IARC use of oxidative stress as key mode of action characteristic for facilitating cancer classification: Glyphosate case example illustrating a lack of robustness in interpretative implementation

• Published in: Regulatory toxicology and pharmacology Vol. 86; pp. 157 - 166
• Main Author: Bus, James S.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01-06-2017
• Subjects: Animals; Cancer classification; Carcinogens - classification; Carcinogens - toxicity; Glycine - administration & dosage; Glycine - analogs & derivatives; Glycine - toxicity; Glyphosate; Humans; IARC; International Agencies; Mechanism of action; Mode of action; Neoplasms - chemically induced; Oxidative Stress; Oxidative stress; IARC; Mechanism of action; Glyphosate; Cancer classification; Mode of action
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2017.03.004

The International Agency for Research on Cancer (IARC) has formulated 10 key characteristics of human carcinogens to incorporate mechanistic data into cancer hazard classifications. The analysis used glyphosate as a case example to examine the robustness of IARC's determination of oxidative stress as “strong” evidence supporting a plausible cancer mechanism in humans. The IARC analysis primarily relied on 14 human/mammalian studies; 19 non-mammalian studies were uninformative of human cancer given the broad spectrum of test species and extensive use of formulations and aquatic testing. The mammalian studies had substantial experimental limitations for informing cancer mechanism including use of: single doses and time points; cytotoxic/toxic test doses; tissues not identified as potential cancer targets; glyphosate formulations or mixtures; technically limited oxidative stress biomarkers. The doses were many orders of magnitude higher than human exposures determined in human biomonitoring studies. The glyphosate case example reveals that the IARC evaluation fell substantially short of “strong” supporting evidence of oxidative stress as a plausible human cancer mechanism, and suggests that other IARC monographs relying on the 10 key characteristics approach should be similarly examined for a lack of robust data integration fundamental to reasonable mode of action evaluations.
•IARC glyphosate oxidative stress mode of action analysis is substantially flawed.•Oxidative stress evidence is not supportive of glyphosate human carcinogenicity.•Oxidative stress mode of action inconsistent with low glyphosate human exposures.•IARC 10 key characteristics of human carcinogens requires further study before use.•IARC should provide more guidance to Working Groups on use of mode of action.