A Quantitative Weight-of-evidence Review of Preclinical Studies Examining the Potential Carcinogenicity of Acetaminophen.

Introduced in the 1950s, acetaminophen is one of the most widely used antipyretics and analgesics worldwide. In 1999, the International Agency for Research on Cancer (IARC) judged the available data inadequate to determine carcinogenicity, and in 2024 an IARC Advisory Group recommended high-priority re-evaluation. Given this context, we conducted a quantitative weight-of-evidence (QWoE) analysis of in vivo rodent carcinogenicity studies using a previously developed framework for biological relevance and methodological quality (Kougias et al., 2025a; Kougias et al., 2025b). A total of 192 QWoE entries were derived from 32 publications assessing two main carcinogenicity-related endpoints-tumorigenicity and tumor-promoting potential-with additional analyses of tissue-specific tumorigenicity. Mean outcome and methods scores (0-4 scale) were calculated overall and by sex for each endpoint. Across endpoints, mean methods scores ranged from 2.1 to 2.5, indicating moderate data quality, while mean outcome scores ranged from 0.0 to 0.4, indicating minimal evidence for biologically relevant carcinogenic responses. Isolated tumor findings were infrequent, inconsistent, not reproducible, and they generally occurred under conditions involving high toxicity and/or interpretive limitations. Accordingly, our quantitative synthesis concludes that there is inadequate evidence to support a carcinogenic effect of acetaminophen, as reflected by the lack of consistent, reproducible, or biologically relevant indications of carcinogenic or tumor-promoting activity in male or female rodents across tested exposure levels.