Rev Environ Health 2019; 34(2): 197–210

Mini Review

María del Pilar Navarrete-Meneses and Patricia Pérez-Vera*

Pyrethroid pesticide exposure and hematological

cancer: epidemiological, biological and molecular
evidence
https://doi.org/10.1515/reveh-2018-0070 for more than 17% of all infectious diseases, causing more
Received November 8, 2018; accepted January 23, 2019; previously than 1 million deaths annually, and has recommended the
­published online March 23, 2019 use of pyrethroids for the treatment of mosquito nets (5).
Pyrethroids are also very important for public health, being
Abstract: Pyrethroid insecticides are commonly used
commonly used in hospitals. Particularly in children, these
worldwide. The chronic effects of these compounds are of
pesticides are frequently used to treat scabies and lice (6).
concern given that epidemiological studies have suggested
Furthermore, a great number of household insecticides
an association with hematological cancer, particularly in
contain pyrethroids (7, 8). All these uses of pyrethroids high-
children. However, the biological evidence at molecular
light their major importance in countless human activities,
and cellular levels is limited. A review on the molecular and
including the control of several vector-borne diseases, such
cellular effects of pyrethroids is helpful to guide the study
as malaria, dengue and Zika. However, there is concern
of the biological plausibility of the association of pyre-
regarding the possible chronic and acute adverse effects of
throids with hematological cancer. We reviewed studies
these insecticides, because millions of people worldwide
suggesting that pyrethroids are genotoxic, induce genetic
may be exposed in different ways to these products (1).
rearrangements, alter gene expression and modify DNA.
This potentially global exposure is of great concern
All of these biological modifications could potentially con-
because pyrethroids could be associated with increased
tribute to the carcinogenic process in hematopoietic cells.
cancer risk. Epidemiological studies have suggested that
Keywords: insecticides; leukemia; lymphoma; perme- the exposure to these insecticides could be associated
thrin; pyrethroids. with hematological cancer, particularly with childhood
leukemia (1). Although epidemiological studies have sug-
gested an association of pyrethroids with hematopoietic
Introduction cancer, these studies show certain limitations given that
are questionnaire-based, making it difficult to accurately
Pyrethroids are among the most commonly used pesticides know the level and type of exposure. In addition, the
worldwide. For example, in China alone 3000 tons are information regarding the biological mechanisms sup-
produced every year (1). Pyrethroids are an essential tool porting this epidemiological association is not completely
in agriculture, vastly reducing crop loss to pests (2). These conclusive and rather controversial. As a consequence,
chemicals are often used for impregnating the clothes the International Agency of Research on Cancer (IARC)
of persons exposed to insects, such as soldiers, travelers considers that certain pyrethroids, such as permethrin
and forestry workers (3, 4). The World Health Organiza- and deltamethrin, are not classifiable with regard to their
tion (WHO) estimates that vector-borne diseases account carcinogenicity to humans, and more research is needed
(9). On the other hand, the U.S. Environmental Protection
Agency (EPA), considers these insecticides as likely to be
*Corresponding author: Patricia Pérez-Vera, PhD, Cancer Genetics carcinogenic (4). Epidemiological studies evaluating the
Laboratory, Human Genetics Department, National Pediatrics association of pyrethroids with cancer have been com-
Institute, Insurgentes Sur 3700-C, C.P. 04530 Mexico City, Mexico, piled (10–13). However, a review synthesizing the avail-
Phone: +52 55 1084090 ext. 1471, E-mail: [email protected] able information regarding the effects of pyrethroids at
María del Pilar Navarrete-Meneses: Cancer Genetics Laboratory,
cellular and molecular levels, focusing on the relationship
Human Genetics Department, National Pediatrics Institute,
of these effects with cancer induction, is still missing.
Mexico City, Mexico; and Graduate Program in Biological Sciences,
National Autonomous University of Mexico (UNAM), Mexico City, Several reports show that pyrethroids alter diverse
Mexico biological functions (14–26). Pyrethroids bind directly
198 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer

to DNA (27, 28), produce epigenetic modifications (21), searched and compiled, duplicates were eliminated, and
disturb endocrine function (29–31), induce oxidative then the papers were selected focusing on the information
stress (32–34) and have many other effects (22, 34–36). The described above. The full texts of the selected papers were
biological activity produced by pyrethroids may be poten- carefully reviewed and the more relevant articles for this
tially related to the carcinogenic process (37). A compi- review were included. Additional studies were selected from
lation of the recent information regarding the biological the references of the reviewed articles. Studies addressing
effects of pyrethroids together with the epidemiological the effect of pyrethroids on insects, on aquatic species or
information would help to better understand the biologi- on neurological system or other effects not associated with
cal plausibility linking these insecticides with cancer. cancer were excluded. Papers written in a language differ-
We review the current information regarding pyre- ent from English or published in non-peer reviewed journals
throids and their association with cancer, focusing on were excluded. Studies involving human or murine models
hematological cancer. We include information regarding were preferred. All the information was searched, selected
the epidemiological studies in adults and children, given and reviewed by both authors.
that there are differences between these groups. We also
include the available studies showing the in vitro and in
vivo biological effects of pyrethroids. Finally, we discuss the
possible carcinogenic effects of pyrethroids, but first we give
Use and exposure to pyrethroid
essential background considerations regarding pyrethroid pesticides
mechanism of action, classification, use and exposure.
Pyrethroids are synthetic insecticides derived from the
natural pyrethrins and are divided into two major groups.
Literature searching Natural pyrethrins are chemical compounds produced by
the chrysanthemum flower (Chrysanthemum cinerariaefo-
Available studies regarding pyrethroid insecticides, their lium) (38). Pyrethroids are synthetic insecticides obtained
global use, epidemiological data on the effect of exposure from pyrethrins. The first pyrethroids obtained were Type
in humans, and their biological and molecular effects in I (first generation) pyrethroids, such as permethrin and
human cells were collected from Pubmed, Google scholar, allethrin (Table 1). Type I pyrethroids are devoid of a cyano
ScienceDirect and Medline databases until August 2018. moiety at the α-position and are less persistent in the envi-
Several combinations of the keywords: pesticides, insec- ronment. Therefore, these insecticides are mainly used
ticides, pyrethroids, permethrin, cypermethrin, del- for control of indoor pests (38, 39). Type II (second gen-
tamethrin, exposure, human, EPA, WHO, IARC, effect, eration) pyrethroids have a cyano group at the α-position
epidemiology, levels, adults, forestry workers, children, and show improved efficacy and persistence. Examples of
cancer, risk, leukemia, lymphoma, hematopoiesis, acute Type II pyrethroids are cypermethrin, fenvalerate and del-
lymphoblastic leukemia, childhood leukemia, multiple tamethrin (Table 1) (7, 38). Both groups of pyrethroids are
myeloma, leukemogeneis, genotoxicity, carcinogenicity, frequently used in countless human activities.
toxicity, chromosome aberrations, micronuclei, comet After the first synthetic pyrethroids were produced,
assay, cellular, apoptosis, proliferation, gene expression, their use and production have increased over decades.
DNA methylation, endocrine disruptor and mechanism The use of pyrethroids increased even more when dichlo-
were applied for searching. rodiphenyltrichloroethane (DDT) was banned. In 2007,
The papers were reviewed with the aim of finding infor- pyrethroids accounted for 17% of global insecticide sales.
mation addressing: 1) general characteristics of pyrethroids, In 2011, the WHO recommended the use of pyrethroid mos-
2) regulatory information regarding pyrethroids, 3) exposure quito nets to tackle malaria (4, 40). Regarding permethrin,
data in humans (adults and children), 4) epidemiological a total of 1000 tonnes are applied each year in the United
studies associating pyrethroids with any type of cancer and States. Approximately 70% of the volume produced is des-
with hematopoietic cancer (lymphoma, leukemia, multiple tined for non-agricultural uses, such as residential settings
myeloma), 5) effect of pyrethroids on human cells, 6) the and mosquito abatement, and 30% is used on crops for
effect of pyrethroids on chromosomes, DNA, gene expres- agriculture. Because the use of pyrethroids has considera-
sion, cell signaling, biological processes, immune system, bly risen worldwide, the human exposure through multiple
endocrinological system, and on oxidative stress, derived routes has correspondingly increased (13, 41).
from in vivo and in vitro studies. All the literature concern- Humans are in contact with pyrethroids through multi-
ing this information was included. Firstly, abstracts were ple routes of exposure. This exposure can be occupational,
 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer 199

Table 1: Pyrethroids Type I and Type II.

Type I Molecule Type II Molecule

Permethrin Cypermethrin

Allethrin Fenvalerate

Bifenthrin Deltamethrin

Phenothrin Cyfluthrin

Resmethrin Fenpropathrin

Tefluthrin Flucythrinate

Tetramethrin Flumethrin

for example, farmers, or non-occupational, for example, and water (8, 46). After pyrethroids enter the organism they
through household products (8, 42, 43). Individuals can are distributed in all the tissues and organs, and quantities
be in direct contact with these chemicals through dietary of these chemicals can be detected.
ingestion, inhalation or non-dietary ingestion (43). The Levels of all pyrethroids have been detected in numer-
reference oral dose for permethrin recommended by U.S. ous human samples. Metabolites of pyrethroids such as
Environmental Protection Agency (EPA) is 0.05 mg/kg/day, permethrin, cypermethrin and deltamethrin, have been
and 0.01 mg/kg/day for cypermethrin (8, 44). Pyrethroids detected in the urine of children and adults (1, 8, 47). The
can also be absorbed through skin, when using household detection of pyrethroid metabolites correlates with expo-
products, impregnated clothes, shampoos or repellents (3, sure to permethrin and other pyrethroids from contami-
7, 43, 45). Particularly children are in contact with pyre- nated food, dust, air and floors (8). Derived from these
throid-based products when treated for lice and scabies (6). studies, an accumulated dose of 0.002 mg/kg/day has
Children can also be exposed through floor dust and floor been estimated (8). Moreover, fetal exposure has been
wipes in addition to dietary ingestion of contaminated food reported because pyrethroids have the potential to cross the
200 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer

placental barrier (48). Metabolite levels of 0.2 ng/mL have permethrin, are in this situation, being considered by
been detected in umbilical cord blood samples (48). Pyre- the IARC as not classifiable regarding its carcinogenicity
throid metabolites have also been detected in breast milk due to the lack of data (9, 10). However, the EPA classi-
(49). Because metabolites of these insecticides have con- fies permethrin as a probable human carcinogen (4, 10).
sistently been detected in numerous human samples, the In addition, numerous studies have shown that several
metabolic reactions of pyrethroids have been of interest. pesticides are genotoxic (38). This damage could lead to
After pyrethroids enter the organism, metabolism and chromosome instability and oncogenic rearrangements,
elimination occur. In mammals, pyrethroids in general are potentially transforming normal cells into malignant
rapidly metabolized and almost completely eliminated in clones (37).
urine and feces several days after exposure (38). Perme- Although epidemiological studies have investigated
thrin reaches a peak of concentration in human plasma the association of pyrethroid exposure with different types
7 h after oral exposure and is excreted almost completely of cancer, such as colon, lung, melanoma, female breast
within the next 48 h through urine (50). Pyrethroids do and prostate, a recent systematic review that included
not leave residues in tissues, given that they are biode- 18 articles, concluded that there is no evidence of an
gradable and are not bio-accumulated (38). The most increased risk of most cancers analyzed and pyrethroid
important metabolic pathways for pyrethroids are ester exposure. However, the association of pyrethroid expo-
hydrolysis and oxidation, which are both mediated by sure with multiple myeloma and with childhood leukemia
carboxyl esterases and several cytochrome P450 family was not ruled out, and further studies were suggested (13).
isoforms (38). Although pyrethroids are relatively rapidly Taken together, this indicates that pyrethroid insecticides
eliminated compared to other pesticides, there is concern may be associated mainly with hematological cancer.
regarding their harmful chronic effects, including cancer This is of great importance because hematological
development. neoplasms are a group of diseases of high incidence and
mortality in adults and children worldwide (41). New
cases of leukemia, lymphoma and myeloma are expected

Pyrethroid insecticides to account for 10% of the estimated 1,735,350 new cancer
cases diagnosed in the US in 2018, and are expected to
and hematological cancer cause the deaths of an estimated 58,100 people, that rep-
resents the 9.5% of the deaths from cancer in 2018, based
Cancer comprises a group of diseases strongly associated on the estimated total of 609,640 cancer deaths (41). In
with environmental and lifestyle causes, so the identifica- addition, leukemia is the most common cancer in chil-
tion of factors that could lead to cancer is of great impor- dren, and its incidence has increased in the last years (55).
tance in the field of cancer prevention (37, 51, 52). Different Thus, it is of great importance to study if the exposure
environmental factors have been associated with cancer, to pesticides is associated with the etiology of these dis-
for example, tobacco, alcohol and ultraviolet irradiation, eases. Although several epidemiological studies analyze
and their potentials to induce cancer have been demon- pesticide exposure and cancer risk (55, 56), few studies
strated, and thus, have been classified as carcinogens by specifically investigate pyrethroid pesticides and hema-
the IARC. However, there are certain groups of environ- tological cancer risk (1, 12, 13). Given that the population
mental factors, such as pesticides, whose carcinogenic potentially exposed to these agents includes children and
effects are still controversial, and thus, are regarded as not adults, studies have been focused on one or another age
classifiable as carcinogens (9, 53). Therefore, it is of great group, and different results have been found. It is both
importance to further study the potential of these pesti- important to evaluate the effects of pyrethroids in adults
cides to contribute to the carcinogenic process. In addi- and in children, given that both groups are exposed glob-
tion, contrary to other types of environmental factors that ally, and in both groups a potentially increase in hemato-
have been regulated or banned (tobacco, DDT), the use logical cancer risk has been suggested.
of some pesticides, including pyrethroids has increased Studies including adult populations are generally
worldwide in the last decades (54). focused on occupational exposure, especially farmers (12,
As mentioned, the WHO, through the IARC, has iden- 56, 57). However, in children the exposure occurs gener-
tified certain potentially carcinogenic agents (52), includ- ally at home (8). There is a close connection between
ing some pesticides. However, there are a large number exposure in adults and in children, because exposure
of pesticides that have not been classified as carcinogens of the parents has an effect on the descendants (58). In
due to the lack of evidence. Several pyrethroids, such as addition, pediatric leukemia likely can originate in utero
 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer 201

as the result of genetic damage in fetal hematopoietic AHS, showed that the exposure to permethrin is signifi-
stem cells, possibly induced by maternal exposure to cantly associated with multiple myeloma risk (RR = 2.2
certain compounds. This injury could cause malignant 95% CI 1.4–3.5), showing an exposure-response trend
cell transformation potentially leading to the develop- (61). On the other hand, pyrethroid exposure is associ-
ment of the disease (58). However, there are few studies ated with a different type of hematological cancer in
that have evaluated the biological basis of the association children.
between pyrethroid exposure and hematological cancer.
Such studies could help support the epidemiological data
that suggests an association between pyrethroids with Childhood pyrethroid exposure
leukemia/lymphoma and could contribute to elucidate and hematological cancer
the mechanisms of carcinogenicity of these compounds,
specifically in cells of hematopoietic origin. In recent decades there has been a growing public
concern regarding childhood exposure to pyrethroids (42,
62). It has been demonstrated in several studies that chil-
Pyrethroid exposure and hematological dren are exposed in different ways to these agents, and
cancer in adults its metabolites can be detected in their urine (1, 8). A 2012
review of data from observational exposure measurement
Almost any individual can be exposed to insecticides. studies that examined children’s exposure to pyrethroids
The adult populations that have been included in epide- in media including floor wipes, floor dust, food, air and/or
miological studies are mainly exposed occupationally, for urine collected at home in the US, showed that the major-
example, farmers and fumigators (12, 57, 59). However, a ity of children (67–100%) were exposed to pyrethroids, as
2010 study on 5046 samples collected from 1999 to 2002, confirmed by the detection of urinary 3-PBA. This review
detected pyrethroid metabolites (3-PBA 3-phenoxi benzoic found that children were likely exposed to low levels of
acid) in the urine of 70% of the US general population several pyrethroids, but primarily permethrin and cyper-
older than 6 years, which means that the majority of indi- methrin, from several sources, including diet (8).
viduals are likely exposed. The concentrations of pyre- Children are particularly vulnerable because of
throid metabolites detected in this study were significantly diverse developmental, physiological and nutritional
higher in children (43). Furthermore, pyrethroid metabo- factors (42). In 2010 a systematic review and meta-analysis
lites have been detected in pregnant women exposed at that included 17 epidemiological case-control studies con-
home (60). It is thus of great importance to evaluate the ducted in the USA, Canada, Mexico, Japan, France, Brazil
effects of these compounds in the general population and Germany, concluded that exposures to residential
besides individuals with occupational exposure. pesticides during pregnancy [odds ratio (OR) = 1.54; 95%
Regarding occupational exposure, a study that CI, 1.13–2.11] and during childhood (OR = 1.38; 95% CI,
included 49,093 fumigators of the prospective cohort, 1.12–1.7), are significantly associated with leukemia risk
Agricultural Health Study (AHS) from North Carolina and (11). However, the type of pesticide was not always speci-
Iowa, concluded that there is no association between per- fied in the reviewed studies. The reports that have specifi-
methrin with most of the types of cancer analyzed, after cally included pyrethroids have suggested an association
conducting a self-reported assessment of exposure (10). with childhood leukemia (1, 63, 64). The use of shampoos
However, relative risks (RR) estimated for lymphohemat- containing pyrethroids, and other insecticides to treat
opoietic cancers and for leukemia were elevated, but the pediculosis, was associated with acute lymphoblastic leu-
findings were not consistent across all exposure metrics. kemia (ALL) in a French hospital-based case-control study
In addition, there was a suggestion of an increased risk that included 280 incident cases of childhood acute leuke-
for multiple myeloma with increased lifetime exposure- mia and 288 controls (OR = 2.0; 95% CI, 1.1–3.4) (6).
days [RR = 5.72; 95% confidence interval (CI), 2.76–11.87], Acute leukemias make up 31% of total pediatric
and other exposure metrics. The results of this study cancer and are the most common type of neoplasm in
were taken with reservations given that the number of children (41). In the US alone, more than 3000 new cases
exposed multiple myeloma cases was very small (15 are diagnosed each year (51, 65). In several countries, the
cases), and a further follow-up of the results, focusing incidence of acute leukemia has increased in recent years
on multiple myeloma, was intended (10). An additional (1, 66). ALL represents 80% of acute leukemias, and the
follow-up, focused on the development of non-Hodgkin most frequent subtype is B-cell ALL (65). In the major-
lymphoma and its subtypes in 54,306 applicators of the ity of cases, this disease apparently has an intrauterine
202 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer

origin, in which maternal exposure to certain agents the Philippines exposed to propoxur and cypermethrin.
could induce genetic damage in fetal hematopoietic They found that the oncogenic fusion was associated with
stem cells, potentially representing the initial events in higher levels of pesticides in the meconium of infants pre-
the development of leukemia (58). The risk for develop- natally exposed. These results showed that the prenatal
ing diseases, such as congenital leukemia, induced by exposure to pesticides might be a causal factor for the
pesticide exposure in children, extends to the prenatal generation of genetic rearrangements associated with leu-
stage (60). kemia (68).
The risk for congenital leukemia, which appears in In addition, studies suggest that pyrethroids exert
the first year of age, has been associated with pyrethroids several biological effects (14, 17, 19, 21–23, 27, 29), which
in various countries. A case-control study in a Brazilian could contribute in different ways and in distinct
population that included 252 cases of childhood acute moments to the carcinogenic process. Currently, the
leukemia and 423 controls, reported a significant asso- biological plausibility of the association of pyrethroids
ciation between in utero pesticide exposure, particularly with hematological cancer in children and adults is not
pyrethroids (permethrin), and the risk of leukemia [(ALL) precisely known. To help guide the study of the current
OR = 2.47; 95% CI 1.17–5.25 and acute myeloid leukemia knowledge regarding pyrethroids and hematopoietic
(AML) OR = 7.28; 95% CI 2.60–20.38] in children under cancer, we compile several studies that report the mole-
2 years of age (64). Because these studies are based only cular and cellular effects of pyrethroids, together with an
on questionnaires to estimate exposure, levels of expo- explanation of the possible relationship of these biologi-
sure could be incorrectly estimated. In 2012 in Shanghai, cal effects to carcinogenesis.
another hospital-based case-control study that included
176 children with ALL and 180 controls, reported that
levels of pyrethroid metabolites in urine correlated with
an increased risk of developing ALL (OR = 2.75; 95% CI
Potential carcinogenic mechanisms
1.43–5.29 for three metabolites combined) (1). This study of pyrethroids
has special relevance because, in contrast to other epide-
miological studies that are based only in questionnaire In vitro and in vivo studies have suggested that pyre-
data, the levels of urine metabolites were measured, throids have diverse genotoxic effects to different extents.
so the exposure to pyrethroids could be precisely deter- However, the number of these studies is limited and not
mined. Although different epidemiological studies have completely concordant. Through genotoxicity assays such
evaluated the association of pyrethroid exposure with as micronucleus, comet assay, sister chromatid exchange
childhood leukemia, there are limited molecular and bio- and chromosomal aberrations, it has been suggested that
logical studies showing the biological plausibility of this these agents induce DNA damage, chromosomal aberra-
association. tions as well as aneuploidy in peripheral blood lympho-
Very few references offer biological and molecular evi- cytes and in other systems (Table 2) (14–16, 18, 19, 69–85).
dence supporting the association of pyrethroids exposure It was reported that the in vitro exposure to 200 μM
with childhood leukemia, and more research is needed in of permethrin for 24 h induces breaks and rearrange-
this area (26, 55, 67, 68). A single case report of a newborn ments in genes associated with childhood and adult leu-
diagnosed with leukemia positive for rearrangement in the kemia and lymphoma, such as the MLL and IGH genes,
MLL gene, suggested a causal relationship between in utero in mononuclear cells from healthy donors, as detected
exposure to permethrin and the development of congenital by fluorescence in situ hybridization (FISH) (74). In addi-
AML in the proband. An additional in vitro experiment was tion, an assay using centromeric FISH probes, showed
included in this case report. A Southern blot showed that that permethrin has the potential to induce aneuploidy
exposure to permethrin induces breaks in the MLL gene in when chromosomes 12, 18 and 14/22 were analyzed (74).
the BV173 cell line. MLL breaks are frequent events seen in Breaks in these genes, particularly IGH, were also found
children less than 1 year old who are diagnosed with leuke- when the mononuclear cells were exposed continuously
mia (67). However, this study is based on a single case report. to very low concentrations of permethrin (0.1 μM, 72 h)
Another study that highlighted the association (78). The rearrangements induced by permethrin were
between pyrethroids with childhood leukemia at a also detected in metaphases, which means that the cells
molecular level was reported in 2007. The incidence of could divide in spite of the damage and could potentially
the oncogenic fusion RUNX1-RUNX1T1 was assessed in transmit the damage to daughter cells (78). This is indica-
umbilical cord blood of newborns in a population from tive of specific mechanisms by which pyrethroids can
Table 2: In vitro studies assessing the genotoxicity of pyrethroids.

Pyrethroid Assay Cellular model Exposure Result (effective concentration) Reference

time

Allethrin Chromosomal aberrations Chinese hamster cells 24 h Strongly positive only with S9 mix Matsuoka et al., 1979 (80)
Permethrin Sister chromatid exchange PBMCs 48 h Induces sister chromatid exchanges (28 μM, 256 μM) Herrera et al., 1992 (14)
Micronucleus 48 h Induces micronuclei (26 μM, 64 μM, 128 μM)
Fenvalerate Chromosome aberrations Chinese hamster ovary Induces chromosome aberrations in the presence of S9 mix Caballo et al., 1992 (70)
cells (238.1 μM–357.2 μM)
Sister chromatid exchanges Induces sister chromatid exchanges with and without S9 mix
(23.8 μM–357.2 μM)
Permethrin Chromosomal aberrations PBMCs 21 h Induces aberrations (192 μM–383 μM) Barrueco et al., 1994 (15)
Chromosomal aberrations 2h Induces aberrations: (383 μM–511 μM)
Permethrin Micronucleus PBMCs and whole 48 h Permethrin: Mostly negative results. Positive in one volunteer, Surrallés et al., 1995 (71)
blood (WB) WB (256 μM)a
Cypermethrin Cypermethrin: Slightly positive. Two volunteers, WB (480.4 μM)
Deltamethrin Deltamethrin: Slightly positive. One volunteer, WB (197.9 μM,
395.8 μM). One volunteer, PBMCs (197.9 μM)
Fenpropathrin Fenpropathrin: Slightly positive. Two volunteers, WB (28.6 μM,
143.1 μM)
Fenvalerate Fenvalerate: Mostly negative results
Deltamethrin Comet assay Human leukocytes 1h Comet assay: Positive with S9 mix (198 μM–792 μM) Villarini et al., 1998 (79)
Sister chromatid exchanges 2h Sister chromatid exchanges: Negative (19.8 μM–148.5 μM)
Micronucleus 2h Micronucleus: Negative (19.8 μM–148.5 μM)
Permethrin Comet assay Primary nasal mucosal 1h Induces DNA damage (500–1000 μM) Tisch et al., 2002 (72)
cells
Permethrin Comet assay PBMCs 0.5 h Permethrin: Induces DNA damage (511 μM) Undeğer and Başaran,
2005 (16)
Cypermethrin Cypermethrin: Induces DNA damage (480.4 μM)
Cypermethrin Comet assay Chinese hamster ovary 3h Induces DNA damage (1000–5000 μM) Patel et al., 2007 (76)
cells
Deltamethrin DNA damage-induced gene HepG2 24 h Induce luciferase activity (DNA damage response 1 μM, 10 μM) Zhang et al., 2009 (82)
expression
Gadd153-Luc test system
α-Cypermethrin Sister chromatid exchange PBMCs 24 and 48 h Induces sister chromatid exchanges and chromosomal Kocaman and Topaktaş,
Chromosomal aberrations aberrations (12, 24, 36, 48 μM) 2009 (83)
micronucleus Induces micronuclei (12 and 24 μM)
Cypermethrin Comet assay Lymphocytes from 1h Induces significant DNA damage in cells from smokers and Sandal and Yilmaz, 2011
healthy smokers and nonsmokers donors (10 μM) (84)
Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer

nonsmoker donors
Permethrin Chromosomal aberrations PBMCs 72 h Induces aberrations (511 μM) Turkez and Aydin, 2012
(18)
Micronucleus Induces micronuclei (511 μM)
203
Table 2 (continued)
204

Pyrethroid Assay Cellular model Exposure Result (effective concentration) Reference

time

Permethrin/ Micronucleus PBMCs 24 and 36 h Induce micronuclei 25 μM/0.46 μM Ramos-Chavez et al., 2015
allethrin (19)
Apoptosis Permethrin/allethrin
Permethrin MTT Erythrocytes and 24, 48, 72 h Cytotoxic Sundaramoorthy et al.,
Nanopermethrin lymphocytes 2016 (73)
Morphology Induces morphological changes
Micronucleus Induce micronucleus (30, 65, 130, 260 μM)
α-Cypermethrin Viability Human lymphocytes 4 and 24 h Reduces significantly cell viability in both lymphocytes and Želježić et al., 2016 (85)
HepG2 cell line HepG2 cells (0.262 μM, 24 h)
Comet assay Increases DNA damage in lymphocytes and HepG2 cells (4 h,
0.262 μM)
Cytokinesis-block Induces micronuclei in both cell types (0.06–0.628 μM, 24 h)
micronucleus cytome
Oxidative stress biomarkers Do not affect oxidative stress biomarkers
Permethrin Aneuploidy and breaks on PBMCs 24 h Induces MLL and IGH breaks 200 μM Navarrete-Meneses et al.,
MLL and IGH genes by FISH 2017 (74)
Oncogenic fusions nested 72 h Induces ETV6-RUNX1 fusion (0.1 μM)
RT-PCR
α-Cypermethrin Comet FISH Lymphocytes 14 days Does not induce significant DNA damage (0.0087 μM–7.2 μM Zeljezic et al., 2017 (81)
TP53 and cMyc genes No significant effect was detected on TP53 and c-Myc genes
(0.0087 μM–7.2 μM)
Permethrin Immunofluorescence for Whole blood 1.5 h Induces DNA DSB (8, 200 μM) Suárez-Larios et al., 2017
detecting phosphorylated No cytotoxic (75)
histone H2AX foci Increase in the amount of proteins participating in DNA
Detection of proteins recombination was not detected
Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer

participating in DNA
recombination by Western
blot
Cytotoxicity
Permethrin MLL and IGH aberrations by PBMCs 72 h Induces damage on MLL and IGH (0.1 μM) Navarrete-Meneses et al.,
FISH 2018 (78)
a
PBMCs, Peripheral blood mononuclear cells. RT-PCR, real-time polymerase chain reaction.
 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer 205

induce oncogenic damage or a particular susceptibility of pyrethroid evaluated and its purity, the source of the cells
the genes assessed. These findings are in accordance with that are studied (frequently from different healthy donors),
an independent study on mononuclear cells from healthy the time of exposure, the concentrations included and the
donors, that showed the potential of permethrin to induce diverse endpoints, which may show different sensibility.
DNA double strand breaks (DSB), detected by immuno- All of these differences could impact the results obtained,
fluorescence through the phosphorylation of the H2AX which have been positive in some studies and negative in
protein (75). However, in the same study, no increase in others, making it difficult to build conclusions (Table 2)
p-Ku80 or Rad51 proteins was detected. Therefore, there (14–16, 18, 19, 70–74, 76, 79–85).
was no evidence of activation of the DNA repair system, In addition, murine models have also suggested that
that could give rise to chromosome rearrangements after pyrethroids generate numerical (aneuploidy) and struc-
permethrin exposure (75). An additional study on mono- tural chromosomal aberrations in vivo (17, 86, 87). These
nuclear cells from a healthy donor found no association genetic abnormalities could lead to leukemic transforma-
between α-cypermethrin exposure with damage in the tion and clonal expansion, depending on the affected cell
TP53 and c-Myc genes, which are also closely related and the specific moment when the genetic lesion occurs
to carcinogenesis (81). Opposing results are often seen (58, 88). Although the potential of pyrethroids to damage
among studies assessing genotoxicity of pyrethroids DNA was reported several years ago, until recently, their
in vitro (Table 2). These rather controversial findings capacity to interact directly with DNA was demonstrated
could be attributed to several reasons, such as the type of (Figure 1) (27, 28). Permethrin interacts through partial

Figure 1: Molecular effects exerted by pyrethroids.

1. Bind directly to DNA. 2. Cause DNA methylation and other epigenetic modifications. 3. Alter gene expression. 4. Disrupt estrogen (ER) and
androgen (AR) receptors, potentially leading to the production of quinones and semiquinones that could affect DNA topoisomerase II, causing
DNA damage. 5. Produce ROS. 6. Alter proliferation and differentiation, possibly by the disrupting AR and ER. 7. Alter cell adhesion. 8. Induce
apoptosis through the increase in DNA damage.
206 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer

intercalation and by direct binding to minor and major reactive oxygen species (ROS) (91). In addition, quinones
DNA groves. Moreover, permethrin has higher affinity in potentially affect DNA topoisomerase II, which could
regions rich in GC base pairs (27), which are characterized lead to breaks in certain susceptible sites of the genome
as having high gene density. In addition to their genotoxic (breakpoint cluster regions of certain genes), given that
effect, the potential epigenetic effects of pesticides have this enzyme participates in DNA repair and recombina-
recently become a concern. tion, modifying DNA topology through the induction of
Recent data suggest that pyrethroids can modify DSB that need to be rejoined (91). Furthermore, there are
gene expression as well as DNA methylation. It was genes, such as MLL, with particular susceptibility to the
found that pyrethroids modify gene methylation affect- breakage by DNA topoisomerase II; the inhibition of this
ing r­eproductive functions (20, 21). However, the DNA enzyme produces ruptures in this gene which participates
methylation produced by pyrethroids needs to be inves- in diverse oncogenic fusions driving the leukemogenic
tigated focusing on other cancers such as hematological process (Figure 1) (77, 92).
neoplasms. Modifications in epigenetic patterns are of Additional evidence showing that the disruption of
great importance, given that they could lead to overex- the endocrine function can damage DNA was described
pression of oncogenes as well as the down regulation of in a large cohort study known as the “NewGeneris
tumor suppressors (Figure 1). Moreover, an in vitro study Project” (Newborns and Genotoxic exposure risks) that
revealed that exposure to pyrethroids can modify the showed that in utero exposure to chemicals with hormo-
expression of the WNT10B gene, which is also strongly nal activity, estrogenic or androgenic, is associated with
implicated in leukemia (24). the presence of micronuclei in the umbilical cord blood
In addition to modifying gene expression and meth- mononuclear lymphocytes of newborns. The detection
ylation, pyrethroids can also act at the cellular func- of micronuclei in these cells gives an estimate of the
tional level, affecting hematopoiesis. In vivo and in vitro genome damage accumulated in stem cells as well as in
studies suggest that pyrethroids, such as cypermethrin, circulating lymphocytes (93). This finding is of impor-
can inhibit the proliferation and differentiation of hemat- tance given that it reflects the effect of maternal expo-
opoietic progenitor and stem cells (22, 23). This inhibition sure on the developing fetus.
is of great importance because progenitor and stem cells Another biological effect exerted by pyrethroids that
produce all blood cells. Moreover, an arrest in the differ- could lead to genomic damage is the induction of ROS,
entiation of progenitor and stem cells is characteristic of which is closely associated with cancer. Oxidative stress
diseases such as leukemia (65). These findings provide can induce cell damage or apoptosis affecting lipids in the
evidence that pyrethroids can affect cells of the hemat- cell membrane, modifying the structure of proteins, and
opoietic system (22, 23); in addition, pyrethroids can directly damaging DNA (94). Oxygen species are involved
affect the immune system at the cellular level, as these in mutagenesis and genomic instability, contribute epi-
insecticides inhibit the production of cytokines and anti- genetically to cancer development and progression, and
bodies and also alter the macrophage function (26, 35, 89, are inducers of genetic programs that lead to cell invasion
90). The disruption of the immune system could further and malignancy (95). It has been shown in in vivo and in
contribute to the development of cancer and is a hallmark vitro studies that pyrethroids induce ROS (Figure 1) (18,
of this disease (37). 34, 96–98).
Pyrethroids can also act as endocrine disruptors, as In sum, the diverse cellular and molecular effects that
agonists or antagonists of the estrogen receptors, androgen pyrethroids exert may be potentially associated with car-
receptors or thyroid hormones (29, 30). This is important cinogenesis. Effects such as high proliferation, chromo-
because endocrine disruptors can influence the regulation some instability, epigenetic modifications, among others,
of the cell cycle (31). Pyrethroids increase the proliferation are hallmarks of cancer (37). It remains to be elucidated
of the breast carcinoma cell line MCF-7 through the activa- whether certain cells, such as the hematopoietic stem and
tion of the estrogen receptor (29). These compounds could progenitor cells, are more affected by pyrethroids com-
affect chromatin remodeling and other epigenetic modi- pared to other cell types, or if there are certain sites of the
fications through the activation of estrogen receptors, genome with increased susceptibility to these chemicals.
which are expressed in several cells, including the hemat- Efforts in the discovery of the mechanism of the potential
opoietic system. Moreover, pyrethroids could alter the carcinogenesis exerted by pyrethroids are very important,
metabolism of catechol estrogens by peroxidases, leading to elucidate the biological plausibility linking pyrethroid
to the production of semiquinones and quinones, which exposure and lymphohematopoietic cancer. At this time,
are capable of forming DNA adducts as well as generating the available evidence is still considered controversial
 Navarrete-Meneses and Pérez Vera: Pyrethroid exposure and hematological cancer 207

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