadox), and chloramphenicol.

Abstract

Many substances are already tested in the long-term (2-year) rodent bioassay (RCB). Nonetheless, statements such as the following are common in the regulatory literature: the significance of the carcinogenicity findings in rodents relative to the therapeutic use of drugs in humans is unknown. (U.S. FDA prescribing information for nitrofurantoin; 2008). In the absence of epidemiological data, chemicals carcinogenic in RCBs are typically classified as either possibly or probably carcinogenic to humans, particularly without any -numerical probability for the carcinogenicity to humans- (PPV) of the classified substances. Through the biostatistics-based and regulatorily pertinent -predictive values approach- (PVA), the present study investigated the PPV of several antimicrobial drugs relevant to human or veterinary medicine. A combination of structure-activity relationship, mutagenicity, and tumor-related histopathology was used to figure reliable PPVs. For 62 specific antimicrobial drugs, a 97.9% (or more) probability of carcinogenicity to humans was estimated. For nitrofurantoin, a 99.9% probability of carcinogenicity to humans was estimated. Therefore, a risk-benefit evaluation on the in-force authorization of nitrofurantoin for uncomplicated human urinary infections is urgently needed. A comprehensive discussion was provided on the involved mechanisms of carcinogenic action and some regulatory implications of the findings. Neither this study nor the PVA aimed to encourage indiscriminate animal testing but the contrary, to reduce unnecessary and redundant in vivo testing by powering nonclinical toxicology predictivity.