carcinogenicity and mutagenicity of malathion and its two
TRANSCRIPT
3273DOI: 10.1590/1413-81232020258.10672018
re
vie
w
Carcinogenicity and mutagenicity of malathion and its two analogues: a systematic review
Abstract Malathion has been widely used world-wide in arbovirus control programs. In 2015, it was classified by the International Agency for Research on Cancer (IARC) as a probable carcin-ogen to humans. This work aimed to systematize the evidence of the carcinogenic and mutagenic effects associated with the exposure of malathion and its analogs, malaoxon and isomalathion. The search was carried out in Toxline, PubMed and Scopus databases for original papers published from 1983 to 2015. In all, 73 papers were selected from a total of 273 eligible papers. The results of in vitro and in vivo studies showed mainly genetic and chromosomal damages caused by malathion. The epidemiological studies evidenced significant positive associations for thyroid, breast, and ovar-ian cancers in menopausal women. This evidence of the carcinogenic effect of malathion should be considered before its use in arbovirus control pro-grams.Key words Malathion, Carcinogenicity Tests, Mutagenicity Tests, Environmental Health
Priscilla Luna Bastos (https://orcid.org/0000-0001-5787-1542) 1
Alyne Fernanda Tôrres de Lima Bastos (https://orcid.org/0000-0001-9485-4776) 1
Aline do Monte Gurgel (https://orcid.org/0000-0002-5981-3597) 2
Idê Gomes Dantas Gurgel (https://orcid.org/0000-0002-2958-683X) 2
1 Secretaria Estadual de Saúde de Pernambuco. R. Dona Maria Augusta Nogueira 519, Bongi. 50751-530 Recife PE Brasil. [email protected] Instituto Aggeu Magalhães, Fundação Oswaldo Cruz. Recife PE Brasil.
3274B
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introduction
Pesticides are chemical compounds used exten-sively in agriculture, for the chemical control of spontaneous species in urban environment and vectors, in public health campaigns1 and are a danger to humans and nature2. Among the wi-dely used is the group of organophosphates (OP), which are irreversible inhibitors of ace-tylcholinesterase (AChE), active in all animal groups that use acetylcholine as a neurotrans-mitter3. The consequent accumulation of this molecule in the body causes toxic effects on the different systems of exposed living beings, such as muscular, nervous, immune and endocrine alterations4-7. Among its possible chronic effects, characterized by late onset, are irreversible dama-ges, such as paralysis and neoplasms8.
In Brazil, with the exponential growth of the dengue epidemic in 2015, when more than 1 million cases were confirmed9, and with the onset of Chikungunya fever (in 2014) and the Zika vi-rus epidemic (in 2015), with consequences even more harmful to the population, a review of the National Aedes aegypti (transmitter mosquito) Control Program was requested, with the inten-sified use of larvicides and adulticides for this mosquito, going back to the 2014 guidelines re-garding the use of UBV spraying with Malathion at 30% diluted in water for the whole national territory10. This was criticized by the Brazilian Association of Public Health, which issued a te-chnical note warning of the dangers to health and the environment11.
Malathion (diethyl (dimethoxythiophos-phorylthio) succinate) is an OP used in various food crops for the control of unwanted species and is often used in insect control12, as a com-mercial or technical quality product containing approximately 90-95% of the product in weight and may contain up to twelve impurities formed during manufacture and storage13. Among the relevant impurities are malaoxon and isomala-thion, produced by oxidation14 and the chemical or thermal isomerization of malathion, respecti-vely15.
Its mutagenic capacity and potential carci-nogenic effect have been discussed16-18. However, despite widespread use, there are surprisingly few studies on the association of malathion and cancer, most of them in North America, others in Europe, while very few have been conducted in less industrialized countries where exposure is likely to be much higher19. Some authors point out their findings as something of concern since
malathion has shown high levels of carcinogenic activity, as well as chemical properties that bring it closer to other notably carcinogenic substances such as aflatoxin and benzopyrene20.
In the 1980s, malathion was considered and evaluated by the International Agency for Rese-arch on Cancer (IARC) Working Group as not classifiable as to its carcinogenicity to humans (Group 3)21,22 because it concluded that there was insufficient evidence for the carcinogenicity of malathion or its metabolite malaoxon in experi-mental animals, and data for humans were not available at the time. However, in 2015, IARC pu-blished a new document, classifying the pesticide as a probable human carcinogen (Group 2A)19.
In view of the widespread use of malathion as a pesticide worldwide, both in agriculture and public health, and in view of the risks that it can bring, this work aimed to systematize the evi-dence of the carcinogenic and mutagenic effects associated with the exposure of this organophos-phate pesticide and its analogues (malaoxon and isomalathion).
Methods
Search data
A systematic review of the literature was per-formed by searching scientific papers published between 1983 and 2015. The year 1983 was cho-sen as the starting point of the research, since the IARC21 monograph published in that year consi-dered malathion as “not classifiable as to its car-cinogenicity to humans (Group 3)”, concluding that there was insufficient evidence for the car-cinogenicity of malathion or its metabolite ma-laoxon in animal experiments, and there were no data regarding humans.
The search was performed in the electronic databases Scopus, PubMed and Toxline (in the latter the results of PubMed were excluded), and two command groups were employed. The first, consisting of terms related to the exposure of in-terest (malathion, malaoxon and isomalathion), and the second containing terms related to the outcome of interest (cancer, carcinogenicity tests, carcinogens, neoplasms, mutagenesis, mutagenici-ty tests and mutagens). A query was made in the Medical Subject Headings (MeSH) to select the descriptors/terms used. Boolean operator “OR” was used for the combination of the terms in each group, and “AND” operator was used for the combination between the groups.
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Selection of papers
We selected original studies that showed re-sults on the carcinogenic or mutagenic effect of malathion, malaoxon and isomalathion in living beings. Review papers, dissertations and theses identified in the search were excluded. English, Portuguese and Spanish manuscripts were con-sidered.
The papers were selected by the researchers (authors of this paper) in two stages. In the first one, two researchers read separately the title and summary of the papers for the selection of tho-se that should be the basis of the research. Those without an abstract or insufficient information to make a decision were kept into the next step. Cases of disagreement were resolved by a third researcher.
In the second step, all papers selected that met the inclusion/exclusion criteria and those with insufficient information for decision-making were analyzed in their entirety. As in the previous stage, the data of both reviewers were again con-fronted, and the differences were solved by the third reviewer.
The selected manuscripts were analyzed for the extraction of the following data: authors, year of publication, journal, study design, target population, country of study population (in epi-demiological studies), exposure (malathion, ma-laoxon, isomalathion, mixed exposure) and main results identified regarding the carcinogenic and mutagenic effect of malathion, malaoxon and isomalathion.
Search was performed between July 4 and 12, 2016. Filters were used to select the languages and the period of publication of the manuscripts in the three databases.
results and discussion
Search returned 178 results in Scopus, 147 in PubMed and 92 in Toxline, totaling 417 papers (Figure 1). A total of 142 duplications were iden-tified, as well as two papers published in other languages (German and Chinese), leaving out 273 papers for eligibility evaluation.
After applying the inclusion and exclusion criteria and the two-step evaluation, 73 papers were included in this study, all in English. Of these, 24 correspond to in vitro experimental studies, including mutagenicity tests and cell cul-tures of both animals and human beings; 24 in vivo experimental studies, including mice, rats,
hamsters, birds, frogs and flies; 25 epidemiologi-cal studies, including cohorts, case-controls and cross-sectional studies (two of them with in vitro experiments as well). The results found in the in vitro experimental studies that evaluated the car-cinogenic or mutagenic effect of malathion and its analogs are summarized in Chart 1.
Three studies have shown significant in-creases in the DNA damage of rat peripheral blood lymphocytes following exposure to ma-lathion1,18,26. Higher frequencies of chromoso-mal changes in bone marrow cells of mice in a dose-dependent manner to malathion were also observed26. Besides observing the significant re-duction of cell viability and the significant incre-ase of breaks in both single and double strand DNA, Ojha and Gupta18 verified the formation of DPC, in time- and dose-dependent fashion after exposure of rats’ lymphocytes to malathion both individually and mixed with two other orga-nophosphates (Chlorpyrifos and Parathion-Me-thyl) when compared to the control. Since DPCs correspond to toxic lesions associated with the toxicity mechanism (s) of carcinogenic compou-nds45, the study shows the carcinogenic effect of malathion. The research further concludes that malathion, along with the other pesticides of the study, should generate oxidative lesions of DNA base pairs, with a genotoxic potential to alter en-zyme expression.
In cultures of human peripheral blood lym-phocytes exposed to malathion, results showed dose-dependent increase of chromosomal chan-ges and sister chromatid exchanges37,39, as well as the alkylating effect of DNA-specific nucle-otides34. No significant changes were observed in the DNA damage of these same cells32 when malathion was evaluated in comparison to its two analogs, unlike malaoxon and isomalathion, which induced DNA damage in a dose-depen-dent fashion. The study by Blasiak et al.32 was the only one to evaluate the three chemical agents in the same study and concluded that the damages caused to the DNA by malaoxon are more pro-nounced than those caused by isomalathion.
Josse et al.23 evaluated the effects of mala-thion and isomalathion individually and com-bined on the human liver HepaRG cell line and showed that, although isomalathion was much more cytotoxic than malathion, both substances showed similar mutagenic effects in these hepa-tocytes. On the other hand, Błasiak and Trzeciak33 claim that DNA damage to human lymphocytes is caused by isomalathion and not by its original compound.
3276B
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Figure 1. Flow chart illustrating the papers that were included and excluded in the systematic review, with reasons for exclusion.
Source: Elaborated by the authors.
178 papers in SCOPUS 92 papers in Toxline147 papers in PubMed
275 papers after excluding repeated papers
142 repeated papers
2 repeated papers in other languages
273 papers selected for eligibility
170 excluded
79 non-originals
91 did not evaluate the carcinogenic/mutagenic
effect of malathion/malaoxon/isomalathion
103 papers selected for full-text reading
73 papers included in the work
27 excluded
3 papers with no access
24 experimental in vitro
24 experimental in vivo
23 epidemiological
2 epidemiol. + exp. in vitro
1st step
2st step
The results are somewhat contradictory re-garding malaoxon exposure. Blasiak and Kowa-lik31 found that malaoxon promoted a significant increase in the level of DNA damage in human peripheral blood lymphocytes in the Comet As-say, and was higher with increasing dose, while in the human lineage choriocarcinoma cell (JAR) assay (model acceptable for human placental cells), malathion, and not the same agent, was found to be responsible for the cytotoxic and genotoxic effects in these cells in vitro. Authors argue that metabolites of pesticides with contra-dictory results regarding their carcinogenic po-tential should be studied, since they may repre-sent the true carcinogens46.
Malathion has also been evaluated in gene mutation tests that employ bacteria, such as the Salmonella lactam test (genotoxin detection method)35, phage-MicroScreen (a miniaturized system that uses the induction of prophylaxis in Escherichia coli X as an indicator of genetic da-mage)41 and the Ames Salmonella test40. In the three studies found, the results were negative for the mutagenic activity of malathion, and no mu-tagenic activities of malathion were observed in
the last test before or after activation of the rat liver S9 fraction in the respective non-toxic do-ses (33 mg/L) and 90% toxic (1650mg/L). In a literature review, Flessel et al.47 also observed the same results and concluded that malathion does not appear to induce timely mutations in DNA in bacterial systems.
Of the 24 in vivo experimental studies fou-nd in this systematic review, twenty performed the experiments on rats, mice or hamsters, while the others evaluated the effects of the pesticide on birds, frog and flies. Chart 2 shows the main results of these studies.
In 1984, Degraeve et al.70 reported that Dy-nafos and Phosan Plus, insecticides containing malathion in their composition, did not indu-ce chromosomal changes in bone marrow cells, spermatogonia or primary spermatocytes, nor alterations in the dominant lethal mutation assay, after intraperitoneal injection of rats of strain Q. However, the study has no data regarding impu-rities, solvents, emulsions and the like in these compounds, which shows its limitation.
In the same year, these authors exposed rats from the same strain to malathion at 99% purity
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Ch
art 1
. Syn
thes
is o
f in
vit
ro s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
, iso
mal
ath
ion
an
d m
alao
xon
wit
h t
he
carc
inog
enic
or
mu
tage
nic
eff
ects
.
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Ojh
a e
Gu
pta,
20
1518
Hu
m E
xp
Toxi
col
Wis
tar
adu
lt m
ale
albi
no
rats
(R
attu
s n
orve
gicu
s)M
alat
hio
n, C
hlo
rpyr
ifos
, M
ethy
l par
ath
ion
(in
divi
dual
ly
and
mix
ed)
Th
e 8h
an
d 12
h e
xpos
ure
of
rat
lym
phoc
ytes
wit
h 1
/10
and
1/4
DL5
0 m
alat
hio
n (
MLT
) ca
use
d a
sign
ifica
nt
(p<
0.05
) le
vel o
f D
NA
dam
age
(dou
ble
DN
A s
tran
d br
eaks
, DSB
s, a
nd
sim
ple
DN
A s
tran
d br
eaks
, SSB
s). T
he
form
atio
n o
f D
NA
-pro
tein
cro
ss-l
inks
(D
PC
), in
tim
e an
d do
se-d
epen
den
t po
st e
xpos
ure
to t
he
MLT
, in
divi
dual
ly a
nd
mix
ed, w
as e
stab
lish
ed in
in
vitr
o co
ndi
tion
s as
com
pare
d to
th
e co
ntr
ol.
Ojh
a e
Sriv
asta
va,
2014
1
Mu
tat
Res
Gen
et
Toxi
col
Env
iron
M
uta
gen
Wis
tar
rats
(p
erip
her
al b
lood
ly
mph
ocyt
es)
Hyd
roge
n p
erox
ide,
C
hlo
rpyr
ifos
, Met
hyl p
arat
hio
n
and
mal
ath
ion
(in
divi
dual
ly
and
mix
ed)
In v
itro
exp
osu
re o
f m
alat
hio
n r
at ly
mph
ocyt
es in
divi
dual
ly o
r m
ixed
for
2h a
nd
4h c
ause
d a
sign
ifica
nt
incr
ease
in D
NA
dam
age
as e
vide
nce
d by
th
e C
omet
ass
ay w
ith
dos
e-de
pen
den
t in
crea
se o
f %
of
tail
DN
A, t
ail l
engt
h a
nd
tail
mom
entu
m. O
Ps in
duce
d ox
idat
ive
stre
ss in
ra
t p
erip
her
al b
lood
lym
phoc
ytes
, res
pon
sibl
e fo
r D
NA
oxi
dati
on.
Joss
e et
al.,
20
1423
Ch
em B
iol
Inte
ract
Hu
man
hep
atic
Hep
aRG
cel
l lin
eM
alat
hio
n a
nd
isom
alat
hio
n,
indi
vidu
ally
an
d co
mbi
ned
Mal
athi
on a
nd
isom
alat
hion
alo
ne
or in
com
bin
atio
n in
duce
d th
e fo
rmat
ion
of
mic
ronu
clei
at
low
con
cen
trat
ion
s an
d ha
d ad
diti
ve g
enot
oxic
eff
ects
whe
n c
ombi
ned
at 2
5 μM
. Iso
mal
athi
on
indi
vidu
ally
or
com
bin
ed d
irec
tly
inhi
bite
d th
e ac
tivi
ty o
f ca
rbox
yles
tera
ses
(inv
olve
d in
m
alat
hion
det
oxifi
cati
on).
Iso
mal
athi
on w
as m
uch
mor
e cy
toto
xic
than
mal
athi
on. B
oth
com
poun
ds h
ad c
ompa
rabl
e ge
not
oxic
eff
ects
on
Hep
aRG
hep
atoc
ytes
at l
ow c
once
ntr
atio
ns.
An
jum
e
Mal
ik, 2
01324
Env
iron
To
xico
l P
har
mac
ol
S. t
yph
imu
riu
m s
trai
ns
TA97
a, T
A98
, TA
100,
TA
102
and
TA10
4 an
d m
uta
nts
of
E.
coli
linea
ge K
-12.
Mal
ath
ion
lin
dan
e, a
lph
a-en
dosu
lfan
, Ch
lorp
yrif
os,
mon
ocro
toph
os a
nd
dim
eth
oate
(m
ixed
)
Th
e te
st s
ampl
es p
refe
ren
tial
ly a
ct o
n t
he
base
pai
r m
uta
nts
GC
(pl
otti
ng)
com
pare
d to
th
ose
wit
h A
T b
ase
pair
s at
th
e m
uta
tion
sit
e an
d al
so in
itia
te t
he
indu
cibl
e er
ror-
pron
e SO
S re
spon
se in
th
e m
uta
nt
E. c
oli w
ater
ext
ract
s. T
he
mu
tage
nic
eff
ect
of t
he
test
sam
ples
wou
ld
evid
entl
y re
pres
ent
a ri
sk o
f n
eopl
asti
c tr
ansf
orm
atio
n in
hu
man
s.
Gal
ánta
i et
al.,
2011
25
J E
nvir
on
Sci H
ealt
h B
Hu
man
lin
eage
of
chor
ioca
rcin
oma
cells
(JA
R)
(mod
el a
ccep
tabl
e fo
r hu
man
pl
acen
ta c
ells
)
Mal
ath
ion
an
d m
alao
xon
Mal
ath
ion
is r
espo
nsi
ble
for
the
cyto
toxi
c an
d ge
not
oxic
eff
ects
obs
erve
d in
vit
ro. T
he
resu
lts
sugg
est
that
mal
ath
ion
may
exe
rt c
ytot
oxic
an
d ge
not
oxic
eff
ects
on
pla
cen
tal c
ells
as
wel
l as
oth
er b
iolo
gica
l sys
tem
s.
Moo
re e
t al
., 20
1126
Mu
tat
Res
Gen
et
Toxi
col
Env
iron
M
uta
gen
Bon
e m
arro
w a
nd
per
iph
eral
bl
ood
cells
from
mal
e ra
ts o
f th
e Sp
ragu
e-D
awle
y st
rain
.
Mal
ath
ion
(98
,2%
of
puri
ty)
Th
e fr
equ
enci
es o
f ch
rom
osom
al c
han
ges
in b
one
mar
row
cel
l ass
ays
incr
ease
d w
ith
in
crea
sin
g do
se o
f m
alat
hio
n. A
ll do
ses
of m
alat
hio
n in
duce
d a
sign
ifica
nt
incr
ease
in
mea
n p
erce
nta
ges
of D
NA
dam
age
(fro
m 4
2 ±
0.8
4 to
86.
5 ±
0.5
7%)
in p
erip
her
al b
lood
ly
mph
ocyt
es t
reat
ed w
ith
mal
ath
ion
com
pare
d to
on
ly 1
3.5
± 0
.2 %
in c
ontr
ol c
ells
. it c
onti
nu
es
3278B
asto
s P
L et
al.
Ch
art 1
. Syn
thes
is o
f in
vit
ro s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
, iso
mal
ath
ion
an
d m
alao
xon
wit
h t
he
carc
inog
enic
or
mu
tage
nic
eff
ects
.
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Jose
et
al.,
2010
27
Mar
E
nvir
on R
esPe
nae
us
mon
odon
(gi
ant
tige
r sh
rim
p) h
emoc
ytes
Mal
ath
ion
(50
%w
/w,
com
erci
al p
repa
rati
on)
and
mon
ocro
toph
os
(org
anop
hos
phat
es),
cad
miu
m
chlo
ride
an
d m
ercu
ry c
hlo
ride
(h
eavy
met
als)
All
the
pollu
tan
ts te
sted
indu
ced
DN
A c
hain
bre
aks
and,
thu
s, c
omet
s in
the
hem
ocyt
es
(Com
et A
ssay
). P
erce
nta
ge o
f ta
iled
cells
was
sig
nifi
can
tly
high
er (
P<
0.05
) th
an t
he C
ontr
ol
for
the
fou
r po
lluta
nts
, in
clu
din
g m
alat
hion
(>
60%
). I
n t
his
stu
dy, m
alat
hion
pro
ved
to b
e ge
not
oxic
to t
he c
ult
ure
of
P. m
onod
on h
emoc
ytes
.
Moo
re e
t al
., 20
1028
Env
iron
To
xico
lH
um
an h
epat
ic c
arci
nom
a ce
lls (
Hep
G2)
Mal
ath
ion
(98
,2%
of
puri
ty)
Mal
ath
ion
indu
ced
a gr
adu
al in
crea
se o
f D
NA
dam
age
in H
epG
2 ce
lls w
ith
incr
easi
ng
con
cen
trat
ion
. Aft
er 4
8 h
ours
of
expo
sure
, th
e m
ean
per
cen
tage
s of
DN
A d
amag
e su
gges
t th
at m
alat
hio
n a
cts
as a
gen
otox
ic c
omp
oun
d es
pec
ially
at
the
hig
hes
t ex
pos
ure
leve
l.
Cal
af e
t al
., 20
0929
Int
J O
nco
lM
CF-
10F
imm
orta
lized
hu
man
bre
ast
epit
hel
ial c
ell
lines
Mal
ath
ion
an
d et
hyl p
arat
hio
n
indi
vidu
ally
an
d co
mbi
ned
wit
h
estr
ogen
.
Mal
ath
ion
an
d et
hyl p
arat
hio
n in
duce
d m
alig
nan
t tr
ansf
orm
atio
n o
f br
east
cel
ls t
hro
ugh
ge
nom
ic in
stab
ility
in t
he
p53
supp
ress
or g
ene
and
the
c-H
a-ra
s on
coge
ne,
con
side
red
to b
e fu
nda
men
tal i
n t
he
can
cer
proc
ess.
Cal
af e
Roy
, 20
0830
Int
J M
ol
Med
Hu
man
bre
ast
epit
hel
ial c
ells
Mal
ath
ion
, eth
yl p
arat
hio
n a
nd
17ß
est
radi
ol (
indi
vidu
ally
an
d co
mbi
ned
)
The
est
roge
n co
mbi
ned
wit
h bo
th m
alat
hion
and
eth
yl p
arat
hion
alte
red
cell
prol
ifera
tion
and
in
duce
d ce
ll tr
ansf
orm
atio
n, a
s w
ell a
s ex
hibi
ted
sign
ifica
nt in
vasi
ve a
bilit
ies
com
pare
d to
the
MC
F-10
F co
ntro
l cel
l lin
e. S
ever
al g
enes
wer
e up
-reg
ulat
ed b
y th
e ef
fect
s of
all
trea
tmen
ts, s
uch
as
cycl
ins,
cyc
lin D
1 an
d cy
clin
-dep
ende
nt k
inas
e 4,
IG
FBP3
and
IG
FBP5
, and
ker
atin
18.
The
c-H
a-ra
s on
coge
ne w
as r
egul
ated
by
the
effe
ct o
f mal
athi
on a
lone
and
a c
ombi
nati
on o
f est
roge
n w
ith
both
mal
athi
on a
nd e
thyl
par
athi
on. T
he D
VL1
gen
e w
as u
p-re
gula
ted
only
wit
h m
alat
hion
alo
ne
and
wit
h th
e co
mbi
nati
on o
f eth
yl p
arat
hion
and
est
roge
n. E
xpre
ssio
n of
HSP
27,
MC
M2
and
TP5
3 in
duci
ble
prot
ein
3 ge
nes
was
up-
regu
late
d w
ith
mal
athi
on a
lone
and
wit
h th
e co
mbi
nati
on
of e
stro
gen
and
mal
athi
on o
r et
hyl p
arat
hion
whi
le T
P53
(Li-
Frau
men
i syn
drom
e) w
as r
egul
ated
by
est
roge
n al
one
and
mal
athi
on a
lone
. An
indu
ctio
n of
mol
ecul
ar c
hang
es in
dica
tive
of
tran
sfor
mat
ion
occu
rred
.
Bła
siak
e
Kow
alik
, 19
9931
Pest
ic
Bio
chem
P
hysi
ol
Hu
man
per
iph
eral
blo
od
lym
phoc
ytes
Mal
aoxo
n a
nd
sodi
um
as
corb
ate
Mal
aoxo
n s
ign
ifica
ntl
y in
crea
sed
the
tail
mom
entu
m (
Com
et A
ssay
an
alys
is)
of ly
mph
ocyt
es
in a
dos
e-de
pen
den
t man
ner
. At t
he h
ighe
st c
once
ntr
atio
n o
f th
e ch
emic
al, t
hat i
s, 2
00 μ
M,
the
incr
ease
d ta
il m
omen
tum
was
sev
en t
imes
hig
her
than
the
init
ial v
alue
(19
.49
± 3
.40
μm
vers
us 2
.61
± 0
.22
μm, P
<0.
001)
. The
hig
her
con
cen
trat
ion
of
mal
aoxo
n c
ause
d an
incr
ease
d fr
acti
on o
f ly
mph
ocyt
es w
ith
grea
ter
tail
mom
entu
ms
of th
e co
met
in c
ompa
riso
n w
ith
that
of
the
con
trol
not
exp
osed
. The
se c
omet
s co
nta
in m
ore
DN
A in
thei
r ta
ils, w
hich
indi
cate
s a
grea
ter
exte
nt o
f D
NA
dam
age
in th
ese
cells
.
it c
onti
nu
es
3279C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
Ch
art 1
. Syn
thes
is o
f in
vit
ro s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
, iso
mal
ath
ion
an
d m
alao
xon
wit
h t
he
carc
inog
enic
or
mu
tage
nic
eff
ects
.
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Bła
siak
et
al.,
1999
32
Mu
tat
Res
Hu
man
per
iph
eral
blo
od
lym
phoc
ytes
Mal
ath
ion
, mal
aoxo
n a
nd
isom
alat
hio
n (
all w
ith
pu
rity
of
at le
ast
99.8
%)
Mal
ath
ion
did
not
cau
se s
ign
ifica
nt
chan
ges
in ly
mph
ocyt
e co
met
len
gth
at
the
con
cen
trat
ion
s te
sted
. Mal
aoxo
n, a
t it
s h
igh
est
con
cen
trat
ion
(20
0 m
M),
pro
duce
d se
vere
ly
dam
aged
cel
ls b
y pr
omot
ing
com
ets
wit
h a
lmos
t al
l of
the
DN
A in
th
e ta
il. T
his
res
ult
ed
in c
omet
len
gth
s ex
ceed
ing
mor
e th
an t
wic
e th
e co
met
len
gth
of
con
trol
lym
phoc
ytes
(p
<0.
001)
. Iso
mal
ath
ion
pro
mot
ed a
n in
crea
sed
com
et le
ngt
h, b
ut
the
chan
ges
wer
e n
ot a
s m
arke
d as
in t
he
case
of
mal
aoxo
n -
at
the
con
cen
trat
ion
of
200
mM
, th
e in
crea
sed
com
et
len
gth
was
72%
in c
ompa
riso
n w
ith
con
trol
. Mal
aoxo
n a
nd
isom
alat
hio
n in
trod
uce
d D
NA
da
mag
e in
a d
ose-
dep
ende
nt
man
ner
. Th
e ef
fect
indu
ced
by m
alao
xon
was
mor
e pr
onou
nce
d th
an t
hat
cau
sed
by is
omal
ath
ion
. Com
ets
resu
ltin
g fr
om ly
mph
ocyt
es e
xpos
ed to
mal
aoxo
n
and
isom
alat
hio
n h
ave
lon
ger
tails
, th
eref
ore,
th
ey c
onta
in m
ore
DN
A in
th
eir
tails
th
an
com
ets
resu
ltin
g fr
om c
ontr
ol ly
mph
ocyt
es a
nd
lym
phoc
ytes
exp
osed
to m
alat
hio
n.
Bła
siak
e
Trze
ciak
, 19
9833
Pol J
E
nvir
on
Stu
d
Hu
man
per
iph
eral
blo
od
lym
phoc
ytes
Mal
ath
ion
an
d is
omal
ath
ion
(b
oth
wit
h p
uri
ty o
f at
leas
t 99
.8%
)
The
com
ets
resu
ltin
g fr
om e
xpos
ure
to m
alat
hion
did
not
dif
fer
from
thos
e of
con
trol
s.
Reg
ardi
ng
the
aver
age
com
et le
ngt
hs fo
r ly
mph
ocyt
es e
xpos
ed fo
r 1h
to m
alat
hion
an
d is
omal
athi
on, i
n c
ompa
riso
n w
ith
the
con
trol
s, it
can
be
obse
rved
that
the
mal
athi
on, a
t the
ap
plie
d co
nce
ntr
atio
ns,
did
not
hav
e a
sign
ifica
nt e
ffec
t on
the
mig
rati
on o
f th
e D
NA
to th
e ta
il of
the
com
et. O
n th
e ot
her
han
d, is
omal
athi
on c
ause
d an
incr
ease
d co
met
len
gth
- in
the
con
cen
trat
ion
of
200
μM, t
he in
crea
se w
as 7
2% in
com
pari
son
wit
h th
e co
ntr
ol. T
he in
crea
se
was
dos
e-de
pen
den
t. C
omet
s re
sult
ing
from
lym
phoc
ytes
exp
osed
to is
omal
athi
on h
ad m
ore
DN
A in
the
tail
than
thos
e re
sult
ing
from
con
trol
lym
phoc
ytes
an
d ly
mph
ocyt
es e
xpos
ed to
m
alat
hion
. The
dat
a pr
esen
ted
indi
cate
d th
at is
omal
athi
on, u
nlik
e m
alat
hion
, can
dam
age
the
DN
A o
f hu
man
lym
phoc
ytes
isol
ated
from
per
iphe
ral b
lood
.
Plu
th e
t al
., 19
9834
Mu
tat
Res
Hu
man
per
iph
eral
blo
od
lym
phoc
ytes
Mal
ath
ion
Mu
tati
ons
at s
ever
al b
ase
pair
sit
es w
ere
freq
uen
t af
ter
exp
osu
re to
mal
ath
ion
an
d w
ere
isol
ated
from
tre
ated
cel
ls fr
om a
t le
ast
two
diff
eren
t in
divi
dual
s. U
sin
g a
hum
an h
prt
mu
tati
on d
atab
ase
for
com
pari
son
, th
e fr
equ
ency
of
mu
tati
ons
at o
ne
of s
aid
base
pai
r si
tes
134
was
fou
nd
to b
e si
gnifi
can
tly
elev
ated
in m
alat
hio
n t
reat
ed c
ells
(p<
0.00
05).
H
prt
mu
tati
ons
in m
alat
hio
n-t
reat
ed c
ells
aro
se p
refe
ren
tial
ly in
G: C
bas
e pa
irs,
wh
ich
is
con
sist
ent
wit
h p
revi
ous
repo
rts
that
mal
ath
ion
is a
n a
lkyl
atin
g of
gu
anin
e n
ucl
eoti
des.
Hou
r et
al.,
19
9835
Mu
tage
nes
isSa
lmon
ella
typ
him
un
um
(J
K3
and
JK94
7) s
trai
ns
14 p
esti
cide
s, in
clu
din
g m
alat
hio
nM
alat
hio
n, a
mon
g se
ven
oth
er p
esti
cide
s, w
as n
ot m
uta
gen
ic in
th
e JK
947
and
JK3
stra
ins
in
the
Salm
onel
la la
ctam
test
(ge
not
oxin
det
ecti
on m
eth
od).
it c
onti
nu
es
3280B
asto
s P
L et
al.
Ch
art 1
. Syn
thes
is o
f in
vit
ro s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
, iso
mal
ath
ion
an
d m
alao
xon
wit
h t
he
carc
inog
enic
or
mu
tage
nic
eff
ects
.
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Gu
pta
et a
l.,
1996
36
Asi
an-
Au
stra
las
J A
nim
Sci
Goa
t p
erip
her
al b
lood
ly
mph
ocyt
esM
alat
hio
n (
MW
330
) an
d pa
rath
ion
indi
vidu
ally
A s
tati
stic
ally
sig
nifi
can
t in
crea
se (
p≤0.
05)
in t
he
freq
uen
cy o
f ch
rom
osom
al a
lter
atio
ns
of
the
lym
phoc
ytes
tre
ated
wit
h 1
00 μ
g/m
l of
mal
ath
ion
(9.
5%)
com
pare
d to
con
trol
(5.
5%)
was
obs
erve
d. A
t h
igh
dos
es (
150
and
200
μg/m
l), t
he
freq
uen
cies
of
indu
ced
chan
ges
wer
e h
igh
ly s
ign
ifica
nt
(p≤0
.01)
. Th
e in
cide
nce
of
chro
mos
omal
bre
aks,
dic
entr
ic c
hro
mos
omes
an
d tr
ansl
ocat
ion
s w
ere
hig
her
th
an t
he
oth
er t
ypes
of
alte
rati
ons
fou
nd.
Bal
aji e
Sa
sika
la,
1993
37
Mu
tat
Res
Hu
man
per
iph
eral
blo
od
lym
phoc
ytes
Mal
ath
ion
The
res
ults
sho
w th
at m
alat
hion
cau
ses
a do
se-d
epen
den
t in
crea
se o
f ch
rom
osom
al c
han
ges
as
wel
l as
- SC
Es
in h
uman
leuk
ocyt
e cu
ltur
es. A
dos
e-de
pen
den
t dec
reas
e in
mit
otic
inde
x w
as
obse
rved
at a
ll co
nce
ntr
atio
ns
in th
is s
tudy
. Thu
s, th
e re
sult
s su
gges
t tha
t mal
athi
on is
a m
ild
mut
agen
an
d m
ay c
ause
gen
otox
icit
y in
hum
ans
at h
ighe
r co
nce
ntr
atio
ns.
Joh
nso
n,
1992
38
Env
iron
To
xico
l C
hem
Var
ian
ts, i
sola
ted
dark
m
uta
nts
, of
the
lum
ines
cen
t ba
cter
ium
Ph
otob
acte
riu
m
phos
phor
eum
.
Pro
gen
otox
ins,
gen
otox
ins,
n
on-g
enot
oxic
(co
ntr
ol g
rou
p,
incl
udi
ng
mal
ath
ion
) an
d so
lven
ts
Mal
ath
ion
an
d ot
her
4 n
on-g
enot
oxic
su
bsta
nce
s (c
arbo
hydr
ate,
di-
2-et
hylh
exyl
ph
thal
ate,
si
min
an
d p
erm
eth
rin
) di
d n
ot s
how
gen
otox
ic o
r cy
toto
xic
resp
onse
s at
test
dos
es o
f ≤
10
μg p
er t
ube
(da
ta n
ot s
how
n).
Gar
ry e
t al
., 19
9039
Tera
tog
Car
cin
og
Mu
tage
n
Hu
man
per
iph
eral
blo
od
lym
phoc
ytes
Mal
ath
ion
, car
bon
te
trac
hlo
ride
, car
bon
di
sulfi
de, m
ethy
l bro
mid
e an
d ch
loro
picr
in
Stat
isti
cally
sig
nifi
can
t (P
<0.
05)
dose
-dep
ende
nt
incr
ease
s in
SC
Es
wer
e ob
serv
ed in
hu
man
ly
mph
ocyt
es t
reat
ed w
ith
sh
ort-
term
mal
ath
ion
(1/
2 h
our)
. Dos
e-de
pen
den
t in
crea
ses
in
chro
mos
omal
abn
orm
alit
ies
wit
h o
r w
ith
out
acti
vati
on o
f th
e m
icro
som
al S
-9 fr
acti
on (
rat
liver
hom
ogen
ate)
wer
e al
so o
bser
ved.
Dic
entr
ic a
nd
tetr
arra
dial
figu
res
wer
e fo
un
d in
hig
h
dose
s of
th
e or
gan
oph
osph
ate.
Pedn
ekar
et
al.,
1987
40
Env
iron
C
onta
m
Toxi
col
Stra
ins
of t
he
test
er
Salm
onel
la T
yph
imu
riu
m T
A
97a,
TA
98
and
TA 1
00
Mal
ath
ion
an
d ph
osal
one
(org
anop
hos
phat
es),
en
dosu
lfan
(or
gan
och
lori
ne)
an
d p
erm
eth
rin
(py
reth
roid
)
No
mu
tage
nic
act
ivit
ies
of m
alat
hio
n w
ere
obse
rved
in t
he
resp
ecti
ve n
on-t
oxic
(33
mg/
L)
and
90%
toxi
c (1
,650
mg/
L) d
oses
, eit
her
bef
ore
or a
fter
th
e ac
tiva
tion
wit
h S
9 (p
ost-
mit
och
ondr
ial)
frac
tion
of
rat
liver
wit
h t
hre
e st
rain
s of
th
e te
ster
Sal
mon
ella
Typ
him
uri
um
TA
97a
, TA
98
and
TA 1
00, i
n t
he
Am
es S
alm
onel
la a
ssay
sys
tem
, nor
aft
er it
s ac
tiva
tion
wit
h
rat
ceca
l mic
robi
al e
xtra
ct in
th
e sa
me
syst
em.
it c
onti
nu
es
3281C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Hou
k e
DeM
arin
i, 19
8741
Mu
tat
Res
Stra
ins
of E
sch
eric
hia
col
i B/r
mal
ath
ion
(73
,5%
of
puri
ty),
m
onu
ron
, p,p
'-D
DT,
mir
ex,
linda
ne,
nit
roph
en, c
hlo
rdan
e,
toxa
phen
e, c
apta
n, a
nd
dich
lorv
os.
Mal
ath
ion
was
not
det
ecte
d by
th
e ph
age-
Mic
roSc
reen
indu
ctio
n a
ssay
(m
inia
turi
zed
syst
em
that
use
s pr
oph
age
indu
ctio
n in
Esc
her
ich
ia c
oli X
as
an in
dica
tor
of g
enet
ic d
amag
e)
Wia
derk
iew
icz
et a
l., 1
98642
Act
a B
ioch
im P
olC
alf
thym
us
DN
AM
alat
hio
n, D
DV
P,
Met
hyl p
arat
hio
n a
nd
met
hylb
rom
phen
vin
phos
All
the
stu
died
org
anop
hos
phat
e in
sect
icid
es r
eact
wit
h t
he
DN
A in
vit
ro c
ausi
ng
met
hyla
tion
of
nit
roge
nou
s ba
ses.
Th
e m
ethy
lati
on k
inet
ics
of p
uri
ne
base
s in
DN
A b
y [1
4C]
mal
ath
ion
sh
owed
th
at t
his
pro
cess
was
a b
it s
low
, rea
chin
g it
s m
axim
um
aft
er 9
6 h
ours
of
the
reac
tion
. Lon
ger
incu
bati
on d
id n
ot r
esu
lt in
a s
ign
ifica
nt
incr
ease
in t
he
nu
mbe
r of
alk
ylat
ed b
ases
(pr
obab
ly d
ue
to t
wo
com
pet
itio
n p
roce
sses
: add
itio
nal
DN
A
alky
lati
on a
nd
hydr
olyt
ic r
emov
al o
f al
kyla
ted
puri
ne
base
s fr
om t
he
pol
ynu
cleo
tide
ch
ain
).
Met
hylb
rom
phen
vin
phos
app
eare
d to
be
the
mos
t re
acti
ve o
rgan
oph
osph
ate
inse
ctic
ide,
fo
llow
ed b
y M
ethy
l par
ath
ion
an
d m
alat
hio
n.
Ma
et
al.1
98343
Env
iron
M
uta
gen
Pla
nt
stak
es o
f th
e Tr
ades
can
tia
clon
e 03
an
d 44
30
Mal
ath
ion
(M
alat
hio
n 5
, em
uls
ifier
, 55
% o
f ac
tive
in
gred
ien
t)
The
gen
otox
icit
y of
liqu
id m
alat
hion
(m
alat
hion
sol
utio
n/de
ioni
zed
wat
er)
abso
rbed
thro
ugh
the
stem
was
ver
y lo
w a
nd o
ften
mas
ked
by h
igh
toxi
city
, cau
sing
cel
l dea
th in
the
stem
, le
aves
and
myo
cyte
s. M
alat
hion
spr
ayin
g at
0.4
35%
dos
age
in a
clo
sed
cham
ber
or in
an
open
po
pula
tion
of
plan
ts a
chie
ved
nega
tive
res
pons
es. M
alat
hion
vap
ors
in d
osag
es o
f 0.
15-0
.25%
in
duce
d si
gnifi
cant
ly h
ighe
r fr
eque
ncie
s (0
.05)
of
mic
ronu
clei
abo
ve th
e co
ntro
ls a
nd a
lter
ed
the
nucl
ear
stru
ctur
e to
form
nuc
lei o
f un
equa
l siz
e an
d m
ulti
ple
brea
ks in
eac
h of
the
four
ce
lls o
f a
tetr
ad. I
t als
o ca
used
nuc
leus
deg
ener
atio
n, "
nucl
eus
prot
rusi
on"
and
inhi
biti
on o
f ce
ll gr
owth
. Hig
her
dosa
ges
(abo
ve 0
.25%
) w
ere
toxi
c.
Gilo
t-D
elh
alle
et
al.,
198
344
Mu
tat
Res
Yeas
t Sc
hiz
osac
char
omyc
es
pom
be (
an is
ogen
ic m
uta
nt
at
the
ade6
locu
s) a
nd
liver
s of
m
ale
Q s
trai
n r
ats
12 o
rgan
oph
osph
ate
inse
ctic
ides
, in
clu
din
g m
alat
hio
n (
com
bin
ed w
ith
tr
ich
lorf
on)
Th
e ef
fect
s of
3 c
ombi
nat
ion
s of
tri
chlo
rfon
wit
h e
ach
der
ivat
ive
of m
ethy
l, m
alat
hio
n,
Met
hyl p
arat
hio
n a
nd
azin
phos
-met
hyl w
ere
inve
stig
ated
. Th
e in
crea
sed
tric
hlo
rfon
-in
duce
d m
uta
tion
freq
uen
cy a
lon
e co
rrob
orat
es t
he
effe
cts
obta
ined
in t
he
firs
t ex
per
imen
ts (
of
mu
tage
nic
ity
in t
he
ad6
forw
ard-
mu
tati
on te
st s
yste
m o
f th
e ye
ast
Sch
izos
acch
arom
yces
po
mbe
) as
wel
l as
the
effi
cien
cy o
f th
e S9
mic
roso
mal
live
r fr
acti
ons.
Th
e sa
me
con
clu
sion
ca
n b
e re
ach
ed fo
r m
alat
hio
n a
nd
the
oth
er t
wo
orga
nop
hos
phat
es c
omp
oun
ds t
hat
pr
odu
ced
posi
tive
eff
ects
. In
all
thre
e ca
ses,
a s
yner
gist
ic e
ffec
t w
as fo
un
d be
twee
n
tric
hlo
rfon
mu
tage
nic
ity
and
the
seco
nd
com
pou
nd
(P<
0.00
1 in
Xc2
). T
his
syn
ergi
stic
eff
ect
was
gre
ater
for
Met
hyl p
arat
hio
n t
han
for
mal
ath
ion
an
d gr
eate
r fo
r th
is la
tter
com
pou
nd
than
for
azin
phos
-met
hyl.
Sou
rce:
Pre
pare
d by
au
thor
s.
Ch
art 1
. Syn
thes
is o
f in
vit
ro s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
, iso
mal
ath
ion
an
d m
alao
xon
wit
h t
he
carc
inog
enic
or
mu
tage
nic
eff
ects
.
3282B
asto
s P
L et
al.
Ch
art 2
. Syn
thes
is o
f in
viv
o ex
per
imen
tal s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
an
d /
or it
s an
alog
ues
to c
arci
nog
enic
an
d /
or m
uta
gen
ic e
ffec
ts.
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Hu
ssai
n e
t al
. 20
1548
Pak
J A
gri S
ciJa
pan
ese
quai
l mal
e (b
ird)
(C
otu
rnix
ja
pon
ica)
Mal
ath
ion
(95
% te
chn
ical
de
gree
)T
he
freq
uen
cy o
f m
icro
nu
clea
ted
and
bin
ucl
eate
d er
yth
rocy
tes
incr
ease
d si
gnifi
can
tly
in b
irds
fr
om g
rou
ps D
(60
day
s) to
F (
100
days
) on
all
exp
erim
enta
l day
s. T
he
freq
uen
cy o
f bl
ebbe
d n
ucl
eate
d er
yth
rocy
tes
on d
ays
34 a
nd
51 in
gro
ups
E (
80 d
ays)
at
G (
120
days
) in
crea
sed
sign
ifica
ntl
y.
Om
ran
e
Om
er, 2
01549
Path
ol R
es P
ract
Wis
tar
fem
ale
mic
eM
alat
hio
n (≥
95%
) an
d A
lph
a lip
oic
acid
His
tolo
gica
l ch
ange
s in
th
e br
east
mar
ked
by fi
broc
ysti
c al
tera
tion
s, a
typi
cal h
yper
plas
ia a
nd
mal
ign
ant
alte
rati
ons,
su
gges
tin
g th
at c
hro
nic
exp
osu
re to
mal
ath
ion
may
hav
e lo
ng-
term
co
nse
quen
ces
for
hum
an h
ealt
h.
Selm
i et
al.
2015
50
Toxi
col I
nd
Hea
lth
Wis
tar
mal
e ra
ts
Mal
ath
ion
(fy
fan
on 5
0 E
C
500
g/L)
It in
duce
d ox
idat
ive
stre
ss e
valu
ated
by
incr
ease
d m
alon
dial
dehy
de c
onte
nt
(MD
A),
refl
ecti
ng
lipop
erox
idat
ion
, dec
reas
ed t
hio
l gro
up
con
ten
t, an
d de
plet
ion
of
enzy
me
acti
viti
es s
uch
as
sup
erox
ide
dism
uta
se (
SOD
) an
d ca
tala
se (
CA
T),
ren
al a
nd
hep
atic
an
tiox
idan
t en
zym
es, a
nd
decr
ease
d si
gnifi
can
tly
(p<
0.01
) th
e ac
tivi
ties
of
thes
e en
zym
es.
Cal
af e
E
chib
urú
-C
hau
, 201
251
On
col R
epFe
mal
e vi
rgin
rat
s of
th
e Sp
ragu
e-D
awle
y st
rain
Est
roge
n a
nd
mal
ath
ion
(i
ndi
vidu
ally
an
d m
ixed
)Si
gnifi
can
t in
crea
sed
size
(p<
0.05
) of
th
e du
cts
in t
he
prol
ifer
atio
n p
has
e (d
sp/m
m2)
of
the
mam
mar
y gl
and,
an
d in
th
e n
um
ber
of e
pith
elia
l lay
ers
in c
ompa
riso
n w
ith
th
e co
ntr
ols.
Th
e in
crea
sed
prol
ifer
ativ
e du
cts
indu
ced
by t
he
effe
ct o
f m
alat
hio
n a
fter
10
and
20 d
ays
coin
cide
d w
ith
incr
ease
d ex
pres
sion
of
the
mu
tan
t p5
3 pr
otei
n. T
he
com
bin
atio
n o
f m
alat
hio
n a
nd
estr
ogen
indu
ced
a gr
eate
r ce
llula
r al
tera
tion
in t
he
mam
mar
y gl
ands
of
the
rat
than
est
roge
n
or m
alat
hio
n a
lon
e.
Alf
aro-
Lira
et
al.,
2012
52
Int
J E
nvir
on R
es
Pu
blic
Hea
lth
Fem
ale
virg
in r
ats
of
the
Spra
gue-
Daw
ley
stra
in
Mal
ath
ion
an
d 17β-
estr
adio
l (e
stro
gen
), in
divi
dual
ly a
nd
mix
ed
Th
e co
mbi
nat
ion
of
mal
ath
ion
an
d es
trog
en in
duce
d gr
eate
r ch
ange
s in
th
e tu
bula
r se
ctio
n o
f th
e ki
dney
s co
mpa
red
to a
ny s
ingl
e su
bsta
nce
. Mal
ath
ion
cau
sed
seve
ral t
ypes
of
dam
age
to
the
con
trol
, su
ch a
s a
sign
ifica
nt
incr
ease
(p<
0.05
) in
th
e de
gree
of
glom
eru
lar
hyp
ertr
ophy
, si
gns
of t
ubu
lar
dam
age
and
prol
ifer
atio
n in
th
e h
ilum
reg
ion
, an
d at
ypic
al p
rolif
erat
ion
in t
he
cort
ical
an
d h
ilar
area
s co
mpa
red
to c
ontr
ol g
rou
p. T
hes
e ab
nor
mal
itie
s m
ay b
e su
gges
ted
as a
si
gn o
f pr
ogre
ssiv
e m
alig
nan
cy.
Gir
i et
al.,
2012
53
Aqu
at T
oxic
olIn
dian
ski
tter
ing
frog
(E
ufl
icti
s cy
anop
hly
ctis
)
Mal
ath
ion
(50
% E
C c
omer
cial
fo
rmu
la)
It in
duce
d th
e fo
rmat
ion
of
mic
ron
ucl
ei (
MN
) in
ery
thro
cyte
s of
tad
pol
es in
a c
once
ntr
atio
n-
dep
ende
nt
man
ner
. Th
e co
nce
ntr
atio
n-d
epen
den
t in
crea
se in
MN
freq
uen
cy in
ery
thro
cyte
s du
rin
g th
e 96
-hou
r st
udy
per
iod
afte
r di
ffer
ent
con
cen
trat
ion
s of
mal
ath
ion
cle
arly
indi
cate
s th
e cl
asto
gen
ic p
oten
tial
of
the
pes
tici
de in
E. c
yan
oph
lyct
is.
Gir
i et
al.,
2011
54
Env
iron
Mol
M
uta
gen
Swis
s al
bin
o m
ice
Mal
ath
ion
(95
% o
f pu
rity
) an
d Fe
nval
erat
eM
alat
hio
n in
duce
s a
dose
-dep
ende
nt
incr
ease
d fr
equ
ency
of
mic
ron
ucl
eate
d p
olyc
hro
mat
ic
eryt
hro
cyte
s (P
CE
s) in
bon
e m
arro
w c
ells
of
mic
e, w
hic
h r
ein
forc
es t
he
clas
toge
nic
an
d/or
an
euge
nic
pot
enti
al o
f m
alat
hio
n.
it c
onti
nu
es
3283C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
Ch
art 2
. Syn
thes
is o
f in
viv
o ex
per
imen
tal s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
an
d /
or it
s an
alog
ues
to c
arci
nog
enic
an
d /
or m
uta
gen
ic e
ffec
ts.
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Cal
af e
G
arri
do,
2011
55
Int
J O
nco
lFe
mal
e vi
rgin
rat
s of
th
e Sp
ragu
e-D
awle
y st
rain
Mal
ath
ion
an
d 17β-
estr
adio
l (e
stro
gen
), b
oth
indi
vidu
ally
an
d m
ixed
Pro
gres
sive
ch
ange
s in
th
e du
cts
of m
amm
ary
cells
wer
e ob
serv
ed b
y th
e ef
fect
of
mal
ath
ion
. Si
gnifi
can
tly
incr
ease
d du
cts
in s
ize
and
nu
mbe
r of
cel
ls p
er s
quar
e m
illim
eter
an
d tu
mor
s as
du
ctal
car
cin
oma
wer
e pr
odu
ced.
Tre
atm
ent
in c
ombi
nat
ion
of
estr
ogen
an
d m
alat
hio
n g
ave
rise
to t
um
ors
con
sist
ing
of b
oth
pro
lifer
ativ
e an
d se
cret
ory
lobe
s.
Ber
nh
ardt
et
al.,
2011
56
Int
J In
tegr
Bio
lSw
iss
albi
no
mic
eC
omm
erci
al c
lass
of
Mal
ath
ion
(50
%)
and
Wit
han
ia s
omn
ifer
a L
(as
anti
gen
otox
ic a
gen
t).
Incr
ease
d co
met
form
atio
n (
Com
et A
ssay
) co
mpa
red
to c
ontr
ol o
f p
ean
ut
oil (
p-va
lue<
0.00
1).
DN
A d
amag
e w
as c
ause
d by
mal
ath
ion
in a
dos
e-de
pen
den
t m
ann
er.
Ech
ibu
rú-
Ch
au e
Cal
af,
2008
57
Int
J O
nco
lFe
mal
e vi
rgin
rat
s of
th
e Sp
ragu
e-D
awle
y st
rain
Mal
ath
ion
an
d 17
ß-e
stra
diol
(i
ndi
vidu
ally
an
d co
mbi
ned
).N
um
erou
s ty
pes
of
pre-
neo
plas
tic
and
neo
plas
tic
lesi
ons
hav
e be
en fo
un
d in
th
e br
onch
iola
r ep
ith
eliu
m o
f ra
ts s
uch
as
hyp
erpl
asia
, squ
amou
s m
etap
lasi
a, c
arci
nom
a in
sit
u a
nd
inva
sive
ca
rcin
oma,
su
gges
tin
g a
sign
of
prog
ress
ive
mal
ign
ancy
wit
h g
reat
er p
ossi
bilit
y of
lun
g ca
nce
r de
velo
pmen
t.
R´e
us
et a
l.,
2008
58
J A
gric
Foo
d C
hem
Wis
tar
adu
lt m
ale
rats
Mal
ath
ion
Incr
ease
d D
NA
dam
age
in w
hol
e bl
ood
of W
ista
r ra
ts, n
otab
ly a
t h
igh
er d
oses
. In
crea
sed
DN
A
dam
age
was
not
ed in
th
e h
ippo
cam
pus.
Gir
ia e
t al
.,200
259
Mu
tat
Res
Swis
s al
bin
o m
ice
Mal
ath
ion
Seve
ral t
ypes
of c
hrom
osom
al a
ltera
tion
s, w
hich
con
sist
ed o
f chr
omat
id a
nd is
ochr
omat
ic ty
pes
of g
aps
and
brea
ks, d
oubl
e m
inut
es (
incl
uded
bet
wee
n is
ochr
omat
ic b
reak
s), s
wap
s, a
nd s
iste
r ch
rom
atid
junc
tion
s (S
CJ)
. Chr
omic
-typ
e br
eaks
wer
e fo
und
to b
e m
ore
freq
uent
than
oth
ers.
M
alat
hion
indu
ced
a si
gnifi
cant
ly h
ighe
r fr
eque
ncy
of c
hang
es (
p <
0.00
1) fo
r al
l thr
ee d
oses
test
ed.
The
dos
e-re
spon
se c
urve
sho
ws
a lin
ear
incr
ease
in th
e fr
eque
ncy
of c
hang
es w
ith
incr
easi
ng d
oses
(r
= 0
.973
4, p
<0.
05).
All
thre
e ac
ute
dose
s of
mal
athi
on in
duce
d a
sign
ifica
ntly
hig
her
freq
uenc
y (p
<
0.00
1) o
f sis
ter
chro
mat
id e
xcha
nge
(SC
E) c
ompa
red
to th
e co
ntro
l val
ue. I
n ad
diti
on, a
t the
sam
e do
ses,
sig
nific
ant i
ncre
ases
(p
<0.
02, 0
.001
and
0.0
01, r
espe
ctiv
ely)
wer
e ob
serv
ed in
the
freq
uenc
y of
spe
rm h
ead
anom
alie
s co
mpa
red
to th
e un
trea
ted
cont
rol.
Cab
ello
et
al.,
2001
60
Env
iron
Hea
lth
Pe
rsp
ect
Fem
ale
rats
of
the
Spra
gue-
Daw
ley
stra
in
Ese
rin
, par
ath
ion
an
d m
alat
hio
n (
chol
ines
tera
se
inh
ibit
ors)
A s
ign
ifica
nt
incr
ease
(p
<0.
05)
in t
he
size
of
the
term
inal
en
d bu
ds (
TE
Bs)
of
the
mam
mar
y gl
and,
as
wel
l as
the
nu
mbe
r of
epi
thel
ial l
ayer
s. T
hes
e st
ruct
ure
s in
crea
sed
in s
ize
and
deve
lopm
ent
of m
amm
ary
carc
inom
as w
as n
oted
.
Am
er e
t al
., 19
9661
J A
ppl T
oxic
olR
ats
Mal
ath
ion
(10
0% p
ure
),
Du
rsba
n, S
evin
, Lan
nat
e,
DM
SO a
nd
DD
T
(in
sect
icid
es)
Indu
ctio
n o
f ch
rom
osom
al c
han
ges
in r
at s
plee
n c
ells
, wh
ose
per
cen
tage
was
hig
hly
sta
tist
ical
ly
sign
ifica
nt.
Stru
ctu
ral a
lter
atio
ns
wer
e ob
serv
ed, s
uch
as
chro
mat
id a
nd
chro
mos
omal
gap
s,
but
the
form
er w
ere
the
dom
inan
t fo
rms.
it c
onti
nu
es
3284B
asto
s P
L et
al.
Ch
art 2
. Syn
thes
is o
f in
viv
o ex
per
imen
tal s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
an
d /
or it
s an
alog
ues
to c
arci
nog
enic
an
d /
or m
uta
gen
ic e
ffec
ts.
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Fou
rern
an e
t al
., 19
9462
Env
iron
Mol
M
uta
gen
Mal
e ad
ults
of
Dro
soph
ila
mel
anog
aste
r
70 c
hem
ical
pro
duct
s,
incl
udi
ng
mal
aoxo
nM
alao
xon
was
con
side
red
a m
uta
gen
, alo
ng
wit
h 1
5 ot
her
ch
emic
al p
rodu
cts,
in t
he
sex-
linke
d re
cess
ive
leth
al te
st (
SLR
L), S
LRL
assa
y.
Hos
hiy
a et
al.,
19
9363
Can
cer
Lett
Mal
e F3
44 r
ats
Die
thyl
nitr
osam
ine
(DE
N),
m
alat
hion
, vin
cloz
olin
, S,S
,S-
trib
utyl
phos
phor
otri
thio
ate
(DE
F), t
echn
azen
e, is
opro
turo
n an
d di
chlo
ran
(ind
ivid
ually
an
d co
mbi
ned
wit
h D
EN
)
Mal
ath
ion
was
pos
itiv
e in
th
e an
alys
is o
f gl
uta
thio
ne
S-tr
ansf
eras
e pl
acen
tal f
orm
(gl
uta
thio
ne
S-tr
ansf
eras
e pl
acen
tal,
GST
-P)
posi
tive
focu
s, a
lon
g w
ith
4 o
ther
pes
tici
des.
Th
e re
sult
s su
gges
t th
at m
alat
hio
n h
as t
um
or-p
rom
otin
g ac
tivi
ty in
th
e liv
er.
Has
egaw
a e
Ito,
199
264
Fd C
hem
Tox
icF3
44 r
ats
94 c
hem
ical
com
pou
nds
, in
clu
din
g m
alat
hio
nSi
gnifi
can
t in
crea
se (
p <
0.05
) in
th
e in
duct
ion
of
GST
-P (
glu
tath
ion
e S-
tran
sfer
ase
plac
enta
l fo
rm)
posi
tive
focu
s co
mpa
red
to c
ontr
ol le
vels
of
hep
atoc
ytes
of
rats
.
Hod
a e
Sin
ha,
19
9065
Inte
rnat
J V
it N
utr
R
es.
Mus
mus
culu
s ra
tsM
alat
hio
n a
nd
Rog
or
(pes
tici
des)
an
d V
itam
ins
B
and
C (
prot
ecti
ve e
ffec
t)
Bot
h p
esti
cide
s si
gnifi
can
tly
incr
ease
d ch
rom
atid
an
d ch
rom
osom
al a
bnor
mal
itie
s in
rat
bon
e m
arro
w c
ells
.
Vel
ázqu
ez e
t al
., 19
8766
Env
iron
Mu
tage
nD
roso
phila
m
elan
ogas
ter
stra
ins
Mal
ath
ion
, 50%
em
uls
ifiab
le
con
cen
trat
e (5
0% o
f ac
tive
in
gred
ien
t, 50
% o
f xy
lol a
nd
disp
ersa
nts
an
d em
uls
ifier
s)
Th
e re
sult
s of
th
e se
x ch
rom
osom
e lo
ss (
SCL)
, SC
L te
st, a
fter
feed
ing
and
adu
lt in
ject
ion
, th
e re
sult
s of
SC
L an
d n
on-d
isju
nct
ion
aft
er t
reat
men
t of
th
ird-
stag
e la
rvae
wer
e n
egat
ive,
in
dica
tin
g th
at M
alat
hio
n is
als
o in
effe
ctiv
e in
pro
duci
ng
tota
l or
part
ial l
osse
s of
sex
ch
rom
osom
es a
nd
non
-dis
jun
ctio
n.
Alin
a D
zwon
kow
ska
e H
enry
k H
iibne
r, 19
8667
Arc
h T
oxic
olSy
rian
ham
ster
(M
esoc
rice
tus
aura
tus)
Mal
ath
ion
, dem
eton
, di
met
hoa
te, d
ich
lorv
os,
endo
sulf
an, t
rich
lorf
on,
carb
aryl
, lin
dan
e,
met
hox
ych
lor
and
prop
oxu
r
Stat
isti
cally
sig
nifi
can
t in
crea
ses
(p <
0.05
) in
th
e n
um
ber
of c
ells
wit
h c
hro
mos
omal
al
tera
tion
s in
th
e bo
ne
mar
row
of
the
mal
ath
ion
-tre
ated
Syr
ian
ham
ster
s.
Deg
raev
e et
al
., 19
8568
Env
iron
Hea
lth
Pe
rsp
ect
Mal
e ra
ts (
Q s
trai
n)
Tric
hlor
fon
indi
vidu
ally
an
d co
mbi
ned
wit
h m
alat
hion
or
Met
hyl p
arat
hion
or
azin
phos
-m
ethy
l (al
l wit
h 99
% p
uri
ty)
Th
e fr
equ
ency
of
chro
mos
omal
ch
ange
s in
bon
e m
arro
w m
etap
has
es w
as n
ot h
igh
er in
tre
ated
m
ale
rats
.
it c
onti
nu
es
3285C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
Au
thor
s, Y
ear
Jou
rnal
Targ
et P
opu
lati
one
xpos
ure
Mai
n r
esu
lts
iden
tifi
ed
Deg
raev
e et
al
., 19
8469
Arc
h T
oxic
olM
ale
rats
(Q
str
ain
)M
alat
hio
n, d
ich
lorv
os,
dim
eth
oate
, Met
hyl p
arat
hio
n
and
tric
hlo
rfon
(al
l wit
h 9
9%
puri
ty)
Th
e p
erce
nta
ge o
f ch
rom
osom
al b
reak
s in
bon
e m
arro
w c
ells
did
not
rea
ch 0
.5%
. A s
impl
e ch
rom
osom
al e
xch
ange
was
obs
erve
d in
th
e gr
oup
trea
ted
wit
h m
alat
hio
n a
nd
the
freq
uen
cy
of g
aps
was
low
er t
han
th
e co
ntr
ol le
vel.
Th
e fr
equ
ency
of
diff
eren
t ty
pes
of
chro
mos
omal
le
sion
s w
as v
ery
low
in s
per
mat
ogon
ia. T
he
nu
mbe
r of
ch
rom
osom
al b
reak
s ob
serv
ed in
pr
imar
y sp
erm
atoc
ytes
was
not
sig
nifi
can
tly
incr
ease
d. S
ome
gaps
(le
ss t
han
0.1
%)
wer
e de
tect
ed, b
ut
tran
sloc
atio
ns
wer
e n
ot o
bser
ved.
In
th
e do
min
ant
leth
al m
uta
tion
ass
ay, f
or
each
tre
ated
gro
up,
th
e n
um
ber
of li
ve e
mbr
yos
per
litt
er w
as n
orm
al. T
he
per
cen
tage
of
pre-
impl
anta
tion
loss
es w
as n
ot s
ign
ifica
ntl
y in
crea
sed
and
the
freq
uen
cy o
f p
ost-
impl
anta
tion
fe
tal m
orta
lity
was
low
er t
han
th
e co
ntr
ol le
vel.
Deg
raev
e et
al
., 19
8470
Fd C
he
Toxi
cR
ats
(Q s
trai
n)
Luxa
n Tu
e-Ta
ons,
M
etad
ipte
rex,
Dyn
afos
(1
55g
of m
alat
hion
, 60g
of
dich
lorv
os a
nd 7
5g o
f ca
rbar
yl/
liter
) an
d P
hosa
n P
lus
(95g
of
dim
etho
ate,
100
g of
mal
athi
on
and
100g
de
met
hoxy
chlo
r/lit
er)
(com
erci
al m
ix o
f in
sect
icid
es)
No
indu
ctio
n o
f ch
rom
osom
al c
han
ges
was
obs
erve
d in
bon
e m
arro
w c
ells
, sp
erm
atog
onia
or
prim
ary
sper
mat
ocyt
es o
f ra
ts in
ject
ed in
trap
erit
onea
lly w
ith
th
e su
bsta
nce
s. N
o ev
iden
ce o
f po
ten
tial
gen
etic
eff
ects
was
obt
ain
ed in
th
e do
min
ant
leth
al m
uta
tion
ass
ay.
Du
lou
t et
al.,
19
8371
Mu
tat
Res
BA
LB
/c s
trai
n r
ats
Mal
ath
ion
(95
,5%
)T
he c
last
ogen
ic e
ffec
t of
mal
athi
on w
as e
vide
nce
d by
the
indu
ctio
n o
f su
b-ch
rom
atid
an
d ch
rom
atid
alt
erat
ion
s co
nce
rnin
g th
e do
se u
sed
in b
one
mar
row
cel
ls o
f ra
ts. T
he a
nim
als
incr
ease
d fr
equ
ency
of
abn
orm
al m
etap
hase
s, g
aps,
bre
aks
and
chro
mat
id e
xcha
nge
s in
rel
atio
n
to t
he c
ontr
ols
duri
ng
the
vari
ous
tim
e in
terv
als,
in a
dir
ect
dose
-res
pon
se r
elat
ion
ship
, an
d th
e ch
rom
osom
al d
amag
e in
duce
d w
as p
ropo
rtio
nal
to t
he d
ose
of m
alat
hion
.So
urc
e: P
repa
red
by a
uth
ors.
Ch
art 2
. Syn
thes
is o
f in
viv
o ex
per
imen
tal s
tudi
es e
valu
atin
g th
e as
soci
atio
n o
f ex
posu
re to
mal
ath
ion
an
d /
or it
s an
alog
ues
to c
arci
nog
enic
an
d /
or m
uta
gen
ic e
ffec
ts.
3286B
asto
s P
L et
al.
by ingestion of water containing small amounts of the organophosphate (8 ppm, corresponding to the highest value allowed in Belgium for pes-ticide residues in fruits and vegetables) five days a week for seven consecutive weeks69. Again, they did not observe a significant increase in chro-mosomal breaks or gaps in the same cell types from the previous work, nor in the dominant lethal mutation assay. However, there is hardly any information on the analytical technique used to search for these changes. In 1985, the group evaluated the effects on rats injected with ma-lathion (150 mg/kg) combined with trichlorfon (50 mg/kg), and also did not show cytogenetic effects (breaks, gaps, and chromatid alterations) of the combination68.
However, of the total in vivo experimental studies found in this study, only four showed no positive association between mutagenic effects and malathion, all from the 1980s. The first three were those mentioned above, the fourth and last of them dating from 1987, which obtained ne-gative results regarding the production of sexu-al chromosome losses and non-disjunction in strains of Drosophila melanogaster exposed to malathion with 50% of the active ingredient, a percentage that may have had a significant in-fluence on the results found66. Since then, there have been a further 17 studies with positive re-sults for carcinogenicity and genotoxicity of ma-lathion, and one for malaoxon genotoxicity.
Honda and Sinha65 showed a significant in-crease (at a level of 0.1%) in the chromatid al-terations of bone marrow cells after exposure of Mus musculus rats. Swiss albino mice strains ex-posed to malathion evidenced bone marrow cell metaphases with various types of chromosomal alterations, and the pesticide-induced signifi-cantly higher frequency of alterations (p<0.001) in the three acute doses tested (2.5, 5 and 10mg/kg) than in control, besides increased frequencies of sister chromatid exchanges and sperm head anomalies59. Giri et al.54 reported the dose-de-pendent increased frequency of micronucleated polychromatic erythrocytes in bone marrow cells of mice of the same species after in vivo exposure to malathion at 95% purity.
Regarding the research on the carcinogenici-ty of malathion in in vivo experiments, the first manuscript found dated back to 1992, in whi-ch the pesticide promoted a significant increa-se (p<0.05) in the induction of GST-P positive focus in hepatocytes of F344 mice compared to control64. The expression of the GST-P enzyme is usually low in fetal hepatocytes, quiescent adults
or in regeneration, placenta, heart and other or-gans of male rats, however, hyperplastic nodu-les and chemically-induced liver tumors exhibit GST-P values of about 20 to 50 times and 10 to 30 times over, respectively, when compared to normal rat liver values72. Thus, the study suggests the possibility of malathion being a weak hepa-tocarcinogenic or hepatopromoting agent. On the other hand, the study by Hoshiya et al.63, also with F344 mice, concludes and states that mala-thion has liver tumor promoting activity.
Studies have investigated the carcinogenic effects of malathion and estrogen in virgin fe-male rats of the Sprague-Dawley strain, indivi-dually and in combination. Calaf and Garrido55 observed progressive changes in the mammary cell ducts of rats treated with isolated malathion compared to control after 240 days of treatment. Besides the significantly increased size (p<0.05) of ducts in the mammary gland proliferation phase of rats treated with the pesticide, Calaf and Chau51 found a growing expression of the mutant p53 tumor marker protein. Several types of pre-neoplasms in the bronchiolar epithelium of rats injected with malathion have also been found, besides carcinomas in situ57. In the renal tissue of malathion-exposed rats, results suggest abnor-malities with signs of malignancy52.
In most of the previously cited studies51,52,57, treatment with the combination of malathion and estrogen-induced more cellular alterations than treatments with the substances alone. Thus, the combination of pesticides found in the en-vironment, widely used in Latin America and many other countries, and an endogenous subs-tance, such as estrogen, has the potential to indu-ce deleterious effects on humans, such as breast cancer, for example51. Estrogen can also be found as a pollutant in surface and groundwater, and its presence in the environment can have severe toxicological and ecotoxicological repercussions since this substance is recognized as an endocrine disrupter, associated with premature puberty, in-fertility and congenital malformation73-75.
The epidemiological studies found in this systematic review are summarized in Chart 3. The types of designs obtained were eleven con-trol case studies, eight cohorts and six cross-sec-tional studies, where two of these also performed in vitro experiments with human peripheral blood lymphocytes.
Most studies (n = 16) investigated the corre-lations between exposure to malathion and the development of cancers. Of the 25 papers, 18 were conducted in North America (12 in the U.S.
3287C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
and 6 in Canada), three in Europe, three in Asia and only one in Latin America (Chile). These fin-dings corroborate the IARC manuscript, which states that very few studies on this approach have been conducted in less industrialized countries19.
As to the evidence of genotoxicity investiga-ted, in a cross-sectional study with male pesticide applicators, Andreotti et al.76 found positive asso-ciations between the recent use of malathion and the shorter telomere relative length (p = 0.03). Telomere shortening is associated with several diseases, and most studies have reported associa-tions between telomere length and increased risk of cancer101,102.
In a prospective cohort with patients who at-tempted suicide by self-poisoning with drugs or insecticides, temporary but significant increases in peripheral blood leukocyte aneuploidy (6.3%, p < 0.01) and chromatid (5.3%, p < 0.01) and chromosomic (1.4%, p < 0.01) alteration rates after intoxication with malathion97 were obser-ved. Also, one of 14 people poisoned by orga-nophosphate died.
Only one of the epidemiological manuscripts addressing the mutagenic effects of malathion and complex mix of pesticides including the organophosphate did not find a positive asso-ciation95. This work was carried out both with a cross-sectional epidemiological study of workers exposed to pesticides and with in vitro experi-mentation of human peripheral blood lympho-cytes also concluded that malathion has a relati-vely low potential to cause chromosomal damage in vitro, and the corresponding doses used in the experiment were much higher than those that professional applicators are likely to be exposed to in vivo.
On the other hand, a cross-sectional study with a worker occupationally exposed to pesti-cides (primarily malathion and phosphine) for more than five years, and an experimental in vitro study with human peripheral blood lymphocytes exposed to malathion revealed that the mutage-nicity of malathion can be detected at a molecu-lar level96. Molecular changes in the hprt assay were observed at doses of malathion that did not produce in vitro cytotoxicity (≤50 mg/ml) and at exposure levels experienced by the individual from which the in vivo mutant was retrieved. The authors state that alterations similar to those re-flected in the hprt in this study may also occur in other loci, especially oncogene or tumor suppres-sor genes sites, and may play a role in inducing malignancies in individuals exposed to this or a similar agent.
In epidemiological studies where exposure to complex mixtures of pesticides or combina-tions including malathion was found, all results found positive associations with genotoxic ef-fects77,92,93,99,100 and carcinogenic effect87. Inves-tigations of pesticides focused on the potential effects of these substances on an individual ba-sis aim to facilitate the analysis and direct public policies. However, although multiple exposures hinder the assessment of the relationships betwe-en pesticides and their mutagenic or carcinoge-nic effect, they more accurately reflect how these compounds are used87.
Among the manuscripts that sought to inves-tigate correlations between malathion exposure and development of different types of cancers, five of them did not find significant positive as-sociations in cases of non-Hodgkin’s lymphoma (NHL)79,91, multiple myeloma82, prostate can-cer85,91, soft tissue sarcoma86, combined lympha-tic-hematopoietic cancers, leukemia, lung, colon and rectum, kidney and bladder cancer, and me-lanoma91. Another three found significant inverse associations between the use of organophospha-te and the appearance of NHL78,84 and pancreatic cancer90.
The other half of them obtained positive associations at statistically significant levels for thyroid cancer78, ovarian cancer in menopausal women78, prostate cancer80,88 and its aggressive type83, breast cancer81, NHL94,98 and between body mass index and cancer colonization among men who used malathion89.
In Chile, about 33 years after the first mal-athion spraying on the city of Arica, Cabello et al.81 conducted a case-control study with wom-en living in the city and women from Iquique, a control city where spraying had never occurred. The authors observed that those with the most extended exposure to malathion were 5.7 times more likely to be diagnosed with breast cancer, besides 30.5% of the cases of metastases found in the exposed group, compared to 16% in the nev-er exposed group (p < 0.05). The study conclud-ed that the increased breast cancer mortality rate in the city of Arica has a significant correlation with exposure to malathion sprayed for more than three decades.
Of all the studies included in this systemat-ic review, only one was carried out in Brazil58, which evidences the lack of research regarding the carcinogenic and genotoxic effects of mala-thion in the country. On the other hand, the use of pesticides, especially in developing countries, has grown over the years, making it necessary to
3288B
asto
s P
L et
al.
Ch
art 3
. Syn
thes
is o
f ep
idem
iolo
gica
l stu
dies
th
at a
sses
sed
the
asso
ciat
ion
of
expo
sure
to m
alat
hio
n a
nd/
or it
s an
alog
ues
to c
arci
nog
enic
an
d/or
mu
tage
nic
eff
ects
.
Au
thor
s,
Year
Jou
rnal
Stud
y de
sign
Targ
et P
opu
lati
onC
oun
try
exp
osu
reM
ain
res
ult
s id
enti
fied
An
dreo
tti
et. a
l.,
2015
76
PLo
S O
NE
Cro
ss-
sect
ion
alM
ale
wor
kers
app
lyin
g p
esti
cide
sU
SAM
alat
hio
nSi
gnifi
can
t as
soci
atio
ns
wer
e fo
un
d be
twee
n t
he
rece
nt
use
of
mal
ath
ion
an
d sh
orte
r re
lati
ve te
lom
ere
len
gth
(p=
0.03
), s
ugg
esti
ng
that
th
e le
ngt
h o
f th
e le
uko
cyte
telo
mer
es m
ay b
e af
fect
ed b
y th
e re
cen
t (a
nd
cum
ula
tive
) u
se o
f ce
rtai
n p
esti
cide
s.
Ars
had
et
al.,
2015
77
Saf
Hea
lth
W
ork
Cro
ss-
sect
ion
alW
orke
rs in
a p
esti
cide
in
dust
ryPa
kist
anC
ompl
ex p
esti
cide
mix
, in
clu
din
g m
alat
hio
nT
he le
ukoc
yte
coun
t inc
reas
ed s
igni
fican
tly
wit
h th
e in
crea
sed
peri
od o
f ex
posu
re a
mon
g ex
pose
d w
orke
rs. I
n th
e C
omet
Ass
ay, t
he m
ean
tail
leng
th
of th
e D
NA
est
imat
ed in
the
expo
sed
bloo
d ce
lls o
f ex
pose
d w
orke
rs w
as
sign
ifica
ntly
hig
her
than
in c
ontr
ol g
roup
indi
vidu
als.
Mal
athi
on w
as
dete
cted
in 7
2% o
f bl
ood
sam
ples
. The
line
ar fi
t cur
ve s
how
ed a
sig
nific
ant
corr
elat
ion
(R2=
0.91
) of
the
conc
entr
atio
n of
mal
athi
on w
ith
the
tail
leng
th o
f th
e co
met
. The
line
ar c
orre
lati
on b
etw
een
the
mal
athi
on r
esid
ues
in th
e bl
ood
and
DN
A d
amag
e is
ver
y al
arm
ing
and
high
light
s th
e ri
sks
invo
lved
in d
irec
t exp
osur
e du
ring
the
prod
ucti
on a
ctiv
ity.
Lerr
o et
al.,
20
1578
Occ
up
Env
iron
Med
Pro
spec
tive
co
hor
tW
omen
spo
use
s of
p
esti
cide
app
licat
ors
USA
10 o
rgan
oph
osph
ates
, in
clu
din
g m
alat
hio
nT
he
use
of
mal
ath
ion
was
ass
ocia
ted
wit
h a
sig
nifi
can
tly
incr
ease
d ri
sk
of t
hyro
id c
ance
r (R
R=
2.04
, 95%
CI:
1.1
4-3.
63).
Sig
nifi
can
t in
tera
ctio
ns
wit
h t
he
men
opau
sal s
tatu
s of
wom
en a
nd
mal
ath
ion
for
the
risk
of
ovar
ian
can
cer
(Pin
tera
ctio
n =
0.0
4) w
ere
also
obs
erve
d.
Ala
van
ja e
t al
., 20
1479
PLo
S O
NE
Pro
spec
tive
co
hor
tFa
rmer
s an
d co
mm
erci
al a
pplic
ator
s of
pes
tici
des
USA
Mal
ath
ion
(am
ong
50 s
pec
ific
pes
tici
des)
Show
ed h
igh
bu
t n
ot s
ign
ifica
nt
risk
s w
ith
res
pec
t to
cas
es o
f n
on-
Hod
gkin
’s ly
mph
oma
(NH
L) fo
llicu
lar
B-c
ell s
ubt
ype.
Kou
tros
et
al.,
2013
80
PLo
S O
NE
Cas
e co
ntr
olLi
cen
sed
pes
tici
de
appl
icat
ors
in I
owa
and
Nor
th C
arol
ina
USA
Mal
ath
ion
(am
ong
50
pes
tici
des)
Am
ong
men
wit
h t
wo
T a
llele
s to
rs2
7106
47 in
EH
-dom
ain
bin
din
g pr
otei
n 1
(E
HB
P1)
, th
e ri
sk o
f pr
osta
te c
ance
r in
pat
ien
ts w
ith
low
m
alat
hio
n u
se w
as 2
.17
tim
es t
hos
e w
ith
out
use
(95
% C
I: 0
.91-
5.14
),
and
in t
hos
e w
ith
hig
h m
alat
hio
n u
se, i
t w
as 3
.43
tim
es t
hos
e w
ith
out
use
(95
% C
I: 1
.44-
8.15
) (P
inte
ract
ion
= 0
.003
).
Cab
ello
et
al.,
2013
81
Int
J M
orph
olC
ase
con
trol
Wom
en li
vin
g in
Ari
ca
and
Iqu
iqu
eC
hile
Mal
ath
ion
Wom
en w
ith
mor
e ex
pos
ure
tim
e to
mal
ath
ion
wer
e 5.
7 ti
mes
mor
e lik
ely
to b
e di
agn
osed
wit
h b
reas
t ca
nce
r (O
R=
5.7,
p<
0.02
). M
etas
tase
s w
ere
fou
nd
in 3
0.5%
of
the
grou
p ex
pos
ed to
mal
ath
ion
an
d on
ly in
16
% in
th
e n
ever
exp
osed
gro
up
(p<
0.05
), s
ugg
esti
ng
that
th
e h
igh
er
rate
of
mor
talit
y fr
om b
reas
t ca
nce
r oc
curr
ing
in A
rica
has
a s
ign
ifica
nt
corr
elat
ion
wit
h t
he
exp
osu
re to
th
e sp
raye
d m
alat
hio
n o
ver
the
city
for
mor
e th
an 3
0 ye
ars.
it c
onti
nu
es
3289C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
Ch
art 3
. Syn
thes
is o
f ep
idem
iolo
gica
l stu
dies
th
at a
sses
sed
the
asso
ciat
ion
of
expo
sure
to m
alat
hio
n a
nd/
or it
s an
alog
ues
to c
arci
nog
enic
an
d/or
mu
tage
nic
eff
ects
.
Au
thor
s,
Year
Jou
rnal
Stud
y de
sign
Targ
et P
opu
lati
onC
oun
try
exp
osu
reM
ain
res
ult
s id
enti
fied
Kac
huri
et
al.,
2013
82
Int
J C
ance
rC
ase
con
trol
Men
res
idin
g in
six
C
anad
ian
pro
vin
ces
Can
ada
Her
bici
des
(2,4
-D; G
lyph
osat
e an
d M
ecop
rop)
, in
sect
icid
es
(Met
hox
ych
lor;
Mal
ath
ion
; C
hlo
rdan
e; D
DT
; Car
bary
l an
d Li
nda
ne)
an
d fu
ngi
cide
s (M
ercu
ry d
ust
; Cap
tan
an
d Fo
rmal
dehy
de)
Th
e O
R r
atio
adj
ust
ed fo
r m
ult
iple
mye
lom
a co
nce
rnin
g ex
pos
ure
to
mal
ath
ion
: OR
(95
% C
I) =
1.1
2 (0
.71,
1.7
4). E
xclu
din
g re
spon
den
ts b
y pr
oxy:
OR
=1.
28 (
0.79
, 2.0
7).
Kou
tros
et
al.,
2012
83
Coo
rte
pros
pec
tiva
Agr
icu
ltor
es e
ap
licad
ores
com
erci
ais
de a
grot
óxic
os
EU
AM
alat
hio
n (
entr
e 48
ag
rotó
xico
s)Q
uat
ro in
seti
cida
s fo
ram
ass
ocia
dos
ao c
ânce
r de
pró
stat
a ag
ress
ivo,
en
tre
eles
o m
alat
hio
n c
om R
R p
ara
Q4
vs. n
ão e
xpos
to =
1,4
3, I
C 9
5%:
1,08
; 1,8
8; P
tren
d =
0,0
4).
Pahw
a et
al
., 20
1284
Am
J
Epi
dem
iol
Pro
spec
tive
co
hor
tFa
rmer
s an
d co
mm
erci
al p
esti
cide
s ap
plic
ator
s
USA
Mal
ath
ion
(am
ong
48
pes
tici
des)
Fou
r in
sect
icid
es w
ere
asso
ciat
ed w
ith
agg
ress
ive
pros
tate
can
cer,
amon
g th
em m
alat
hio
n, w
ith
RR
for
Q4
vs. n
on-e
xpos
ed =
1.4
3, 9
5% C
I: 1
.08;
1.
88; P
tren
d =
0.0
4).
Bar
ry e
t al
., 20
1185
Int
J C
ance
rC
ase
con
trol
Men
age
d ≥
19 y
ears
Can
ada
[1,1
’-(2
,2,2
-tri
chlo
roet
hylid
ene)
bis[
4-ch
loro
ben
zen
e];
1,1,
1-tr
ich
loro
-2,2
bis(
4-ch
loro
phen
yl)
eth
ane
(DD
T),
m
alat
hio
n, (
4-ch
loro
-2-
met
hylp
hen
oxy)
ace
tic
acid
(M
CPA
), M
ecop
rop
and
(2,4
dich
loro
phen
oxy)
ace
tic
acid
(2,
4-D
)
Indi
vidu
als
wit
h a
sth
ma,
alle
rgie
s or
hay
feve
r w
ho
rep
orte
d m
alat
hio
n
use
, con
trov
ersi
ally
, had
a lo
wer
ris
k of
NH
L (O
R=
1.25
, 95%
CI:
0.6
9-2.
26)
than
th
ose
wit
h n
one
of t
hes
e co
ndi
tion
s (O
R=
2.44
, 95%
CI:
1.6
5-3.
61).
Sim
ilar
effe
cts
wer
e ob
serv
ed fo
r as
thm
a an
d al
lerg
ies
eval
uat
ed
indi
vidu
ally
.
Pahw
a et
al
., 20
1186
Cas
o co
ntr
ole
Hom
ens
resi
den
tes
de s
eis
prov
ínci
as
can
aden
ses
Can
adá
Mal
ath
ion
en
tre
outr
os
agro
tóxi
cos
(her
bici
das,
in
seti
cida
s, fu
ngi
cida
s)
Não
fora
m e
nco
ntr
adas
ass
ocia
ções
sig
nifi
cati
vas
entr
e a
inci
dên
cia
de S
arco
ma
de te
cido
mol
e (S
TS)
e a
freq
uên
cia
da e
xpos
ição
ao
mal
ath
ion
.
Hoh
enad
el
et a
l.,
2011
87
Env
iron
H
ealt
h
Pers
pec
t
Cas
e co
ntr
olW
hit
e Pe
stic
ides
A
pplic
ator
s fr
om t
he
Agr
icu
ltu
ral H
ealt
h
Stu
dy (
AH
S)
USA
Mal
ath
ion
(am
ong
39
pes
tici
des)
Th
ere
was
no
posi
tive
ass
ocia
tion
bet
wee
n m
alat
hio
n e
xpos
ure
an
d pr
osta
te c
ance
r (l
ow e
xpos
ure
: OR
(95
% C
I) =
0.8
8 (0
.69,
1.1
3). H
igh
ex
posu
re: O
R (
95%
CI)
= 8
0 (0
.62,
1.0
4).
it c
onti
nu
es
3290B
asto
s P
L et
al.
Au
thor
s,
Year
Jou
rnal
Stud
y de
sign
Targ
et P
opu
lati
onC
oun
try
exp
osu
reM
ain
res
ult
s id
enti
fied
Ban
d et
al.,
20
1188
J O
ccu
p E
nvir
on M
edC
ase
con
trol
Men
res
idin
g in
six
C
anad
ian
pro
vin
ces
Can
ada
Mal
ath
ion
am
ong
oth
er
pes
tici
des
(Her
bici
des,
in
sect
icid
es, f
un
gici
des)
No
sign
ifica
nt
asso
ciat
ion
s w
ere
fou
nd
betw
een
th
e in
cide
nce
of
soft
ti
ssu
e sa
rcom
a (S
TS)
an
d th
e fr
equ
ency
of
expo
sure
to m
alat
hio
n.
An
dreo
tti
et a
l.,
2010
89
Int
J E
nvir
on
Res
Pu
blic
H
ealt
h
Cas
e co
ntr
olM
en fr
om s
ix C
anad
ian
pr
ovin
ces
Can
ada
Mal
ath
ion
am
ong
oth
er
pes
tici
des
(Her
bici
des,
in
sect
icid
es, f
un
gici
des)
- 3
6 co
mbi
nat
ion
s of
pes
tici
des
Incr
ease
d ri
sk o
f n
on-H
odgk
in's
lym
phom
a as
soci
ated
wit
h m
alat
hio
n
in c
ombi
nat
ion
wit
h 2
,4-D
, Mec
opro
p, C
arba
ryl,
Gly
phos
ate,
an
d D
DT,
w
her
e od
ds r
atio
was
hig
her
th
an t
he
use
of
each
pes
tici
de in
divi
dual
ly.
An
dreo
tti
et a
l.,
2008
90
Pro
stat
eC
ase
con
trol
Mal
e pa
tien
ts w
ith
pr
osta
te c
ance
r fr
om
the
popu
lati
on-b
ased
B
riti
sh C
olu
mbi
a C
ance
r R
egis
try
(BC
CR
) an
d B
C fa
rmer
s fr
om t
he
occu
pati
onal
ex
posu
re m
atri
x (J
EM
)
Can
ada
290
diff
eren
t ch
emic
al a
gen
ts
(of
thes
e, 1
80 p
esti
cide
s,
incl
udi
ng
mal
ath
ion
)
Exp
osu
re to
mal
ath
ion
sh
owed
an
exc
ess
risk
to s
ign
ifica
nt
pros
tate
ca
nce
r (O
R=
1.34
, 95%
CI:
1.0
1-1.
78),
an
d a
dose
-res
pon
se r
elat
ion
ship
.
Bon
ner
et
al.,
2007
91
Can
cer
Cau
ses
Con
trol
Coh
ort
L ice
nsed
pri
vate
pes
tici
de
appl
icat
ors
and
thei
r sp
ouse
s re
sidi
ng in
Iow
a an
d N
orth
Car
olin
a, a
nd
com
mer
cial
app
licat
ors
resi
ding
in Io
wa,
all
from
th
e A
gric
ultu
ral H
ealt
h St
udy
(AH
S)
USA
50 p
esti
cide
s (i
ncl
udi
ng
Mal
ath
ion
)Si
gnifi
can
t po
siti
ve a
ssoc
iati
ons
betw
een
bod
y m
ass
inde
x (B
MI)
an
d co
lon
can
cer
amon
g m
en w
ho
use
d m
alat
hio
n.
Zel
jezi
c e
Gar
aj-
Vrh
ovac
, 20
0292
Int
J C
ance
rC
ase
con
trol
Pest
icid
e ap
plic
ator
s an
d sp
ouse
s w
ith
pan
crea
tic
can
cer,
resi
din
g in
Iow
a an
d N
orth
Car
olin
a of
th
e A
gric
ult
ura
l Hea
lth
Stu
dy (
AH
S)
USA
50 p
esti
cide
s (i
nclu
ding
M
alat
hion
), o
f w
hich
24
pest
icid
es e
xam
ined
for
expo
sure
al
way
s/ne
ver,
and
13 p
esti
cide
s fo
r da
ys o
f ex
posu
re in
life
tim
e w
ith
wei
ghte
d in
tens
ity.
Th
e u
se (
alw
ays)
of
mal
ath
ion
was
sig
nifi
can
tly
inve
rsel
y as
soci
ated
w
ith
th
e ri
sk o
f pa
ncr
eati
c ca
nce
r (O
R=
0.4,
95%
CI
0.2-
0.9)
.
Ch
art 3
. Syn
thes
is o
f ep
idem
iolo
gica
l stu
dies
th
at a
sses
sed
the
asso
ciat
ion
of
expo
sure
to m
alat
hio
n a
nd/
or it
s an
alog
ues
to c
arci
nog
enic
an
d/or
mu
tage
nic
eff
ects
.
it c
onti
nu
es
3291C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
Au
thor
s,
Year
Jou
rnal
Stud
y de
sign
Targ
et P
opu
lati
onC
oun
try
exp
osu
reM
ain
res
ult
s id
enti
fied
Gar
aj-
Vrh
ovac
e
Zel
jezi
c,
2001
93
Am
J
Epi
dem
iol
Pro
spec
tive
co
hor
tPe
stic
ide
appl
icat
ors
and
thei
r sp
ouse
s re
sidi
ng in
Io
wa
and
Nor
th C
arol
ina
of th
e A
gric
ultu
ral
Hea
lth
Stud
y (A
HS)
USA
Mal
ath
ion
am
ong
50 p
esti
cide
sN
o co
ncl
usi
ve e
vide
nce
has
bee
n fo
un
d th
at o
ccu
pati
onal
exp
osu
re
to m
alat
hion
is a
ssoc
iate
d w
ith
incr
ease
d ri
sk o
f ca
nce
rs: c
ombi
ned
ly
mph
atic
-hem
atop
oiet
ic c
ance
rs (
mu
ltip
le m
yelo
ma,
leu
kem
ia,
Hod
gkin
's ly
mph
oma
and
NH
L); l
euke
mia
; NH
L; L
un
g, p
rost
ate,
col
on
and
rect
um
, kid
ney
an
d bl
adde
r ca
nce
rs; a
nd
mel
anom
a.
McD
uffi
e et
al.,
20
0194
Ch
emos
pher
eC
ohor
tW
orke
rs e
mpl
oyed
in
thre
e di
ffer
ent p
esti
cide
pr
oduc
tion
un
its
(the
pe
stic
ide
syn
thes
is
unit
, the
em
ulsi
on-
con
cen
trat
ed p
rodu
ctio
n
unit
an
d th
e po
wde
r an
d liq
uid
pest
icid
e pr
oduc
tion
un
it)
Cro
atia
C
ompl
ex p
esti
cide
mix
(a
traz
ine,
ala
chlo
r, cy
anaz
ine,
2,
4-di
chlo
roph
enox
yace
tic
acid
an
d m
alat
hio
n)
Th
e m
ean
val
ue
of s
iste
r ch
rom
atid
exc
han
ges
(SC
E)
in t
he
expo
sed
grou
p w
as s
ign
ifica
ntl
y h
igh
er c
ompa
red
to t
he
con
trol
gro
up.
Th
e n
um
ber
of s
iste
r ch
rom
atid
exc
han
ges
(HFC
s) in
th
e ex
pos
ed g
rou
p at
all
sam
plin
g p
erio
ds w
as s
ign
ifica
ntl
y h
igh
er c
ompa
red
to t
he
con
trol
gro
up.
Th
e re
sult
s su
gges
t th
at t
he
incr
ease
d n
um
ber
of S
CE
s fo
un
d in
exp
osed
indi
vidu
als
is n
ot t
he
resu
lt o
f th
e cy
toto
xic
acti
on
or e
pige
net
ic a
ctio
n o
f th
e p
esti
cide
mix
, bu
t ra
ther
th
e ch
ron
ic
occu
pati
onal
exp
osu
re to
th
e p
esti
cide
mix
.
Tit
enko
-H
olla
nd
et
al.,
1997
95
Toxi
colo
gyC
ohor
tW
orke
rs e
mpl
oyed
in
thre
e di
ffer
ent p
esti
cide
pr
oduc
tion
un
its
(the
pe
stic
ides
syn
thes
is
unit
, the
em
ulsi
on-
con
cen
trat
ed p
rodu
ctio
n
plan
t an
d th
e po
wde
r an
d liq
uid
pest
icid
es
prod
ucti
on u
nit
)
Cro
atia
Com
plex
pes
tici
de m
ix
(atr
azin
e, a
lach
lor,
cyan
azin
e,
2,4-
dich
loro
phen
oxya
ceti
c ac
id
and
mal
ath
ion
)
The
exp
osed
gro
up s
how
ed a
n in
crea
sed
num
ber
of c
hrom
osom
al
and
chro
mat
id c
han
ges,
reg
ardl
ess
of th
e sa
mpl
ing
tim
e. T
he r
esul
ts o
f th
e fi
rst s
ampl
ing
seri
es r
evea
led
dice
ntr
ic c
hrom
osom
es (
n=
17)
and
chro
mat
id c
han
ges
(n=
4) in
the
expo
sed
grou
p, b
ut n
one
of th
em in
the
con
trol
gro
up. I
n th
e se
con
d se
ries
of
sam
plin
g, o
nly
dic
entr
ic (
n=
4) w
ere
obse
rved
in th
e ex
pose
d gr
oup,
that
is, t
he n
umbe
r re
duce
d si
gnifi
can
tly
afte
r 8
mon
ths
of n
on-e
xpos
ure.
A h
ighe
r m
icro
nucl
eus
(MN
) fr
eque
ncy
w
as o
bser
ved
in th
e ex
pose
d gr
oup
com
pare
d to
con
trol
s, r
egar
dles
s of
sam
plin
g ti
me.
In
the
com
et a
ssay
, the
lym
phoc
ytes
of
the
expo
sed
wor
kers
exp
ress
ed a
gre
ater
DN
A m
igra
tion
than
the
con
trol
.
Plu
th e
t al
., 19
9696
Can
cer
Epi
de-m
iol
Bio
-mar
kers
P
rev
Cas
e co
ntro
lM
en li
vin
g in
six
C
anad
ian
pro
vin
ces
Can
ada
Her
bici
des,
fun
gici
des,
fu
mig
ants
an
d in
sect
icid
es,
incl
udi
ng
mal
ath
ion
Mal
ath
ion
was
th
e on
ly o
rgan
oph
osph
ate
of in
divi
dual
exp
osu
re
asso
ciat
ed s
tati
stic
ally
wit
h N
on-H
odgk
in's
Lym
phom
a: O
Ra
(95%
CI)
=
1.7
7 (1
.28-
2.46
).
Cze
izel
, 19
9497
Mu
tat
Res
Cro
ss-
sect
ion
al/
In v
itro
ex
per
imen
tal
stu
dy
Hu
man
per
iph
eral
bl
ood
lym
phoc
ytes
/ W
orke
rs w
ho
wer
e in
volv
ed in
th
e m
osqu
ito
erad
icat
ion
pr
ogra
m c
ondu
cted
by
th
e C
alif
orn
ia
Dep
artm
ent
of F
ood
and
Agr
icu
ltu
re –
USA
USA
Mal
ath
ion
(95
% o
f pu
rity
an
d 5%
de
impu
rity
, in
clu
din
g m
alao
xon
)
A s
ign
ifica
nt
incr
ease
in m
icro
nu
clea
ted
cells
(47
.5/1
000
bin
ucl
eate
d ly
mph
ocyt
es v
ersu
s 16
.0/1
000
in t
he
dim
ethy
l su
lfox
ide
con
trol
, p
<0.
001)
was
fou
nd
on is
olat
ed ly
mph
ocyt
es a
t h
igh
dos
e le
vels
(75
-10
0 μg
/ml)
, con
com
itan
tly
wit
h c
ytot
oxic
ity
and
stro
ng
inh
ibit
ion
of
prol
ifer
atio
n (
p<0.
001)
. Man
y of
th
e tr
eate
d ce
lls a
lso
had
mu
ltip
le
mic
ron
ucl
ei.
Ch
art 3
. Syn
thes
is o
f ep
idem
iolo
gica
l stu
dies
th
at a
sses
sed
the
asso
ciat
ion
of
expo
sure
to m
alat
hio
n a
nd/
or it
s an
alog
ues
to c
arci
nog
enic
an
d/or
mu
tage
nic
eff
ects
.
it c
onti
nu
es
3292B
asto
s P
L et
al.
Au
thor
s,
Year
Jou
rnal
Stud
y de
sign
Targ
et P
opu
lati
onC
oun
try
exp
osu
reM
ain
res
ult
s id
enti
fied
Can
tor
et
al.,
1992
98
Can
cer
Res
Cro
ss-
sect
ion
al/
In v
itro
ex
per
imen
tal
stu
dy
Occ
upa
tion
ally
exp
osed
w
orke
r. (>
5 y
ears
) /
Hu
man
per
iph
eral
bl
ood
lym
phoc
ytes
USA
Mal
ath
ion
(ba
tch
es w
ith
1
to 3
% c
onta
min
atio
n b
y is
omal
ath
ion
an
d m
alao
xon
) an
d ph
osph
ine
/ M
alat
hio
n
The
mut
ant f
requ
enci
es o
f th
e tr
eate
d sa
mpl
es s
how
ed in
tra-
and
inte
r-in
divi
dual
var
iabi
lity
and,
in s
ome
case
s, n
eglig
ible
incr
ease
s on
the
cont
rols
. Thi
s st
udy
prov
ided
the
first
evi
denc
e of
an
asso
ciat
ion
betw
een
expo
sure
to m
alat
hion
and
spe
cific
mut
atio
ns in
hum
an T
lym
phoc
ytes
.
Ru
pa e
t al
., 19
9199
Mu
tat
Res
Pro
spec
tive
co
hor
tSe
lf-i
nto
xica
tin
g in
divi
dual
s (a
ttem
pted
su
icid
e)
Hu
nga
ryD
rugs
an
d in
sect
icid
es,
incl
udin
g m
alat
hion
A te
mpo
rary
, bu
t si
gnifi
can
t in
crea
se in
per
iph
eral
blo
od le
uko
cyte
an
eupl
oidy
from
th
e fi
rst
sam
ples
col
lect
ed 3
to 6
day
s af
ter
mal
ath
ion
in
toxi
cati
on (
6.3%
, p<
0.01
). T
emp
orar
y in
crea
se in
th
e ra
te o
f ch
rom
atid
an
d ch
rom
osom
al c
han
ges
afte
r m
alat
hio
n in
toxi
cati
on.
Ru
pa e
t al
., 19
8910
0
Can
cer
Res
Cas
e co
ntr
olN
ewly
dia
gnos
ed m
en
wit
h n
on-H
odgk
in's
ly
mph
oma
and
leu
kem
ia in
th
e st
ates
of
Min
nes
ota
and
Iow
a.
USA
23 s
pec
ific
inse
ctic
ides
use
d in
an
imal
s (i
ncl
udi
ng
mal
ath
ion
),
34 in
sect
icid
es a
pplie
d to
cro
ps
(in
clu
din
g m
alat
hio
n),
38
her
bici
des
and
16 fu
ngi
cide
s.
Th
e fi
rst
use
bef
ore
1965
was
ass
ocia
ted
wit
h a
hig
her
ris
k (O
R=
1.8
/ C
I=1.
0, 3
.3)
than
th
ose
wh
o h
ad a
lway
s h
and
led
(OR
=1.
3 /
CI=
0.9,
2.
1), a
nd
was
sig
nifi
can
t fo
r th
e ea
rly
rep
orte
d u
se o
f m
alat
hio
n, a
s an
an
imal
inse
ctic
ide.
Th
e O
R fo
r th
e m
anag
emen
t, bl
endi
ng
or p
erso
nal
ap
plic
atio
n o
f sp
ecifi
c in
sect
icid
es t
hat
cou
ld h
ave
been
use
d in
bot
h
anim
als
and
crop
s be
fore
196
5 sh
ows
a si
gnifi
can
tly
elev
ated
ris
k fo
r m
alat
hio
n (
OR
=1.
8, C
I=1.
1-3.
1, 3
1 ca
ses)
.
Env
iron
Mol
M
uta
gen
Cro
ss-
sect
ion
alM
ale
pes
tici
de
appl
icat
ors
Indi
aM
ix o
f D
DT,
BH
C, e
ndo
sulf
an
(35%
), m
alat
hio
n, M
ethy
l pa
rath
ion
, ph
osph
amid
on,
mon
ocro
toph
os, q
uin
alph
os,
dim
eth
oate
, fen
vale
rate
or
cyp
erm
eth
rin
A s
tati
stic
ally
sig
nifi
can
t di
ffer
ence
(p<
0.05
) w
as o
bser
ved
betw
een
th
e m
ean
freq
uen
cy o
f si
ster
ch
rom
atid
exc
han
ges
per
cel
l in
th
e co
ntr
ol g
rou
p (3
.57)
an
d th
e fr
equ
ency
of
the
exp
osed
gro
up
(8.4
6).
SCE
freq
uen
cy w
as a
lso
sign
ifica
ntl
y h
igh
er in
th
e ex
pos
ed g
rou
p at
all
expo
sure
du
rati
ons
(1-1
0 ye
ars,
11-
20 y
ears
an
d >
20
year
s).
Mu
tat
Res
Cro
ss-
sect
ion
alSm
oker
s ex
pose
d to
p
esti
cide
s, n
onsm
oker
s (c
ontr
ol I
) e
non
-ex
pose
d sm
oker
s (c
ontr
ol I
I)
Indi
aM
ix o
f m
alat
hio
n, D
DT,
BH
C,
endo
sulf
an, M
ethy
l par
ath
ion
, m
onoc
roto
phos
, qu
inal
phos
, di
met
hoa
te, p
hos
pham
idon
, cy
per
met
hri
n a
nd
fenv
aler
ate
Cha
nge
s in
the
chr
omat
id t
ype
wer
e hi
gher
in c
ontr
ol I
I co
mpa
red
to
con
trol
I. C
han
ges
in t
he is
ochr
omic
typ
e (g
aps
(0.0
4), b
reak
s (0
.02)
, fr
agm
ents
(0.
13))
an
d di
cen
tric
(0,
52)
in c
ontr
ol I
I w
hile
the
y w
ere
abse
nt
in c
ontr
ol I
. In
the
pes
tici
de-e
xpos
ed p
opu
lati
on, t
he n
um
ber
of
gaps
an
d ch
rom
osom
al b
reak
s in
crea
sed
whe
n c
ompa
red
to c
ontr
ol I
I. A
si
mila
r in
crea
se w
as o
bser
ved
in t
he fr
agm
ents
, del
etio
ns
and
dice
ntr
ic
in t
he e
xpos
ed p
opu
lati
on c
ompa
red
to c
ontr
ol I
I. P
olyp
loid
s in
crea
sed
the
dura
tion
of
expo
sure
to p
esti
cide
s. T
he s
tati
stic
al a
nal
ysis
rev
eale
d a
sign
ifica
nt
(p<
0.05
) in
crea
se in
tota
l chr
omos
omal
cha
nge
s in
pes
tici
de-
expo
sed
smok
ers
com
pare
d to
non
-pes
tici
de-e
xpos
ed s
mok
ers.
Sou
rce:
Pre
pare
d by
au
thor
s.
Ch
art 3
. Syn
thes
is o
f ep
idem
iolo
gica
l stu
dies
th
at a
sses
sed
the
asso
ciat
ion
of
expo
sure
to m
alat
hio
n a
nd/
or it
s an
alog
ues
to c
arci
nog
enic
an
d/or
mu
tage
nic
eff
ects
.
3293C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
carry out further studies on occupational and en-vironmental exposure to these pesticides103.
The Brazilian Association of Collective Health (ABRASCO) has produced a Technical Note11 warning about products such as malathi-on, among others, currently used in vector con-trol of arboviruses, since the real damages caused to the environment and human health have not yet been adequately studied or revealed to vul-nerable populations, including Public Health workers. Its harmful effects have been disregard-ed both in the aggravation of viruses and in the emergence of other pathologies such as allergies, immunotoxicity, cancer, hormonal disorders, neurotoxicity, among others11.
Conclusion
This systematic returned results that evidenced the mutagenic effect of malathion used as a com-mercial formulation, that is, containing its ana-
logs malaoxon and isomalathion, and its ability to promote changes in DNA in vivo. Thus, neo-plastic processes can be triggered both in animals and in exposed humans once such changes can reach regions of oncogenes or tumor suppressors in the DNA.
The results of the in vitro studies in both animal and human cell cultures exposed to malathion showed DNA damage, chromosom-al alterations, sister chromatid exchanges and micronuclei. In vivo experimental studies have shown sufficient evidence regarding the potential of the pesticide both in inducing genetic damage and inducing neoplasms in mammals. Epidemi-ological studies have shown statistically signifi-cant positive associations for thyroid, breast, and ovarian cancer in menopausal women.
The carcinogenic effect of this pesticide and its implications on the environment and humans should be considered, particularly in the context of arbovirus control.
3294B
asto
s P
L et
al.
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Collaborations
PL Bastos participated in the collection and anal-ysis of the data, in the design and final writing of the article. AFT Lima participated in the collec-tion and analysis of data and review of the final text. AM Gurgel participated in the design of the article, in the analysis of the data and in the revi-sion of the final text. IGD Gurgel participated in the data analysis, in the design, writing and final review of the article.
3295C
iência &
Saúde C
oletiva, 25(8):3273-3297, 2020
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