HomeSafetyGlyphosate and neurotoxicity, doubts and questions from a toxicologist

Glyphosate and neurotoxicity, doubts and questions from a toxicologist

While awaiting the decision of the Member States on the renewal of the authorization for the use of glyphosate in the European Union, Professor Alberto Mantovani – internationally renowned toxicologist, former president of the European Society of Teratology and member for many years of the EFSA panels on feed and pesticides – expresses doubts and questions regarding the possible neurotoxicity of the substance.

1) Pesticides and neurotoxicity risks, introduction

'The emerging aspects of neurotoxicity associated with exposure to pesticides can be considered from two different perspectives', explains Professor Alberto Mantovani:

– correlations with the pathogenesis and/or increased risk of onset of chronic neurodegenerative diseases, such as Parkinson's disease,

– developmental neurotoxicity. It refers to a wide range of cognitive and behavioral disorders, from learning disorders to autism spectrum diseases. In
in this case the exposure during the maturation of the nervous system is decisive,
from intrauterine life to early childhood.

2) Exposure to pesticides and Parkinson's disease. Epidemiological studies and AOP (Adverse Outcome Pathway)

EFSA (European Food Safety Authority), in 2013 and 2016, published two important scientific documents on epidemiological studies correlating exposure to pesticides and serious diseases such as Parkinson's disease (PD) and childhood leukemia (CHL).

The intrinsic weakness of epidemiological studies - which rarely allow us to draw firm conclusions on causal relationships - has led researchers to integrate epidemiological analysis with knowledge of the pathogenesis of diseases and the examination of experimental data on the mechanisms of pesticides to reach 'evidence of neurotoxic effects and biologically plausible mechanisms linking pesticides to Parkinson's disease'.

The opinion EFSA's scientific report (2017) on the potential link between pesticide-induced mechanisms and Parkinson's disease and childhood leukemia has adopted a new approach in risk analysis ('Integrated Approach for Testing and Assessment', IATA). Using the conceptual framework of 'Adverse Outcome Pathway' (AOP), according to OECD criteria (2013, 2014), to define the biological plausibility of correlations through the identification of:

– specific symptoms of diseases ('Adverse Outcome', AO),

– link between a molecular initiating event (MIE) and the AO through a series of key events (KEs). (1)

– finally the analysis of the mechanisms of chemical substances that can coincide with MIE and KE, thus connecting with the pathogenesis of AO.

In practice, the AOP can solidly link the toxicity mechanisms induced by a substance at the level of cellular physiology (interactions with receptors, enzymes, etc.) and the risk of specific pathologies.

Figure 1: New science. Adverse Outcome Pathway. (2)

2.1) Glyphosate, epidemiological studies and AOP

'AOP combines multiple pieces of information and provides knowledge about biological pathways, highlights differences and similarities between species, identifies research needs and should support regulatory decisions. In this context, the AOP approach could help to organize the available experimental knowledge to evaluate biological plausibility, biologically plausible and essential' (EFSA, 2017). (1)

The EFSA assessment on glyphosate (2023), six years after the one on AOPs developed by the same Authority, does not use the same AOPs to verify whether the controversial epidemiological associations between glyphosate and Parkinson's disease may have biological plausibility.

The use of AOPs in this area is particularly important. In fact, while Parkinson's disease is a serious and important chronic neurological disease that shows epidemiological associations with pesticide exposure, there are no toxicological tests,
among those required for the evaluation of pesticides, which are able to identify this
effect. The identification of pesticides (or other substances) that induce Parkinson's disease
therefore, there remains a serious scientific "gap" that the use of AOP could reduce.
In the case of glyphosate, explains Professor Alberto Mantovani, the two elements to consider are on the one hand the existence of epidemiological correlations between glyphosate and PD which, although insufficient and controversial, should not be ignored. The other element is the possible significant human exposure, as it is the most used herbicide in Europe and in the world. (4)

3) Pesticides and developmental neurotoxicity

The risks of neurotoxicity on the development of the structures and functions of the nervous system (developmental neurotoxicity) associated with exposure to pesticides can be verified through consolidated tests, in vitro and in vivo (on rats). Industries that request authorization to introduce active ingredients for phytosanitary use in the USA are always obliged to carry out these analyses. Not so in the European Union, due to a grotesque regulatory gap in the Pesticides Regulation (EC) No 1107/2009.

The agrochemical industry is under accusation by environmentalist associations for having hidden studies on the developmental neurotoxicity of glyphosate, as we have seen. (6) A recent Swedish scientific study (Mie et al., 2023) has in fact demonstrated how the Big 4 - the global monopolists of pesticides and seeds (7) - have failed to submit a third of the studies on developmental neurotoxicity to EFSA instead provided to EPA (Environmental Protection Agency, USA), also in relation to glyphosate. (8)

3.1) Glyphosate and 'developmental neurotoxicity'

European Food Safety Authority, in its opinion on glyphosate (2023):

– recognizes that there is evidence of developmental neurotoxicity on formulations with glyphosate and a similar substance (glyphosate salt, not authorized in the EU), and yet

– detect 'data gaps that cannot be definitively resolved', among other things, the negative effects on the development of the nervous system (as well as some scientific gaps at a general level such as effects on the microbiome).

'This lack of studies on a molecule patented 50 years ago, at the basis of the most used 'plant protection products' in Europe and on a global level, is surprising to say the least.', explains professor Alberto Mantovani. 'Developmental neurotoxicity is a very serious health risk. The presence of well-founded suspicions justifies decisions based on the precautionary principle by the European legislator'. Even more so since in vivo studies on rats are still insufficient to evaluate the pathogenesis of exclusively human neurological diseases (Mie et al., 2023).

4) Glyphosate, risks of neurotoxicity and precautionary principle

Glyphosate and its metabolite AMPA (aminomethylphosphonic acid) were detected in 42% and 68% of surface and groundwater analyzed by ISPRA, in the two-year period 2019-2020, in 14 Italian regions. (9) Professor Alberto Mantovani underlines how the two serious aspects of neurotoxicity mentioned in the preview – pathogenesis and/or increased risk of chronic diseases (i.e. Parkinson's Disease) and 'neurodevelopmental toxicity' – remain unresolved concerns, for the reasons mentioned in the previous paragraphs.

To these must be added information on the direct impact of glyphosate on the microbiota that constantly interacts with the central nervous system. (10) EFSA's assessment certainly identified these and other shortcomings, such as the effects of dietary exposure to glyphosate residues and environmental impact aspects. However, the serious impact of the gaps on the safety assessment has not been clearly highlighted.

Dario Dongo

Cover image by: Lyydia Leino, Tuomas Tall, Marjo Helander, Irma Saloniemi, Kari Saikkonen, Suvi Ruuskanen, Pere Puigbò. Classification of the glyphosate target enzyme (5-enolpyruvylshikimate-3-phosphate synthase) for assessing sensitivity of organisms to the herbicide. Journal of Hazardous Materials, Volume 408, 2021, 124556.
https://doi.org/10.1016/j.jhazmat.2020.124556

Footnotes

(1) EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues),
2017. Scientific Opinion on the investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia. EFSA Journal 2017; 15(3):4691, 325 pp. doi:10.2903/j.efsa.2017.4691

(2) Dr Jose V. Tarazona, Head Pesticides Unit. EFSA (2018) Setting the basis for future health risk assessments: A case study on Parkinson's disease and paraquat. Presentation at the European Parliament https://tinyurl.com/nw6vjrzy

(3) Dario Dongo, Alessandra Mei. EFSA glosses over the safety risks of glyphosate. 'Stop Glyphosate'! GIFT (Great Italian Food Trade). 22.7.23

(4) Marta Strinati. Glyphosate in the urine of 99,8% of French people. GIFT (Great Italian Food Trade). 30.1.22

(5) Marta Strinati. Glyphosate causes leukemia in young rats even at low doses. GIFT (Great Italian Food Trade). 26.10.23

(6) Dario Dongo. Glyphosate, civil society denounces fraud in view of the ten-year renewal in the EU. GIFT (Great Italian Food Trade). 3.10.23

(7) Marta Strinati, Dario Dongo. Pesticides, we're all Big 4 guinea pigs. GIFT (Great Italian Food Trade). 23.8.19

(8) Dario Dongo. How the agrochemical industry hides the toxicity of pesticides. New studies. GIFT (Great Italian Food Trade). 13.6.23

(9) Gabriele Sapienza. ISPRA, 2022 report on pesticides in Italian waters. GIFT (Great Italian Food Trade).

(10) Dario Dongo. Pesticides and microbiome, interview with Prof. Alberto Mantovani. GIFT (Great Italian Food Trade). 22.5.19

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Dario Dongo, lawyer and journalist, PhD in international food law, founder of WIISE (FARE - GIFT - Food Times) and Égalité.

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