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Toxicity of the herbicides used on herbicide-tolerant crops, and societal consequences of their use in France

June 2020
Drug and Chemical Toxicology 45(4):1-24

June 2020
45(4):1-24

DOI:10.1080/01480545.2020.1770781

Authors:

University of Bordeaux

In France, the implementation of mutant herbicide-tolerant crops and the use of the related herbicides – sulfonylureas and imidazolinones – have triggered a strong societal reaction illustrated by the intervening actions of environmentalist groups illegally mowing such crops. Trials are in progress, and therefore should be addressed the questions of the environmental risks and the toxicity of these herbicides for the animals and humans consuming the products derived from these plants. Regulatory authorities have allowed these mutant and herbicide-tolerant plants arguing that the herbicides against which they resist only target an enzyme found in ‘weeds’ (the acetolactate synthase, ALS), and that therefore all organisms lacking this enzyme would be endowed with immunity to these herbicides. The toxicological literature does not match with this argument: 1) Even in organisms displaying the enzyme ALS, these herbicides impact other molecular targets than ALS; 2) These herbicides are toxic for animals, organisms that do not possess the enzyme ALS, and especially invertebrates, amphibians and fish. In humans, epidemiological studies have shown that the use and handling of these toxins are associated with a significantly increased risk of colon and bladder cancers, and miscarriages. In agricultural soils, these herbicides have a persistence of up to several months, and water samples have concentrations of some of these herbicides above the limit value in drinking water.

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Toxicity of the herbicides used on herbicide-tolerant crops, and societal

consequences of their use in France.

Jean-Paul Bourdineauda,b

Published in Drug and Chemical Toxicology, accepted the 2nd of May 2020

DOI: 10.1080/01480545.2020.1770781

To link to this article: https://doi.org/10.1080/01480545.2020.1770781

Published online: 16 Jun 2020.

aUniversity of Bordeaux, CNRS, Laboratory of Fundamental Microbiology and

Pathogenicity, European Institute of Chemistry and Biology, 2 rue Robert

Escarpit, 33607 Pessac, France; bCRIIGEN, Paris, France.

(jean-paul.bourdineaud@u-bordeaux.fr).

Abstract

In France, the implementation of mutant herbicide-tolerant crops and the

use of the related herbicides – sulfonylureas and imidazolinones - have triggered

a strong societal reaction illustrated by the intervening actions of

environmentalist groups illegally mowing such crops. Trials are in progress, and

therefore should be addressed the questions of the environmental risks and the

toxicity of these herbicides for the animals and humans consuming the products

derived from these plants.

Regulatory authorities have allowed these mutant and herbicide-tolerant

plants arguing that the herbicides against which they resist only target an

enzyme found in "weeds" (the acetolactate synthase, ALS), and that therefore all

organisms lacking this enzyme would be endowed with immunity to these

herbicides. The toxicological literature does not match with this argument: 1 /

Even in organisms displaying the enzyme ALS, these herbicides impact other

molecular targets than ALS; 2 / These herbicides are toxic for animals,

organisms that do not possess the enzyme ALS, and especially invertebrates,

amphibians and fish. In humans, epidemiological studies have shown that the

use and handling of these toxins are associated with a significantly increased risk

of colon and bladder cancers, and miscarriages. In agricultural soils, these

herbicides have a persistence of up to several months, and water samples have

concentrations of some of these herbicides above the limit value in drinking

water.

Keywords : herbicides ; sulfonylurea; imidazolinone; herbicide-tolerant plants;

chemical mutagenesis; acetolactate synthase

Introduction

The molecules of the imidazolinone (IMI) and sulfonylurea (SUL) chemical

families are used as herbicides. Their primary site of action is the enzyme

acetolactate synthase (ALS), also known as acetohydroxyacid synthase (AHAS),

of which they are inhibitors (the molecules of the triazolopyrimidine sulfonamide,

pyrimidinylthiobenzoate, and sulfonylamino-carbonyltriazolinone chemical

families are also inhibitors of ALS: Mallory-Smith and Retzinger 2003). This

enzyme is involved in the synthesis of the amino acids valine, leucine and

isoleucine (Zhou et al. 2007). The inhibition of this enzyme by this type of

herbicides consequently causes a toxic accumulation of α-ketoglutarate along

with a deficit of protein synthesis in the polluted plants, and in the long term the

inability to grow or death. Bacteria, fungi and yeasts also have this enzyme,

making all of the species represented by these branches of life potential targets

(Boldt and Jacobsen 1998; Desai et al. 2009; Duggleby et al. 2003; Rachedi et

al. 2018). Aquatic plants such as the duckweed Lemna minor are also affected by

these herbicides (Peterson et al. 1994).

The continuous overuse of a single herbicide multiple times in a growing

season is leading to a “naturally” acquired resistance to this herbicide. As for the

ALS gene, point mutations making the enzyme, and consequently the plant,

resistant to ALS-inhibiting herbicides are known and detailed not only in many

weeds but also in crops (Kolkman et al. 2004; Powles and Yu 2010; Shimizu et

al. 2005). In 2014, 404 unique cases of herbicide resistant weeds were known.

ALS inhibitor-resistant weeds accounted for about a third of all cases (Heap

2014). Ian Heap has established the most extensive database in the world

displaying the herbicide-resistant weeds to ALS-inhibiting herbicides that can be

consulted in weedscience.org. Ironically, these herbicides are used as an

alternative to glyphosate in crops where weeds have become resistant to

Roundup. Sunflowers made resistant to these herbicides were created by

chemical mutagenesis and first patented by Du Pont De Nemours (Gabard and

Huby 2001). Sunflower, rapeseed, soy, wheat, rice and maize resistant to these

herbicides are now marketed and planted (Tan et al. 2005).

The International Maize and Wheat Improvement Center (CIMMYT)

developed through a partnership herbicide tolerant maize lines based on a

natural mutation in maize (Gressel 2009). However, environmentalists consider

that the “naturally” acquired mutations found in such crops are the result of a

selection pressure exerted by sprayed herbicides, so that these field mutants can

be considered as the products of a field-scale chemical mutagenesis. Beside ALS

mutations, plants can to some extent tolerate ALS-inhibiting herbicides through

the activation of detoxification genes or induction of related enzymes such as

cytochrome P450 monooxygenases (Barrett 1995; Pan et al. 2006; Persans and

Schuler 1995; Powles and Yu 2010; Saika et al. 2014; Duhoux and Délye 2013;

Liu et al. 2015; Domínguez-Mendez et al 2017; Yang et al. 2018), glutathione S-

transferases (Liu et al. 2015; Balabanova et al. 2018; Sun et al. 2017 and

2018), glycosyltransferase genes (Liu et al. 2015) and the multidrug resistance-

associated protein MRP1 (Liu et al. 2015; Sun et al. 2018). For instance, a hybrid

maize line is resisting to the SUL foramsulfuron through the intervening action of

a P450 gene (Paporisch and Rubin 2017). However, the metabolization of the

herbicide is not possible without the combined use of another chemical called

“safener” (isoxadifen in the case of SUL herbicides) that protects the plant from

the toxic effects of the herbicide through the activation of a cognate P450 gene

or enzyme (Hatzios and Burgos 2004; Paporisch and Rubin 2017; Yun et al.

2001).

In France, an environmentalist protest movement has emerged, and during

militant actions have been illegally mown mutant rapeseed, soya and maize

cultures made resistant to ALS inhibitory herbicides, and these actions strongly

remind the struggle of luddites of the 18th and 19

th centuries (Chevassus-au-

Louis 2006; Thompson 1966).

Although these plants are genetic mutants selected through an artificial

chemical mutagenesis and therefore true genetically modified organisms (GMOs)

on a biological ground, an institutional trick is that they are not legally

recognized as such (since a foreign and transgenic gene has not been inserted in

their genome and also because the technological process used is leading to the

same type of mutations than those arising through a “naturally” acquired

resistance). Consequently, these plants are excluded from the scope of the

European directive on GMOs, which exempts them from any evaluation,

traceability and labeling. Militant environmentalists are contesting this

institutional position and point of view and are worrying about the environmental

and possible health consequences of the use of herbicides of the IMI and SUL

families. Trials are in progress and in this context the aims of the present review

are first to address the question of the risks, potential toxicity and health

consequences of the use of such mutant plants regularly sprayed with herbicides

not only for the environment but also for the animals and humans consuming the

products derived from these plants. And second to discuss the flaws of the

official regulation during the marketing approval process of these mutant plants

and the corresponding herbicides.

1/ The toxicity of these herbicides to living organisms goes far beyond

the recognized molecular target ALS/AHAS enzyme.

Organisms carrying the genuine ALS enzyme are not only facing the

inhibitory effects of IMI and SUL herbicides on ALS: many other intracellular and

molecular actors are targeted by these herbicides.

1.1. Genotoxic outcomes

The IMI imazethapyr causes chromosomal abnormalities during the mitosis

process, including an increased frequency of micronuclei in root cells of durum

wheat (Triticum durum) and bean (Vicia faba) (El-Nahas 2000; Rad et al. 2011).

In onions (Allium cepa), imazethapyr causes DNA damage (Liman et al. 2015),

and micronuclei and chromosomal aberrations after 4 days of exposure to

concentrations of 10 and 1 µg/L, respectively (Magdaleno et al. 2015).

1.2. Deregulation of the expression of genes at the whole genome scale

A concentration as low as 10 µg/L of imazethapyr in the culture medium of

A. thaliana affects sexual organ development and reproductive success through

the repression of genes involved in the synthesis of anthers and pollen (Qian et

al. 2015a). Indeed, the exposure of plants to ALS-inhibiting herbicides modifies

the expression of hundreds to thousands of genes in various plants (Table 1). In

rice, genes involved in photosynthesis and carbon fixation are repressed, as well

as genes for glucose consumption and starch mobilization, and amino acids

synthesis. Genes encoding enzymes of the Krebs cycles are up-regulated, along

with stress response and defense genes such as glutathione S-transferase (GST).

In maize, up-regulated genes are those encoding proteins involved in

translation, ribosomal structure and biogenesis, DNA replication, recombination

and repair. Down regulated genes are mainly involved in translation, ribosomal

structure and biogenesis, posttranslational modification, protein turnover, and

chaperones.

In rapeseed, in the anthers of large buds, up-regulated genes are involved

in degradation of carbohydrates, lipids, proteins, nucleic acids and cell wall

degradation, and down-regulated genes are involved in the synthesis of

carbohydrates, lipids, proteins, nucleic acids, and cell wall synthesis.

In wheat, down-regulated genes are encoding proteins involved in stress

response and defense, carbohydrate metabolism and transport, and DNA

methylation.

In Arabidopsis thaliana, up-regulated genes are those encoding enzymes

involved in the metabolization of herbicides such as cytochrome P450 (CYP), GST

and UDP glycosyl transferases (UGT), and allowing detoxification such as ATP-

binding cassette (ABC) transporters and multidrug resistance (MRP) and toxin

extrusion (MATE) protein families, and the iron superoxide dismutase Fe-SOD

genes (FSD). Also up-regulated genes comprise those encoding ribosome

associated proteins or protein synthesis initiation factors (eIF4A, eIF4E and

eIF5), and some involved in amino acid synthesis. The mitochondrial function is

also impacted since the genes encoding mitochondrial genes alternative oxidases

ATAOX1a and ATAOX1b, along with two mitochondrial NADH dehydrogenases,

NDB2 and NDB4 are up-regulated. Down-regulated genes are those involved in

cell wall biosynthesis, along with genes involved in the neutralization of the

oxidative stress such as those encoding copper-zinc superoxide dismutases

Cu/ZnSOD (CSD), ascorbate peroxidases (APX) and glutathione peroxidases

(GPX).

In keeping with these gene deregulations, the SUL tribenuron-methyl

triggers the increase of the release rate of the plant hormone ethylene in the

flower buds of rapeseed (Lian et al. 2019). This herbicide causes starch or

soluble sugar accumulation in rice (Qian et al. 2011b), Arabidopsis thaliana (Qian

et al. 2011a) and peas (Gaston et al. 2002; Royuela et al. 2000). Also, ALS-

inhibiting herbicides are strong promoters of an oxidative stress with an

important increase of lipid peroxidation, and of the concentrations in superoxide

radicals and hydrogen peroxide, and most often an anti-adaptive decrease of the

activity of the oxidative stress-neutralizing enzymes (Table 2).

1.3. Deregulation of the expression of proteins at the whole cell scale

Upon exposure of rapeseed seedlings to 1.5 µg of monosulfuron sprayed on

leaves, a proteomic analysis performed on whole tissues after one week showed

a total of 131 differentially expressed proteins between the treated and control

plants (Cheng et al. 2013): 34 proteins up-regulated and 97 down-regulated.

Up-regulated proteins comprised the metabolizing enzymes GSTs, UGTs and a

peroxidase, and proteins involved in photosynthesis and energy production.

Down-regulated proteins comprised those involved in cell defense and protein

synthesis and degradation, in carbohydrate, cell wall, energy metabolisms and

cytoskeleton dynamics. In another study rapeseed plants were foliar-sprayed

with a single quantity of 15 µg of the sulfonylurea SX-1 each. Compared to

control, 87, 25, 74 and 60 proteins were found to be up-regulated over two-fold

at young buds, short, mid and late anther stages respectively, and the decreased

ones were 130, 220, 329 and 366, respectively. These proteins were involved in

protein, energy, carbohydrate and amino acid metabolisms, and defense (Ning et

al. 2018).

1.4. Chloroplasts destruction and induction of male sterility

In rapeseed, at a dose so little as 1 µg sprayed on leaves of a single plant,

amidosulfuron causes chloroplast destruction as soon as 3 days after treatment

(Liu et al. 2017), chlorsulfuron causes six hours later thylakoids swelling and

chloroplast disorganization (Kim and Vanden Born 1997), and exposure of A.

thaliana to 2.5 µg/L of imazethapyr for 4 weeks also causes a 2-fold decrease in

the number of chloroplasts (Qian et al. 2011a).

In rapeseed, monosulfuron is a male gametocide inducing male sterility

(Cheng et al. 2015), and transcriptomic analysis showed this is linked to

disruptions in pollen wall formation, chloroplast structure, cell cycle and tissue

autophagy (Ning et al. 2018; Lian et al. 2019). Tribenuron-methyl causes male

sterility not only in rapeseed but also in 17 species of cruciferous plants (Yu et al.

2017) through the onset of an autophagic cell death in anthers (Zhao et al.

2015). Recently, it has been shown that 18 SULs and 2 IMIs could induce male

sterility in rapeseed (Yu et al. 2020).

1.5. Poisoning of the mitochondrial respiration

Sulfonylureas and imidazolinone herbicides poison the mitochondrial

respiration in sycamore cultured cells (Aubert et al. 1997). Sulfometuron at a

dose so little as 1 nM completely blocked the mitochondrial respiratory chain

after 5 days of exposure leading to cell death. The mitochondrial alternative

oxidase AOX activity was 6-fold induced after three days of exposure to 1 nM

sulfometuron, 1 nm chlorsulfuron, 1 µM of the IMI Scepter, but not when

exposed even for 5 days to 1 mM glyphosate. AOX dissipates as heat the

electron flow that is not used to yield ATP (only the complex I can contribute to

the proton gradient and ATP synthesis when electrons flow through AOX). The

herbicides-linked increased activity of this enzyme was paralleled by an up-

10!

regulation of the Aox1 gene and an increased mitochondrial concentration of the

AOX enzyme.

1.6. Effects on non-target aquatic microorganisms

The photosynthetic potential of the cyanobacteria Microcystis aeruginosa

suffered 29 and 14 % decreases after 16 h exposure to 67 µg/L of the IMI

imazethapyr and 3 µg/L of the SUL metsulfuron-methyl (MSM), respectively, and

that of the algae Selenastrum capricornutum presented a 27 % decrease after

exposure to 3 µg/L of MSM (Peterson et al. 1994). The SUL nicosulfuron had an

impact on algal community diversity (it inhibited diatoms more than

chlorophytes) and on the photosynthetic yield at a concentration of 30 µg/L

(Seguin et al. 2001). SUL herbicides affected growth and reproduction of

Chlorella fusca at concentrations between 0.08 and 1.2 ppm (Fahl et al. 1995),

and those of Scenedesmus acutus at about 0.1 ppm (Grossmann et al. 1992;

Sabater and Carrasco 1997). SUL herbicides could inhibit the incorporation of

adenine and thymidine of periphyton communities from natural creeks for

concentration as little as 3 nM (Nyström et al. 1999).

If these herbicides target other molecular actors than the ALS enzyme, then

could organisms without ALS be sensitive to the deleterious effects of these

chemicals as well?

2/ These herbicides are toxic, including organisms that do not have the

enzyme ALS/AHAS.

The pesticide lobby and several French institutions such as the national

agronomic research institute INRA, the national federation of agricultural unions

11!

FNSEA, and the Ministry of Agriculture all pretend that the only molecular target

of IMI and SUL herbicides would be the enzyme ALS, and that consequently all

the organisms deprived of this enzyme would be tolerant to these herbicides.

This belief does not match with the literature.

2.1. Invertebrate species

In rice paddy water, the half-lives (time required for 50 % dissipation of the

herbicide) of the IMIs imazethapyr and imazapic were equal to 4.5 and 11.9

days, respectively (Reimche et al. 2015). In such artificial environment, a

combined treatment of imazethapyr and imazapic at concentrations equal to 17.4

and 9.5 µg/L at time 0 resulted in a very significant decrease in the density of

several rotifer species. At day 56, 3.4-, 10- and 15-times lower densities

compared to unexposed control were observed for the genera Keratella,

Polyarthra and Trichocerca, respectively. At that time, the calculated residual

concentrations could be calculated to be 0.24 and 20.0 ng/L (0.8 and 73 pM) for

imazethapyr and imazapic, respectively, meaning that these IMIs can still slow

down animal growth at the range of pmol/L. The recovery of densities similar to

those of the control experiment was observed after 88 days (Reimche et al.

2015). The SUL metsulfuron-methyl combined with its adjuvant Assist proved to

decrease the reproductive success of Enchytraeus crypticus oligochaeta worms

and Proisotoma minuta collembolans (de Santo et al. 2019) and to trigger an

avoidance behavior in earthworms Eisenia andrei and Folsomia candida

collembolans (de Santo et al. 2018).

IMIs imazamox Sweeper and imazaquin Scepter 70 DG from BASF are

genotoxic for Drosophila (Fragiorge et al. 2008). Genotoxicity has also been

proven in Drosophila melanogaster for the SUL triasulfuron Amber 75WG from

12!

Novartis when the feed was containing the herbicide or an aqueous extract of

wheat previously exposed to the herbicide (Heres-Pulido et al. 2008).

The bioaccumulation of IMI herbicides in Eisenia fetida earthworms (the

ratio of the herbicide concentration in earthworms to that in soil) is depending

upon the richness of the soil in its organic matter. When soils were spiked with 2

mg herbicide/kg, earthworm concentrations up to 170, 140 and 240 µg herbicide

per kg were recorded for both enantiomers of imazapic, imazamox and

imazethapyr, respectively, and after 6 weeks of exposure bioaccumulation

factors were varying according to the quality of soil with values ranging between

0.2 and 0.45 for imazapic, 0.25 and 1 for imazamox, and 0.4 to 0.8 for

imazethapyr (Hu et al. 2018).!

In the earthworm species Dendrobaena veneta, the SUL nicosulfuron

caused after 28 days of exposure to a soil concentration of 0.3 mg/kg, a relevant

environmental one, a 20 % increase in lipid peroxidation compared to the control

animals, and a 60 % drop in the activity of the glutathione-S-transferase enzyme

(GST, involved in the neutralization of oxidative radical species) (Hackenberger

et al. 2018). In the earthworm Eisenia fetida, the SUL tribenuron-methyl at a

concentration of 52 mg/kg of soil (5 % of the LC50 on day 7) triggered after 3

days of exposure the decreased activity of SOD and cellulase enzymes, the latter

playing an important role in the processing of organic matter in worms’ gut (- 14

and – 61 %, respectively), whereas that of catalase enzyme was increased by 41

% (Chen et al. 2018). The activities were fully recovered after 14 days probably

due to the degradation of the herbicide and its adsorption on soil particles

thereby decreasing its the bioavailability as exemplified for IMIs in earthworm-

soil microcosms (Hu et al. 2018).

13!

2.2. Amphibians

IMI imazethapyr in its Pivot formulation (10.6%) is very toxic to Hypsiboas

pulchellus tadpoles (LD50 at 96 hrs equal to 1.55 ± 0.05 mg/L) altering the

swimming behavior of animals and displaying a genotoxicity (increased

frequency of micronuclei and lobed nuclei in erythrocytes) as soon as 0.39 mg/L

after 48 hours (Pérez-Iglesias et al. 2015). This concentration at 48 h also

caused mutations of the DNA (by oxidation of the nucleic bases) in the blood

cells (Pérez-Iglesias et al. 2017). Boana pulchella tadpoles exposed for 4 days at

this concentration had oral morphological abnormalities (loss of rows of

keratodonts), which persisted 21 days after transfer to a healthy medium. In

addition, another type of caudal morphological anomaly (lateral torsion)

appeared after 14 and 21 consecutive days of transfer to a healthy medium

(Pérez-Iglesias et al. 2018). DNA damage were observed in blood erythrocytes of

Rhinella arenarum and Leptodactylus latinasus tadpoles exposed for 96 h to a

concentration of Pivot imazethapyr equal to 0.05 mg/L (5 % of the LC50 at 96 h)

and 0.07 mg/L, respectively (Carvalho et al. 2019; Pérez-Iglesias et al. 2020). In

L. latinasus tadpoles, this herbicide also caused irregular swimming (LOAEL

48h

equal to 0.81 mg/L), loss of keratodonts (LOAEL48h equal to 0.81 mg/L), and

nuclear abnormalities in blood erythrocytes as soon as 48h after exposure to

0.07 mg/L (Pérez-Iglesias et al. 2020). The SULs sulfometuron methyl and

nicosulfuron proved to be teratogenic in embryos of the frog Xenopus laevis, and

the median teratogenic concentrations EC50 were equal to 4.2 and 3.1 mg/L,

respectively (Fort et al. 1999).!

2.3. Fish

14!

The toxicity of ALS-inhibiting herbicides is well documented in the

toxicological literature in freshwater fish (Table 3). Recorded are a decrease in

the activity of several enzymes including catalase, GST, and acetylcholine

esterase (AchE) in several tissues, changes in swimming behavior, increased

oxidative stress-related processes such as lipid peroxidation and protein

carbonylation, increased blood glucose, decreased muscle glycogen

concentration, and decreased total protein concentration in several tissues.

Histological alterations and morphological degeneration of mitochondria were

demonstrated by electron microscopy. The toxicity of these herbicides is also

accompanied by a change in the homeostasis of several amino acids and of that

of neurotransmitters glutamate, taurine and glycine (the corresponding

references are collected in Table 3).!

2.4. Mammalian cells

Chinese hamster ovary cells (CHO-K1) exposed for 90 min to the IMI

imazethapyr exhibited DNA damage at the lowest concentration tested (100

µg/L), which were five times more numerous than in unexposed control cells.

Damage were essentially related to the oxidation of the DNA bases, and caused

by the herbicide's only molecule, because the commercial Pivot formulation

tested at the IMI equivalent concentration caused the same increase in DNA

damage as the IMI alone (Soloneski et al. 2017).

The IMIs iodosulfuron-methyl-sodium, mesosulfuron-methyl, and

metsulfuron-methyl proved to be agonists of the soluble AhR dioxin receptor

(aromatic hydrocarbon receptor) for a concentration of 0.1 mM applied for 4 h to

human hepatocytes Hepa 1.12cR (Ghisari et al. 2015). The AhR-controlled

pathway is responsible for most of the toxic and biological effects of polycyclic

and halogenated aromatic hydrocarbons (Puga et al. 2009).

15!

A panoptic figure is summarizing the main toxic effects of ALS-inhibiting

herbicides on plants and animals (Figure 1).

3/ The problem of testing herbicides out of their commercial

formulation.

Official regulatory agencies - pushed by industrial lobbies - consider that the

toxicology of pesticides must be conducted on the active ingredient or molecule,

and not on the total formulation, the same used in fields. However, the

toxicological literature undeniably shows that the formulation including the active

molecule is always significantly more toxic than the latter used alone. The

examples developed below in the case of ALS inhibitory herbicides are illustrating

that matter of fact.

In the onion, after 5 days of exposure, no effect on root growth was

observed until the highest dose tested of 80 mg imazethapyr/L (Liman et al.

2015). However, in lettuce, the Verosil formulation of Agrofina (10.6%

imazethapyr) showed a 34 % inhibition of root growth after 5 days of exposure

for the smallest tested dose of 10 mg imazethapyr/L (Magdaleno et al. 2015).

In the onion, after 4 days of exposure to the Verosil formulation, this

herbicide caused the appearance of micronuclei and chromosomal aberrations at

concentrations equal to 10 and 1 µg imazethapyr/L, respectively (Magdaleno et

al. 2015); on the other hand, when added pure in the medium, a concentration

2000-times higher (20 mg/L) was required to observe DNA damage after 4 days

of exposure (Liman et al. 2015).

The Verosil formulation was significantly more toxic than 2ASU whereas it

contains half as much active compound (10.6 and 22.2% imazethapyr,

16!

respectively), which highlights the important role of adjuvants in the overall

toxicity (Table 4).

Metsulfuron-methyl is a herbicide belonging to the family of SULs, and is

sold in Brazil under the brand Ally by Du Pont. The adjuvant (mineral oil)

associated is marketed by BASF under the brand Assist. Toxic avoidance tests in

earthworms Eisenia andrei and in collembolans Folsomia candida (pancrustacean

arthropod) showed that the SUL Ally was significantly more toxic in combination

with its adjuvant Assist (de Santo et al. 2018). The observed LOAELs (smaller

doses for which a significant effect is observed) showed that the adjuvant greatly

magnified the toxicity of the herbicide in these animals (Table 5). Also, the

reproductive success of Enchytraeus crypticus oligochaeta worms and Proisotoma

minuta collembolans was significantly reduced (Table 5) when the exposure to

the SUL Ally was combined with its adjuvant Assist (de Santo et al. 2019).

Using the marine bacterium Vibrio fischeri as a model organism, it has been

observed that the growth inhibitory concentration (IC50) of the SUL nicosulfuron

was reduced from 168 down to 4 mg/L when comparing the active ingredient

alone or the Milagro (Syngenta) formulation, respectively (Joly et al., 2013).

The IMI imazapyr is marketed under the brand name Arsenal 250 NA by

BASF. This formulation contains 25 g/L of imazapyr, 186 g/L of ammonium

hydroxide, and 18 g/L of nonylphenol ethoxylate in water. Imazapyr is

significantly more toxic in its Arsenal formulation (Grisolia et al. 2004). In three

different animals (aquatic snail, vinegar fly, and mouse), the LD50 were

significantly lower after exposure to the Arsenal formulation; and the onion

exhibited chromosome separation aberrations during mitosis for an equivalent

imazapyr concentration 8,000 times lower in its Arsenal formulation (Table 6).

17!

In addition to the presence of adjuvants, another herbicide may be added to

the commercial formulation of a product. This is the case for BASF's Cleravis and

Cleranda formulations used on Clearfield plants, which contain 17.5 g/L of the

IMI imazamox and 375 g/L of metazachlor. Metazachlor is a chloroacetamide for

which mutant plants tolerant to SULs and IMIs have no tolerance or resistance.

However, the toxicity of these compounds is not assessed in combination or even

in their commercial formulation in the presence of all the adjuvants used in the

composition. However, the use of metazachlor has caused an environmental

disaster in Luxembourg, with the regulatory concentration limit for drinking

water being exceeded for several months, and the main drinking water reservoir

in Luxembourg being contaminated (Karier et al. 2017). In France, an episode of

drinking water pollution by metazachlor led to a five-week ban on drinking water

consumption (from February 17 to March 21, 2016) in several villages in

Burgundy (l’Yonne Républicaine 2016; a local newspaper).

4/ Epidemiological and pharmacological data on human populations.

Regulatory authorities minimize the toxicity of ALS inhibitory herbicides

because SULs and IMIs are rapidly excreted from mammalian organisms,

although intestinal absorption is also recognized high and rapid. Thus, in animals

receiving an oral dose of the SUL MSM, this toxic and its metabolites are found 3

to 4 days later up to 71 to 95 % in urine and 5 to 13 % in excrements (Health

Canada 2008, page 10). In the rat, almost 100 % of the radioactive IMI

imazethapyr administered was found in the following 4 days at 89 to 95 % in the

urine and 6 to 11 % in the excrement (Toxnet 2012).

However, IMIs have a wide variety of pharmacological effects:

anticonvulsant, sedative, antihistaminic, fungicidal, bactericidal, anti-

18!

inflammatory, monoamine oxidase (thus anti-depressive), and antihypertensive

(Desai et al. 2009). It is therefore unreasonable to imagine that these herbicide

molecules once transferred to human organisms would be devoid of activity.

When herbicide molecules have entered our body by air or intestinal tract,

human serum albumin binds these toxins and transports them into the blood,

distributing these toxins to tissues (Ding et al. 2010). This process is very

effective since human serum albumin is the most abundant protein in serum with

a concentration of 35 to 50 g/L of serum.

Cases of acute poisoning with the IMI imazapyr (Arsenal) have been

reported and the toxic panel resulting from an ingestion of over 100 mL of

Arsenal consisted of hypotension, pulmonary dysfunction, oral mucosal and

gastrointestinal irritation, and transient liver and renal dysfunction (Lee et al.

1999). In one case a cardiac arrest has been observed and this correlated with a

serum imazapyr concentration of 0.71 mg/mL (Wu et al. 2019).

Epidemiological studies performed on a cohort of 20,646 IMI herbicide

applicators have shown that the use and handling of these toxins is associated

with a significantly increased risk of colon and bladder cancer (Lee et al. 2007;

Koutros et al. 2009 and 2016; Weichenthal et al. 2010; Alexander et al. 2012).

In regions of rural Minnesota where soybean is cultivated and imazethapyr used

in combination with other pesticides, increased mortality rates by cancer have

been observed in women (nasopharynx and non-Hodgkin’s lymphoma)

(Schreinemachers et al. 1999).

Inhibitors of ALS are known to impact the human reproduction since the use

of herbicides containing sulfonylurea and imidizolinone by male applicators was

correlated with increased miscarriage risk in the spring, at the time herbicides

are applied in fields (Garry et al. 2002; Colborn and Carroll 2007). Conceptions

19!

in the spring also led to significantly more birth defects among children of rural

Minnesota (Garry et al. 1996). In Brazil also, some soybean farmers exposed to

33 different pesticides reported that their wives had experienced spontaneous

abortion (Bernieri et al. 2019).

SULs are also endocrine disrupters and this effect has been harnessed for

therapeutic strategies. Indeed, SULs are also used in human therapy as

hypoglycemic agents in the treatment of type II diabetes. Their action depends

on their binding to the pancreatic β-cell SUL receptor SUR1 (SUR1 is the

regulatory subunit of the ATP-sensitive potassium channel, KATP, the closure of

which triggers the secretion of insulin). The SUL depuration metabolism is

catalyzed by the cytochrome P450 CYP2C9. The CYP2C9*2 and CYP2C9*3 alleles

are associated with hypoglycemic events in diabetic patients taking Glimepiride

or Gliclazide SULs (Ragia et al. 2009), since these molecules are no longer

effectively detoxified. Also, deleterious drug interactions may occur: voriconazole

and fluconazole antifungals, for example in the treatment of fungal pneumonias,

are also CYP2C9 inhibitors, and may lead to hypoglycemia in diabetic patients

treated with SULs (Gunaratne et al. 2018).

Cohort studies show that the risk of cancer is greater in diabetic patients

using SULs rather than the metformin hypoglycemic agent (Chen et al. 2017).

Given the great similarity of the SULs used as a herbicide with those used as a

hypoglycemic agent, it would be unreasonable to imagine that this type of

herbicides do not bind to the SUR-1 SUL receptor, from which it can be

formulated the hypothesis that this class of herbicides plays a role in blood

glucose after accumulation in our bodies. For instances, fish exposed for 90 days

in rice field to Ally herbicides (MSM, 5.8 µg/L) or Only (at concentrations of 14.8

µg/L of imazethapyr and 3.1 µg/L of imazapic) present, among other effects (see

20!

Table 1), 15 and 80 % increases in blood glucose levels compared to unexposed

animals (Pretto et al. 2011; Moraes et al. 2011). This strongly suggests that

these herbicide molecules trigger the opening of KATP channels in β-cells of the

pancreas in these fish, and therefore mimic the effects of diazoxide, a SUR-1

receptor ligand (Emfinger et al. 2017), the active principle of the hyperglycemic

drug Proglicem proposed to hyperinsulinic patients.

5/ Impact of ALS-inhibiting herbicides on biodiversity and their fate in

the environment.

5.1. Loss of biodiversity

ALS-inhibiting enzymes are contributing among several other causes and

chemicals to the loss of biodiversity. The representative tree species of the

Brazilian forest Dipteryx alata, ranked by the International Union for

Conservation of Nature among the vulnerable species, has been shown to be

sensitive to recommended dose of the SUL nicosulfuron, with the onset of an

oxidative stress and the alteration of the photosynthetic potential (Silva et al.

2020). The ALS-inhibiting herbicide bispyribac at the recommended dose of 35

g/ha triggered a decrease of the soil microbial population and of microbial

diversity, and a decrease of microbial enzyme activities such as dehydrogenases

and urease (Kumar et al. 2020). In soils from fields treated with 30 g of the SUL

chlorimuron-ethyl/ha for 5 and 10 years, in which soybean had been cropped

continuously, the residual herbicide concentrations were 3.4 and 8.5 µg/kg, and

the soil microbial population presented a 33 and 51 % decrease, with a shift of

the soil bacterial and fungal community structure. In particular, after 10 years of

21!

treatment, the actinomycete titer decreased 7.5-fold whereas the fungal titer

increased 2.5-fold (Zhang et al. 2011).

5.2. Onset of ALS-inhibiting herbicides resistant weeds, and mutant ALS

gene transfer

The Clearfield technology has allowed the emergence of herbicide-tolerant

weeds, and this has been described in the case of the rice Clearfield where

resistant weedy red rice evolved both from selection pressure due to continuous

exposure to herbicide and gene transfer from Clearfield rice (Sudianto et al.

2013). The Clearfield plants and those harboring a mutated and tolerant form of

the ALS enzyme are resisting to concentrations much higher than their sensitive

counterparts (Table 7). After only one year of Clearfield rice cultivation, the ALS

resistant allele transfer was made evident and the outcrosses amounted to a

mean of 0.17 % (Zhang et al. 2006). The gene transfer from Clearfield rice to

weedy rice has been reported in several places around the world (Villa et al.

2006; Shivrain et al. 2007; Burgos et al. 2008; Shivrain et al. 2009a and 2009b;

Busconi et al. 2012; Dauer et al. 2018). Weeds sampled from fields with a

history of Clearfield rice had at least 20 % resistant offspring (Burgos et al.

2014). Resistant gene transfer also occurred from Clearfield rapeseed to the wild

turnip (Brassica rapa) weed (Ureta et al. 2017).

5.3. Persistence of ALS-inhibiting herbicides in soils and in the

environment

SUL and IMI herbicides are degraded in soils by microbes, and both bacteria

and fungi participate to this process (Goetz et al. 1990; Flint and Witt 1997;

Kraemer et al. 2009a; Singh and Singh 2014; Arya et al. 2016). The application

22!

rates in fields of ALS-inhibiting herbicides, along with their half-lives and

environmental recorded concentrations have been collected (Table 8). The half-

life of the IMI imazamox depends on the type of soil and varies from 2 to more

than 120 days. The rate of degradation is faster in neutral rather than acidic soils

(Buerge et al. 2019). In the aquatic environment, the half-life of the MSM SUL

was 8 days at an initial concentration of 5.8 µg/L (Pretto et al. 2011), and those

of imazethapyr and imazapic IMIs were equal to 6 days for initial concentrations

of 14.8 and 3.1 µg/L, respectively (Moraes et al. 2011). Although the persistence

of these molecules in aquatic environments was low, fish exposed to these

molecules showed obvious signs of toxicity after 90 days of exposure to a single

dose added the first day in rice field, that is after 15 half-lives of the compounds

and residual calculated concentrations of 0.45 and 0.1 ng/L (1.6 and 0.35 pM,

respectively) (Table 3, Moraes et al. 2011; Pretto et al. 2011). The fish are

therefore permanently intoxicated by low doses to which they were exposed

weeks earlier and commensurate with the picomolar range. SUL herbicides such

as chlorsulfuron can present high persistence in soil: recorded half-lives range

from 2 weeks (Fredrickson and Shea 1986) to 7.5 months (Thirunarayanan et al.

1985).

In agricultural soils and wetland sediments, the three most persistent

environmental SULs, ethametsulfuron-methyl, sulfosulfuron, and MSM, were

detected at mean concentrations ranging from 1.2 to 10 µg/kg (Degenhardt et

al. 2010), and thus already toxic levels for organisms. Nicosulfuron has been

detected in freshwater rivers and reservoirs in the United States at median and

maximum concentrations of 10 and 270 ng/L (Battaglin et al. 2000). The half-

lives measured in grasslands for thifensulfuron-methyl, ethametsulfuron-methyl,

and MSM were 16, 30, and 84 days, respectively (Cessna et al. 2006). MSM

23!

showed a dissipation rate of only 34 % at 20°C after 35 days of incubation in an

experimental biobed matrix (Cessna et al. 2017). In pools adjacent to farms, the

measured half-lives of nicosulfuron, sulfosulfuron, and rimsulfuron were 75, 44,

and 10 days, respectively (Cessna et al. 2015). The leaching of IMIs from fields

during rainfall and irrigation has been estimated to range between 0.7 to 3.1 and

0.6 to 2.8 % of the total amount initially applied for imazethapyr and imazamox,

respectively (Cessna et al. 2012). In a 1998 study, in 129 water samples from

US Midwestern streams and rivers, 108 tested positive for the sum of 16

herbicides (comprising 1 sulfonamide, 3 IMIs and 12 SULs) with median and

maximum concentrations of 137 ng/L and 2100 ng/L, respectively (Battaglin et

al. 2000). A study extending from 2009 to 2011 in the Saint-François Bay,

adjacent to the Saint Lawrence River, showed that among 70 water samples, the

detection frequencies (> 10 ng/L) of the SULs ethametsulfuron-methyl, MSM,

nicosulfuron and sulfosulfuron reached 4.3, 10.0, 8.6 and 7.1 %, respectively (de

Lafontaine et al. 2014). Maximum concentrations equal to 148 and 223 ng/L

were sporadically above the baseline level (100 ng/L) for aquatic plant toxicity,

meaning potential toxic stress to flora in the streams (de Lafontaine et al. 2014).

The IMI imazethapyr was detected in 71 % of water samples collected from 75

sites in the United States (Upper Mississippi, Missouri and Ohio River basins) with

median and maximum concentrations of 30 and 700 ng/L (Battaglin et al. 2000).

By way of comparison, the European Community has set a limit value of

pesticides in drinking water at 100 ng/L (quoted by Ding et al. 2010). This IMI is

degraded in soils with the following measured half-lives: 2.6 to 10.6 months

(Goetz et al. 1990), 23.5 to 62 days (Ramezani et al. 2010), and 73 to 257 days

(Vischetti 1995).

24!

5.4. Carry-over of herbicides and impact on rotational crops

Another problem beside resistance gene transfer is the persistence in soils

of ALS-inhibiting herbicides linked to repeated application and the poisoning of

the next rotational crops. The concentrations of SUL herbicides necessary to

inhibit the growth of some plants by 10 % has been recorded: 340, 180, 90 and

30 ng/kg of soil for barley, corn, sugar beet and oilseed rape, respectively,

exposed to tribenuron-methyl; 140, 70, 50, and 40 ng/kg of soil for barley,

sugar beet, corn and oilseed rape, respectively, exposed to sulfosulfuron

(Mehdizadeh et al. 2016). Given the application rates commonly used and

recommended by manufacturers, the half-lives in soils of ALS-inhibiting

herbicides, and the concentrations found in agricultural soils (Table 8), it is not

surprising that carry-over effects can be observed on rotational crops. In rice

paddy soil imazethapyr and imazapic (Only formulation, BASF) used with

Clearfield rice still remained up to 20 cm of depth 540 days after the last

application with surface concentration equal to 1281 µg imazethapyr/m2

(equivalent to 12.8 g/ha) (Kraemer et al. 2009b). After use of a mixture of

imazapic and imazapyr on an IMI-tolerant corn, the growth ability of non-tolerant

rotational crops, such as corn, cucumber, wheat, sugar beet, chili pepper,

tomato, melon, barley, oat, pea, and edible bean was impacted by the carried-

over herbicides (Alister and Kogan 2005; Ulbrich et al. 2005). The yield of non-

tolerant rice was reduced up to 55 % when planted 705 days after application of

the IMI herbicide Only formulation (Marchesan et al. 2010). Also the yields of

sorghum and of ryegrass, the most widely used pasture grass in Brazil, were

deeply impacted after being planted in rotation with Clearfield rice treated with

the Only formulation (Pinto et al. 2009a and 2009b). Carry-over of imazaquin

caused corn and sunflower injury and yields reduction of corn and cotton (Barnes

25!

et al. 1989; Loux and Reese 1993; Fleck and Vidal 1994; Marsh and Lloyd 1996).

Imazethapyr application proved to cause yield losses of sorghum seeded 120

days later (da Silva et al. 1999), flax, corn, mustard, sunflower and wheat

seeded one year later; canola seeded up to two years later, and sugarbeet and

potato seeded up to three years later (Moyer and Esau 1996). Imazamox applied

to IMI-tolerant wheat damaged barley and canola grown one year after

imazamox treatment (Ball et al. 2003). Application of the SUL sulfosulfuron

inhibited nine months later the growth of seeded sunflower (Alonso-Prados et al.

2002), and caused 40 % of reduction in yield to winter rape seeded in crop

rotation (Adamczewski and Paradowski 2004). The mixture of the SULs

amidosulfuron and tribenuron-methyl also decreased the yields of sugar beet,

beans and winter rape seeded in crop rotation (Adamczewski et al. 2004), and

MSM affected growth of lettuce and sugar beet sown one year later (Walker and

Welch 1989). The SULs chlorsulfuron, triasulfuron and MSM affected sunflower,

lentil and sugar beet sown 8 months after initial treatment of wheat (Kotoula-

Syka et al. 1993). Triasulfuron at 22 g/ha reduced the growth of alfalfa, canola,

corn, lentil, pea, potato, and sugarbeet the year after application, and at 11 g/ha

increased injury on alfalfa, lentil and sugar beet one year after treatment (Moyer

1995; Shinn et al. 1998). Sulfosulfuron treatment of wheat reduced one year

later the growth of barley, pea and canola, for an application rate of 36, 18 and

18 g/ha, respectively (Shinn et al. 1998).

Finally, although these herbicides are intended to increase yields by

reducing competition from weeds, sometimes yields or benefits may be lower

than those obtained without the herbicide with hand weeding. For example, after

treating potatoes with sulfosulfuron at a rate of 25 g/ha, total yield was 24 t/ha

compared to 29.6 t/ha with hand weeding. Operating profits (difference between

26!

selling price and operating costs) amounted to 59,000 Indian rupees per ha

compared to 81,000/ha with hand weeding. Increasing the herbicide application

rate to 50 or 75 g/ha did not improve yields or benefits (Singh et al. 2017).

Lower yields after treatment with the IMIs imazaquin or imazethapyr than with

hand weeding have also been observed with soybean (Mills and Witt 1989) and

corn (Curran et al. 1992).

6/ The official regulation and its shortcomings.

If we take as examples an IMI molecule, imazethapyr, and a SUL one, MSM,

it can be found that the toxic potential of these inhibitors of ALS is minimized by

the regulatory authorities in each country. Thus, it is said that MSM has no toxic

effects on terrestrial invertebrates, birds or mammals through food and no

effects on reproduction; the same applies for freshwater invertebrates and fish in

acute exposure mode, so that chronic effects can not be predicted (Health-

Canada 2008, p. 19-20), in contradiction with all published results in the

literature and explained above in this short review. SUL-type herbicides are

applied in Canadian fields at a concentration of 3 to 40 g per hectare to wheat,

barley, oats, rapeseed, corn, soybean, and forage crops (Saskatchewan Ministry

of Agriculture, cited by Cessna et al. 2015). However, concentrations of these

herbicides applied in fields planted with herbicide-tolerant crops or labeled

Clearfield technology are much higher (Table 8). Tolerable doses of MSM and its

metabolites in food and cereals are as follows: barley and wheat kernels: 0.1

mg/kg; sugar cane: 0.05 mg/kg; meat (cattle, sheep, pigs, horse): 0.1 mg/kg;

milk: 0.1 mg/kg (Toxnet 2006). The tolerable daily intake (TDI) is the dose at

which an individual can be exposed during his life without damaging his health.

MSM TDI equals 83.3 µg/kg body weight/day (Health-Canada 2008, p. 16). For a

27!

person of mass equal to 60 kg, this represents 5 mg/d. However, a diabetic

patient who takes as hypoglycemic drug the SUL glimepiride will ingest 1 to 6 mg

of this compound per day (the common posology), and if that person takes

gliclazide, then it will be 30 to 120 mg/d (the common posology). It is obvious

that any addition of this type of molecule by food will contribute to the exceeding

of the TDI (this is already the case for those treated with gliclazide).

Imazethapyr is classified as a weakly toxic compound (Class III) by the EPA

(Environmental Protection Agency) in the United States (2002), and claimed

unlikely to be hazardous by the WHO (Pesticide Action Network), in contradiction

with the published literature quoted above in this short review. Tolerable doses

of imazethapyr and its metabolites in food and cereals are: rapeseed and soya

beans, corn kernels, vegetables, peanuts: 0.1 mg/kg; meat (cattle, sheep, pigs,

horse): 0.1 mg/kg; crayfish: 0.15 mg/kg; grains of rice: 0.3 mg/kg (Toxnet

2012). The TDI of imazethapyr is 0.56 mg/kg body weight/day. However,

exposure of the general population through food and drink is 0.050 mg/kg bw/d

(8.9% of TDI). In children 1 to 2 years of age, exposure is greater: 0.24 mg/kg

bw/day (43% of TDI) (Health-Canada 2010, p. 45). What will happen when

these children will consume food from plants resistant to ALS-inhibiting

herbicides? With the use of such mutant plants resistant to this herbicide, it can

be feared that the doses and applications will increase with the result that

children will exceed the TDI.

Other limits and shortcomings of the regulation: there is no obligation

pending on agrochemical companies offering the mutant plants to the market to

publish analytical dosages of the IMI and SUL herbicides in the tissues, grains or

seeds of these mutant plants after treatment and harvest at the doses they are

recommending. In the literature, no data are available on the IMIs and SULs

28!

accumulated in seeds and cereals produced and consumed by humans. An

experimental study could give the remaining concentrations of the IMI

imazosulfuron applied on rice at a dose rate of 60 g/ha: 60 days after treatment

the soil contained 10 ng/g and the plant tissues 64 ng/g (32 ng/g 90 d after

treatment). At harvest the rice grains and straw contained 9 and 39 ng/g,

respectively (Sondhia 2008). Because of the resistance of these mutant plants,

the concentration is necessarily much higher than in non-resistant plants for

which the intensity of treatment must be limited so as not to kill the producing

plant. Similarly, there is no requirement for companies or independent

laboratories to submit a study in which animals are fed for life long with food

derived from crops resistant to ALS-inhibiting herbicides, with an analysis of the

transfer of toxic molecules into animal tissues. The few weeks or less frequently

the three months usually used for this type of studies are far too short in relation

to the longevity of human beings whose chronic exposure spread over decades

(nobody has contracted lung cancer after only three months of smoking, even

exaggerated).

7. The paradigmatic case of the marketing authorization for Zeneca

mutant maize.

Another problem, the regulatory authorities do not take into consideration

that the toxicity can reside in the amounts of pesticides present in the tissues

and seeds of the mutant plants consumed. Thus, and to take an example, when

Zeneca deposited its new EXP1910IT maize hybrid made resistant to the IMI

imazethapyr by chemical mutagenesis, Health Canada stated in its information

bulletin that after having reviewed “the information presented in support of the

food use of imazethapyr tolerant corn hybrid EXP1910IT, it was concluded that

29!

this corn does not raise concerns related to human food safety. Products from

EXP1910IT corn are as safe and nutritious as those available from current

commercial field corn varieties” (Health Canada 1999). The regulatory authorities

are indeed backing their recommendations, and as amazing as it may seem, on

the data and studies put forward by the company applying for the marketing

authorization, and not on studies independent from the manufacturer led by

laboratories that do not maintain any link with the industry and, as a result,

would escape the conflict of interest. Moreover, if one reads why Health Canada

accepts Zeneca corn and declares it to be harmless, one can only be struck by

what can only be described as denial of reality (denial of the presence of

herbicide and adjuvant molecules in the sold maize after applications of the

recommended treatments). First, Health Canada recognizes that the chemical

composition of Zeneca mutant maize is identical to natural corn in terms of

protein, fat, fiber, starch and minerals. This is the principle of equivalence in

substances. However, herbicide and adjuvant concentrations in the mutant maize

have not been measured after treatments. If they had been, the principle of

equivalence in substances would have been reduced to nothingness. Rather than

conducting these herbicide and adjuvants analysis, Zeneca insisted that "the

amino acid sequence of the mutant form of ALS present in EXP1910IT corn is

identical, except for a single amino acid substitution, with the wild-type form of

this enzyme” (Health Canada 1999). As a result, “the mutated form of this

enzyme is not judged to have any potential for human toxicity” (but who claimed

the opposite?) In addition, " the imazethapyr tolerant form of ALS is extremely

unlikely to be allergenic » (Health Canada 1999). It is clear that in the mind of

the manufacturer and experts of the regulatory institution, the only difference

that deserves attention is the mutated amino acid of the mutant form of the

30!

enzyme, whereas the health problem obviously concerns the quantities of

herbicides and adjuvants present after harvest in the plant material and which

must necessarily be much higher than in non-resistant maize since the mutant

plant can resist up to 0.5 mM of the herbicide.

In fact, it has been observed that the treatment of maize with the SUL

nicosulfuron in combination with the “safener” isoxadifen-ethyl altered the

nutritional content and the taste of the edible crop (Cutulle et al. 2018). In the

case of the Clearfield canola, lepidopteran animals can make the difference

between three canola varieties: Clearfield, Roundup Ready and a common one.

Even without herbicide or pesticide treatment, most eggs were laid on the

common canola. In addition, for the same amount of fertilizer used, the common

variety presented the highest potassium content, and a higher calcium and

magnesium content than the Clearfield variety (Weeraddana and Evenden 2018).

8/ The precautionary principle and the Dijon trial

A social movement protesting against these new mutant plants has

emerged in France these last recent years. Illegal mowings have taken place,

and lawsuits are ongoing. In particular, by November 28, 2016, 67 volunteer

mowers have neutralized Clearfield rapeseed (BASF) test plots used with the

herbicides Cleranda and Cleravis. These activists wanted to demonstrate that

GMOs are grown in France (despite the moratorium applied in France), and to

trigger the constitutional principle of precaution.

Indeed, the Environmental Chart promulgated on March 1

st, 2005 by the

French Republic, which has constitutional value, specifies that "everyone has the

right to live in an equilibrated environment that respects health". It also

establishes the precautionary principle with regard to potentially serious and

31!

irreversible damage to the environment, even if it is uncertain in the light of

current scientific knowledge. However, pesticides are by definition toxic to living

things, and even when they target organisms other than animals, they can still

be harmful to the health of animals. The accumulated toxicological and

epidemiological data on ALS-inhibiting herbicides, synthesized in this review, are

sufficient to claim that the state of scientific knowledge is not uncertain but more

than likely as to their dangerousness. However, the ANSES for France (French

Agency for Food, Environmental and Occupational Health and Safety) and the

EFSA for Europe (European Food Safety Authority) do not require any

independent studies from industry or independent laboratories to quantify the

concentrations of herbicides contained in foodstuffs, and to control the

toxicological effects of the lifetime intake of these foods by animals. Launched in

2007 by the French Ministry of the Environment, the Ecophyto plan provided for

a 50 % reduction in pesticide use over ten years. However, the opposite has

happened: a 20% increase in pesticides between 2007 and 2017 (Nicolino and

Veillerette 2018). These mutant plants will necessarily accelerate this process.

The 67 activists were tried in Dijon (Burgundy) on 15 November 2018, and

the French edition of this toxicological review was sent to the defence lawyer and

then to the president of the court, at their request. The judgment was handed

down on 17 January 2019, and all the activists were released.

Declaration of interest statement

The author declares that there are no potential conflicts of interest.

32!

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Legend to figure

Figure 1. Synthetic panoptic of the toxicological effects of ALS-inhibiting

herbicides. The solid line arrows indicate the different effects of herbicides used

against herbicide-resistant plants. Dotted line arrows indicate possible

interactions between effects. For example, the onset of an oxidative stress in

turn leads to genotoxicity, and thus cancer and teratogenicity.

Herbicides

Oxidative stress

(earthworms, fish)

Genotoxicity

(drosophila,

tadpoles,

human cells)

Teratogenicity

(tadpoles)

Pharmacological effects

(various models)

SUR receptor

(fish, humans)

Mortality

(rotifers,

phytoplankton)

Avoidance strategy

(springtails,

earthworms)

Neurotransmitters

(fish)

Impact on

reproduction

(humans, plants

invertebrates)

Altered glycaemia

(fish, humans)

AhR receptor

(human cells)

Amino acids

(fish)

Cancers

(humans)

Deregulation of gene

and protein

expression (plants)

Chloroplast

destruction

(plants)

Tables

Table 1. Effects of ALS-inhibiting herbicides on the transcriptome and the

regulation of gene expression in plants.

Species

Treatment

Reference

Arabidopsis

thaliana

weed

Arabidopsis plants

were sprayed with

750 µg/m2

primisulfuron-

methyl, and 1.5

µg/m2 prosulfuron.

Whole leaves were

harvested after 24

Microarray containing

genes encoding for 109

glycosyltransferases, 63

glutathione enzymes, 62

CYP and 26 drug resistance

transporters.

Up-regulated genes by both

herbicides: 3 CYPs, 4 GSTs,

6 UGTs, 1 GR, MRP3 and

PDR8. a

Glombitza

et al.

2004

Wheat

Triticum

aestivum

Spraying

tribenuron-methyl

at 25 g ai/ha.

One week of

exposure.

Microchips containing 600

genes.

Genes differentially

expressed by at least a

factor 1.9 were 15 down-

regulated and were

encoding proteins involved

in stress response and

defense, carbohydrate

metabolism and transport,

and DNA methylation.

Pasquer et

al. 2006

Arabidopsis

thaliana

weed

Seedlings were

exposed to 100

µg/L imazapyr for

48 h and shoots

harvested.

Microarray.

1001 genes were up-

regulated and 597 genes

were down-regulated.

Early-response genes

included those encoding

members of the UGT, GST,

CYP, ABC, MRP and MATE

protein families, and

mitochondrial alternative

oxidase (ATOX1a) and

NADH dehydrogenase

NDB2. Later stages of the

imazapyr response involved

regulation of genes

participating in biosynthesis

of amino acids, secondary

metabolites and tRNA.

Manabe et

al. 2007

Rice

Oryza

sativa L.

6 days of exposure

to 50 µg/L R(-)-

imazethapyr

qPCR.

In roots: OSPC b gene: 1.5-

fold repressed

Qian et al.

2009

japonica

cv. Xiushui

In seeds:

OSPC gene: 7.2-fold

repressed

ALS gene: 1.5-fold

repressed

α-amy c: 1.4-fold repressed

β-amy d: 3.9-fold repressed

In shoots:

ALS gene: 7-fold repressed

β-amy: 5.6-fold repressed

Arabidopsis

thaliana

weed

Plants have been

sprayed with four

ALS-inhibiting

herbicides at their

EC50

concentrations:

0.13 g/ha for

sulfometuron-

methyl, 0.16 g/ha

for cloransulam-

methyl, 0.40 g/ha

for imazapyr, and

0.59 g/ha for

primisulfuron-

methyl.

Comparison with

Roundup

(glyphosate at 10.6

g ai/ha). Leaves

were harvested 24 h

later.

Microarray.

16 genes upregulated by

Roundup: genes allowing

detoxification genes

encoding multidrug

transporters, and

metabolizing enzymes

(CYP71A13, GST and UGT).

478 genes affected by

the four herbicides: 82

were down-regulated and

396 were up-regulated.

Up-regulated genes were

encoding ribosome-

associated proteins, CYP

enzymes linked to the

biosynthesis of the

defensive alkaloid

camalexin, and genes

involved in protein

synthesis initiation, and

amino acid synthesis.

Highly up-regulated genes

were 5 CYPs, 3 GSTs, and 3

UGTs.

Genes encoding

mitochondrial alternative

oxidases ATAOX1a and

ATAOX1b, along with two

mitochondrial NADH

dehydrogenases, NDB2 and

NDB4 were up-regulated.

Cell wall biosynthesis genes

were down regulated.

Das et al.

2010

Rice

Oryza

sativa ssp.

japonica

cv.

Seedlings exposed

in water to 0.2 g/L

of chlorsulfuron

for 6 h

qPCR.

The glutathione S-

transferase OsGSTL2 gene

was up-regulated 3-times

Hu et al.

2011

Zhonghua

Arabidopsis

thaliana

weed

Exposure to 2.5

µg/L R(-)

imazethapyr

enantiomer for 4

weeks

Genes selected were

encoding 3 FSD, 3

CSD, one

manganese

superoxide

dismutase, one

catalase, 6 APX and

8 GPX.!

qPCR.

The following gene

expressions were observed:

Down-regulation:

CSD1: 2 x

CSD2: 3 x

APX1: 2 x

APX5: 1.5 x

GPX1: 1.7 x

GPX2: 1.9 x

GPX5: 1.5 x

GPX7: 2.4 x

Up-regulation:

FSD1: 3 x

FSD2: 3 x

Qian et al.

2011a

Rice

Oryza

sativa L.

japonica

cv. Xiushui

0.05 mg/L of R(-)-

imazethapyr for 7

days.

Microarray.

In the leaves 2507 genes

are overexpressed and

2607 repressed, and in the

roots 1882 genes are

overexpressed and 2012

repressed. In particular,

genes involved in

photosynthesis and carbon

fixation are repressed, as

well as genes for glucose

consumption and starch

mobilization, and amino

acids synthesis. Genes

encoding enzymes of the

Krebs cycles were up-

regulated.

Qian et al.

2011b

Rye-grass

Lolium sp.

Pyroxsulam (Abak,

7.5 %; Dow

AgroScience) at

18.75 g/ha for 48h.

RNA sequencing 48 h after

treatment.

15590 transcripts were up-

regulated and 13759 down-

regulated. Major up-

regulated genes were

involved in gene expression

regulation, amino-acid

metabolism and

detoxification (CYP450,

glycosyl- and GSH-S-

transferases, multidrug

resistance and drug

transporters). Major down-

regulated genes were

Duhoux et

al. 2015

involved in photosynthesis

and gene expression

regulation.

Rapeseed

Brassica

napus L.

Leaves of each plant

were sprayed with

15 mL of a solution

containing 1.5 µg of

monosulfuron

(approximately 1%

of the concentration

required for its

herbicide action in

wheat field to

control broadleaf

weeds) during the

entire flowering

period (about one

week), making 0.24

g/ha MES.

Microarray.

In the anthers of large

buds, 415 up-regulated

genes involved in

degradation of

carbohydrates, lipids,

proteins, nucleic acids and

cell wall degradation, and

1238 down-regulated genes

involved in the synthesis of

carbohydrates, lipids,

proteins, nucleic acids, and

cell wall synthesis.

Li et al.

2015

Maize

Zea mays

Seedlings treated

with 60 g ai/ha

nicosulfuron for 24

h. RNA extracted

from leaves.

RNA-seq: There were 2100

genes were differentially

expressed: 1391

upregulated and 709 down-

regulated.

Up-regulated genes were

those encoding proteins

involved in translation,

ribosomal structure and

biogenesis, DNA replication,

recombination and repair.

Down regulated genes were

mainly involved in

translation, ribosomal

structure and biogenesis,

posttranslational

modification, protein

turnover, and chaperones.

Liu et al.

2015

Rapeseed

Brassica

napus L.

Plants were foliar-

sprayed with a

single quantity of 1

µg of

amidosulfuron

each (in presence of

of 1 µl of the Bayer

Biopower

alkylethersulfate

surfactant).

RNA sequencing 5 days

after treatment.

142 up-regulated and 201

down-regulated differential

expression transcripts in

young flower buds. Affected

genes showed functional

abnormalities linked to cell

cycle, cell wall formation,

chloroplast structure, and

tissue autophagy. Ethylene-

Liu et al.

2017

responsive transcription

factor RAP2-11-like was

up-regulated in the flower

buds paralleling the

increased ethylene release

rate.

Maize

Zea mays

Exposure to 80 mg

nicosulfuron per

kg of soil for 7 days.

qPCR.

Isogenic nicosulfuron-

resistant and sensitive lines

have been compared as for

the expression of genes

encoding antioxidant

enzymes.

In the resistant maize,

nicosulfuron treatment

increased the transcript

levels of most of the

ascorbate peroxidase APX

genes along with those of

SOD9, MDHAR e, DHAR f,

and GR a as compared to

the sensitive line.

Wang et

al. 2018b

Rapeseed

Brassica

napus L.

Plants were foliar-

sprayed with a

single quantity of 15

µg of the

sulfonylurea SX-1

each.

RNA sequencing at various

anther development stages.

998, 2194, 2428 and

10,627 up-regulated genes

and 1177, 2488, 827 and

9745 down-regulated genes

at young buds, short, mid

and late anther stages,

respectively.

Affected genes showed

altered protein processing

in ER, pollen wall

development, and

flavonoids biosynthesis at

early stage. At later stages

hormone signal

transduction, biosynthesis

of amino acids, fatty acids

and steroid were

down-regulated.

Ning et al.

2018

Junglerice

Echinochloa

colona

The treated plants

were sprayed with

imazamox

(Beyond, BASF) at a

rate of 53 g/ha.

RNA were isolated

from leaves 1 h

RNA sequencing.

136 differentially expressed

transcripts: 82 upregulated

and 54 downregulated.

These transcripts are

encoding proteins involved

in metabolism,

Wright et

al. 2018

after spraying.

transcription, protein

modification, signaling, cell

wall modification, and

transport.

Rapeseed

Brassica

napus L.

Plants were foliar-

sprayed with a

single quantity of 1

µg of tribenuron-

methyl each

(Express, equivalent

to 0.15 g/ha), in

presence of 1 µl of

the Bayer Biopower

alkylethersulfate

surfactant.

RNA sequencing 5 days

after treatment.

200 up-regulated and 163

down-regulated differential

expression transcripts in

young flower buds. The top

50 up-regulated genes

were involved in stress

response and

detoxification, including 4

MRP and 1 MDR efflux

transporters, 4

mitochondrial heat shock

proteins, 1 GST, 5

sulfotransferases, and 5

UGTs. The top 50 down-

regulated genes were

involved in carbohydrates,

lipid and flavonoids

synthesis.

Lian et al.

2019

a GR: glutathione reductase gene; MRP3: multidrug resistance associated protein 3

gene; PDR8: pleiotropic drug resistance proteins.!

b The OSPC gene is encoding a GRAS transcription factor involved in plant

development.

c α-amy: α-amylase gene.

d β-amy: β-amylase gene.

e MDHAR: monodehydroascorbate reductase gene.

f DHAR: dehydroascorbate reductase gene.!

Table 2. Oxidative damage caused by ALS-inhibiting herbicides on plants.

Species

Treatment

Reference

Rice

Oryza

sativa L.

japonica

cv. Xiushui

6 days of exposure

to 50 µg/L R(-)-

imazethapyr.

In rice seedlings:

glutathione peroxidase

enzyme activity: 3.4-fold

increase.

MDA a content: 2.2-fold

increase.

Qian et al.

2009

Arabidopsis

thaliana

weed

Exposure to 2.5

µg/L R(-)

imazethapyr

enantiomer for 4

weeks.

MDA content:

x 6 with R(-)-IM

x 3 with racemate-IM

superoxide radical O2.-

concentration:

+ 50 % with R(-)-IM

CAT b activity: reduced 3.6-

fold with R(-)-IM

SOD activity: reduced 2.4-

fold with R(-)-IM

Qian et al.

2011a

Maize

Zea mays

Exposure to 80 mg

nicosulfuron per

kg of soil for 7 days.

O2.- production: x 2.2

H2O2 production: x 1.6

MDA concentration: x 3.2

Dehydroascorbate content:

x 0.48

Ascorbate peroxidase APX

activity: - 33 %

Glutathione peroxidase GPX

activity: x 0.45

Wang et

al. 2018a

a MDA: malondialdehyde, a biomarker of lipid peroxidation.!

b CAT: catalase enzyme.!

Table 3. Toxicity of ALS inhibitory herbicides in fish.

Goldfish Carassus auratus exposed for 48 h to nicosulfuron (Bretaud et

al. 2000).

Treatment

Activity of the enzyme acetylcholine esterase (AchE)

50 µg/L

In brain, decrease between 9.2 et 9.8 %. No effect in

muscles.

100 µg/L

In brain, decrease between 11.4 et 12.8 %. No effect in

muscles.

Goldfish Carassus auratus exposed for 15 minutes to nicosulfuron

(Saglio et al. 2001).

Swimming behavior

LOAELa

Increase of the number of feeding attempts

10 µg/L

Increase of the number of social groupings

10 mg/L

aLOAEL : lowest observed adverse effect level

Tilapia Tilapia rendalli given a dose of imazapyr injected abdominally.

Erythrocytes have been sampled from gills 4 days later (Grisolia 2000).

Result: at a dose of 80 mg/kg, the frequency of appearance of micronuclei in

erythrocytes increased 10-fold, a sign of genotoxicity.

Goldfish Carassus auratus exposed to nicosulfuron (Saglio et al. 2003).

Duration of treatment

(h)

Swimming behavior

Number of swimming bursts: x 7 at 50 µg/L ; x 9,5

at 100 µg/L

Number of social groupings: x 2 at 100 µg/L

Number of social groupings: x 2 at 25 µg/L

Silver catfish Rhamdia quelen exposed for 96 h to 400 mg/L of Ally

herbicide (metsulfuron-methyl without adjuvant) (dos Santos et al.

2005).

Activity of AchE

Brain

95 % increase

Muscle

56 % decrease

Fish Leporinus obtusidens exposed for 90 days in rice field at 5.8 µg/L

of Ally herbicide (metsulfuron-methyl) (Pretto et al. 2011).

Biochemical parameter

Effect

AchE activity

50 % decrease in the brain and 60 %

in muscles

Catalase activity (CAT)

50 % decrease in the liver

Lipid peroxidation

Four-fold decrease in muscles, 2.5-

fold in the brain and 3-fold in the liver

Muscle glycogen

36 % decrease

Lactate

15 % decrease in muscles; 2.5-fold

increase in plasma, increase of 19 %

in liver

Plasma glucose

15 % increase

Muscle proteins

7 % decrease

Carp Cyprinus carpio exposed for 90 d to BASF herbicide Only at 14.8

µg/L of imazethapyr and 3.1 µg/L of imazapic (Moraes et al. 2011).

Biochemical parameter

Effect

Activity of muscular AchE

40 % decrease

Activity of hepatic GST

45 % decrease

Protein carbonylation

91 % increase in liver

Lipid peroxidation

4- and 2.1-fold increases in brain

and muscles, respectively

Plasmatic glucose

80 % increase

Lactate

30 % increase in muscles

Proteins

29 % and 19 % decreases in liver

and plasma, respectively

Ammonium ion

2.9-fold decrease in liver

Amino acids

3.1-fold decrease in muscles

Climbing perch Anabas testudineus exposed in rice field for 30 d to

Almix 20WP herbicide (DuPont) at a surface concentration of 2 mg/m2.

Almix is composed of 10.1 % metsulfuron-methyl, 10.1% chlorimuron-

ethyl and 79.8 % adjuvants (Samanta et al. 2015).

Tissues

Histopathological and ultrastructural effects

Gills

Hypertrophy and oedema. Degenerative changes in

mitochondria

Liver

Lipid deposits. Dilatation and swelling of mitochondria

Kidneys

Degenerative changes in mitochondria

Zebra fish Danio rerio exposed for 4 d to a concentration of 3.5 mg/L of

halosulfuron-methyl herbicide (LD50/10) (Zhang and Zhao 2017). By

gas chromatography coupled with mass spectrometry, the

concentrations of 51 metabolites have been measured.

Results: in the head, serum and liver the concentrations of several metabolites

were increased:

- the amino acids leucine, valine, serine, glycine, proline, and alanine

- the Krebs’ cycle metabolites malate and fumarate

- the neurotransmitters glutamate, taurine, and glycine

Delta smelt Hypomesus transpacificus (critically endangered species,

IUCN) exposed for 6 h to penoxsulam or imazamox (Jin et al. 2018).

In the brain, 20 to 33 % decrease in the activity of AchE enzyme:

- as soon as 0.01 and 0.53 µM penoxsulam in females and males,

respectively.

- as soon as 0.036 µM imazamox for both females and males.

Nile tilapia exposed to bispyribac-sodium, bensulfuron-methyl and

halosulfuron-methyl at 0.8, 2.5, and 1.275 mg/L, respectively for 96 h

(Fathy et al. 2019).

Bispyribac-sodium: counts of red blood cells (RBC) and platelets decreased; the

concentration of aspartate aminotransferase (AST) and cholesterol increased.

Halosulfuron-methyl: the concentration of AST and cholesterol increased.

10!

Bensulfuron-methyl: the count of RBC decreased; the concentration of AST and

cholesterol increased.

Table 5. Decisive influence of the adjuvant Assist in the toxicity of the herbicide

metsulfuron-methyl.

Animal avoidance strategy for metsulfuron-methyl herbicide.a

(de Santo et al. 2018).

Ally

Ally + Assist

Collembola Folsomia candida

> 300

0.07

Earthworms Eisenia andrei

150

0.59

Impact of metsulfuron-methyl herbicide on animal reproduction.a

(de Santo et al. 2019).

Ally

Ally + Assist

Collembola Proisotoma minuta

> 10

0.003 (0-0.010)

Oligochaeta worms Enchytraeus crypticus

> 33.3

5.7 (1.7-13.2)

a After 48 hours of exposure to varying doses of the herbicide, LOAELs were

recorded (mg metsulfuron-methyl/kg soil). The Assist adjuvant was added to

dilutions of the herbicide in water at a concentration of 5 mL/L of water.

Table 4. Impact of the SUL imazethapyr herbicide on the growth of several

organisms exposed for 4 days to two commercial formulations.

Species

Formulation

IC50 (mg/L) a

Reference

Green algae Pseudokirchneriella

subcapitata

V b

1.05

Magdaleno et al.

2015

P. subcapitata

2ASU c

22.4

Health Canada

2010

Cyanobacterium Anabaena flos-

aquae

2ASU

4.8

Health Canada

2010

Diatom Navicula pelliculosa

2ASU

22.9

Health Canada

2010

a (IC50: concentration inhibiting growth at 50 %); b V: Verosil Agrofina,

containing 10.6 % of the active ingredient imazethapyr; c 2ASU: 22.2 % of the

active ingredient imazethapyr.

11!

Table 6. The Arsenal herbicide is significantly more toxic than its active

ingredient imazapyr.

Species

Effect

Imazapyr

NPE a

Arsenal

Freshwater snail

Biomphalaria

tenagophila

LC50 at 3 days

(mg/L)

12.6

20.1

Vinegar fly

Drosophila

melanogaster

LD50 at 5 days

(oral) (mg/L)

> 2000

0.043

0.174

Mouse

LD50 at 7 days

(i.p.) (mg/kg)

1498

262

Onion Allium cepa

Mitosis after a

48 h exposure

(LOAEL in µl/L)

2000

0.25

a Nonylphenol ethoxylate, one of the Arsenal adjuvants (Grisolia et al. 2004).

12!

Table 7. Compared growth of ALS-mutated plants and their sensitive counterparts:

a few examples.

Plant

Herbicide

Growth phenotype

Reference

Resistant

Sensitive

Arabidopsis

thaliana

Imazapyr

Upper limit in concentration

allowing growth

Manabe et

al. 2007

Mutant csr1-

2D: 1000

µg/L

Wild-type:

25 µg/L

Junglerice

Schoenoplectus

juncoides

Resistance factors a

Sada et al.

2013

Imazosulfuron

Bensulfuron-

methyl

Metsulfuron-

methyl

Bispyribac-

sodium

Imazaquin

176

5.2

1.5

Maize Zea

mays

Nicosulfuron

at 60 g ai/ha

Normal

growth

No growth

allowed

Liu et al.

2015

Wheat

Imazamox

Resistance factors a

Dominguez-

Mendez et

al. 2017

Triticum

aestivum

Triticum durum

Clearfield

Rafalín: 93.7

Clearfield

Antoñín:

43.7

Gazul: 1

Simeto: 1

Maize Zea

mays

Nicosulfuron

at 80 mg ai/kg

of soil

SN509-R:

normal

growth

SN509-S:

no growth

allowed

Wang et al.

2018a

Weed

Euphorbia

heterophylla

Imazamox

GR50: 1250

g/ha

GR50: 7.4

g/ha

Rojano-

Delgado et

al. 2019

a Resistance factors between resistant and sensitive plants are calculated as the

ratio of the concentration inhibiting 50 % of the growth (GR50) in the resistant

variety over that in the sensitive one.

Table 8. Application rates, half-lives and environmental persistence of the most used ALS-inhibiting herbicides.

Herbicide

Manufacturer

Brand

Recommended dose

Reported use

Half-life

Environmental persistence

Imidazolinones

Imazamox

BASF

Pulsar 40 (4 %)

Beyond (12.1 %)

Cleranda: 17.5 g/L

imazamox and 375 g/l

metazachlor

Cleravis:

17.5 g/l imazamox, 375

g/l metazachlor, and

100 g/L quinmerac

50 g/ha in combination

with the Dash adjuvant

(1.25 L/ha).

Intended for soybean

and Clearfield

sunflower.

35-53 g/ha after Prowl

treatment

(pendimethalin

herbicide).

Intended for

Clearfield canola,

lentil, wheat,

sunflower, and

Clearfield Plus

wheat and

sunflower.

2 L/ha + Dash HC 1

l/ha

Intended for

Clearfield rapeseed

2 L/ha + Dash HC 1

l/ha

Intended for

Clearfield rapeseed

50 and 100 g/ha on

soybean (da Silva

et al. 1999)

45 g/ha at fall and

90 g/ha at spring

on wheat (Ball et

al. 2003)

70 and 140 g/ha

(Rani et al. 2019)

In soil: 9.8 d (Aichele

and Penner 2005); 25

d (Müller and

Applebyki 2012); at

140 g/ha (t0): 29.5

and 34.3 d in sandy

and clay loam soils,

respectively (Rani et

al. 2019)

Terrestrial field

dissipation: 15 to 130

d (US EPA 2008); 1.8

to > 120 d (Buerge et

al. 2019)

In water-sediment:

half-life of 142 d

(Müller and Applebyki

2012)

< LOQa (5 µg/kg) in all of 22

Brazilian soils (Kemmerich et al.

2015).

Imazapic

BASF

Plateau DG

28.5-85 g/ha

Intended for prairie

grass

147 g/ha on

sugarcane (Simoni

et al. 2006)

With Clearfield

maize: 17.5%

imazapyr + 52.5%

imazapic mixture,

at two doses of 80

and 160 g/ha, with

a 31% hydrocarbon

petroleum (Dash)

at 0.125 and 0.250

L/ha, respectively

(Alister and Kogan

2005)

32-66 d at 52.5 g/ha

(t0)(Ulbrich et al.

2005); 120 d (Müller

and Applebyki 2012);

40 to 64 d (da Costa

Marinho et al. 2019)

In rice paddy water:

8.1 to 11.9 d at 25

g/ha (t0) (Reimche et

al. 2005)

In 2 out of 22 Brazilian soils, 5.8

and 12.1 µg/kg, respectively

(Kemmerich et al. 2015)

Imazapyr

BASF

Arsenal Power (240

g/L); also marketed as

Assault, Chopper,

Contain, and Pivot.

504-2016 g/ha

Intended for sugarcane

With Clearfield

corn: 52.5 + 17.5,

and 105 + 35 g/ha

for imazapic and

imazapyr,

respectively

(Ulbrich et al.

2005)

In soil:

43-53 d at 17.5 g/ha

(t0) (Ulbrich et al.

2005); 26-44 d (Wang

et al. 2006); 11 d

(Müller and Applebyki

2012); 37 to 121 d

(Gianelli et al. 2014)

In water:

30 d (Müller and

Applebyki 2012)

In 1 out of 22 Brazilian soils, 5.3

µg/kg (Kemmerich et al. 2015).

In soil: 5.3 µg/kg; in water: 50

ng/L (Börjesson et al. 2004)

Imazaquin

BASF

Image 70 DG

Scepter 70DG

440-582 g/ha

Intended for turf grass

71.5-143 g/ha

Intended for soybean

140 g/ha (Barnes

et al. 1989); 140

and 280 g/ha on

maize (Loux et al.

1993); 150 and

300 g/ha on maize

(Gazziero et al.

1997)

In fields:

39 to 150 d (Curran et

al. 1992); 43 d (Mills

et al. 1989)

In soil:

1337 d (Aichele and

Penner 2005); 60 d

(Müller and Applebyki

2012)

In water-sediment:

516 d (Müller and

Applebyki 2012)

In fields:

4 µg/kg both in 1985 and 1986

(Mills and Witt 1989)

In ground water:

in 2 out of 25 samples (LOQ: <

10 ng/L), max. conc.: 24 ng/L

(Battaglin et al. 2000)

Imazethapyr

BASF

Only (75 g/L

imazethapyr, 25 g/L

imazapic)

Newpath

Pursuit

100-200 g/ha

Intended for

Clearfield rice

67-100 g/ha

Intended for

Clearfield rice

50-100 g/ha

Intended for alfalfa,

clover, beans and

peas, peanut, and

soybean

75 g/ha

imazethapyr + 25

g/ha imazapic

(Marchesan et al.

2010)

1.8 L Only/ha plus

surfactant Dash at

0.5% v/v to select

tolerant plants,

then 1 L/ha plus

Dash for Clearfield

rice (Rangel et al.

2010)

Imazethapyr was

applied up to 105

g/ha on Clearfield

rice (Norsworthy et

al. 2008)

With Clearfield

maize: 17.5%

In soils:

silty-clay: 192 to 318

d; silty-loam: 78 to

270 d (Goetz et al.

1990); 73 to 257 d

(Vischetti 1995); 112 d

(Aichele and Penner

2005); 63 to 112 d

(Zhang et al. 2010);

90 d (Müller and

Applebyki 2012); 36 to

98 d (da Costa Marinho

et al. 2019); at 140

g/ha (t0): 39.8 and

43.3 d in sandy and

clay loam soils,

respectively (Rani et

al. 2019)

In fields:

49 to 122 d (Curran et

al. 1992); 60 d (Mills

and Witt 1989); 30 to

In 2 out of 22 Brazilian soils, 24

and 37.7 µg/kg, respectively

(Kemmerich et al. 2015)

In fields:

13 and 5 µg/kg in 1985 and

1986, respectively (Mills and Witt

1989)

In paddy field: mean of 4.5 µg/kg

up to 15 cm of depth, 540 days

after the last treatment (Kraemer

et al. 2009b)

In ground water:

in 4 out of 25 samples (LOQ: <

10 ng/L), max. conc.: 59 ng/L

(Battaglin et al. 2000)

imazapyr + 52.5%

imazethapyr

mixture, at two

doses of 80 and

160 g/ha, with a

31% hydrocarbon

petroleum (Dash)

at 0.125 and 0.250

L/ha, respectively

(Alister and Kogan

2005)

43 d (Xu et al. 2013);

28 to 42 d (Jovanović-

Rodovanov 2017)

In rice paddy water:

1.6 to 5.2 d at 75 g/ha

(t0) (Santos et al.

2008); 4.5 to 5.3 d at

75 g/ha (t0) (Reimche

et al. 2005)

Sulfonylureas

Ethametsulfuron-

methyl

DuPont

Muster Toss-N-Go (75

Salsa (75 %)

20 to 30 g/ha

+ surfactant Agral 90,

AG-Surf ou Citowett+

25 g/ha + surfactant

Trend 90

Intended for rapeseed

Not documented

In soil:

13 to 67 d

(Si et al. 2005); 70 d

(Müller and Applebyki

2012)

In ponds :

30 d (Cessna et al.

2006)

Drinking water in Canada (2003-

2005), detected in 35 % of

samples, max. conc.: 80.4 ng/L;

mean of 8.5 ng/L in July 2005

(Donald et al. 2007)

Wetland sediment: max. conc.:

10 µg/kg; > LOQ in 39 % of

samples (Degenhardt et al. 2010)

In Canadian streams (2009-

2011):

17 % of samples above the limit

of detection; max. conc.: 148

ng/L (de Lafontaine et al. 2014)

Metsulfuron

methyl

DuPont

Ally (600g/kg)

5 to 7 g/ha

Intended for barley,

rye, triticale, wheat,

linseed, safflower!

6 g/ha on winter

wheat (Rouchaud

et al. 1999)

10, 20 and 40 g/ha

on wheat (Kotoula-

Syka et al. 1993)

In soils:

from 33 d at pH 5.8 to

120 d at pH 7.4 for 32

g/ha (t0) (Walker and

Welch 1989); 8 to 36 d

at pH 5.7 (James et al.

1995); from 12 to 28 d

in Colorado soils

(Cranmer et al. 1999);

67 to 78 d at 6 g/ha

(t0) (Rouchaud et al.

1999); from 51 d at pH

5.9 to 82 d at pH 6.8

for 4.6 ng/g soil (t0)

(Bedmar et al. 2006);

89.3, 84, and 67.6 d at

5, 13, and 20 °C,

respectively (Cessna et

al. 2017)

Drinking water in Canada (2003-

2005), detected in 2 % of

samples, max. con.: 2.1 ng/L

(Donald et al. 2007)

Wetland sediment: max. conc.:

1.4 µg/kg; > LOQ in 11 % of

samples (Degenhardt et al. 2010)

In Ontario streams (2006-2008):

2 % of samples above the limit of

detection; max. conc.: 57 ng/L

(Struger et al. 2011)

In Canadian streams (2009-

2011):

18.5 % of samples above the

limit of detection; max. conc.: 48

ng/L (de Lafontaine et al. 2014)

In ponds :

84 d (Cessna et al.

2006)

In water-sediment:

140 d (Müller and

Applebyki 2012)

Nicosulfuron

DuPont

Syngenta

Accent Q (54 %)

Zest (75 %)

Pastora (56 %

nicosulfuron + 15 %

metsulfuron-methyl)

Milagro (4 %)

36 to 72 g/ha

Intended for corn

37 to 73 g/ha

Intended for

herbicide-tolerant

INZEN sorghum

52 to 130 g/ha

Intended for wheat,

barley, oat, soybean,

corn, alfalfa, clover,

ryegrass

60 g/ha

60 g/ha on maize

(Liu et al. 2015)

In field:

13.6 d at 202 g/ha (t0)

(Wu et al. 2010); 26 d

(Müller and Applebyki

2012)

In corn plants: 0.53 to

0.73 d at 202 g/ha (t0)

(Wu et al. 2010)

In water-sediment:

41.5 d (Müller and

Applebyki 2012)

In ponds :

75 d (Cessna et al.

2015)

US streams and rivers: maximal

concentration in 2005-2006:

3290 ng/L (Battaglin et al. 2009)

In ground water:

in 2 out of 25 samples (LOQ: <

10 ng/L), max. conc.: 16 ng/L

(Battaglin et al. 2000)

In Ontario streams (2006-2008):

11 % of samples above the limit

of detection; max. conc.: 525

ng/L (Struger et al. 2011)

In Canadian streams (2009-

2011):

10 % of samples above the limit

of detection; max. conc.: 84 ng/L

(de Lafontaine et al. 2014)

Sulfosulfuron

Monsanto

Apyros (75% WG)

Monitor 75% WG

20-35 g/ha + adjuvant

Genamin.

Intended for wheat

and potato

40 g/ha+ surfactant

Villa 51

Intended for wheat

and tomato

20 and 40 g/ha on

winter wheat + the

adjuvant Genamin

(Alonso-Prados et

al. 2002)

37.5, 75 and 112.5

g/ha on tomato +

surfactant DX

(Eizenberg et al.

2003)

26.5 g/ha on winter

wheat

(Adamczewski and

Paradowski 2004)

50 and 100 g/ha on

wheat crop

(Ramesh et al.

2007a)

20 g/ha on wheat

In field:

105 to 125 d (from 30

to 60 cm of depth) at

50 g/ha (t0) (Ramesh

et al. 2007a); 14.4 d

at 25 g/ha (t0)

(Sondhia 2008b); 3.4

to 3.6 d at 34 g/ha (t0)

(Ghosh et al. 2014);

4.6 to 11.6 d at 20

g/ha (t0) (Yousefi et al.

2016); 5.4 to 10.8 d at

26 g/ha (t0)

(Mehdizadeh et al.

2017)

In soil:

24 d (Müller and

Applebyki 2012)

In water: 67 to 76 d

(Ramesh et al. 2007b);

168 d (Müller and

Drinking water in Canada (2003-

2005), detected in 10 % of

samples, max. conc.: 36.1 ng/L

(Donald et al. 2007)

Wetland sediment: max. conc.:

7.1 µg/kg; > LOQ in 39 % of

samples (Degenhardt et al. 2010)

In Canadian streams (2009-

2011):

31 % of samples above the limit

of detection; max. conc.: 28 ng/L

(de Lafontaine et al. 2014)

Sulfosulfuron

Monsanto

Apyros (75% WG)

Monitor 75% WG

20-35 g/ha + adjuvant

Genamin.

Intended for wheat

and potato

40 g/ha+ surfactant

Villa 51

Intended for wheat

and tomato

20 and 40 g/ha on

winter wheat + the

adjuvant Genamin

(Alonso-Prados et

al. 2002)

37.5, 75 and 112.5

g/ha on tomato +

surfactant DX

(Eizenberg et al.

2003)

26.5 g/ha on winter

wheat

(Adamczewski and

Paradowski 2004)

50 and 100 g/ha on

wheat crop

(Ramesh et al.

2007a)

20 g/ha on wheat

(Yousefi et al.

2016)

In field:

105 to 125 d (from 30

to 60 cm of depth) at

50 g/ha (t0) (Ramesh

et al. 2007a); 14.4 d

at 25 g/ha (t0)

(Sondhia 2008b); 3.4

to 3.6 d at 34 g/ha (t0)

(Ghosh et al. 2014);

4.6 to 11.6 d at 20

g/ha (t0) (Yousefi et al.

2016); 5.4 to 10.8 d at

26 g/ha (t0)

(Mehdizadeh et al.

2017)

In soil:

24 d (Müller and

Applebyki 2012)

In water: 67 to 76 d

(Ramesh et al. 2007b);

168 d (Müller and

Applebyki 2012)

In water-sediment:

26 d (Müller and

Applebyki 2012)

In ponds :

44 d (Cessna et al.

2015)

In wheat plant: 2.5 to

3.0 d at 34 g/ha (t0)

(Ghosh et al. 2014)

Drinking water in Canada (2003-

2005), detected in 10 % of

samples, max. conc.: 36.1 ng/L

(Donald et al. 2007)

Wetland sediment: max. conc.:

7.1 µg/kg; > LOQ in 39 % of

samples (Degenhardt et al. 2010)

In Canadian streams (2009-

2011):

31 % of samples above the limit

of detection; max. conc.: 28 ng/L

(de Lafontaine et al. 2014)

Tribenuron-

methyl

DuPont

Express

(50 %)

Express SX

(50 %)

9.1 to 18.25 g/ha

Intended for wheat,

barley, triticale, fallow

45 to 60 g/ha +

surfactant Trend 90

Intended for sunflower

25 g/ha on spring

wheat (Pasquer et

al. 2006)

10, 20 and 40 g/ha

on wheat (Kotoula-

Syka et al. 1993)

In field: 3.2 to 5.7 d at

15 g/ha (t0)

(Mehdizadeh et al.

2017)

In soil:

14 d (Müller and

Applebyki 2012); 56.4,

26.3, and 10.3 d at 5,

13, and 20 °C,

respectively (Cessna et

al. 2017)

In water:

16 d (Müller and

Applebyki 2012)

In water-sediment:

26 d (Müller and

Applebyki 2012)

Drinking water in Canada (2003-

2005), detected in 20 % of

samples, max. conc.: 30.1 ng/L;

mean of 4.9 ng/L in July 2005

(Donald et al. 2007)

Pyrimidinyl

carboxy

compound

Bispyribac-

sodium

Arysta

LifeScience

Nominee Gold 10SC

37.5 g/ha

Intended for rice

In paddy field: 25

g/ha (Jabran et al.

2012); From 37.5

to 75 g/ha in paddy

field (Zhang et al.

2013)

In rice paddy water:

8.9 to 15.5 d at 50

g/ha (t0) (Reimche et

al. 2005)

In water-sediment:

35 d (Müller and

Applebyki 2012)

In soil: 45-131 d and

30-51 d under

anaerobic and aerobic

conditions (López-

Piñeiro et al. 2011); 13

d (Müller and

Applebyki 2012); 13.1,

10.2 and 9.9 d at 40,

25 and 20 g/ha (t0),

respectively

(Ramprakash et al.

2015)

In paddy soil: 1.4 to

5.6 d at 75 g/ha (t0)

(Zhang et al. 2013);

17.7 and 23.2 d at 70

and 140 g/ha (t0),

respectively (Saha et

al. 2016)

In loamy sand: 27.3 d

at 50 g/ha (t0), and

41.0 d under

submerged condition

(Kalsi and Kaur 2019)

In paddy soil: 0.18 to 0.2 µg/kg

at harvest for a treatment of 37.5

g/ha (t0) (Zhang et al. 2013)

a: LOQ: limit of quantification.

Effects of Temperature on Plants and High Temperature Stress

Article

Full-text available

Aug 2022

Bitki ekosistemi içerisinde bitkilerin çimlenme, gelişme ve dağılımında etkili olan faktörler mevcuttur. Bu faktörlerin bitkinin istediği optimum koşullarda gerçekleşmesi durumunda, sağlıklı bir büyüme gerçekleşir. Bu faktörlerin en önemlilerinden birisi de sıcaklıktır. Bu kaynak ihtiyacını karşılamada yaşanacak aksaklık, bitkilerde olumsuz etkilere neden olmaktadır. Küresel iklim değişikliğine bağlı olarak artan sıcaklık faktörünün bitkiler üzerindeki etkilerinin bilinmesi ve bitkinin buna karşı oluşturduğu cevap mekanizmalarının iyi anlaşılması oldukça önemlidir. Bununla birlikte artan sıcaklık stresinin bitkilerde morfolojik, fizyolojik ve verimsel açıdan meydana getirdiği etkileri anlamak ve bitkilerin buna karşı verdikleri tepkileri öğrenmek, sıcaklığa toleranslı genotiplerin geliştirilmesine yönelik adımları atmada önem arz etmektedir. Bu derlemede, sıcaklığın bitkiler üzerindeki etkileri ve yüksek sıcaklık stresine karşı verdiği cevaplar tartışılmıştır.

Imidazolinone-Tolerant Crop Plants and Their Use in Weed Control (İMİDAZOLİNONE HERBİSİTLERİNE TOLERANT KÜLTÜR BİTKİLERİ VE YABANCI OT MÜCADELESİNDE KULLANIMI)

Article

Full-text available

Dec 2021

Fulya Hizar Başaran

Weeds cause damage by competing with crops for resources such as water, nutrients, light and space. In its control, chemical control methods are preferred due to its advantages such as short-term results and ease of use. However, the problem of resistance, which arises as a result of intensive use of herbicides, has increased with the development of selective herbicides. In particular, the problem of resistance to ALS (Acetolactate synthase) inhibitor herbicides is in the first place. Imidazolinones, one of the active substances in the sulfonylurea class from the ALS inhibitor herbicide group, are widely used against narrow and broad-leaved weeds. Imidazolinones have a very broad weed spectrum that is effective even at low doses, and are herbicides with a relatively environmental profile, with low toxicity to animals, birds, fish and invertebrates. These features have enabled the development of imidazolinone-tolerant (IMI-tolerant) crops with traditional production (non-transgenic) techniques. IMI-tolerant crops mean that are tolerant to imidazolinone group herbicides. While controlling weeds in the production areas where these crops are used, it is aimed to prevent the product from being damaged. It has advantages such as low cost, better and more effective control of weeds, increasing the yield in agricultural production. However, there may be some disadvantages such as negative environmental effects due to intensive use of herbicides in the areas where IMI-tolerant plants are cultivated, gene escape to weed species related to the cultivated plant and the emergence of resistant weeds accordingly. In this review, the advantages and disadvantages of using IMI-tolerant plants in weed control are discussed.

Negative Effects of Imidazolinone Herbicides Usage: Problems and Desicions

Article

Feb 2023

Currently, in industrial agricultural production, the best results are demonstrated by technological schemes for weed control based on the use of complexes of non-selective and selective herbicides in crop rotations. Herbicides of the imidazolinone group are well-known representatives of selective herbicides class. Commercial drugs based on them are widely represented on the market. At the same time, the negative consequences of using herbicides of the imidazolinone group are well known. They lead to disruption of natural soil biodiversity, inhibition of growth and decreasing in the yield of subsequent crops in crop rotations and the emergence of resistant weeds. The manuscript discusses the mechanisms of action of herbicides of the imidazolinone group, the current state of methods of their analysis in the soil, as well as approaches to reducing the negative effects of their usage.

Nontarget effects of pre‐emergent herbicides and a bioherbicide on soil resources, processes, and communities

Article

Apr 2024

Community‐type conversions, such as replacement of perennials by exotic annual grasses in semiarid desert communities, are occurring due to plant invasions that often create positive plant–soil feedbacks, which favor invaders and make restoration of native perennials difficult. Exotic annual grass control measures, such as pre‐emergent herbicides, can also alter soil ecosystems directly or indirectly (i.e. via the plant community), yet there are few studies on the topic in natural, non‐cropped landscapes. We asked how spray treatments applied to soil post‐fire with the intention of inhibiting invasive annual grasses (such as Bromus tectorum L.) and releasing existing native perennial grasses affected soil resources, a microbial process, and invertebrates in three climatically varied sagebrush steppe sites. Spray treatments included chemical herbicides (imazapic and rimsulfuron) that strongly affected plant communities and a bioherbicide ( Pseudomonas fluorescens strain D7) that did not. Chemical herbicides increased soil mineral nitrogen in proportion to their negative effects on plant cover for 2 years after treatments in all sites and increased soil water and net N mineralization (measured at one site) but did not affect total carbon, nitrogen, or organic matter. Invertebrate responses to herbicides varied by site, and invertebrates increased with chemical herbicides at the highest, wettest site. We show that herbicide treatments can exacerbate pulses of mineral nutrients, which previous studies have shown can weaken ecosystem resistance to invasion. Thus, restoration strategies that increase the likelihood that desired plants can capture mineralized nutrients after herbicide application will likely be more successful.

Sustainable Water Resources Management Hydrodynamic and hydrogeochemical evaluation of groundwater and linkage with herbicide pollution: Central Argentina

Article

Full-text available

Aug 2023

Surface water and unconfined and semiconfined (SAC B) aquifers of Marcos Juárez plain, in the central Pampa of Argentina, were studied to assess hydrogeological features and the presence and distribution of herbicides in water. The studied area, located near a regional hydrological discharge area shows streams and channels of high salinity fed by the groundwater with low values of herbicides as a consequence of hydrodynamic dispersion. The unconfined and semiconfined aquifers (SAC B) are impacted by the presence of herbicides although the percentage of positive samples is low. The unconfined aquifer, directly connected to the atmospheric phase, has a shallow water table being more likely to be reached by effective water infiltration. Despite their high Koc and low GUS index, glyphosate and AMPA were present in the highest concentrations in the unconfined aquifer. It is assumed that this situation is the result of its widespread use, its high solubility in water, and its high persistence. The chemical characteristics of metolachlor and imazethapyr, such as their relatively low Koc, moderate and high GUS index, and high persistence have allowed also their leaching into groundwater. Herbicide migration from the unconfined aquifer to the semiconfined aquifer layer in the loessical plain can occur due to the differences in their hydraulic potential. This situation facilitates the mixing of water, a process that is interpreted through fractures or cracks in the confining units (aquitards) or due to the presence of broken old pipes. The multivariate statistical analysis of the unconfined groundwater chemistry leads us to the conclusion that approximately 53% of the variance is explained by different levels of salinization resulting from natural geochemical processes (such as cation exchange, dissolution of salts, etc.), while the remaining 47% is attributed to contamination processes (arrival of herbicides and nitrates). The second and third positions of herbicides in the PCA analysis demonstrate the impact of agricultural activity, especially in the unconfined aquifer.

Evaluation of Herbicides on the Control of Weeds and Phytotoxicity in a Habanero Pepper Crop (Capsicum chinense Jacq.) in the State of Yucatan, Mexico

Article

Full-text available

Jan 2022

Directions for improvement of the herbicide assortment in Russia at the beginning of the 21st century

Article

Full-text available

Oct 2022

Artem Golubev

Changes in herbicides recommended for the use in Russian Federation between 2000 and 2022 are analyzed. The main directions of iimproving chemical control of weeds are identified based on the integration of domestic market with the world market. Only a limited number of active ingredients was introduced in Russia during the last decade, including pinoxaden, thiencarbazone-methyl, piroxulam, sodium flucarbazone, topramezone, diclosulam, tembotrione, and metamifop. Improved formulations of herbicides such as colloidal solution concentrate with increased penetrability due to the particle size reduced by an order of magnitude became widely available. Premix herbicides were developed based on tribenuronmethyl, metsulfuron-methyl, florasulam, clopiralid, picloram, imazamox, imazapyr, imazethapyr, etc.Parameters for herbicide application were optimized to consider phenology of weeds. Novel technologies were implemented, such as growing hybrids resistant to certain active ingredients to allow their application during crop vegetation.

Legumes for eco-friendly weed management in agroecosystem

Chapter

Full-text available

Jul 2022

Food and nutritional security, environmental sustainability, mitigating climatic vulnerability, shifting of weed flora, weed developed resistance against the herbicide, high capital investment through manual weed management, and increasing the requirement for energy input in the agriculture sector are the major issues in crop production in the coming years. It is no doubt that the introduction of herbicide in the agriculture sector increases the income of farmers, which boost the economy of the nation, but its improper uses create several problems. The consumption of herbicide in the world during 2018 was 1.30Mt. The excess uses of herbicide in agriculture pose several consequences such as environmental pollution, increasing demand for energy in the industrial sector, increase resistance in different weed species, appearing novel weed flora in the cropping system, and incurred higher cost of cultivation in crop production. Sustainable food production is one of the important tools in maintaining ecological balance and soil health. In this circumstance, integrating legumes into cropping systems provides several ecosystem services which fulfill the objectives of ecological weed management. Sustainable intensification is fulfilling the demand for food and ensuring nutritional security in a sustainable manner while maintaining biodiversity and providing many ecosystem services. In a cropping system or single crop production weeds are poses a serious loss by reducing crop growth, yield, quality, depletes fertility status of soil, and act as an alternate host for several insects, pest, and diseases. The yields reduction in direct-seeded rice due to weeds was reported up to 90%. Globally, more than US$ 100 billion was a loss due to infestation of weed in annual crops. The weed seed of Argemone mexicana crushed mustard seed and the oil feed by human beings causes glaucoma or dropsy. The weed green Amaranthus (Amaranthus viridis) can accumulate about 3% N in its biomass and causes severe depletion of nitrogen (N) economy in soil. The three solanaceous weeds such as Solanum nigrum, Datura stramonium, and Datura ferox are act as an alternate host for tomato leaf minor. The application of herbicides during the crop production causes adverse effects on the environment, soil ecosystem, pollute ground water, damage ecological diversity, and affects human health. Besides, the use of herbicide for weed management incurred about US$ 25 billion annually across the globe. Therefore, to tackle such issues of weed the integration of legumes in the different crop production systems as cover crop, relay crop, green manure crop, brown manuring crop play a key role in providing many ecosystem services such as suppressing weed species by smothering or by allelopathy effect, break the life cycle of disease and pest, increasing carbon (C) and N pool in soil, enhancing soil organic matter content, enhance soil health by improving physical, chemical and biological properties of soil. In intercropping system, legumes have better suppression on weed flora by reducing their density and biomass. Further, legumes fulfill the requirement of N of the component crop. Legumes in the crop rotation system break the infestation of frequently occurrence weeds due to its allelopathic effects or smothering effects on the weed seed bank. Based on the diverse benefits of legumes, it is ensured that legumes either in the cropping system or alone as crop residue plays a key role in driving sustainable intensification.

Chemical Structural Features Affecting the Soil Sorption of Sulfonylurea Herbicides

Article

May 2023

Evolution of herbicide resistance in common ragweed (Ambrosia artemisiifolia L.): search for genetic determinisms and application to molecular diagnosis

Thesis

Full-text available

May 2022

Ingvild Loubet

Common ragweed (Ambrosia artemisiifolia L.), a particularly troublesome and allergenic weed, is mainly controlled in agricultural fields using ALS inhibitor herbicides. Recent cases of herbicide resistance have been reported in France and are jeopardising the efficacy of this mode of action. Both target site resistance (TSR, structural mutation in ALS gene) and non target site resistance (NTSR, regulatory and/or structural mutations in secondary metabolism) are involved. The fundamental aim of this work was to identify the genetic determinisms of resistance to ALS inhibitors that have evolved in common ragweed populations in France. As an applied objective, this work also aimed to prepare the development of a high- throughput molecular diagnostic tool that would ensure a rapid detection of resistance. We first assessed the situation of common ragweed resistance in France and identified the mechanisms involved and their modalities of evolution. Using herbicide sensitivity bioassays coupled with ALS gene sequencing, we showed that ragweed resistance to two active substances, imazamox and tribenuron, is emerging in France and is mainly due to NTSR mechanisms. The observed resistance patterns suggest that a diversity of NTSR mechanisms are evolving in France. Furthermore, we demonstrated that TSR evolved locally, through multiple and independent appearance of mutations in the ALS gene. Thanks to the innovative application of high- throughput sequencing for the diagnosis of TSR on a national scale, we identified several foci of TSR emergence, as well as an unsuspected diversity of mutations in the ALS gene. We then studied the genetic determinisms of NTSR. A transcriptomic approach (RNASeq) associated with an analysis of nucleotide polymorphisms was conducted, based on the hypothesis that genes and/or markers of NTSR differed by their expression level and/or by sequence polymorphisms between plants resistant or sensitive to ALS inhibitors. For the first time, this approach was conducted directly on field plant material, i.e. six populations with distinct geographical origins and/or resistance profiles. Constitutive expression differences between resistant and sensitive plants were identified, especially in genes from families known to be involved in herbicide metabolism (cytochromes P450, transferase enzymes, transporters, etc.), but also in genes that may be involved in regulatory cascades activated by the herbicide. Validation of their relative expression levels and their ability to predict NTSR was performed on a massive sampling of plants. Taken together, the results indicate that a very high diversity of mechanisms is involved in RNLC within and between populations, highlighting the highly polygenic nature of RNLC in ragweed. In addition, assessment of the early response of plants to herbicide application showed that genes involved in secondary plant metabolism are specifically induced by treatment in resistant plants from different populations. Finally, sequence variants potentially correlated with NTSR were identified. Their validity as resistance markers remains to be confirmed. The diversity of resistance mechanisms identified within each population renders the development of a molecular diagnosis tool complex. On the other hand, it opens exciting perspectives for the study of the evolutionary dynamics of the adaptation of an invasive species subjected to a particularly intense anthropogenic selection pressure.

Dissipation kinetics of a new mixture formulation of bispyribac-sodium and metamifop in rice

Article

Full-text available

Jun 2016

A supervised field trial on rice was conducted at the experimental farm, BCKV, West Bengal where the mixture formulation of bispyribac sodium 4% + metamifop 10% was applied at 14 days after transplanting of the rice seedlings at three doses viz. recommended dose i.e. @ 70 g a.i. ha-1 and double dose i.e. @ 140 g a.i. ha-1and another is untreated control The residue was extracted by QuEChERS method and quantified by liquid chromatography electrospray ionization tandem mass spectrometry. The limit of quantification of both the compound was 0.02mg kg-1in all the substrates (rice green plant, straw, grain, husk, and soil).The half-life (T1/2) value of Bbispyribac sodium in soil ranged from 17.71 -23.16 days where as the T1/2 value of metamifop in soil and rice green plant ranged from 12.54 - 15.84 and 1.91-2.71 days respectively. No residue of bispyribac sodium and metamifop was quantified in harvested rice straw, grain, husk and soil. Keywords : Bispyribac sodium, half-life, metamifop, persistence, rice, soil

Sublethal application of various sulfonylurea and imidazolinone herbicides favors outcrossing and hybrid seed production in oilseed rape

Article

Full-text available

Feb 2020
BMC PLANT BIOL

Background: Acetolactate synthase (ALS)-inhibiting herbicides from the chemical families of sulfonylureas and imidazolinones are used worldwide. However, drift or sprayer contamination from some sulfonylurea herbicides causes a high level of male sterility in cruciferous species, especially oilseed rape (OSR). In this paper, we evaluated the gametocidal effects of 27 ALS-inhibiting herbicides that were sprayed on OSR plants at the bolting stage. Results: OSR anther development was very sensitive to sublethal exposure to most ALS-inhibiting herbicides. The application of 18 out of the 20 tested sulfonylureas (except ethametsulfuron and ethoxysulfuron), two imidazolinones (imazethapyr and imazamox), and one sulfonylamino-carbonyltriazolinone (flucarbazone-sodium) at suitable rates could induce male sterility. Eight of the herbicides, including chlorsulfuron (at application rates of 60-120 mg/ha), halosulfuron-methyl (300-600 mg/ha), sulfosulfuron (400-600 mg/ha), triflusulfuron-methyl (500-750 mg/ha), pyrazosulfuron-ethyl (150-225 mg/ha), nicosulfuron (200-300 mg/ha), imazethapyr (750-1125 mg/ha), and imazamox (400-800 mg/ha), could induce over 90% male sterility and over 60% relative outcrossed seed set in six cultivars with different origins. These eight chemicals could be used as new gametocides for hybrid seed production. This study also examined the possibility of external application of these gametocides on several unstable Polima cytoplasmic male sterile and thermosensitive genic male sterile lines. Although the outcrossed seed set of the treated lines was slightly reduced, the gametocide application significantly increased the seed purity of the resulting hybrid. Conclusion: The finding of the gametocidal effects of most sulfonylureas and imidazolinones are of great importance for developing new functions for ALS-inhibiting herbicides. The application of gametocides will also greatly promote the safe utilization of environment-sensitive male sterility in hybrid seed production. Unexpectedly, the application of three triazolopyrimidines (florasulam, flumetsulam, and penoxsulam) and one pyrimidinylthiobenzoate (bispyribac-sodium) did not cause male sterility, although these herbicides obviously inhibited the activity of ALS and plant growth. This result suggests that inhibition of ALS activity does not always lead to male sterility in plants, and these gametocides may also inhibit other biological functions vital for microspore development.

Dipteryx alata, a tree native to the Brazilian Cerrado, is sensitive to the herbicide nicosulfuron

Article

Full-text available

Mar 2020
ECOTOXICOLOGY

The expansion of land use for agricultural interests and the excessive use of herbicides are among the causes of biodiversity losses in the Brazilian Cerrado biome. Therefore, we aimed to test the hypothesis that Dipteryx alata Vogel, a common species in this biome, is sensitive to nicosulfuron because of its high phytotoxicity. We evaluated physiological, biochemical and morphological responses in D. alata plants exposed to increasing doses of the herbicide. Young plants were transplanted to 10 L pots containing substrate composed of soil and sand (2:1) after fertilization. After an acclimation period, the following doses of nicosulfuron were applied: 0 (control), 6, 12, 24, 48, and 60 g a.e. ha−1. The experiment was conducted in a randomized block design factorial scheme with six doses of nicosulfuron, three evaluation times, and five replicates per treatment. The effects of the herbicide were assessed by measuring gas exchange, chlorophyll a fluorescence, photosynthetic pigments, membrane permeability, antioxidant enzymes and acetolactate synthase. Nicosulfuron altered the photosynthetic machinery and enzymatic metabolism of D. alata. Reductions in physiological traits, increased catalase and ascorbate peroxidase activities, enhanced malondialdehyde concentrations rate of electrolyte leakage and decreased acetolactate synthase activity in response to nicosulfuron all suggest that D. alata is sensitive to this herbicide. As part of the Springer Nature SharedIt initiative, we can now publicly share a full-text view-only version of our paper using the link: https://rdcu.be/b1kuh

An imazethapyr-based herbicide formulation induces genotoxic, biochemical, and individual organizational effects in Leptodactylus latinasus tadpoles (Anura: Leptodactylidae)

Article

Full-text available

Jan 2020
ENVIRON SCI POLLUT R

Genotoxic, biochemical and individual organizational effects on Leptodactylus latinasus tadpoles were evaluated after exposure to an imazethapyr (IMZT)-based commercial herbicide formulation, Pivot® H (10.59% IMZT). A determination of the value of the lethal concentration (LC50) was determined as a toxicological endpoint. Alterations in animal behaviour and morphological abnormalities as well as cholinesterase (ChE), catalase (CAT) and glutathione S-transferase (GST) activities were employed as individual sublethal endpoints. Micronuclei frequencies (MNs), binucleated cells (BNs), blebbed nuclei (BLs), lobed nuclei (LBs), notched nuclei (NTs), erythroplastids (EPs), and evaluation of DNA strand breaks were employed as genotoxic endpoints. All biomarkers were evaluated after 48 and 96 h of exposure to concentrations of IMZT within 0.07-4.89 mg/L. LC5096h values of 1.01 and 0.29 mg/L IMZT were obtained for Gosner stages 25 and 36, respectively. Irregular swimming, diamond body shape and decreased frequency of keratodonts were detected at both sampling times. Results showed that IMZT increased GST activity and MNs frequency at 48 and 96 h of exposure. Other nuclear abnormalities were also observed in the circulating erythrocytes of tadpoles, i.e., NTs and BLs values after 48 h, and LNs, BLs and EPs values after 96 h. Finally, results showed that IMZT within 0.07-0.22 mg/L increased the genetic damage index in tadpoles exposed for both exposure times (48 and 96 h). This study is the first to report the sublethal biochemical effects of IMZT in anurans and is also the first report using L. latinasus tadpoles as a bioindicator for ecotoxicological studies.

Target site as the main mechanism of resistance to imazamox in a Euphorbia heterophylla biotype

Article

Full-text available

Oct 2019

Euphorbia heterophylla is a weed species that invades extensive crop areas in subtropical regions of Brazil. This species was previously controlled by imazamox, but the continuous use of this herbicide has selected for resistant biotypes. Two biotypes of E. heterophylla from southern Brazil, one resistant (R) and one susceptible (S) to imazamox, were compared. The resistance of the R biotype was confirmed by dose-response assays since it required 1250.2 g ai ha-1 to reduce the fresh weight by 50 % versus 7.4 g ai ha-1 for the S biotype. The acetolactate synthase (ALS) enzyme activity was studied using ALS-inhibiting herbicides from five different chemical families. The R biotype required the highest concentrations to reduce this enzyme activity by 50 %. A Ser653Asn mutation was found in the ALS gene of the R biotype. The experiments carried out showed that imazamox absorption and metabolism were not involved in resistance. However, greater 14C-imazamox root exudation was found in the R biotype (~70 % of the total absorbed imazamox). Target site mutation in the ALS gene is the principal mechanism that explains the imazamox resistance of the R biotype, but root exudation seems to also contribute to the resistance of this biotype.

Hemotoxic effects of Some Herbicides on Juvenile of Nile tilapia Oreochromis niloticus

Article

Full-text available

Oct 2019
ENVIRON SCI POLLUT R

Recently, the residues of some common and widely used herbicides (acetochlor, bispyribac-sodium, bentazon, bensulfuron-methyl, halosulfuron-methyl, and quinclorac) were detected in the surface water, soil, sediments, and fish tissues as the agricultural drainage problems. In this study, juveniles of Nile tilapia Oreochromis niloticus were exposed to sub-lethal concentrations of these herbicides as 2.625, 0.800, 36.00, 2.50, 1.275, and 11.250 mg/l for acetochlor, bispyribac-sodium, bentazon, bensulfuron-methyl, halosulfuron-methyl, and quinclorac respectively for 96 h. Some hemato-biochemical parameters were evaluated. In comparison with the control group, sub-lethal concentrations of all tested herbicides induced alterations in the shape of erythrocytes. Also, in all tested herbicides, hematological parameters of exposed fish exhibited a significant decrease in red blood cell count except bentazon. However, all tested herbicides showed an insignificant reduction in mean corpuscular hemoglobin concentration and total white blood cells except bensulfuron-methyl. For biochemical parameters, most tested herbicides induced a significant increase in levels of cholesterol, albumin, globulin, albumin/globulin ratio, activity of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total plasma protein (only with acetochlor), urea, and creatinine (except bentazon and halosulfuron-methyl that exhibited non-significant decrease in creatinine level) compared with the control. In conclusion, the fish blood profiles can be used as good biomarkers for laboratory study to assess the toxicity of the tested rice herbicides at a sub-acute level especially acetochlor on O. niloticus. Graphical Abstract

Method validation, storage stability and field trial for residues of florasulam and pyroxsulam in cereal by liquid chromatography with tandem mass spectrometry

Article

Feb 2020

A QuEChERS method with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was modified and validated for the determination of florasulam and pyroxsulam residues in wheat grain and straw. The validated method was applied to cereals including oat, millet, corn and rice. Average recoveries were 76-113% with RSDs 2-15%. The limits of quantitation (LOQ) were 0.005 mg/kg for wheat grain and 0.01 mg/kg for wheat straw and four cereals. Ion suppression for florasulam (−28% to −76%) was observed in all the matrices except corn, whereas ion enhancement were shown for pyroxsulam (44% to 83%). Degradation rates of florasulam and pyroxsulam were 6% and 23%, respectively, in wheat grain and straw after eight-week storage at −20°C. The ultimate residues in field trials in ten regions were all ≤0.05 mg/kg, and long term dietary risk assessment indicated that hazard quotients were 0.02% and 0.001% for florasulam and pyroxsulam, respectively, which shows that it is safe to spray the two herbicides on wheat.

Non-target effect of bispyribac sodium on soil microbial community in paddy soil

Article

Dec 2019
ECOTOX ENVIRON SAFE

Bispyribac sodium is frequently used herbicide in the rice field. Though, it has been targeted to kill rice weeds, but its non-target effect on soil microbes in paddy soil was largely unknown. Therefore, in the present study, an attempt was made to assess the non-target effect of bispyribac sodium on alteration of functional variation of soil microbial community and their correlation with microbial biomass carbon (MBC) and soil enzymes. A microcosm experiment set up was made comprising three treatments viz., control (CON) (without application of bispyribac sodium), recommended dose of bispyribac sodium (35 g ha-1) (BS), and double the dose of BS (70 g ha-1) (DBS). Results indicated that the MBC and soil enzyme activities (dehydrogenase, alkaline phosphatase and urease) in BS and DBS-treated soil were significantly (p < 0.05) declined from 1st to 30th day after application as compared to CON. Counts of heterotrophic bacteria, actinomycetes and fungal population were also decreased in BS and DBS-treated soil. The average well color development (AWCD) values derived from Biolog®ecoplates followed the order of DBS ˂ BS ˂ CON. Shannon index value was high (p ≤ 0.05) in CON compared to soil-treated with BS and DBS. Principal component analysis (PCA) showed a clear distinction of the cluster of treatments between CON, BS and DBS. Biplot analysis and heatmap suggested that carboxylic compounds and amino acids showed positive response towards BS-treated soil, whereas phenolic compounds had positive correlation with DBS-treated soil. PCA analysis indicated that oligotrophs was rich in BS-treated paddy soil, whereas copiotrophs and asymbiotic nitrogen fixers were richer in DBS treatment. Overall, the present study revealed that application of recommended dose of BS and its double dose alter the soil microbial population, enzyme activities and functional microbial diversity in paddy soil.

Behavior of imidazolinone herbicide enantiomers in earthworm-soil microcosms: Degradation and bioaccumulation

Article

Nov 2019
SCI TOTAL ENVIRON

Imidazolinone herbicides are a group of chiral herbicides that are widely used to control weeds in crops. Despite their wide use, few studies on the behavior of enantiomers in terrestrial systems have been reported. In this study, the bioaccumulation of imazamox, imazapic, and imazethapyr enantiomers in earthworm and their degradation in soils were assessed using earthworm-soil microcosms. The bioaccumulation of the three herbicides in earthworm was not significantly enantioselective. Imazamox and imazethapyr did not significant stereoselective degradation in soil (p > 0.05), while the enantioselectivity of the degradation of imazapic was significant (p < 0.05). Furthermore, biota to soil accumulation factor (BSAF) values were also calculated for three herbicides. Relationships between BSAF values and organic matter content of soil and log KOW of herbicides were investigated. The BSAFs values were negatively correlated with the log KOW of herbicides, and were positively correlated with organic matter content of soil in earthworm-soil microcosms. These relationships indicated that chemical hydrophobicity (Kow) and organic matter content of soil were good predictors to estimate the bioavailability of imidazolinone herbicides to earthworm.

Effects of Imazaquin Residues on Cotton ( Gossypium hirsutum )

Article

Nov 1989

Field and laboratory studies were conducted in 1987 and 1988 on several Arkansas soils to determine the effects of residual levels of imazaquin on cotton. Imazaquin concentrations ranging from 0.007 to 0.024 μg/g and 0.00 to 0.015 μg/g were found in soil samples taken 12 and 24 months, respectively, following preplant-incorporated applications at rates of 140 g/ha. Cotton yields were reduced from 7 to 42% in 1987 as the soil concentration of imazaquin increased from 0.007 to 0.024 μg/g. Imazaquin persistence was greater in clay soils than loams or sandy loams. Imazaquin was weakly adsorbed to a clay, loam, and sandy loam soil in laboratory studies; the adsorption isotherms did not differ significantly by soil texture. A bioassay utilizing cotton as the indicator species was developed to determine imazaquin concentrations in soils ranging from 0 to 0.06 μg/g. Imazaquin concentrations determined by the bioassay method were found to be 75, 77, and 80% of those determined by chemical extractions for a clay, loam, and sandy loam soil, respectively.

Toxicity of the herbicides used on herbicide-tolerant crops, and societal consequences of their use in France

Abstract

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