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Effect of Endocrine Disruptor Pesticides: A Review

Authors:
  • University of Bisha - University of Manouba

Abstract and Figures

Endocrine disrupting chemicals (EDC) are compounds that alter the normal functioning of the endocrine system of both wildlife and humans. A huge number of chemicals have been identified as endocrine disruptors, among them several pesticides. Pesticides are used to kill unwanted organisms in crops, public areas, homes and gardens, and parasites in medicine. Human are exposed to pesticides due to their occupations or through dietary and environmental exposure (water, soil, air). For several years, there have been enquiries about the impact of environmental factors on the occurrence of human pathologies. This paper reviews the current knowledge of the potential impacts of endocrine disruptor pesticides on human health.
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Int. J. Environ. Res. Public Health 2011, 8, 2265-2303; doi:10.3390/ijerph8062265
International Journal of
Environmental Research and
Public Health
ISSN 1660-4601
www.mdpi.com/journal/ijerph
Review
Effect of Endocrine Disruptor Pesticides: A Review
Wissem Mnif 1,2, Aziza Ibn Hadj Hassine 1, Aicha Bouaziz 1, Aghleb Bartegi 3, Olivier Thomas 4
and Benoit Roig 4,*
1 Laboratoire de Biochimie, Unité de Recherche 02/UR/09-01, Institut Supérieur de Biotechnologie,
de Monastir, BP 74, 5019 Monastir, Tunisia; E-Mails: w_mnif@yahoo.fr (W.M.);
aziza.hadjhassine@gmail.com (A.I.H.H); w_bouaziz.aicha@yahoo.fr (A.B.);
2 Institut Supérieur de Biotechnologie de Sidi Thabet, Pole Technologie Sidi Thabet, 2020
Ariana, Tunisia
3 Department of Biology, Faculty of Sciences, King Faisal University, P.O. Box 1759, 31982, Al
Hassa, Saudi Arabia; E-Mail: bartagi_fsm@yahoo.com
4 Environment and Health Research laboratory (LERES), Advanced School of Public Health
(EHESP), Avenue du Professeur Léon Bernard - CS 74312, 35043 Rennes Cedex, France;
E-Mail: olivier.thomas@ehesp.fr (O.T.)
* Author to whom correspondence should be addressed; E-Mail: benoit.roig@ehesp.fr;
Tel.: +33-786-284-551; Fax: +33-299-022-921.
Received: 20 May 2011; in revised form: 8 June 2011 / Accepted: 9 June 2011 /
Published: 17 June 2011
Abstract: Endocrine disrupting chemicals (EDC) are compounds that alter the normal
functioning of the endocrine system of both wildlife and humans. A huge number of
chemicals have been identified as endocrine disruptors, among them several pesticides.
Pesticides are used to kill unwanted organisms in crops, public areas, homes and gardens,
and parasites in medicine. Human are exposed to pesticides due to their occupations or
through dietary and environmental exposure (water, soil, air). For several years, there have
been enquiries about the impact of environmental factors on the occurrence of human
pathologies. This paper reviews the current knowledge of the potential impacts of
endocrine disruptor pesticides on human health.
Keywords: endocrine disruptors; pesticides; biomonitoring; human effect
OPEN ACCESS
Int. J. Environ. Res. Public Health 2011, 8
2266
Abbreviations: ADI: Acceptable Daily Intake; AhR: ArylHydrocarbon Receptor; AR: Androgen
Receptor; CA: Concentration Addition; CAR: Constitutive Androstane Receptor; EDC: Endocrine
Disruptor Chemical; ER: Estrogen Receptor; ERR: Estrogen Related Receptor;
HCH: Hexachlorocyclohexane; IA: Independent Action; LOD: Limit of Detection;
PCB: PolyChloroBiphenyl; PXR: Pregnane X Receptor; WHO: World Health Organisation
1. Introduction
Since the discovery of DDT in 1939 [1], numerous pesticides (organochlorides, organophosphates,
carbamates) have been developed and used extensively worldwide with few guidelines or restrictions.
In industrialized countries, the Green Revolution of the 1960s significantly increased agricultural
productivity by increasing the cultivated surfaces, mechanization, planting of hybrid crops with higher
yields, and pest control [2]. This fight requires the massive use of pesticides, which are hazardous
chemicals designed to repel or kill rodents, fungi, insects, and weeds that undermine intensive
farming. The main effects of pesticides represent a great benefit for human health. Indeed, they help
control agricultural pests (including diseases and weeds) and plant disease vectors, human and
livestock disease vectors and nuisance organisms, and organisms that harm other human activities and
structures (gardens, recreational areas, etc.). Moreover, they insure increased food production, a safe
and secure food supply, and other secondary benefits [3]. However, many first generation pesticides
have been found to be harmful to the environment. Some of them can persist in soils and aquatic
sediments, bioconcentrate in the tissues of invertebrates and vertebrates, move up trophic chains, and
affect top predators.
Rachel Carson’s book Silent Spring‖, published in 1962 [4], first drew attention to the hazard of
the widespread extensive use of pesticides for the environment (namely birds) and also for human
health. The book resulted in big modifications to the US national policy on pesticides, leading to a
national ban on DDT and certain other pesticides.
Worldwide consumption of pesticides for agricultural use is constantly increasing, rising from
0.49 kg/ha in 1961 to 2 kg/ha in 2004 (see various web sources, such as for example
http://ec.europa.eu/agriculture/envir/report/fr/pest_fr/report.htm#fig6; http://faostat.fao.org/site/424/
default.aspx#ancor; http://www.goodplanet.info/eng/Food-Agriculture/Pesticides/Pesticides/(theme)/
266), and humans and wildlife are today continuously exposed to a number of pesticides via the
environment (surface water, ground water, soil), food and drinking water [5].
The World Health Organization (WHO) has reported that roughly three million pesticide poisonings
occur annually, resulting in 220,000 deaths worldwide [6]. In some cases, it has been suggested that
diseases such as cancer, allergies, neurological disorders and reproductive disorders may be connected
to pesticide exposure.
This article focuses on pesticides that act as endocrine disruptors, and reviews the available
information about the exposure and effects of such pesticides, as well as human biomonitoring for
human health risk assessment.
Int. J. Environ. Res. Public Health 2011, 8
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2. Effects of Endocrine Disruptor Pesticides
Many chemicals that have been identified as endocrine disruptors are pesticides [7-11]. About
105 substances can be listed, and most of them are shown in Table 1. Of these, 46% are insecticides,
21% herbicides and 31% fungicides; some of them were withdrawn from general use many years ago
but are still found in the environment (ex. DDT and atrazine in several countries).
EDCs act mainly by interfering with natural hormones because of their strong potential to bind to
estrogen or androgen receptors [12] as shown in Table 1. In particular, EDCs can bind to and activate
various hormone receptors (AR, ER, AhR, PXR, CAR, ERR) and then mimic the natural hormones
action (agonist action). EDCs may also bind to these receptors without activating them. This
antagonist action blocks the receptors and inhibits their action. Finally, EDCs may also interfere with
the synthesis, transport, metabolism and elimination of hormones, thereby decreasing the concentration
of natural hormones. For example, thyroid hormone production can be inhibited by some ten endocrine
disruptor pesticides (amitrole, cyhalothrin, fipronil, ioxynil, maneb, mancozeb, pentachloronitro-
benzene, prodiamine, pyrimethanil, thiazopyr, ziram, zineb, not shown in Table 1) [13-16].
At the environmental level, wildlife is particularly vulnerable to the endocrine disrupting effects of
pesticides. Effects linked to endocrine disruption have been largely noted in invertebrates [17-21],
reptiles [22-27], fish [28,29], birds [30-34] and mammals [35-38] as reviewed by Mnif et al. [39].
Most of them are linked to exposure to organochlorine pesticides (OC) and affect the reproductive
function. For example, a study on Daphnia magna has shown that endosulfan sulphate disrupts the
ecdysteroidal system (regulating processes such as molting and embryonic development) and juvenile
hormone activity (regulating the sex ratio) of crustaceans [40,41]. Another example is the influence of
linuron on reproductive hormone production [42], testosterone production in rats being significantly
reduced after in utero exposure to linuron, whereas progesterone production was not affected [42].
At the human level, endocrine disruptor pesticides have also been shown to disrupt reproductive
and sexual development, and these effects seem to depend on several factors, including gender, age,
diet, and occupation.
Age is a particularly sensitive factor. Human fetuses, infants and children show greater
susceptibility than adults [43-45]. Much of the damage caused by EDC occurs during gametogenesis
and the early development of the fetus [45-48]. However, the effects may not become apparent until
adulthood. Moreover, fetuses and infants receive greater doses due to the mobilization of maternal fat
reserves during pregnancy [47-50] and breastfeeding [49,51]. Infants are extremely vulnerable to pre
and postnatal exposure to endocrine disruptor pesticides, resulting in a wide range of adverse health
effects including possible long-term impacts on intellectual function [52,53] and delayed effects on the
central nervous system functioning [54,55].
Likewise, residential proximity to agricultural activity is a factor often described to explain
developmental abnormalities in epidemiological studies of low birth weight [56], fetal death [57], and
childhood cancers [58]. Additionally, a higher prevalence of cryptorchidism and hypospadias [59,60]
was found in areas with extensive farming and pesticide use and in sons of women working as
gardeners [61]. Recently, a relation has been reported between cryptorchidism and persistent pesticide
concentration in maternal breast milk [47,62,63]. The impact of endocrine disruptor pesticides on
fertility has also been discussed [64].
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Effects of different groups of endocrine disruptorpesticides and their chemical structures (adapted from [65]).
Pesticides [66]
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
2,4-D (H)
M(g/Mol) = 221
pKa = 2.73
logP: 2.81
Synergistic androgenic effects when combined
with testosterone [67]
U: <LOD598 ng/mL [68]
S : 0.070.56 g/g creatinine [69]
Acephate (I)
M(g/Mol) = 183.2
pKa = 8.35
logP: 0.85
OPNH CH3
S
O
CH3
CH3O
Disruption of hormone expression in the
hypothalamus [70]
U: <LOD0.26 ng/mL [68]
H.S: 7.2 g/mL [71] **
Acetochlor (H)
M(g/Mol) = 269.8
pKa = n.a
logP: 4.14
CH3
CH3
NCl
O
O
CH3
Interaction with uterine estrogen receptors,
alteration of thyroid hormone dependant gene
expression [72,73]
U: <LOD10.9 ng/mL [68]
S: 0.080.10 g/g creatinine [69]
Alachlor (H)
M(g/Mol) = 269.8
pKa = 0.62
logP: 3.09
CH3
NCl
OCH3
O
CH3
Competitive binding to estrogen and progesterone
receptors. Interaction with the pregnane X cellular
receptor, interfering with the production of
enzymes responsible for steroid hormone
metabolism [13,74]
U: <LOD305 ng/mL [68]
S: 0.310.72 g/g creatinine [69]
Aldicarb (I)
M(g/Mol) = 190.3
pKa = n.a
logP: 1.15
CH3NH ONSCH3
CH3CH3
O
Inhibition of 17 beta-estradiol and progesterone
activity [13,75]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human
samples
Aldrin (I)
M(g/Mol) = 364.9
pKa = n.a
logP: 6.5
Cl
Cl
Cl
Cl
Cl
Competitive binding to androgen receptors [76]
H.S: 2.17372 g/L [77,78]
H.M: mean 0.03 mg/L ± 0.03 [79]
A.T: 25.6137.2 ng/g lipid [78]
Atrazine (H)
M(g/Mol) = 215.7
PKa = 4.14, 10.7
logP: −0.97
NN
NNH
Cl CH3
NH
CH3
CH3
Androgen inhibition, weak estrogenic effect.
Disruption of the hypothalamic control of lutenising
hormone and prolactin levels. Induction of
aromatase activity, increase estrogen production.
Adrenal glands damages and reduction of steroid
hormone metabolism [13,80-83]
U: <LOD9.2 ng/mL [68,84]
H.S: mean 2 pg/g [76,85]
S: 0.070.17 g/g creatinine [69]
Bendiocarb (I)
M(g/Mol) = 223.2
pKa = 8.8
logP: 1.7
O
O
O
O
NH
CH3
CH3
CH3
Weak estrogen effect [13]
Benomyl (F)
M(g/Mol) = 290.3
pKa = 4.48
logP: 1.4
N
NOCH3
O
NH
O
CH3
Increase of estrogen production and aromatase
activity [86]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Bioallethrin (I)
M(g/Mol) = 302.4
pKa = n.a
logP: 4.68
H
CH3
CH3
H
O
O
CH3
CH2
O
CH3
CH3
Inhibition of estrogen-sensitive cells proliferation
[87]
M: 0.611.79 g/mL [88]
H: 1.082.74 g/mL [88]
Bitertanol (F)
M(g/Mol) = 337.4
pKa = n.a
logP: 4.1
O
t-Bu
OH N
NN
Inhibition of aromatase activity, decrease of
estrogens production and increase of androgens
availability [89]
Bupirimate (F)
M(g/Mol) = 316.4
pKa = 4.4
logP: 3.68
N
N
NH CH2CH3
CH3
H3C(H2C)3
O
S
OO
(H3C)2N
Activation of Pregnane X cellular receptor [11]
Captan (F)
M(g/Mol) = 300.6
pKa = n.a
logP: 2.5
N
O
O
SCl
Cl
Cl
Inhibition of estrogen action [90]
Carbaryl (I)
M(g/Mol) = 201.2
pKa = 10.4
logP: 2.36
ONH
CH3
O
Weak estrogen effect [13]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Carbendazim (F)
M(g/Mol) = 191.2
pKa = 4.2
logP: 1.48
N
H
NNH OCH3
O
Increase of estrogen production and aromatase
activity [86]
Carbofuran (I)
M(g/Mol) = 221.2
pKa = n.a
logP: 1.8
OCH3
O
O
NH CH3
CH3
Increase of progesterone, cortisol and estradiol
level and decrease of testosterone one [91]
M.S: 0.00717.63 ng/g [92]
U.C: 0.00713.97 ng/g [92]
Chlorothalonil (F)
M(g/Mol) = 265.9
pKa = n.a
logP: 2.94
CN
Cl
CN
Cl
Cl
Cl
Activation of androgen-sensitive cells
proliferation [93]
M.S: 0.00725.31 ng/g [92]
U.C: 0.00725.12 ng/g [92]
H.S: mean 6 pg/g [85]
Chlordane (I)
M(g/Mol) = 409.8
pKa = n.a
logP: 2.78
Cl
Cl
Cl
Cl
Cl Cl
Cl
Cl
Competitive binding to androgen receptors [76]
Anti-estrogenic effect, inhibition of estradiol
binding [13]
M.P: 02.7 ng/g lipid [94]
B.S: <LOD0.9 ng/g lipid [95]
H.M: 0.02437 ng/g lipid [79,96-99]
FF: 0.10.3 ng/L [100]
Chlordecone (I)
M(g/Mol) = 490.6
pKa = n.a
logP: 4.5
OCl Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Binding to estrogen and androgen receptors
[90,101,102]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Chlorfenviphos (I)
M(g/Mol) = 359.6
pKa = n.a
logP: 1.36
Cl CH3
CH3OP
OEt
OEt
O
Cl
Cl
Weak estrogen effect [103]
Chlorpyrifos
methyl (I)
M(g/Mol) = 322.5
pKa = n.a
logP: 4
N
O
SH OCH3
OCH3
Cl
Cl
Cl
Antagonist to androgen activity [104]
U : <LOD57.7 ng/mL* [68,84]
M.S: 0.000710.1 ng/g [92]
U.C: 0.00071.84 ng/g [92]
H.S: mean 9 pg/g [85]
H: 1.772.16 1.83 g/mL [88]
Cypermethrin (I)
M(g/Mol) = 416.3
pKa = n.a
logP: 5.3
Estrogenic effect [105,106]
U: 0.5100.4 g/g * [107]
M: 1.852.43 g/mL [88]
Cyproconazole (F)
M(g/Mol) = 291.8
pKa = n.a
logP:3.09
Cl
OH
CH3
NN
N
Inhibition of aromatase activity, decrease of
estrogens production and increase of androgens
availability [89]
Int. J. Environ. Res. Public Health 2011, 8
2273
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
DDT and
metabolites (I)
M(g/Mol) = 354.5
pKa = n.a
logP:6.91
Cl Cl
Cl
Cl
Cl
Competitive binding to androgen receptors,
activation of androgen-sensitive cells
proliferation.
Stimulation of estrogen receptor production,
estrogen receptor agonist and PR antagonist
[76,93,108,109]
M.P: 0.23588 ng/g lipid [94]
B.S: <LOD40.9 ng/g lipid [95]
HM: 3.94700 ng/g lipid
[110,96-99,111]
A.F: 0.10.63 mg/L [112]
M: 1.12.8 g/mL [88]
H: 0.170.65 g/mL [88,113]
M.B: 06168 ng/g lipid [110,114]
H.S: 12.5814.9 ng/mL [77]
U.C: 1893296 ng/g lipid [110]
Deltamethrin (I)
M(g/Mol) = 505.2
pKa = n.a
logP: 4.6
OO
N
O
Br
Br
CH3
CH3
Weak estrogenic activity [8]
U: 0.557.7 g/g * [107]
Diazinon (I)
M(g/Mol) = 304.4
pKa = 2.6
logP: 3.69
NN
CH3
CH3
CH3OPOEt
SOEt
Estrogenic effect [115]
S: 1.844.96 g/g creatinine * [69]
H.S: mean 2 pg/g [85]
Dichlorvos (I)
M(g/Mol) = 221
pKa = n.a
logP: 1.9
OCH3
OP
OOCH3
Cl
Cl
Weak androgen-receptor antagonist [8]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Dicofol (I)
M(g/Mol) = 370.5
pKa = n.a
logP: 4.3
Cl Cl
Cl
Cl
Cl OH
Inhibition of androgen synthesis, increase of
estrogens synthesis, binding to estrogen receptor
[90,83]
Dieldrin (I)
M(g/Mol) = 380.9
pKa = n.a
logP: 3.7
Cl
Cl
Cl
Cl
Cl Cl
O
Competitive binding to androgen receptors,
estrogenic effect, stimulation of estrogen receptor
production [8,76,108,116]
H.M: <0.164 ng/g lipid [111]
Diflubenzuron (I)
M(g/Mol) = 310.7
pKa = n.a
logP: 3.89
Cl
NH
NH
OO
F
F
Pregnane X cellular receptor activation [11]
H.S: 1.21356.4 g/L [77,78]
H.M: mean 0.66 mg/L ± 1.75 [79]
A.T: 17.0184.05 [78]
Dimethoate (I)
M(g/Mol) = 229.3
pKa = n.a
logP: 0.704
H3CO SP
S
OCH3
NH
CH3
O
Disruption of thyroid hormones action. Increase of
insulin blood concentration, decrease of
luteinizing hormone blood concentration
[117,118]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Diuron (H)
M(g/Mol) = 233.1
pKa = n.a
logP: 2.87
NH CH3
N
O
Cl
Cl
CH3
Inhibition of androgens action [83]
Endosulfan (I)
M(g/Mol) = 406.9
pKa = n.a
logP: 4.75
Cl
Cl
Cl
Cl
Cl Cl
O
O
S
O
Competitive binding to androgen receptors,
estrogenic effect, stimulation of estrogen receptor
production, inhibition of aromatase activity
[8,76,109,116]
H.S: 8.85547.6 g/L [77,78]
A.T: 21.4417.6 ng/g lipid [78]
Endrin (I)
M(g/Mol) = 380.9
pKa = n.a
logP: 3.2
Cl
Cl
Cl
Cl
Cl Cl
Competitive binding to androgen receptors [76]
H.M: mean 0.65 mg/L ± 1.63 [79]
H.S: 1.216.35 g/L [78]
A.T: 47.43148.13 ng/g lipid [78]
Epoxyconazole (F)
M(g/Mol) = 329.8
pKa = n.a
logP: 3.3
O
N
N
N
Cl
F
Inhibition of aromatase activity, decrease of
estrogen production and increase available
androgens [89,119]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Fenarimol (F)
M(g/Mol) = 331.2
pKa = n.a
logP: 3.69
NN
OH
Cl
Cl
Antagonist of androgenic action. Potential
aromatase inhibition. Pregnane X cellular receptor
activation [8,11,120]
Fenbuconazole (F)
M(g/Mol) = 336.8
pKa = n.a
logP: 3.79
N
N
Cl
N
N
Inhibition of thyroid hormones production,
Pregnane X cellular receptor activation [11,13]
Fenitrothion (I)
M(g/Mol) = 277.2
pKa = n.a
logP: 3.32
OP
S
OCH3
OCH3
O2N
CH3
Competitive binding to androgen receptor,
inhibition of estrogens action [90,121]
H.S: 4.5 g/mL [71] **
Fenoxycarb (I)
M(g/Mol) = 301.3
pKa = n.a
logP: 4.07
O
ONH
O
OEt
Interference with testosterone metabolism [122]
Fenvalerate (I)
M(g/Mol) = 419.9
pKa = n.a
logP: 5.01
O
O
CN
O
CH3
CH3
Cl
Inhibition of estrogen-sensitive cells proliferation,
antagonist of the progesterone action [86,123]
Int. J. Environ. Res. Public Health 2011, 8
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Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Fluvalinate (I)
M(g/Mol) = 502.9
pKa = n.a
logP: 3.85
O
O
NH O
CH3
CH3
CN
Cl
F3C
Binding to human sex hormone, Inhibition of
progesterone production [124,125]
Flusilazole (F)
M(g/Mol) = 315.4
pKa = 2.5
logP: 3.87
Si
CH3
CH2
NN
N
FF
Inhibition of aromatase activity, decrease of
estrogens production, increase of available
androgens [89]
Flutriafol (F)
M(g/Mol) = 301.3
pKa = 2.3
logP: 2.3
C
OH
CH2
NN
N
F
F
Weak estrogen inhibition [119]
Glyphosphate (H)
M(g/Mol) = 168.1
pKa = 0.78; 2.34;
5.96; 10.98
logP: −3.2
(HO)2PNH OH
O
O
Disruption of aromatase activity, preventing the
production of estrogens [126]
U: 1.12.1 ng/mL [84]
Int. J. Environ. Res. Public Health 2011, 8
2278
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
HCB (F)
M(g/Mol) = 284.8
pKa = n.a
logP: 3.93
Cl
Cl
Cl
Cl
Cl
Cl
Severely disruption of thyroid hormone
production. Enhancement of androgen action at
low doses, but inhibition at high levels [127,128]
M.P: 1.644.3 ng/g lipid [94]
B.S: 7.437.2 ng/g lipid [95]
H.M: 0.4472 ng/g lipid [79,96-99]
H.S: 12.5393.3 g/L [77]
H 1.215.9 pg/mg [113]
F.F: 0.110.2 ng/L [100]
A.F: [112]
HCH (lindane) (I)
M(g/Mol) = 290.8
pKa = n.a
logP: 3.61
Cl
Cl
Cl
Cl
Cl
Cl
Reduction of oestrous cycles and luteal
progesterone concentrations. Increase of insulin
and estradiol blood serum concentrations,
decrease thyroxine concentrations. Competitive
binding to AR, ER and PR [117,129]
M.P: 0.42839 ng/g lipid [94]
B.S: <LOD134 ng/g lipid [95]
H.M: 4.78700 ng/g lipid [80,110,96-99]
H.S: 1.08265.8 g/L [77,78]
H: 50.7235 pg/mg [113]
A.T: 17.44113.31 ng/g lipid [78]
M.B: 1.9386.6 ng/g lipid [110, 114]
A.F: 0.10.26 ng/mL [112]
U.C: 4130 ng/g lipid [110]
Heptachlor (I)
M(g/Mol) = 373.3
pKa = n.a
logP: 5.44
Cl
Cl
Cl
Cl
Cl Cl
Cl
Binding to cellular estrogen and androgen
receptors [130,131]
M.P: 0.25.2 ng/g lipid [94]
B.S: <LOD0.9 ng/g lipid [95]
Human serum: 12.5139.1 g/L [77]
H.M: mean 0.07 mg/L ± 0.34 [79]
Int. J. Environ. Res. Public Health 2011, 8
2279
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Hexaconazole (F)
M(g/Mol) = 314.2
pKa = 2.3
logP: 3.9
CH3
CH3
(CH2)3CH3
CH2
OH N
N
N
Inhibition of aromatase activity, decrease of the
estrogens production and increase of available
androgens [89]
Isoproturon (H)
M(g/Mol) = 206.3
pKa = n.a
logP: 2.5
NH NCH3
CH3
O
CH3
CH3
Pregnane X cellular receptor activation [11]
Iprodione (F)
M(g/Mol) = 330.2
pKa = n.a
logP: 3.1
NN
Cl
Cl
O
O
O
NH
CH3
CH3
Increase weakly aromatase activity, and estrogen
production [8]
Linuron (H)
M(g/Mol) = 249.1
pKa = n.a
logP: 3
NH
Cl
Cl NOCH3
CH3
O
Competitive binding to androgen receptor, thyroid
receptor agonist [131,132]
Int. J. Environ. Res. Public Health 2011, 8
2280
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Malathion (I)
M(g/Mol) = 330.4
pKa = n.a
logP: 2.75
S
OOEt
OOEt
P
S
MeO
MeO
Inhibition of catecholamine secretion, binding to
thyroid hormone receptors [13,133]
U: <LOD3195 ng/mL [68] *
M: 2.925.38 g/mL [88]
H: 1.622.12 g/mL [88]
S: 0.370.92 g/g creatinine [69]
Methiocarb (H)
M(g/Mol) = 225.3
pKa = n.a
logP: 3.18
ONH
CH3
CH3
S
CH3
CH3
O
Inhibition of androgen activity and increase of
estrogen one [8]
Methomyl (I)
M(g/Mol) = 162.2
pKa = n.a
logP: 1.24
CH3NH ONSCH3
CH3
O
Weak increase of aromatase activity and estrogen
production [8,13]
Methoxychlor (I)
M(g/Mol) = 345.7
pKa = n.a
logP: 5.83
MeO OMe
Cl
Cl
Cl
Strong estrogenic effect. Competitive binding to
androgen receptor, interaction with the pregnane
X cellular receptor [13,74,76]
H.S: 0.380.39 g/L [78]
A.T: 29.86155.58 ng/g lipid [78]
Metolachlor
M(g/Mol) = 283.8
pKa = n.a
logP: 3.4
CH3
CH3N
OCl
CH3OMe
Pregnane X cellular receptor activation [11]
U: <LOD4.5 ng/mL [68,84]
H.S: mean 2 pg/g [85]
M.S: 0.0071.96 ng/g [92]
U.C: 0.0072.37 ng/g [92]
S: 0.200.48 g/g creatinine [69]
Int. J. Environ. Res. Public Health 2011, 8
2281
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Metribuzin (H)
M(g/Mol) = 214.3
pKa = 0.99
logP: 1.65
N
N
NNH2
SCH3
CH3
CH3
CH3
Hyperthyroidism, alteration of somatotropin levels
[134]
Mirex (I)
M(g/Mol) = 545.5
pKa = n.a
logP: 5.28
Cl
Cl Cl Cl Cl Cl
Cl
Cl Cl
Cl
Cl
Cl
Weak estrogen effect [13]
M.P: 0.21.5 ng/g lipid [94]
B.S: <LOD7.2 ng/g lipid [95]
H.M: 0.21.7 ng/g lipid [98]
Molinate (H)
M(g/Mol) = 187.3
pKa = n.a
logP: 2.86
N
EtS O
Reproductive tract damage, reduction of fertility
[13]
Myclobutanil (F)
M(g/Mol) = 288.8
pKa = 2.3
logP: 2.89
CH3CN
Cl
N
N
N
Weak estrogen and androgen inhibition, Binding
to estrogen and androgen receptors, aromatase
inhibition [89,90,119]
Int. J. Environ. Res. Public Health 2011, 8
2282
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Nitrofen (H)
M(g/Mol) = 284.1
pKa = n.a
logP: 3.4
CNO2
Cl
Cl
Estrogen and androgen inhibition [90]
Oxamyl (I)
M(g/Mol) = 219.3
pKa = n.a
logP: −0.44
CH3
NH O
N
O
N
CH3
CH3
SCH3
Weak estrogen effect [13]
Parathion (I)
M(g/Mol) = 291.3
pKa = n.a
logP: 3.83
OP
S
OEt
OEt
O2N
Inhibition of catecholamine secretion, increase of
melatonin synthesis, inhibition of gonadotrophic
hormone [13]
U: <LOD84 ng/mL * [68]
Penconazole (F)
M(g/Mol) = 284.2
pKa = 1.51
logP: 3.72
Cl
Cl N
(CH2)2CH3
N
N
Weak estrogenic effect. Inhibition of aromatase
activity, decrease of estrogens production and
increase androgens availability [89,119]
Pentachlorophenol
(H, F, I)
M(g/Mol) = 266.3
pKa = 4.73
logP: 3.32
OH
Cl
Cl
Cl
Cl
Cl
Weak estrogenic and anti-androgenic affect [13]
A.F : 0.150.54 ng/mL [135]
Int. J. Environ. Res. Public Health 2011, 8
2283
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Permethrin (I)
M(g/Mol) = 391.3
pKa = n.a
logP: 6.1
O
O
Cl
CH3
CH3
Cl
O
Inhibition of estrogen-sensitive cells proliferation
[87,106]
U: 1150 g/g * [107]
Phenylphenol (F)
M(g/Mol) = 170.2
pKa = 9.97
logP:3.09
OH
Estrogen agonist [136]
A.F: 0.10.17 ng/mL [135]
Prochloraz (F)
M(g/Mol) = 376.7
pKa = 3.8
logP: 3.53
Cl
Cl ONCH3
ON
N
Activation of Pregnane X cellular receptor.
Antagonist to cellular androgen and estrogen
receptors, agonist to Ah receptor and inhibition of
aromatase activity [8,11,120,137]
Procymidone (F)
M(g/Mol) = 284.1
pKa = n.a
logP: 3.3
N
Cl
Cl
O
O
CH3
CH3
Competitive binding to androgen receptor [131]
Propamocarb (F)
M(g/Mol) = 188.3
pKa = 9.5
logP: 0.84
CH3
ONH N
O
CH3
CH3
Weak increase of aromatase activity and estrogen
production [8]
Int. J. Environ. Res. Public Health 2011, 8
2284
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Propanil (H)
M(g/Mol) = 318.1
pKa = n.a
logP: 2.29
Cl
ClNH
CH3
O
Increase of cellular response to estrogen [138]
Propazine (H)
M(g/Mol) = 229.8
pKa = 1.7
logP: 3.95
N N
NNH
NH CH3
CH3CH3
CH3
Cl
Induction of aromatase activity and increase of
estrogen production [81]
Propiconazole (F)
M(g/Mol) = 342.2
pKa = 1.09
logP: 3.72
Cl
Cl
O
OCH3
N
NN
Weak estrogen and aromatase activity inhibition.
Decrease estrogens production and increase of
androgens availability [89,119]
Propoxur (I)
M(g/Mol) = 209.2
pKa = n.a
logP: 0.14
OO
O
NHCH3
CH3
CH3
Weak estrogenic effect [13]
M: 0.241.50 g/mL [88]
C.B: 0.77 g/mL [88]
H: 0.220.42 g/mL [88]
M.B: 0.670.77 g/mL [88]
Prothiophos (I)
M(g/Mol) = 345.3
pKa = n.a
logP: 5.67
Cl
Cl
OPS
SO
CH3
CH3
Estrogenic effect [115]
Int. J. Environ. Res. Public Health 2011, 8
2285
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Pyridate (H)
M(g/Mol) = 378.9
pKa = n.a
logP: 0.5
NN Cl
O
O
SCH3
Binding to estrogen and androgen receptors [90]
Pyrifenox (F)
M(g/Mol) = 295.2
pKa = 4.61
logP: 3.4
Cl
Cl
N
NOMe
Weak estrogen inhibition [119]
Pyripyroxifen (I)
M(g/Mol) = 321.4
pKa = 6.87
logP: 5.37
N
S
N
N
t-Bu
t-Bu
Estrogenic effect [115]
Resmethrin (I)
M(g/Mol) = 338.4
pKa = n.a
logP: 5.43
O
O
O
R
R
R
R
Binding to sex hormone [124]
Simazine (H)
M(g/Mol) = 201.7
pKa = 1.62
logP: 2.3
N
N
N
NHEt
Cl
EtHN
Induction of aromatase activity, increase of
estrogen production [81]
Int. J. Environ. Res. Public Health 2011, 8
2286
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human
samples
Sumithrin (I)
M(g/Mol) = 350.5
pKa = n.a
logP: 6.01
O
O
O
R
R
R
R
Increase of estrogen-sensitive cells proliferation,
antagonist of the progesterone action [87,123]
Tebuconazole (F)
M(g/Mol) = 307.8
pKa = n.a
logP: 3.7
Cl
t-Bu
OH
N
N
N
Inhibition of aromatase activity, decrease the
estrogens production and increase androgens
availability [89]
Tetramethrin (I)
M(g/Mol) = 331.4
pKa = n.a
logP: 4.6
N
O
O
R
R
R
RO
O
Estrogen-antagonistic effects in females only [139]
Tolchlofos-methyl
(I)
M(g/Mol) = 301.1
pKa = n.a
logP: 4.56
CH3
Cl
OPO
SO
CH3
CH3
Cl
Competitive binding to cellular estrogen receptors
[120]
Toxaphene (I)
M(g/Mol) = 411.8
pKa = n.a
logP: 3.3
CH2
CH3
CH3
Cln
Increase of estrogen-sensitive cells proliferation.
Inhibition of corticosterone synthesis in the adrenal
cortex [13,116]
Int. J. Environ. Res. Public Health 2011, 8
2287
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Triadimefon (F)
M(g/Mol) = 293.8
pKa = n.a
logP: 3.18
Cl
O
Ot-Bu
NN
N
Estrogenic effect, inhibition of aromatase activity,
decrease of estrogens production and increase
androgens availability [90]
Triadimenol (F)
M(g/Mol) = 295.8
pKa = n.a
logP: 3.18
Cl
O
OH t-Bu
NN
N
Estrogenic effect, inhibition of aromatase activity,
decrease of estrogens production and increase
androgens availability [89,90]
Tribenuron-
methyl (H)
M(g/Mol) = 395.4
pKa = 4.7
logP: 0.78
N
N
N
CH3
H3CO
N
CH3
O
NH S
O
O
OCH3
O
Weak estrogenic effect [8]
Trichlorfon (I)
M(g/Mol) = 257.4
pKa = n.a
logP: 0.43
P
OH
O
H3CO
H3CO Cl
Cl
Cl
Alteration of thyroid function [140]
Trifluralin (H)
M(g/Mol) = 335.3
pKa = n.a
logP: 5.27
F
FF
NO2
NO2
N
CH2CH2CH3
CH2CH2CH3
Interaction withs pregnane X cellular receptor,
interference steroid hormone metabolism [74]
M.S: 0.008.5 ng/g [92]
U.C: 0.0074.42 ng/g [92]
Int. J. Environ. Res. Public Health 2011, 8
2288
Table 1. Cont.
Pesticides
Chemical structure
Endocrine Disruptor Effects
Biomonitoring in human samples
Vinclozolin (F)
M(g/Mol) = 286.1
pKa = n.a
logP: 3.02
N
Cl
Cl
O
O
OCH3
CH2
Competitive binding to androgen receptor
Interactions with pregnane X cellular receptor,
interference with steroid hormone metabolism.
[8,74,131]
(H): Herbicide, (F): Fungicide, (I): Insecticide, (AFA): Antifouling agent, (T): Termiticide, U: urine, S: semen, H.S: human serum, H.M
human milk, M: mecomium, H = hair, A.T: adipose tissues, F.F: follicular fluid, M.P: maternal plasma, U.C: umbilical cord.
* Measured by the presence of its metabolite. ** Case of poisoning patient.
Int. J. Environ. Res. Public Health 2011, 8 2289
Based on the epidemiological studies since 2000, the study concluded that pesticide exposure may
affect spermatogenesis leading to poor semen quality and reduced male fertility. Furthermore, an
increasing number of epidemiological studies tend to link environmental exposure to pesticides and
hormone-dependent cancer risks. High levels of PCBs, DDE, and DDT have been found in fat samples
from women with breast cancer [141]. The risk of breast cancer is said to be four times greater in
women with increased blood levels of DDE 142]. One of the latest epidemiological studies performed
in Spain between 1999 and 2009 shows that among a total of 2,661 cases of breast
cancer reported in the female population, 2,173 (81%) were observed in areas of high pesticide
contamination [143]. Moreover, it was also suggested that women with hormone responsive breast
cancer have a higher DDE body burden than women with benign breast disease [144]. Similar studies
have revealed correlations between damage to the immune system and increased amounts of
organochlorine residues in certain cancerous tissues [145]. Numerous other studies support the
hypothesis that pesticide exposure influences the risk of breast cancer [146], but few of them are really
conclusive due to some inconsistent data across the study. Further research is required to explore
long-term follow-up beginning in early life, with opportunities for exposure measurement at critical
periods of vulnerability. Moreover, improvements are needed in the cohort sample size and
standardization of exposure assessments methods. Finally, researchers also need to consider
simultaneous co-exposures to these substances and other chemicals and whether they may act in an
additive, synergistic, or antagonistic manner [147].
There may also be a connection between pesticide exposure and prostate cancer. Various
studies have consistently demonstrated a higher risk in agricultural populations than in the general
population [148-150]. For example, pesticides (in particular DDT) were associated with a statistically
significant higher rate of prostate cancer among farmers (exposed to organochloride pesticides) in a
multi-site case-control study carried out in five rural areas between 199092 in Italy [151]. Several
studies in the USA and Sweden showed that farmers and commercial pesticide applicators have a
slightly and/or significantly higher rate of prostate cancer than the general population [148,152,153].
Several meta-analyses, cohort studies and case-control studies on the risk of prostate cancer in
populations exposed occupationally or professionally to pesticides have been conducted in recent
years [154] (and reference therein). They all showed a significantly higher risk of prostate cancer
estimated at between 10 and 40%, the higher values being for professional exposure. Quite recently, a
study analyzed the relationship between exposure to chlordecone (organochloride pesticide extensively
used for more than 30 years in the French West Indies to control the banana root borer) and the risk of
prostate cancer [155]. It showed a significant increase in the risk of prostate cancer with increasing
plasma chlordecone concentrations and supported the hypothesis that exposure to environmental
estrogens may increase the risk of prostate cancer.
However, in spite of these outcomes, the hypothesis that such excess risk is related to the use of
pesticides has not yet been formally demonstrated. Various other factors have been suggested to
explain the increase in prostate cancer in agricultural or rural populations, such as dietary issues,
contact with infectious agents via livestock, dust, tobacco and chemical products [154]. Rigorous
studies with larger cases that accurately and objectively estimate pesticide exposures and consider
gene-environment interactions are needed to determine a potential relationship between pesticides and
prostate cancer.
Int. J. Environ. Res. Public Health 2011, 8
2290
3. Biomonitoring for Human Exposure Assessment
Exposure to pesticides can occur via numerous pathways, including household use of pesticide
products, dietary exposure to pesticide residues, and exposure to agricultural drift. Biological
monitoring studies indicate that pesticide exposures are widespread in the human population. Dietary
exposure comes from residues in fruits, vegetables, and from contaminated meat, fish, rice and dairy
products. The European Commission [156] estimated that, in 2005, consumer intake was always below
the acceptable daily intakes (ADI) for long-term exposures. Several recent studies also show the
difference between EDI and ADI [157-159]. However, according to the European report, the acute
reference dose (a parameter for high short-term intakes, usually in one day or one meal) was exceeded
for some pesticides in different vegetables and fruits and 26.7% of samples show residues of more than
one pesticide, with a significant upward trend as compared to previous years. Food intake is not the
only exposure pathway for the general population. Living near sites where pesticides are used,
manufactured or disposed of may significantly increase environmental exposure through inhalation
and contact with air, water and soil [160-163].
Human exposure to pesticides is assessed by measuring the levels of pesticides in human samples
such as breast milk, maternal blood and serum, urine and sometime umbilical cord blood.
Improvements in analytical techniques have made it possible to detect pesticides and their metabolites
at trace levels (from milligrams per kilogram to femtograms per kilogram in some laboratories) in
almost all human samples. Table 1 reports the detection of pesticides in human samples.
Most of these studies show evidence of higher levels of pesticides in the exposed population (for
example due to their occupation or geographical location) than in non-exposed control people. For
example, a relation was established between employment in agriculture of Spanish women during
pregnancy and serum levels of organochlorine endocrine disruptor pesticides, including DDT and
isomers (despite their being banned in Spain since 1977) [164]. Also, higher levels of DDTs and HCHs
were found in maternal milk and blood samples in Chinese provinces than in developed or
industrialized countries [110]. Finally, higher concentrations of several pesticides were also found in
urine and plasma of pregnant Israeli women compared to other populations of pregnant women in the
United States and the Netherlands.
Pesticide metabolites are also monitored in human samples because they can be representative of a
global contamination. This is particularly true for organophosphorus compounds. Alkyl phosphates
have been reported in human samples (urine, hair) as representative of exposure to organophosphate
pesticides [165-168], and some authors have observed a significant difference in the levels of total
dialkyl phosphates among exposed and no exposed groups.
4. Discussion and Perspectives
Endocrine disruptor pesticides are widely used for agricultural, municipal, home and medical
purposes worldwide. Humans are exposed to these compounds, and due to their toxic properties, the
consequences of this exposure on human hormoel-dependent pathologies are being established. Most
risk assessment studies and some epidemiologic studies have looked at the exposure and toxicology of
a single compound. However, two other considerations must be included: the presence of pesticide
by-products and the cumulative exposure to pesticides multiresidue.
Int. J. Environ. Res. Public Health 2011, 8
2291
It is undisputed that in some cases, pesticide by-products can exhibit greater harmful effects than
their parent compounds. For example, one study showed that, at the organism level, the only sublethal
effect seen was an increase in heart rate at low concentration and a decrease at higher concentration
with the use of aldicarb-sulfoxide but not with aldicarb [169]. Another study reported that the oxons
of methyl-parathion, chlorpyrifos and diazinon were 15 to 10 times more toxic (to sperm DNA) than
their corresponding parent compounds [170]. As another example, in vitro studies confirmed that
2,4-dichlorophenoxyacetic acid (2,4-D), a commonly used organophosphate herbicide promoting the
proliferation of androgen-sensitive cells [171], is a known estrogen receptor ligand [172]. Vinclozolin
degrades to several metabolites in the soil, in the plants and in animal organisms [173]. Two
hydrolytic degradation products, 2-[[(3,5- dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid
and 3',5"-dichloro-2-hydroxy-methylbut-3-enalide, have been identified as anti-androgenic compounds
that mediate the adverse effects of vinclozolin [173].
Furthermore, the combined actions of pesticides also need also to be addressed in the risk
assessment process because mixtures of these substances may cause higher toxic effects than those
expected from the single compounds [174]. For example an equimolar mixture of three pesticides
(deltamethrin, methiocarb, and prochloraz) suppressed androgen receptor (AR) activation
in vitro [175]. Also, under the additional presence of simazin and tribenuronmethyl, weight changes of
the adrenal gland and alterations in gene expression of AR-associated genes were observed in vivo in
castrated testosterone-treated rats. The question of the combined effect of mixtures of contaminants
has attracted the attention of the scientific community. Predictive approaches are generally based on
the mathematical concepts of Concentration Addition (CA) and Independent Action (IA), both
predicting the toxicity of a mixture based on the individual toxicities of the mixture components
(e.g., [176] and references therein). Recently, a review showed that some other models could be useful
as tools to assess combined tissue doses and to help predict potential interactions including thresholds
for such effects [177].
Finally, the impact of synthetic pesticides, due in particular to an excessive use (including
environmental pollution and implications to human health) have led to modifications in agricultural
practices and various national and international regulations limiting their use. Further limitations
and/or bans should be sought, along with alternative solutions that are safer and non-toxic to the
environment and humans. One such alternative is so called ―natural pesticides‖ that are not
synthetically produced, but are derived from nature such as botanicals pesticides (pyrethrum, limonene,
and many others), microbial/biological agents (microbes, parasites) and inorganic minerals (boric acid,
limestone, diatomaceous earth). These solutions are generally assumed to be less toxic for human
health than synthetic pesticides and could represent an interesting alternative. But their usefulness is
actually questionable because some such pesticides are not potent enough to control pests but at the
same time do exhibit adverse effects for human health (i.e. ―natural pyrethroids). Further studies are
needed on the occurrence, fate and impact of such pesticides on the ecosystem and public health.
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... These strong positive correlations found between the OCPs studied indicate eventual interactions between them. This can probably indicate increase in their toxic effects in children even at a low environmental level of exposure [46][47][48][49][50][51][52][53][54][55][56]. Meanwhile in urine only mirex-dieldrin (0.725) and lindane-DDT (0.787) showed strong correlations. ...
... The linear regression provides important information on association between the OCPs variables in the two media (i.e., blood and urine). The extent of association is measured on a scale 1 (perfect positive relationship), 0 (no relationship) and -1 (perfect negative relationship) [56][57][58][59][60]. The regression, although positive is poorly linear with r values less than 0.5 except for DDT. ...
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... (1) Indiscriminate use of this herbicide may harm the environment as well as animal and human health (2) due to increased exposure via contaminated soil, water and food. (3) Glyphosate-based herbicides (GBH) are the most commonly used pesticides worldwide. Herbicides such as GBH account for approximately 45% of pesticides used in Brazilian agriculture. ...
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... To begin, pesticides are divided into categories based on their pest targets, such as fungicides, insecticides, herbicides, and rodenticides. Fungicides, for example, are used to kill fungus, insecticides to kill insects, and herbicides to destroy weeds (Amaral, 2014;Mnif et al., 2011). Pesticides are divided into organic and inorganic compounds in terms of chemical classifications. ...
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Pesticides are applied to protect crops from insects, weeds, and bacterial or fungal diseases during the growth. There would be a 78 percent loss of fruit output, a 54 percent loss of vegetable production, and a 32 percent loss of cereal production if pesticides were not used. When pesticides are applied to a target plant, they have the potential to enter the environment where they can affect non target organisms. Concerns have also been raised about pesticide currently uses and its impact on the environment with the possibility for hazardous or carcinogenic residues. This review paper provides basic information about the general types of pesticide in use and the role of pesticides in agriculture with its impact in environmental components.
... An unknown number of less serious health effects would add to the overall disease burden, while precise estimation of these effects requires future epidemiological studies. Children, pregnant women, aging populations, and workers directly exposed to pesticides are at higher risk of being affected by pesticides and their related diseases [14,130,131]. ...
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Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.
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Xenoestrogens can mimic or antagonize the activity of physiological estrogens, and the suggested mechanism of xenoestrogen action involves binding to estrogen receptors (ERs). However, the failure of various in vitro or in vivo assays to show strong genomic activity of xenoestrogens compared with estradiol (E2) makes it difficult to explain their ability to cause abnormalities in animal (and perhaps human) reproductive functions via this pathway of steroid action. E2 has also been shown to initiate rapid intracellular signaling, such as changes in levels of intracellular calcium, cAMP, and nitric oxide, and activations of a variety of kinases, via action at the membrane. In this study, we demonstrate that several xenoestrogens can rapidly activate extracellular-regulated kinases (ERKs) in the pituitary tumor cell line GH3/B6/F10, which expresses high levels of the membrane receptor for ER-α(mER). We tested a phytoestrogen (coumestrol), organochlorine pesticides or their metabolites (endosulfan, dieldrin, and DDE), and detergent by-products of plastics manufacturing (p-nonylphenol and bisphenol A). These xenoestrogens (except bisphenol A) produced rapid (3–30 min after application), concentration (10−14–10−8 M)-dependent ERK-1/2 phosphorylation but with distinctly different activation patterns. To identify signaling pathways involved in ERK activation, we used specific inhibitors of ERs, epidermal growth factor receptors, Ca2+ signaling, Src and phosphoinositide-3 kinases, and a membrane structure disruption agent. Multiple inhibitors blocked ERK activation, suggesting simultaneous use of multiple pathways and complex signaling web interactions. However, inhibitors differentially affected each xenoestrogen response examined. These actions may help to explain the distinct abilities of xenoestrogens to disrupt reproductive functions at low concentrations.
Article
Imposex (male genitalia imposed on females) in shoreline whelks and other Neogastropod molluscs is reported here from S.E. Asia (Singapore, Malyasia and Indonesia). In Singapore imposex occurred at all sites where females were available. In remote Ambon Bay, Indonesia, imposex also occurred widely, and was particularly severe in two harbours for high seas and inter-island vessels. There was a low incidence of imposex near Port Dickson, a small port in Malaysia. As whelk imposex occurs widely in North Atlantic and Pacific Oceans, we conclude that it is now global not just regionally localized. From the association of Neogastropod imposex with tributyltin (TBT) contamination derived from boat and ship anti-fouling paints, it follows that TBT contamination and its human consequences should be considered a contemporary global threat. We present here an imposex survey protocol for Neogastropod species in general. This should facilitate testing in new regions with new species, and indicate where chemical measures for TBT contamination are needed.