ORIGINAL ABSTRACT

Glyphosate-based formulations (GBFs), such as Roundup, are the most heavily used herbicides in the world. In 2015, the International Agency for Research on Cancer (IARC) concluded that glyphosate and GBFs are probably carcinogenic to humans (group 2A), mainly for non-Hodgkin lymphoma (NHL). However, this finding has been controversial, and most pesticide regulatory agencies have not followed their lead. The purpose of this review was to examine the scientific literature linking exposure to glyphosate and GBFs to the development of NHL, with emphasis on new findings since publication of the IARC report. The epidemiologic studies provide ample evidence for an association between exposure to GBFs and an increased risk of NHL. Animal studies have shown that glyphosate is carcinogenic in rodents and causes NHL in mice. Mechanistic studies have demonstrated that glyphosate and GBFs are genotoxic to human lymphocytes, the normal cell of origin of NHL, both in vitro and in vivo. Genotoxic and other biological effects have also been shown in various animal and cell models with these agents even at low doses. A novel mechanism underlying the specificity of glyphosate for NHL, that is upregulation of the B-cell genome mutator enzyme activation-induced cytidine deaminase, has recently been demonstrated. These findings were evaluated holistically using the guidelines for evaluation of general causation set forth by Bradford Hill. This evaluation provides coherent and compelling evidence that glyphosate and GBFs are a cause of NHL in humans exposed to these agents. These findings should prompt new reviews by pesticide regulatory agencies around the world.