Evgenios Agathokleous

Abstract The European Federation of Food,Agriculture,and Tourism Trade Unions (EFFAT) called for the immediate ban on glyphosate in the 2022 renewal process,promoting the use of natural herbicides and recommending against the use of other harmful or hazardous chemicals.The new chemical testing and selection research agendas should consider the hormetic effects of individual natural herbicides,and their potential mixtures,on targeted and non-targeted organisms to avoid stimulation of pests and negative effects on non-targeted organisms.New scientific research programs are needed to study the effects of mixtures of natural pesticides on soils,plants,animals,and microorganisms within the context of agroforestry.

Keywords Agroforestry protection·Biphasic response·Dose–response relationship·Pesticide toxicology·Toxicological assays

The herbicide glyphosate has received heightened attention because of its accumulation in the environment and thereby its effects on the environment and humans (Duke 2018,2021;Van Bruggen et al.2018;Gillezeau et al.2019;Kudsk and Mathiassen 2020).For example,dose-and time-dependent effects of glyphosate-based herbicides may be associated with impacted female reproductive systems in various animals such as rodent,lamb,and fish (Kaboli Kafshgiri et al.2021),as well as suppressed and/or impaired immune systems in fish and mammals (Peillex and Pelletier 2020).Although several dose-and time-dependent effects have been observed in toxicological studies with human cells,epidemiological studies show contradictory findings (Agostini et al.2020).Hence,the debate of whether glyphosate is carcinogenic continues,while different regulatory agencies have drawn different conclusions (Cressey 2015;Tarazona et al.2017 ;Gillezeau et al.2019).The International Agency for Research on Cancer (IARC) considers it as“probably carcinogenic to humans”,the European Food Safety Authority (EFSA) found it“unlikely to pose a carcinogenic hazard to humans”,and the US Environmental Protection Agency(EPA) found it“not likely to be carcinogenic in humans”(Gillezeau et al.2019).It is also widely documented that chronic exposure to glyphosate affects various organisms,alters the composition of microbial communities in animal guts,plants,and soil,and promotes drug resistance (Van Bruggen et al.2018;Duke 2021).Such effects of glyphosate often occur at low,subtoxic concentrations (Belz and Duke 2017;Duke 2020,2021;Jalal et al.2021;Belz et al.2022).

Pesticides are key to plant protection to ensure food security,and their abolition could translate to as much as 20–40% losses in yield (Lykogianni et al.2021).Sustainable use of pesticides can decrease the contamination burden to the environment,prevent environmental degradation,and protect the anthroposphere and biosphere (Lykogianni et al.2021).The European Union’s (EU) current glyphosate approval expires at the end of 2022,1For more information the reader may refer to https:// www.echa.europa.eu/ en/ web/ guest/ hot-topics/ glyph osate20 years after its first approval by the Union,requiring the implementation of new cropping practices (Kudsk and Mathiassen 2020).At the end of June 2021,the European Federation of Food,Agriculture,and Tourism Trade Unions (EFFAT) called for the glyphosate’s ban in the 2022 renewal process,promoted the use of natural herbicides,and recommended against the use of other harmful or hazardous chemicals (https:// effat.org/ wp-conte nt/ uploa ds/ 2021/ 06/ EFFAT-Posit ion-Paper-Ending-the-use-of-glyph osate-and-build ing-a-more-susta inable-a gric ulture.p df).A ban on glyphosate may translate to high economic costs,e.g.,a loss of more than USD 1.1 billion per year for UK farmers (Kudsk and Mathiassen 2020).The issue about the use of glyphosate,the world’s most used herbicide,has extended to other parts of the world,including the ban by the Mexican government that will be effective from January 2024 (Alcántara-de la Cruz et al.2021) and the ban or phasing out by several local councils in Australia,despite the Australian Pesticides and Veterinary Medicines Authority (APVMA) support for glyphosate use (Walsh and Kingwell 2021).A ban on glyphosate may result in significant economic impacts for Australia as well,for example,heavy-soils farms may face a decrease in prof it of over USD 260 thousand (? 57%) per year because of increased costs associated with weed control and decreases in crop yields stemming from less effective weed control in the absence of glyphosate and paraquat and no offset of grain prices (Walsh and Kingwell 2021).An 11.1% increase in grain prices may be required to keep farm prof its unchanged when both herbicides are banned (Walsh and Kingwell 2021).A global ban on glyphosate may bring an end to the cultivation of genetically modified herbicide-tolerant (GM-HT) crops,which could lead to a loss of farmers’ benefits from using this technology,such as easier control of weeds and lower costs (Brookes et al.2017).This could result in an annual loss of farm income gains of USD 6.8 billion,while global prices of various economically important crops may increase by 0.4% (rice) to 5.4% (soybeans) (Brookes et al.2017).Hence,the imminent ban on glyphosate may bring about a burden for the global economy,reinforcing the notion that more focus should be paid to the supply and correct use of pesticides,instead of merely banning specific ones.

The EU’s proposed replacement of glyphosate with natural herbicides may be an ineffective solution because natural pesticides do not differ from synthetic pesticides in their dose–response behaviour (Agathokleous and Calabrese 2020,2021;Agathokleous et al.2022a).The general occurrence of hormesis (Fig.1) across pesticides,allelochemicals,and other types of chemicals with significant subtoxic responses,suggests that all pesticides would affect sensitive or resistant targeted and non-targeted organisms depending on concentration and time (Duke et al.2006;Belz and Duke 2017;Carvalho et al.2020;Shahid et al.2020;Duke 2021;Erofeeva 2021,2022;Jalal et al.2021;Agathokleous et al.2022a;Cutler et al.2022;Rix and Cutler 2022).Hence,pesticide effects cannot be prevented by simply turning them into natural ones.

Fig.1 EU sets forth to ban glyphosate and promote the use of natural pesticides.Hormesis,a biphasic dose response with significant responses to doses/concentrations smaller than the toxicological threshold,should be considered in the new chemical testing

Nevertheless,considering the occurrence of the hormetic-biphasic dose–response relationship (Agathokleous et al.2020b),the screening and selection of new,natural herbicides in research programs should cover the full dose–response spectrum,taking into account the potential effects of subtoxic doses on targeted and non-targeted organisms.Subtoxic effects should also be considered in research evaluating the effects and risks of pesticide mixtures because they can have antagonistic,additive,or synergistic effects on targeted and non-targeted organisms (Thrupp et al.2018;Cong et al.2019;Zhang et al.2019;Kumari and Kumar 2020;Wang et al.2020,2021;Agathokleous et al.2020b,2022a;Huang et al.2021;Li et al.2021;Rui et al.2021).Such effects are extended to microbiota,presenting an additional challenge of the implications to biodiversity conservation as well as to trees and forest health due to changes in pests dynamics,symbiotic relationships,and beneficial insects such as pollinators and natural enemies of pests(Cong et al.2019;Zhang et al.2019;Hu et al.2020;Agathokleous et al.2022a,b;Guedes et al.2022;Tang et al.2022).Hormetic responses have been largely neglected in ecotoxicological studies (Guedes et al.2022;Sebastiano et al.2022),but recent research programs have led to understanding its general occurrence.To ensure environmental health and minimize risks,the chemical testing and selection in the framework of the new EU policy should consider such sub-NOAEL (no observed adverse effect levels) effects on non-targeted organisms but to do so,improved experimental designs are needed to capture subtoxic effects such as by considerably increasing the sample size and number of doses(Calabrese et al.2019;Agathokleous and Calabrese 2020;Sebastiano et al.2022).Nanotechnology-based interventions with bio-encapsulated pesticides can also mitigate the adverse effects of pesticides on the environment and human health (Grillo et al.2016;Camara et al.2019;Hassanisaadi et al.2022),offering a perspective for eco-friendlier pesticides.However,even if nano pesticides were to be promoted,relevant research should consider hormetic effects for their development and selection (Agathokleous et al.2020a).Improved mathematical models of dose–response relationships,which account for sub-NOAEL effects and adequately capture hormesis,are also available and permit more sophisticated assessments (Belz and Duke 2022).

Agroforestry can mitigate agricultural impacts and improve ecosystem services by enhancing biodiversity,modifying climate,improving soil properties (e.g.,carbon and nitrogen levels and enzyme activities) and the quality of the environment,by improving soil water relations (e.g.,increase in storage and decreased evaporation),and by facilitating pest control (Tscharntke et al.2005;Bianchi et al.2006;Udawatta et al.2008;Siriri et al.2012;Smith et al.2013).Expanding the conversion of cropping systems into agroforestry systems may accelerate the transition to a more sustainable food system in line with the European Commission’s“Farm to Fork Strategy”aiming at making food systems fair,healthy and environmentally friendly (https:// ec.europa.eu/ food/ horizo ntal-t opics/ farm-fork-strat egy_en).In light of the recent reconsideration of the EU’s pesticide use practices and the imminent ban of glyphosate,agroforestry systems may play a more important role in pest management.However,it is reasonable to assume that pesticides would still be required in agroforestry practices,although the use of alternative methods for weed control could also be expanded,such as incorporation of various agronomic practices and an integrated control of weeds,potentially including redesigned crop rotations,mixed cropping and diversification of plantations,selection of optimum seeding rates,proper use of approved biostimulants,seed priming etc.Numerous weed species have developed resistance to current herbicides,and therefore it is urgent for the development of herbicides with new modes of action (Duke and Dayan 2021;Belz et al.2022).Hormesis occurs independently of pesticide mode of action (Agathokleous et al.2022a),indicating a need to consider hormetic responses in research programs to develop new pesticides,synthetic or natural ones.

Overall,recent bans on glyphosate by various countries and the imminent EU ban and their implications highlight the dependence on such pesticides for food security,national economies,and agroecosystems health.To facilitate the EU’s initiative to turn to natural herbicides,hormetic effects should be considered in research evaluations of the effects of individual pesticides and mixtures of pesticides on targeted and non-targeted (e.g.,soil microbiota) organisms.

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