UCLA on GBH: a post-IARC decision review: glyphosate “safe” levels too high!

 “Current glyphosate cRfD levels of 1.75 mg/kg/day should be reduced to 0.175 mg/kg/day, bringing the value beneath the 0.3 mg/kg/day level used by the E.U. and closer to that recommended by multiple research groups (Antoniou et al. 2012; Myers et al. 2016). “

Carcinogenesis. 2018 Oct 8;39(10):1207-1215. doi: 10.1093/carcin/bgy105.

Glyphosate-based herbicides and cancer risk: a post-IARC decision review of potential mechanisms, policy and avenues of research.

Davoren MJ 1Schiestl RH 1, 2, 3.

Author information

1
Molecular Toxicology Interdepartmental Program, University of California, Los Angeles, CA, USA.
2
Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
3
Environmental Health Science, University of California, Los Angeles, CA, USA.

Abstract

Since its initial sales in the 1970s, the herbicide glyphosate attained widespread use in modern agriculture, becoming the most commercially successful and widely used herbicide of all time as of 2016. Despite a primary mechanism that targets a pathway absent from animal cells and regulatory studies showing safety margins orders of magnitude better than many other, more directly toxic herbicides, the safety status of glyphosate has recently been brought into question by a slow accumulation of studies suggesting more subtle health risks, especially when considered in combination with the surfactants it is usually applied with. Current, official views of respected international regulatory and health bodies remain divided on glyphosate’s status as a human carcinogen, but the 2015 International Agency for Research on Cancer decision to reclassify the compound as Category 2A (probably carcinogenic to humans) marked a sea change in the scientific community’s consensus view. The goal of this review is to consider the state of science regarding glyphosate’s potential as a human carcinogen and genotoxin, with particular focus on studies suggesting mechanisms that would go largely undetected in traditional toxicology studies, such as microbiome disruption and endocrine mimicry at very low concentrations.
PMID:30060078
DOI:10.1093/carcin/bgy105
Date: April 28, 2019 at 7:53:44 AM PDT
To: CHE Science listserv <chescience@healthandenvironment.org>

…recommendations:

1. In light of reports of possible genotoxic, and especially developmental, effects of glyphosate on the human body, we suggest the United States invoke the Food Quality Protection Act’s enforcement of a tenfold safety margin for pesticides or herbicides without reliable data showing no risk to children (Code 1996). Current glyphosate cRfD levels of 1.75 mg/kg/day should be reduced to 0.175 mg/kg/day, bringing the value beneath the 0.3 mg/kg/day level used by the E.U. and closer to that recommended by multiple research groups (Antoniou et al. 2012; Myers et al. 2016). The vast majority of human urine samples collected from herbicide workers still fall well below this level, so enforcement to this standard is not unreasonable (Niemann et al. 2015). Debate over the E.U.’s re-approval of glyphosate, and whether to change the ADI levels, is still ongoing near the close of 2017.

  1. Much of the debate over glyphosate’s safety is marred by accusations of politically and economically motivated study findings. Each party has accused the other of disregarding and withholding data that do not fit the set of conclusions they seek to promote. We hold the opinion that the principle of free and open peer review is the best method to put these issues to rest. We call on researchers of glyphosate toxicity and carcinogenicity to place extra effort into keeping all raw data publicly available for perusal and comment. In particular, we call on corporate entities that maintain proprietary datasets, especially those used to comply with government registration and regulation processes, to voluntarily make this information freely available for independent review.

  2. Given that glyphosate inhibits the shikimate pathway, which is critical to the metabolism of many species in the human gut microbiome, and that adjuvants present in GBHs may induce other changes in the microbiota profile, both direct toxicity and epidemiology studies should be conducted to evaluate the potential for GBH consumption through the diet to increase cancer risk. Studies should include the effects of GBH-treated and GBH-free food diets on the composition of the human microbiome, as well as the secondary gut and systemic inflammatory conditions at doses relevant to anticipated exposure levels.

  3. The testing of different formulations of GBHs should occur alongside and in addition to the testing of glyphosate alone at every level, and especially at the regulatory stage. Many regulatory agencies do not require retesting of chemical combinations, especially those at levels deemed “safe” on their own (Mesnage et al. 2014). Despite this policy, it is well accepted that surfactant compounds can act to increase the rate of cell entry or systemic absorption of glyphosate, which may have relevance to the potential carcinogenicity of GBHs (Mesnage et al. 2013).

  4. If glyphosate is a human carcinogen, the mechanisms by which it acts are likely obfuscated behind such complex mechanisms as nonmonotonic endocrine mimicry and indirect initiation of inflammation and genotoxicity through microbiome mediators. These events can require large studies to elucidate with significant statistical power. Therefore, relying solely on the often used, three-tier system for genotoxicity risk assessment (generally Ames test, in vitro mammalian cell mutation, and in vivo chromosomal aberration) is insufficient. This approach is currently favored by such bodies as the OECD and the US EPA (Cimino 2006). Results that do not adhere to this accepted framework are given less weight by both regulatory agencies and scientists associated with glyphosate-registering corporations. Additional investigations of glyphosate with regards to specific mechanisms of toxicity in specialized models must be completed. For example, the DEL assay, a yeast-based test that drastically outperforms the traditional Ames test in carcinogen detection, could be used to examine induction of DSBs in exposed cells (Brennan and Schiestl 2004; Carls and Schiestl 1994).

6. With regards to carcinogenesis itself, animal results are often taken less seriously if they do not adhere to standard dose and number criteria such as those advanced by the OECD (Hsu and Stedeford 2010). While this may be warranted in some situations, these criteria could cause low-dose, nonmonotonic responses, such as those observed in cases of cases of endocrine disruption, to remain overlooked. New regulatory testing protocols must be established to determine whether a given compound has a nonmonotonic dose response (Lagarde et al. 2015; Vandenberg et al. 2012; vom Saal et al. 2010). In addition, the scientific community should continue to critically examine every carcinogenesis study by its own merits in consideration of the totality of evidence, rather than completely disregarding studies that do not meet current criteria for standardized carcinogenicity testing for reasons such as sample size (Zoeller and Vandenberg 2015). 

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