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Biomedicine & Pharmacotherapy 63 (2009) 383e395

Review

Why pesticides could be a common cause of prostate and breast cancers

in the French Caribbean Island, Martinique. An overview on key
mechanisms of pesticide-induced cancer
M. Landau-Ossondo a,b, N. Rabia c, J. Jos-Pelage b,d, L.M. Marquet b,e, Y. Isidore b,f,
C. Saint-Aimé b,d,g, M. Martin h, P. Irigaray h, D. Belpomme h,i,*
ARTAC international research group on pesticides
a
Anatomopathology Laboratory, Centre Hospitalier Universitaire de Fort de France, French West Indies, F-97200 Fort de France, Martinique
b
Joint Committee of Medical Doctors for Martinique’s Environmental Health, Martinique
c
Department of Urology, Centre Hospitalier Universitaire de Fort de France, French West Indies, F-97200 Fort de France, Martinique
d
French West Indies, F-97200 Fort de France, Martinique
e
Department of Obstetrics and Gynaecology, Centre Hospitalier Universitaire de Fort de France, French West Indies, F-97200 Fort de France, Martinique
f
Department of Paediatrics, Centre Hospitalier Régional du Lamentin, French West Indies, F-97232 Lamentin, Martinique
g
Department of Paediatrics, Centre Hospitalier Universitaire de Fort de France, French West Indies, F-97200 Fort de France, Martinique
h
Cancer Research Center, Association for Research and Treatments Against Cancer (ARTAC), 57-59 rue de la convention, F-75015 Paris, France
i
Paris V University, Department of Medical Oncology, European Hospital Georges Pompidou (HEGP), F-75015 Paris, France
Received 16 March 2009; accepted 15 April 2009
Available online 12 June 2009

Abstract

Prostate and breast cancers have become very frequent in Martinique. We previously conducted a multifactorial analysis in the French
Caribbean Island, Martinique, in order to elucidate the aetiology of prostate cancer. Using a linear regression analysis, we found that the growth
curves of incidence rates for Martinique and metropolitan France have been significantly diverging since 1983. Although a Caribbean genetic
susceptibility factor may be involved in prostate carcinogenesis: this factor, because it could not have changed during the observation period,
cannot per se account for the growing incidence of this cancer in the island. We therefore suggested that among possible environmental factors,
the intensive and prolonged exposure to Carcinogenic, Mutagenic and/or Reprotoxic (CMR) or presumed CMR pesticides may account for the
observed growing incidence of prostate cancer and thus may be involved in prostate carcinogenesis.
In this study, we further attempt to show that due to their carcinogenic properties, pesticides and especially organochlorine pesticides may in
fact be causally implicated in the growing incidence of prostate cancer in Martinique. Also, we suggest that CMR or presumed CMR pesticides
may be causally involved in the growing incidence of breast cancer through a common endocrine disruption mechanism.
We therefore propose that protective medical recommendations should be immediately set up and carried out by general practitioners,
paediatricians, obstetricians, gynaecologists and urologists; and that public health measures of primary precaution and prevention should be
urgently taken in close collaboration with health professionals in order to protect population, more especially pregnant women and children, with
the final objective perhaps that these medical recommendations and public health measures will stop Martinique’s cancer epidemic.
Ó 2009 Elsevier Masson SAS. All rights reserved.

Keywords: Endocrine disruptors; Prostate cancer; Breast cancer; Cancer; Carcinogenesis; Pesticides; Foetus-susceptibility; Obesity; Low dose

Abbreviations: AMREC, association martiniquaise de recherche et d’épidémiologie sur le cancer; ARs, androgenic receptors; BPA, bisphenol A; CMR,
carcinogenic mutagenic and/or reprotoxic; CYP450, cytochrome P450; DDE, 1,1-dichloro-2,20 -bis-p-chlorophenyl-ethylene; DDT, dichloro-diphenyl-trichloro-
ethane; DHT, dihydrotestosterone; ERs, estrogen receptors; GJIC, gap junctional intercellular communication; HCB, hexachlorobenzene; HCH, hexachlorohexane;
IARC, international agency for research on cancer; InVS, institut national de veille sanitaire; PCBs, polychlorobiphenyls; PIN, precancerous prostate intraneoplasic.
* Corresponding author at: ARTAC, 57-59 rue de la convention, 75015 Paris, France. Tel.: þ33 (0)1 45 78 53 53; fax: þ33 (0)1 45 78 53 50.
E-mail address: artac.cerc@wanadoo.fr (D. Belpomme).

0753-3322/$ - see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.biopha.2009.04.043
384 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395

1. Introduction As in our previous multidisciplinary life course study

aiming to determine factors involved in prostate carcinogen-
Using a linear regression analysis, we have found that the esis [1], we used data from official institutional documents,
growth curves of prostate cancer incidence rates for scientific publications and specific investigations. For drawing
Martinique and metropolitan France have been significantly epidemiological curves, we used data from the Institut
diverging since 1983 [1]. Because these curves are not National de Veille Sanitaire (InVS), the French institute of
parallel, this suggests that although a Caribbean genetic sanitary control. For histograms of age-related cancer inci-
susceptibility factor may be involved in prostate carcinogen- dence rates in Martinique, we used data from the Martinican
esis, this factor, because it could not have changed during the cancer registry of the association Martiniquaise de recherche
observation period e the duration of this period is too short for et d’épidémiologie sur le cancer (AMREC). Statistical anal-
effective genetic change associated with gene segregation -, yses were done as previously described [1].
cannot per se account for the observed growing incidence of As indicated in Table 1, in 2002, the standardized incidence
prostate cancer in the island. rate of prostate cancer reaches a value twice metropolitan
Estimation of the total amount of pesticides brought to the France. Albeit it is less frequent than in metropolitan France
island and mapping analysis of soil pollution showed that water (see Table 1), breast cancer is also clearly associated with
contamination originates from banana plantations and that increasing rates of incidence. Figs. 1 and 2 show that since
people were permanently contaminated since 1955 by huge 1985 (1983e1987) and 1990 (1988e1992), incidence rates are
quantities of pesticides. Indeed, our analysis in 1972 revealed that growing for prostate and breast cancer respectively, while
all subjects investigated for the presence of pesticides in their during the subsequent period, despite the fact that therapeutic
adipose tissue have been contaminated by extremely high levels progresses have been made, mortality did not tend to decrease.
of organochlorine pesticides such as dichloro-diphenyl-tri- This may be due to a younger age at diagnosis and increasing
chloroethane (DDT), 1,1-dichloro-2,20 -bis-p-chlorophenyl- disease aggressivity as it is suggested for metropolitan France
ethylene (DDE), a, b and several of them by g Hexachlorohexane from studies showing a continuous higher relative risk increase
(HCH), and aldrin and dieldrin. of prostate and breast cancers in more recent birth cohorts [2].
We therefore have suggested that environmental factors For prostate cancer, median age of patients ranges a similar
such as the intensive and prolonged exposure to Carcinogenic, value in Martinique and metropolitan France, because of
Mutagenic and/or Reprotoxic (CMR) or presumed CMR a large excess of prostate cancer cases after the age of 85 in
pesticides may account for the observed growing incidence of Martinique (see Fig. 3), while for all younger age categories,
prostate cancer and thus may be involved in prostate prostate cancer rates are higher in Martinique than in metro-
carcinogenesis. politan France. This is in contrast to breast cancer, since in
In the present paper, we further attempt to show that due to Martinique, at the exception of categories before the age of 39,
their carcinogenic properties, pesticides and especially incidence rates are much lower than in metropolitan France
organochlorine pesticides may in fact be causally implicated (see Fig. 4). This relative discrepancy for cancer rates in
in the growing incidence of prostate cancer in Martinique. younger age categories between prostate and breast cancers in
Also, we suggest that these pesticides may be implicated in the Martinique may be due for prostate cancer, to a higher genetic
growing incidence of breast cancer, since rise of incidence of susceptibility of martinicans to their environment, and for
breast and prostate cancers occurred approximately at breast cancer to a lower genetic susceptibility to this envi-
a similar time and pesticides used in the island have been ronment, as compared to the genetic susceptibility of
experimentally shown to cause both cancer types through
common endocrine disrupting mechanisms. We therefore
Table 1
propose that public health measures of primary precaution and Incidence of prostate and breast cancers in 2002 in Martinique in comparison
prevention should be immediately taken in order to protect with metropolitan France.
population from pesticide exposure. Region Prostate Breast Life expectancy Life expectancy
cancer cancer at birth at birth
2. Demographic figures and epidemiological data incidencea incidencea (males)b (females)b
Metropolitan France 75.3 91.9 77 82.5
Martinique is one of the two main tropical islands in the
Metropolitan departments
French West Indies. Its relative geographical isolation, its Bas-Rhin 69.34 70.73 75 81.9
limited land surface (1080 km2), the low number of inhabi- Calvados 72.12 71.48 74.5 82.5
tants (393,000), a presumably similar health care system and Doubs 47.53 67.36 75.6 82.7
medical practice as in metropolitan France, the availability of Isère 70.70 80.57 76.3 83.1
Somme 52.26 74.82 73.3 81.3
a cancer registry using internationally-recognized standardized
Tarn 80.77 66.05 76.4 83
procedures and the possibility of estimating environment- and/
or lifestyle-related factors and their time-related modifica- Martinique 152.7 65.3 75.3 82.1
tions; all these factors help to explain why Martinique a
World standardized rates per 100,000; data source was obtained from
constitutes a particularly relevant model for the investigation Globocan 2002 [140].
b
of environmental cancer-causing agents in humans. Data source was obtained from Score santé [141] (year 1999).
 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395
Fig. 1. Incidence and mortality for prostate cancer in Martinique. Evolution of
the incidence - in comparison with the mortality B for prostate cancer.
metropolitan populations to their environment. That genetic
susceptibility to the environment is lower in Martinique than
in metropolitan France for breast cancer is a further argument
suggesting that genetic susceptibility cannot explain why
incidence rates are increasing for both cancers in Martinique.
Also, the demographic figures and especially the persisting
high mortality rates associated with both cancers strongly
suggest that albeit improvement in diagnosis methods and
screening tests may lead to treat more efficiently earlier
detected cancer cases, this improvement cannot account for
the growing incidence of both of these cancer types since the
detected cases included in the AMREC registry are docu-
mented as true invasive cases. Moreover, since diagnosis
methods and screening tests were carried out approximately at
the same time period in Martinique and in metropolitan
France, the higher growing incidence of prostate cancer (see
Fig. 5) and of breast cancer (data not shown) in Martinique as
compared to metropolitan France cannot be explained by the
use of these methods and tests. Furthermore, given that the
growing incidence of prostate and breast cancers started
approximately at a similar time (see Figs. 1 and 2), i.e.
between 1985 and 1990, this suggests that genesis and
development of both cancer types may be causally related to
Fig. 2. Incidence and mortality for breast cancer in Martinique. Evolution of
the incidence - in comparison with the mortality B for breast cancer.
385
Fig. 3. Age distribution for prostate cancer for 2002 in Martinique in
comparison with metropole France. Median age (years) is 75e79 for
Martinique and similar for metropolitan France.
common aetiological factors. These observations therefore
bring about a further argument suggesting that the recent
drastic rise in incidence of prostate and breast cancers in
Martinique may correspond to a genuine public health plague.
As indicated in Fig. 5, using a linear regression analysis, we
have shown that the growth curve of prostate cancer incidence
rates during the period 1983e2002 significantly differs from
the one observed in metropolitan France, as determined from
the 11 official metropolitan departmental registries used as
reference, and that the latter curve fits in perfectly with the
extrapolated curve for overall metropolitan France. Since the
growth curve of prostate cancer incidence rates in Martinique
has been significantly diverging from the one in metropolitan
France, on the basis that gene segregation in one generation
cannot account for change in genetic susceptibility to cancer,
we therefore proposed that non genetic, i.e. environmental
factors may be involved to account for the higher growing
Fig. 4. Age distribution for breast cancer for 2002 in Martinique in comparison
with metropole France. Median age (years) is 60e69 for Martinique and
similar for metropolitan France.
386 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395
Fig. 5. Evolution of the incidence rates of prostate cancer in Martinique - in
comparison with the ones for 11 metropolitan departmental registries A and
with the ones extrapolated for overall metropolitan France . Although the
best modelisation was found to fit exponential growth equations, we evaluated
the divergence of the different incidence growth curves, by using rights instead
of exponentials. Values of R2 were 0.9675 for Martinique, 0.9391 for the 11
metropolitan departmental registries and 0.9641 for overall metropolitan
France [1].
incidence of prostate cancer in the island as compared to
metropolitan France [1]. In addition, given that rise in inci-
dence for breast cancer occurred at approximately a similar
time as for prostate cancer, we hypothesized that common
environmental factors might be involved in breast and prostate
carcinogenesis. Consequently, this prompted us to search for
exogenous cancer-causing agents which may account for the
growing incidence both of prostate and breast cancers in
Martinique, and thus for a common biological pathway that
may contribute to generate both cancer types.
3. Martinique’s pesticide exposure
During the last five decades, the soil and fresh water in
Martinique as well as local agricultural food were highly and
continuously contaminated by large amounts of numerous
persisting organic pesticides, such as organochlorines [3,4].
Indeed, using a first desorption kinetics-based leaching model,
it has been recently estimated that andosol pollution by
chlordecone, a CMR organochlorine pesticide, may last half
a millennium [5]. Fig. 6 shows the estimated total amount of
pesticides (in tons) which has been brought to Martinique
since 1955. Initially, most insecticides and nematicides used in
banana plantations were organochlorines. In the 1960s, the
main compounds were hexachlorobenzene (HCB), which is
structurally a cyclic form of HCH; technical DDT; technical
HCH and its g isomere, lindane; chlordanes such as heptachlor
and one of its major metabolite, oxychlordane; aldrin and its
metabolite dieldrin and endrin. During the 1970s, following
DDT, toxaphene was massively used as well as chlordecone
until its prohibition in 1993. In the 1980s, a first generation of
organophosphorous pesticides such as malathion and para-
thion was used in replacement of organochlorines and these
Fig. 6. Amounts of pesticides used in Martinique according to [1].
pesticides were replaced in the 1990s by a second generation
of apparently less toxic organophosphorous pesticides. In
addition, the main herbicides used until recently or still now
used are triazines such as simazine, diuron and the quaternary
ammoniums, paraquat, diquat and glycophosate. Table 2
shows among many different pesticides, some of the CMR or
presumed CMR pesticides marketed since 1933 in metropol-
itan France and progressively used since 1955 in Martinique
mainly for the culture of bananas. Table 3 indicates the
concentrations of several organochlorinated CMR pesticides
that we have measured in 1972 in the adipose tissue of 34
martinicans operated for benign diseases. An important
finding in our study is that all subjects tested, whatever their
place of residence in the island, were contaminated by
extremely high doses of these organochlorine pesticides [6].
As indicated in Table 3, high mean values of DDT and DDE
have been detected in all subjects tested with extreme values
up to 9 mg/kg bw of DDT and 16 mg/kg bw of DDE in adults
and 8 mg/kg bw of DDT and 7 mg/kg bw of DDE in children
aged between 11 and 16 years. Likewise, the three isomers of
HCH have been detected in all subjects tested, but at relatively
weaker concentrations, with extreme values up to 0.6 mg/kg
bw for aHCH, 2 mg/kg bw for bHCH and 0.2 mg/kg bw for
lindane (gHCH) in adults and up to 0.3 mg/kg bw for aHCH
and 0.6 mg/kg bw for bHCH in children.
4. Search for correlation between pesticide exposure and
increasing risk of prostate and breast cancers
All pesticides reported in Table 2 are CMR or presumed
CMR substances and, at the exception of simazine, aldrin and
dieldrin, and endrin (rated Group 3) and endosulfan (not
classified), have been rated as possibly carcinogenic (Group
2B) by the International Agency for Research on Cancer
(IARC). All of them have been however directly or indirectly
implicated in prostate and/or breast carcinogenesis. Indeed,
many but not all epidemiological studies have shown that
chronic exposure to these pesticides or to cocktails of them is
associated with a significant increase in prostate and/or breast
cancer risk.
Several case-control studies have reported that exposure to
pesticides and more especially to organochlorine pesticides is
 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395 387

Table 2
CMR and presumed CMR pesticides used intensively since 1955 in Martinique.
On the market Maximum of use Withdrawal from the Continuation of use IARC classification
market for agricultural use
HCB 1933 1978 2B
Technical DDTa 1939 1960e90 1972 2B
Technical HCHb 1940c 1950e60 1988 1998 2B
Lindane 1940c 1950e60 1992 2B
Toxaphene 1945 1972e84 2004 2B
Aldrin/dieldrin 1950c 1960 1972 1992 3
Endosulfan 1954c 1980e90 NCh
Endrind 1960c 1992 3
Chlordanese 1960c 2B
Chlordecone 1972 1980 1990 1993 2B
Perchlordecone (mirex)f 1977c 1980 1990 2B
Simazineg 1991c 2001 3
a
Technical DDT is a mixture of the isomers p,p0 -DDT (85%), o,p0 -DDT (15%) and o,o0 -DDT (<1%).
b
Technical HCH is a mixture of the isomers a, b and g.
c
Official data not available.
d
Endrin is a dieldrin stereoisomer.
e
Chlordanes include trans-chlordane, cis-chlordane, trans-nonachlor, cis-nonachlor and heptachlor.
f
To our knowledge, mirex was not used intensively in Martinique, but in Guadeloupe.
g
Simazine, a non organochlorinated molecule, is associated with an increased risk of prostate cancer [19].
h
Not classified.

associated with an increased risk of human prostate cancer
[7e13]. In particular, a large epidemiological agricultural
health study in the USA thanks to a collaboration between the
National Cancer Institute, the National Institute of Environ-
mental Health Sciences and the Environmental Protection
Agency revealed a direct associative link between exposure to
the fungicide methyl-bromide and increased prostate cancer
risk [14,15]. Likewise, exposure to chlopyrifos, fonofos,
coumaphos, phorate, permetrin and butylate [9,16] has been
correlated with an increased prostate cancer risk in men with
familial history of prostate cancer, and a suspected action
mechanism for chlopyrifos, fonofos, and phorate has been
proposed suggesting that they may strongly inhibit CYP1A2
and CYP3A4 cytochrome P450 (CYP) monooxydases, which
normally inactivate estradiol, estrone and testosterone [17]. As
a consequence of enzymatic inhibition, increase in endoge-
nous natural estrogens and androgens may thus occur. Albeit it
is possible, it is not clear whether these pesticides were used in
Martinique. However, among pesticides which were certainly
intensively used in Martinique (See Table 2), DDT and its
metabolite derivative p,p0 -DDE [9,18], lindane [19], HCB
[20], aldrin and dieldrin [9], chlordanes [9] such as heptachlor
[9,19] and oxychlordane [8,20], and simazine [19] have been
associated with significantly increased risk of prostate cancer
in case-control studies and/or have been detected at signifi-
cantly higher concentrations in the blood and/or the adipose
tissue of prostate cancer patients. Moreover as previously
indicated, risk increase of pesticide-associated prostate cancer
has been mostly observed in subjects with family history of
prostate cancer, meaning that pesticide exposure may increase
prostate cancer risk especially in genetically susceptible
subjects [9].
Likewise, although not all epidemiological studies were
positive [21e24], breast cancer risk has been also associated
with the same types of pesticides as those used since 1955 in
Martinique (see Table 2). Indeed, it has been shown that
pesticides contamination by DDT can induce both early
puberty, which is recognized as a breast cancer risk factor [25]
and breast cancer increase risk [26]. Also pesticides of the
triazine group (to which simazine belongs) and of the chlor-
dane family have been proved to induce mammary tumors in
animals [27], and case-control studies have shown an
increased breast cancer risk associated with exposure to
toxaphene [28] or pesticides such as those of the triazine group
[29]. Also, an increased risk of breast cancer has been found to
be associated with exposure to mixture of pesticides, but

Table 3
Mean concentrations and extremes values of organochlorinated pesticides dosed in the adipose tissue of normal subjects in 1972 in Martinique.a,b
DDT DDE aHCH bHCH gHCH
16e68 years 2.5 2.66 0.14 0.30 0.10
(28) (0.7e9) (0.3e16) (0.01e0.6) (0.06e2) (0.03e0.24)
11e16 years 1.1 2 0.14 0.36 0.2
(6) (0.8e8) (1.4e7) (0.04e0.3) (0.14e0.6) e
a
Values are expressed in mg/kg of lipids extracted from adipose tissue.
b
Detection of aldrin and dieldrin was negative in most subjects but positive in several subjects where concentration mean values were between 0.05 and
0.08 mg/kg.
388 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395
unfortunately case-control studies could not discriminate
which pesticide is implicated [30e33].
However, following the pioneer works of Wassermann et al.
[34] and Unger [35,36], pesticides such as those used in
Martinique, i.e. DDT [37], p,p0 -DDE [38e41], HCB [37,42],
Lindane [43], bHCH [44], heptachlor [45], aldrin [43] and
dieldrin [46,47] or cocktails of DDT, DDE and poly-
chlorobiphenyls (PCBs) [48,49], have been clearly evidenced
to be at significantly higher concentration in breast tumors or
in the serum and/or the adipose tissue of breast cancer patients
[40,50e52]. These data therefore strongly suggest that the
aforementioned pesticides may be involved in breast carci-
nogenesis. In addition, it has been shown that the total effec-
tive xenoestrogen burden of mixture of 16 different
organochlorine pesticides measured in the adipose tissue of
breast cancer women is associated with an increased risk for
breast cancer, especially in postmenopausal learner women
[43]. Moreover, due to their estrogenic properties, organo-
chlorine pesticides such as DDT and p,p0 -DDE, HCB,
Lindane, chlordanes, aldrin, dieldrin and endrin, endosulfan
and toxaphene are thought to possibly induce human breast
cancer through endocrine disruption [50,53e55].
Since due to their endocrine disrupting properties pesticides
used in Martinique (see Table 2) have been experimentally
shown to cause both prostate and breast cancer types, we
hypothesize that these pesticides may account for the growing
incidence of both prostate and breast cancers in the island
through a common endocrine disruption mechanism.
5. Pesticides as carcinogens and endocrine disruption as
a common causal mechanism of prostate and breast
exogenous chemical carcinogenesis
Despite the fact that prostate and breast cancers are the
most commonly diagnosed cancer in Western countries, their
aetiology remains unclear. On the basis of epidemiological
data, the most consistent risk factors for prostate cancer are
advancing age, family history and ethnic origin [56,57]; while
for breast cancer, in addition to advancing age and family
history, the most consistent risk factors are radiation exposure
after the age of 10, age-dependent hormonal status, such as
age at puberty, age at menopause and age at first child, and
hormone intake for oral contraception or postmenopausal
hormone replacement therapy [58]. All these factors e other
than aging, family history and radiation e are interpretated as
resulting from estrogenic impregnation. In addition, animal
fat-rich diet and body weight gain are also suspected to be risk
factors for postmenopausal breast cancer, but these risk factors
are not evidenced for prostate cancer.
Indeed risk factors as determined through epidemiological
studies may contribute to explain no more than 50% of breast
cancer cases [59] and this is probably less for prostate cancer.
Furthermore, risk factors are not necessarily cancer-causing
agents, i.e. carcinogens or cocarcinogens directly involved in
the carcinogenic process, but are most often factors indirectly
associated with genetic susceptibility and/or exposure to
cancer-causing agents. Because epidemiological studies
cannot evidence a causal link between cancer-causing agents
and cancer, and risk factors are most often not cancer-causing
agents, epidemiological studies without the complementary
help of toxicology and biology, may therefore lead to unsus-
pected biases and misinterpretations [60].
Carcinogenesis is indeed an extremely complex and long-
lasting biological process involving initiation, promotion and
progression, which are three individualized steps that chro-
nologically and sequentially contribute to cancer genesis and
development through the interplay of a myriad of endogenous
and exogenous causal factors [61]. Since prostate and breast
cancers are two hormone-dependent cancers, the question is
whether their apparently synchronous growing incidence in
Martinique, instead of being interpretated as a consequence of
the different progresses made in early detection and screening,
may in fact be caused by a common set of causally-related
factors. More precisely, the question is whether among the
numerous man made environmental chemicals that have been
brought in Martinique, pesticides, because of their estrogenic
properties and carcinogenic potential, may in fact be common
causal agents of prostate and breast cancers.
5.1. Pesticides as tumor promoters
Lifetime exposure to endogenous estrogens has been firstly
established as a common risk factor for breast cancer in
women [62] and for prostate cancer [63]. However, as previ-
ously outlined, the growing incidence of these cancers in more
recent birth cohorts, i.e. in younger patients [2,64] strongly
suggests that environmental xenoestrogens such as pesticides
may also be involved. Some xenoestrogens may possess
a 1000 times lower affinity for nuclear estrogen receptors
(ERs) than estradiol [65], meaning that they could not effi-
ciently combine with and activate or inhibit ERs. However
activation or inhibition of ERs is an extremely complex
ligand-structure-dependent phenomenon, which also depends
on several other factors including cell tumor-specific expres-
sion of coactivator/coregulatory proteins, gene promoters and
cell environment [66]. More precisely, mechanisms of
estrogen activation involve ligand-induced dimerization of
ERs, interactions with estrogen responsive elements in target
gene promoters and transcriptional activation [67]. ERa and
ERb are two major ER subtypes that have been evidenced in
estrogen-dependent tissues. Activation of ERa stimulates cell
proliferation and is associated with cancer-causing effects
through tumor promotion, whereas activation of ERb stimu-
lates terminal cell differentiation and may contribute to anti-
cancer effects [68]. Many xenoestrogens, especially
organochlorine pesticides have been shown to disrupt endo-
crine processes by acting as agonists on ERa and/or antago-
nists on ERb [65] and also possibly as antagonists on
androgenic receptors (ARs) [69,70]. Indeed, in addition to the
induction of a more or less agonistic effects by interacting
with ERa, many pesticides used in Martinique such as
chlordecone, endosulfan, aldrin, dieldrin and endrin have been
shown to be associated with antagonistic effects by activating
ERb, meaning that agonistic effects involving ERa in addition
 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395
to antagonistic effects involving ERb may strongly contribute
to the tumor promoting effects of these pesticides [65]. As
a result, among organochlorine pesticides used in Martinique,
DDT [71e75], bHCH [75e77], lindane [78,79], HCB [80],
aldrin and dieldrin [73,78,81] and chlordecone [79,81e83],
have been shown to possess estrogenic properties in vivo in the
uterotrophic assay and/or in vitro, and therefore are tumor
promoters. These properties are thought to occur in humans
since estrogen-dependent human tissues contain both ERa and
ERb. Note that chlordecone, which was used extensively
between 1970 and 1993 and caused severe and persistent
contamination of soil, water, and food in the French West
Indies [5] is as potent as the endogenous estrogen 17bestradiol
in the uterotrophic assay and is a stronger in vitro estrogenic
agonist for ERa relatively to other pesticides [82,83].
In addition, several of the aforementioned pesticides used in
Martinique or their metabolites have been shown to exhibit
antiandrogenic effects by binding to ARs and competing with
endogenous androgens, a property that reinforce their estro-
genic effect. This is particularly true for p,p0 -DDE [84e87],
HCH [87], dieldrin [88] and chlordecone [84,87]. Until
recently, endocrine disruption involving interferences with
synthesis, metabolism, transport and clearance of steroid
hormones have received little attention in comparison with
steroid receptor interactions, although many pesticides may
also disrupt endocrine processes by modifying the activity of
key enzymes involved in steroid synthesis and metabolism [89].
Because prostate and breast tissues and also adipose tissue
are equipped with many key enzymes of steroid metabolism,
and particularly with the CYP19 a-aromatase that converts
testosterone to 17bestradiol and androstenedione to estrone,
we propose that as a consequence of a-aromatase induction
[90], pesticides which stimulate a-aromatase such as those
used in Martinique, more precisely p,p0 -DDE [91], chlordanes,
aldrin and dieldrin [92], toxaphene [93] and atrazin [89,92]
may also indirectly contribute to prostate and breast cancer
promotion by increasing concentration of endogenous natural
estrogens in peripheral tissues as well as in the intratumoral
milieu.
For breast cancer, a basic observation is that due to their
agonistic effect on ERa, natural estrogens stimulate the
growth of hormone-dependent target tissues e mainly the
mammary gland and the endometrium and therefore are
endogenous tumor promoters. However, on the basis of the
aforementioned data, pesticides may also act as exogenous
tumor promoters not only through direct and/or indirect
promoting effect on ERa- and ERb-containing tissues but also
by activating a-aromatase.
A similar but more complex picture deals with the tumor
promotion effects of estrogens in prostate carcinogenesis. An
intriguing question is how xenoestrogens such as pesticides
could enhance prostate carcinogenesis. Because the normal
development of the prostate gland depends on the production
and recognition of androgens e particularly of the active
metabolite of testosterone, dihydrotestosterone (DHT)-, and
prostate cancer retains a dependence on the androgen pathway
[94], it is indeed widely accepted that androgens are prostate
389
cancer promoters. However the concept that neither androgens
nor estrogens have a sexual specificity has been developed
[95], leading to recognize that prostate tissue can express in
addition to ARs, both ERa and ERb as breast tissue [96]. And
because of this finding it has been hypothesized that estrogens
may also be involved in prostate carcinogenesis as tumor
promoters. Indeed, a major observation based on rat experi-
ments is that, when estradiol is added to testosterone [97],
prostate cancer incidence markedly increases [98]. A basic
finding which could account for this experimental data may
relate to the high complexity of the steroid-induced AR-ERb-
Erc complex that triggers prostate cancer cell proliferation
[99]. Also, it has been shown in vitro that p,p0 -DDE at high
concentrations could function as an inhibitor of 5a-reductase,
an intraprostatic enzyme that converts testosterone to DHT
[100]. However because it cannot be aromatized to estrogen,
DHT hardly induces prostate cancer, suggesting that in addi-
tion to androgens, estrogens may play locally a major critical
role in prostate carcinogenesis [101]. On the basis of these
findings, it has been thus proposed that estrogens could create
an appropriate estrogenic intraprostatic milieu capable of
promoting prostate cancer genesis by inducing transition of
precancerous prostate intraneoplasic (PIN) lesions into pros-
tate carcinoma [102].
Consequently, several hypothetic models have been so far
proposed, based on the presumed complementary role both of
endogenous androgens and estrogens in prostate carcinogen-
esis [63,98,103]. However, these are purely endogenous-cause
models, and because our previous study in Martinique clearly
revealed that environmental factors may play a critical role in
prostate carcinogenesis [1], we strongly suggest that xen-
ochemicals such as organochlorine pesticides may also caus-
ally contribute to prostate cancer genesis, as is suggested for
breast cancer.
5.2. Pesticides as tumor initiators
In addition to tumor promotion-induced endocrine disrup-
tion mechanisms, pesticides may be directly or indirectly
mutagenic through free radical production [45] and may cause
both tumor initiation and subsequent tumor promotion by
inhibiting Gap junctional intercellular communication (GJIC)
[104]. Inhibition of GJIC has clearly been shown in normal
epithelial breast tissue exposed to relatively high concentra-
tions of organochlorine pesticides such as those used in
Martinique. Indeed DDT, dieldrin, toxaphene or mixtures of
one of these pesticides with HCB [104] have been shown to
inhibit GJIC and therefore may contribute to carcinogenesis
through this mechanism. Indeed, during tumor initiation,
blockage of GJIC between normal and preneoplasic cells
consequently create an appropriate intratissue microenviron-
ment leading initiated cells to escape growth control from
normal surrounding cells and therefore indirectly contribute to
tumor promotion [105,106]. This may also be the case for
several non organochlorine pesticides more recently used in
Martinique, such as the quinonoid herbicide Paraquat [107],
which has been proved to block GJIC in mouse hepatocytes
390 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395
[105,108] and thus possibly contribute to carcinogenesis
through this mechanism.
In addition to non-endocrine tumor initiation-associated
mechanisms involving mature tissues, pesticide-induced tumor
initiation may also concern foetal and/or neonatal tissues. The
different window susceptibility periods of the organism to
endocrine disruptors and especially the specific vulnerability
of foetus and children to endocrine disruption shall be dis-
cussed [109]. It has been fully established in animal models
that gestational exposure of normal foetal prostate tissues to
low-dose xenoestrogens [110e112] or postnatally exposure of
normal newborn prostate tissues to higher dose xenoestrogens
[113], e a process referred in both cases as ‘‘estrogen
imprinting’’ e may increase susceptibility to carcinogenesis
[114,115], cause permanent alterations of prostate develop-
ment [116] and result in precancerous PIN lesions and genesis
of prostate or breast adulthood cancers [113,117,118]. Like-
wise, in several animal models [119] it has been shown that
following perinatal exposure to xenoestrogens, estrogen
sensibility of the mammary gland increases, and that following
gestational or neonatal exposure to low dose or higher dose
xenoestrogens respectively, preneoplasic lesions and
mammary tumors occur [120,121], meaning that due to
estrogenic imprinting, initiation of breast cancer may started
in the womb [122], as it may also be the case for prostate
cancer. Estrogenic imprinting has been clearly evidenced in
animal models not only for estradiol, but also for synthetic
xenoestrogens such as diethylstilbestrol [110,123] and
bisphenol A (BPA) [118,124,125] and also for pesticides such
as DDT and DDE following in utero exposure [126]. In
humans, it has been confirmed that the prenatal period
constitutes an important window of vulnerability not only for
cancer but also for obesity [127]. Prenatal exposure to several
organochlorine pesticides such as DDT and DDE [128] or
HCB [129] has been shown to increase the risk of overweight/
obesity during childhood or at puberty. In addition to carci-
nogenic endocrine disrupting properties, DDT, DDE and HCB
might therefore be also indirectly carcinogenic through
adipose tissue mass increase, see section 6. Furthermore,
a retrospective analysis of sera coming from females exposed
early in life to p,p0 -DDT revealed that high levels of p,p0 -DDT
before the age of 14 can predict a statistically significant 5-
fold increased risk of adulthood breast cancer [26]. These data
which suggest a tumor initiating effect of pesticides early in
life of women with breast cancer may also apply for prostate
cancer, since animal experiments showed that exposure to
pesticides in the very early period of life can initiate prostate
cancer as well. In Martinique, the median age of patients at
which prostate and breast cancers are diagnosed is between
65e70 and 50e54 years respectively (see Figs. 3 and 4). If we
extrapolate the animal data to humans, the mean time scale of
human prostate and breast carcinogenesis would span
approximately 65e70 and 50e54 years respectively before
clinical occurrence.
Given that pesticide use started in 1955 in Martinique, our
hypothesis is that for prostate cancer, pesticide exposure may
have mostly contributed to promotion rather than initiation;
while for breast cancer due to a shorter latency period, it might
have contributed to both initiation and promotion. For prostate
cancer, our hypothesis is further supported by previous patho-
logical observations of frequent preneoplasic lesions in Asiatic
people suggesting that exogenous promotion may account for
the higher prostate cancer incidence rates in the American
people living in the US in comparison with the low prostate
cancer incidence rates in Asiatic people living in their countries
[130] and for the subsequent rise of prostate cancer incidence in
first generation Asiatic people having migrated in the US [131].
6. Carcinogenic low-dose effects of chronic exposure
to pesticides. Adipose tissue as a reservoir for lipophilic
organic pesticides
Contrary to some unfounded claims [132], cancer is
a disease that may basically be caused by chronic exposure to
low-dose chemical carcinogens [110,133]. Indeed as for
ionizing radiation, there is no clearly demonstrated threshold
for chemical mutagens. This may also apply to both endoge-
nous and exogenous tumor promoters, since as for endogenous
natural hormones, tumor promotion caused by endocrine
chemical disruptors may also depend on the sensitivity of
receptors. Indeed, as for endogenous hormones, there is a non-
monotonic U or inverted U-shape doseeresponse relationship,
indicating a lack of threshold-dependant dose effect for
endocrine disruptors [125,134]. Accordingly, pesticides, be
they mutagens or tumor promoters, can in fact be carcinogenic
at doses lower than those at which no effect level is observed
in classical rodent tests [133]. Moreover, since many envi-
ronmental organic pollutants, such as organochlorine pesti-
cides are lipophilic molecules which bioaccumulate in the
adipose tissue as we have shown, this tissue may function as
a transit reservoir for organic pollutants [133,135]. As previ-
ously indicated, following perinatal exposure, and/or adult-
hood exposure, pesticides such as DDT and DDE [128] or
HCB [129] (as we have demonstrated for benzo[a]pyrene
[136]) can increase the adipose tissue mass, thus indirectly
contributing to carcinogenesis by increasing the capacity of
this tissue to bioaccumulate other carcinogenic pollutants
[135]. Moreover, following bioaccumulation in adipose tissue,
pesticides can be steadily released in the organism at doses
which do not correspond to those found in the environment
[134,135] and thus may be carcinogenic at environmental
extremely low doses. Moreover, occurrence of fasting episodes
or pregnancy stimulates release of organic pollutants from the
adipose tissue to the blood circulation [134,135], and this
phenomenon may explain why breast cancer risk may increase
in postmenopausal learner women [43] and why due to foetal
contamination during pregnancy, cancer initiation, as showed
in animal models [122] might occur in utero.
Low-dose carcinogenesis is indeed clearly evidenced for the
foetus, for which interactions between exogenous chemicals and
receptors (be they hormonal receptors or enzymes) can trigger
biological response at extremely low-dose of chemicals [137].
This may especially account for the extreme susceptibility of
foetus to many xenochemicals. Moreover, according to the
 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395
classical concept of carcinogenesis, duration of exposure rather
than dose intensity alone must be considered, i.e. the longer the
exposure period to carcinogens is, the greater probability of
mutations and hence of cancer genesis [138].
These biological considerations therefore led us to conceive
that in Martinique chronic exposure to environmental cocktails
of low-dose potentially carcinogenic pesticides may have been
and continue to be a major contributing cause of cancer.
7. Arguments for a causal relationship between pesticide
exposure and the growing incidence of prostate
and breast cancers in Martinique. Compliance
to Bradford Hill criteria
The causal implication of pesticides used since 1955 in
Martinique in prostate and breast cancer genesis is based on
the following arguments:
1. In our previous ecological study, we showed that the
growing incidence of prostate cancer in Martinique cannot
be explained by genetic (ethnographic) factors, but instead
may be caused by environmental factors.
2. Many pesticides used in Martinique since 1955 are CMR
or presumed CMR molecules, which at the exception of
simazine, aldrin and dieldrin, and endrin have been rated
as possible carcinogens (group 2B) by IARC.
3. Despite the fact that some case-control studies were
negative, many pesticides or cocktails of pesticides such
as those used in Martinique have been shown to be
associated with an excess of prostate and/or breast cancer
risk in careful epidemiological studies. This is particularly
true for studies having correlated cancer risk with levels of
pesticides in tumor, blood and/or adipose tissue.
4. Although exposure to carcinogenic endocrine disrupters
such as PCBs, BPA and other marketed man-made
chemicals, might be involved both in prostate and breast
carcinogenesis, there is clearly no reason to believe that at
the difference of pesticides, the use of other imported
xenochemicals have quantitatively differed from metro-
politan France. We however cannot exclude a role for
PCBs, BPA and other marketed man-made chemicals
since additional exposure to pesticides may produce
cocktail effects.
5. In Martinique, we observed a temporal relationship
between the intensive use of pesticides and the rise in
incidence of prostate and breast cancers.
6. Experimentally low-dose environmental pollution by
pesticides may cause cancer, since due to their lipophilicity,
pesticides can enter cells and especially bioaccumulate in
the adipose tissue from which they may be steadily released
in the blood circulation at doses which do not correspond to
those found in the environment and therefore may target
peripheral tissue at adequate dose for carcinogenesis.
7. Martinique’s rise of incidence rates of prostate and of
breast cancers approximately started approximately at the
same time, i.e. between 1985 and 1990. In addition to or
alternatively to progresses in cancer detection, this
391
synchronous rise in incidence suggests a common etio-
logical mechanism.
8. Both prostate and breast cancer are hormone-dependent
tumors.
9. Experimentally all pesticides used in Martinique can
cause prostate and breast cancers through a common
endocrine disruption mechanism leading to tumor
promotion. Moreover endocrine disrupters such as pesti-
cides may also cause tumor initiation through direct or
indirect mutagenesis, especially through foetal and/or
neonatal hormonal imprinting and/or tissue disorganiza-
tion of prostate or mammary glands.
10. Since the use of pesticides started in 1955 in Martinique, the
presently observed growing incidence of prostate cancer
may mostly be due to tumor promotion rather than tumor
initiation, while for breast cancer, because the whole process
of carcinogenesis may last a shorter time period, tumor
promotion as well as tumor initiation may be involved.
11. As pesticide soil retention and consequently fresh water
pollution will persist during a very long time, contami-
nation of food and all living organisms may unfortunately
continue. Given that carcinogenesis is a long latency
process, cancers that are presently detected may result
from environmental exposure that started probably several
decades ago. Unfortunately, we therefore expect that the
growing incidence of prostate and breast cancers will
continue because of persisting environmental pollution of
the island, and as much as the intensive use of CMR or
presumed CMR pesticides is still not forbidden. That
prostate and breast carcinogenesis definitely involve both
pesticide-induced tumor initiation and tumor promotion
suggests that in the future the process will progressively
enhance.
12. Chlordecone, a CMR pesticide presently rated as 2B
carcinogen by IARC is an extremely toxic endocrine
disruptor, due to strong estrogenic and antiandrogenic
properties. This presumably explains why despite its
categorization as 2B carcinogen, chlordecone is thought to
have higher carcinogenic potential relatively to other
endocrine disruptors. In addition, because chlordecone has
12 chlorine atoms, and there is at present no means of soil
remediation, andosol soil type pollution by chlordecone
may unfortunably last half a millennium, meaning that
contamination will concern at least 20 generations of
Antilleans. Albeit there is at present no data showing
a causal relationship between chlordecone exposure and
human prostate and breast cancer genesis, we cannot
exclude this possibility, even if future epidemiological
case-control studies are negative. Since chlordecone use
reached a maximum in 1980 and rise in incidence of
prostate cancer started 5 years later, we believe that the
estimated preclinical latency period is too short to impli-
cate chlordecone in the presently observed growing inci-
dence of prostate and breast cancers, although we cannot
exclude that in addition to the earlier use of other pesti-
cides, chlordecone may have already contributed to the
genesis of a few cases through cocktail effects.
392 M. Landau-Ossondo et al. / Biomedicine & Pharmacotherapy 63 (2009) 383e395
Our present hypothesis is based on the 12 aforementioned
arguments that fit in perfectly with Bradford Hill criteria
1,2,3,4,5 and 9 for causation and partially with criteria 6,7 and
8 [139]. That is, our hypothesis fully met temporal sequence,
experimental evidence, biological plausibility, reasoning by
analogy, coherence with biological background and previous
knowledge and analogy (1,2,3,4,5 and 9 respectively); while
biological gradient, strength of association and specificity
(criteria 6,7 and 8) are partially met.
8. Public health consequences
On the basis of our previous ecological study [1] and of this
review on key mechanisms of pesticide-induced cancer, we
strongly suggest that pesticides may be causally involved in the
growing incidence of prostate and breast cancers in Martinique
through a common carcinogenic endocrine disruption mecha-
nism. Drastic public health measures of primary precaution and
prevention should be therefore urgently taken in order to stop
the cancer epidemic observed in Martinique and more generally
in the French West Indies. Individual protection from pesticide
exposure is compulsory, but unfortunately it may be insufficient
because of persisting toxic pollution. However, since foetus and
children are extremely susceptible to pesticide exposure, drastic
protection of pregnant women and children should be imme-
diately set up and carried out, in order to avoid further occur-
rence of adulthood cancer as well as other pesticide-related
diseases. To this end, mobilisation of general practitioners,
gynaecologists, obstetricians, paediatricians and urologists is an
urgent necessary step to set up and carry out a set of precau-
tionary and preventive medical recommendations. Also,
science-based public health measures should be urgently taken,
in close collaboration with medical professionals. Drastic
policy measures should also be urgently taken to suppress the
use of all CMR or presumed CMR pesticides as islands are
especially extremely vulnerable to any forms of chemical
pollution, due to limited resources of fresh water and arable
land. Consequently, pesticide pollution-caused diseases such as
prostate and breast cancers may constitute a public health
disaster on islands such as Martinique and of course elsewhere,
until public health and policy measures are actually applied.
Acknowledgments
This work was supported by a specific grant from ARTAC
provided by patient’s donations.
We thank Tony Tweedale (UK) for having reviewed this
manuscript.
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