Chlordecone Exposure and Risk of Prostate Cancer

Luc Multigner, Jean Rodrigue Ndong, Arnaud Giusti, Marc Romana, Helene Delacroix-Maillard,

Sylvaine Cordier, Bernard Je´gou, Jean Pierre Thome, and Pascal Blanchet

From the Institut National de la Sante´

et de la Recherche Me´ dicale (Inserm) U

625, Pointe a` Pitre; Inserm U 763;

Centre d’Examens de Sante´ Sainte

Genevie` ve; Service d’Urologie, Centre

Hospitalier Universitaire de la Guade-

loupe; Universite´ des Antilles et de la

Guyane, Pointe a` Pitre, Guadeloupe,

French West Indies; Inserm U 625,

Rennes; Universite´ Rennes 1, Rennes,

France; and the Laboratoire d’Ecologie

Animale et d’Ecotoxicologie, Center for

Analytical and Research Technology,

Universite´ de Lie` ge, Lie` ge, Belgium.

Submitted November 28, 2009;

accepted May 4, 2010; published online

ahead of print at www.jco.org on June

21, 2010.

Supported by the Programme Hospi-

talier de Recherche Clinique, the Plan

Pluri-Formation from the French Minis-

try of Education and Research, the

French Ministry of Overseas Territories,

the French Agency for Environmental

and Occupational Health Safety, the

Guadeloupean Division of Social,

Health, and Welfare Affairs Directorate,

the National Health Directorate, the

Association pour la Recherche sur le

Cancer, the Comite´ Guadeloupe Ligue

contre le Cancer; Grant No. 212844

from the European Union (Developmen-

tal Effects of Environment on Repro-

ductive Health).

Authors’ disclosures of potential con-

ﬂicts of interest and author contribu-

tions are found at the end of this

article.

Corresponding author: Luc Multigner,

MD, Institut National de la Sante´etde

la Recherche Me´ dicale U625, Faculte´

de Me´ decine, Campus de Fouillole,

BP145, 97154 Pointe a` Pitre, Guade-

loupe, French West Indies; e-mail:

[email protected].

Oncology

0732-183X/10/2821-3457/$20.00

DOI: 10.1200/JCO.2009.27.2153

ABSTRACT

Purpose

Determining whether environmental estrogens are associated with the risk of prostate cancer may

have important implications for our general understanding of this disease. The estrogenic

insecticide chlordecone was used extensively in the French West Indies, contaminating the

population for more than 30 years. We analyzed the relationship between exposure to chlordecone

and the risk of prostate cancer.

Patients and Methods

We investigated 623 men with prostate cancer and 671 controls. Exposure was analyzed

according to case-control status, using either current plasma concentration or a cumulative

exposure index based on years of exposure. We genotyped two single-nucleotide polymorphisms

(rs3829125 and rs17134592) in the gene encoding chlordecone reductase.

Results

We found a signiﬁcant increase in the risk of prostate cancer with increasing plasma chlordecone

concentration (odds ratio [OR], 1.77; 95% CI, 1.21 to 2.58 for the highest tertile of values above

the limit of detection [LD]; P trend ⫽ .002) and for cumulative exposure index (OR, 1.73; 95% CI,

1.04 to 2.88 for the highest quartile; P trend ⫽ .004). Stronger associations were observed among

those with a positive family history of prostate cancer and among those who had lived in a

Western country. The rs3829125 and rs17134592 allele variants were in complete linkage

disequilibrium and were found at low frequency (0.04). Among subjects with plasma chlordecone

concentrations above the LD, carriers of the allele variants had a higher risk of prostate cancer (OR,

5.23; 95% CI, 0.82 to 33.32).

Conclusion

These ﬁndings support the hypothesis that exposure to environmental estrogens increases the

risk of prostate cancer.

INTRODUCTION

Prostate cancer is the most commonly diagnosed

cancer among men in developed countries. How-

ever, little is known about the risk factors associ-

ated with this cancer. Advancing age, ethnic

origins, and a family history of prostate cancer are

the only established risk factors.

1,2

Many lifestyle-

related risk factors have been implicated, but their

roles in prostate cancer etiology remain unclear.

1,2

The effect of exposure to synthetic chemicals in the

environment on prostate cancer development re-

mains a matter of debate with implications for pub-

lic health. Chemicals with hormonal properties, also

called endocrine disruptors, are thought to be in-

volved.

3,4

However, no epidemiologic evidence of a

positive link between environmental exposure to

endocrine chemicals and prostate cancer has yet

been established.

Chlordecone (also known as Kepone) is an or-

ganochlorine insecticide with well deﬁned estro-

genic properties.

5,6

It was extensively used from

1973 to 1993 in the French West Indies, to control

the banana root borer. A few years after the intro-

duction of chlordecone, the widespread pollution of

soils, river water, wild animals, and vegetables grow-

ing in polluted soils was reported.

7,8

This pesticide

undergoes no signiﬁcant biotic or abiotic degrada-

tion in the environment, so permanently polluted

soils and waters have remained the primary source

of foodstuffs contamination, and human beings

continue to be exposed to this chemical.

9-13

Chlordecone is a potential carcinogen and has

been shown to cause hepatic tumors in laboratory

rats and mice.

The carcinogenic and hormonal

properties of chlordecone and its long biologic half-

life raise the possibility of long-term effects, such as

cancer. We tested the hypothesis that chlordecone

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ORIGINAL REPORT

VOLUME 28 䡠 NUMBER 21 䡠 JULY 20 2010

3457

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exposure in adulthood, over a 30-year period, favors the development

of prostate cancer in the French West Indies, where the incidence of

this disease is particularly high.

Chlordecone reductase catalyzes

the reduction of chlordecone to chlordecone alcohol, increasing the

biliary excretion of chlordecone and decreasing its toxicity.

therefore hypothesized that the prostate cancer-causing effects of

chlordecone would be stronger in individuals with functional variants

of the chlordecone reductase gene, rs3829125 and rs17134592, result-

ing in the production of a protein with low levels of enzymatic activity.

We report the results of a case-control study in which chlorde-

cone exposure was evaluated by measuring its concentration in

the blood.

PATIENTS AND METHODS

Study Population

This study was conducted in Guadeloupe, a French archipelago in the

Caribbean, most of the 405,000 inhabitants of which are of African descent.

This study was carried out on 709 consecutive incident cases of histologically

conﬁrmed prostate cancer (June 2004 to December 2007) and 723 controls

without prostate cancer (January 2005 to December 2006). For details of the

selection of cases and controls, see the Appendix (online only).

Trained nurses obtained information for both patients and controls,

concerning demographic characteristics, anthropometrics, periods and places

of residence since birth, lifestyle, occupational data, family history of prostate

cancer, medical background, use of medication, and prostate cancer screening

history. Weight, height, and the circumferences of the waist and hips were

measured at the end of the face-to-face interview. Participants were also asked

to provide a blood sample. The study was approved by the Guadeloupean

ethics committee for studies involving human subjects. Each participant pro-

vided written informed consent.

Laboratory Procedures and Data Management and

Statistical Analyses

Chlordecone analysis, total lipid determination, genotyping methods

and linkage analysis are described in the Appendix (online only).

A reference date was assigned to each participant, corresponding to the

date of histopathologic diagnosis of prostate cancer for patients and the last

date of prostate-speciﬁc antigen (PSA) determination for controls. Plasma

chlordecone concentrations were classiﬁed according to their distribution

among control samples. Values equal to or below the limit of detection (LD)

were used as the reference group and values above the LD were grouped into

tertiles. Based on the realistic assumption that the Guadeloupean population

has been continuously exposed from 1973 to the present day, we obtained a

cumulative exposure index score for each subject. This score was calculated as

the product of current plasma chlordecone concentration and the number of

years of residence in the French West Indies between 1973 and the year of the

reference date. We calculated such scores for subjects with plasma chlordecone

concentrations above LD. The cumulative exposure scores were grouped into

quartiles, based on their distribution among controls, the lowest quartile being

the reference group.

Baseline covariates were compared between patients and controls (Table

1). Odds ratios (OR) and 95% CIs for the risk of prostate cancer were estimated

by unconditional logistic regression. We investigated whether covariates were

confounding factors or effect modiﬁers, by looking at the association between

chlordecone exposure and prostate cancer separately for each of the following

covariates: age, Caribbean origin, education, body mass index, waist to hip

ratio, alcohol use, smoking, past urogenital infections, diabetes (type 2), viral

infections, prostate cancer screening history (during the last 5 years), family

history of prostate cancer (ﬁrst degree), banana farming, past residence in

Western countries, year of reference date, total plasma lipid concentration,

and the series and batch number of chlordecone analysis. Missing data for

covariates varied from none to lower than 5%, except for waist to hip ratio and

genotype, for which 17% and 8.6%, respectively, of the data were missing.

Categorical covariates, including missing data as an additional response, were

modeled as dummy variables representing the different levels. Confounding

covariates were included into the logistic model if they modiﬁed the OR

estimates by more than 10%. Tests for linear trend across exposure categories

were performed, with the natural log-transformed chlordecone concentration

treated as a continuous variable. For values equal to or below the LD, we

assigned a value of the LD divided by 2. We tested for a modiﬁer effect, by

creating an interaction term based on the cross product of these variables and

exposure categories (treated as a continuous variable). Interactions were ex-

amined by entering the interaction terms into the logistic regression model.

We quantiﬁed the signiﬁcance of the interaction term using the Wald test. We

used polytomous logistic regression to estimate risk simultaneously among

controls and non ordered subgroups of cases, as a function of age at onset

(⬍ 60 v ⬎ 60) and prostate cancer stage (local v regional/distant stage). We also

used a composite index of prostate cancer aggressiveness at diagnosis: high

aggressive potential (PSA ⬎ 30 ng/mL or regional/distant stage or Gleason

score of 4 ⫹ 3 and higher) and low aggressive potential (PSA ⬍ 30 ng/mL, local

stage, and Gleason score of 3 ⫹ 4 and lower).

P values lower than .05 were

considered signiﬁcant. All statistical tests were two tailed and were carried out

with SAS version 9.1 (SAS Institute Inc, Cary, NC).

RESULTS

The results presented here were obtained from a study population

comprising 623 of the 709 eligible prostate cancer cases and 671 of the

eligible 722 controls, from whom we were able to obtain blood sam-

ples and determinations of plasma chlordecone concentration. The

baseline characteristics of the study participants are summarized in

Table 1. Chlordecone was detected in the plasma of 68.7% of the cases

and 66.8% of the controls.

Age-adjusted (5-year intervals) and multivariable-adjusted ORs

and 95% CI for the association between prostate cancer and plasma

chlordecone concentrations are presented in Table 2. Using plasma

chlordecone concentration as a means of measuring exposure, we

found that the highest exposure categories were associated with a

signiﬁcantly higher risk. Moreover, the relationship between exposure

and response was signiﬁcant (P ⫽ .002). When we used the cumula-

tive exposure index as a means of measuring exposure, we found that

the highest quartile was associated with a signiﬁcantly higher risk of

prostate cancer and that the exposure-response relationship was sig-

niﬁcant (P ⫽ .004).

When we looked for potential interactions, no modiﬁer effects

were observed for any covariates, other than a history of prostate

cancer in ﬁrst-degree relatives and previous residence in a Western

country. Results for analyses stratiﬁed for these two covariates are

presented in Table 3. Associations between chlordecone exposure and

prostate cancer were stronger in men with a family history of prostate

cancer and in men who had previously lived in Western countries,

with signiﬁcant linear relationships (P ⫽ .03 and P ⫽ .005, respec-

tively). The interaction terms were found to be signiﬁcant for family

history of prostate cancer and past residence in a Western country

(Table 3). Using chlordecone concentrations below the LD as the

reference category and concentrations above LD as the exposure cat-

egory, we carried out a double stratiﬁcation, according to family his-

tory of prostate cancer and past residence in Western countries.

Subjects with both a family history of prostate cancer and previous

residence in a Western country had a higher risk of prostate cancer

(OR, 4.94; 95% CI, 1.15 to 21.23). The risk did not differ from one for

those with neither or only one of these factors (data not shown).

Multigner et al

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We determined whether the chlordecone-prostate cancer associ-

ation depended on clinical characteristics. We found a signiﬁcantly

higher risk for patients age 60 years or older (for the highest tertiles of

detectable values, OR, 1.91; 95% CI, 1.24 to 2.94; P for trend ⬍ .001)

whereas, for patients younger than 60 years, the OR was 1.22 (95%

CI, 0.58 to 2.57; P for trend ⫽ .94). We found that the risk was

signiﬁcantly higher for both local (OR, 1.58; 95% CI, 1.07 to 2.35;

P for trend ⫽ .021) and regional/distant stage (OR, 2.25; 95% CI,

Table 1. Baseline Characteristics of Patients and Controls

Characteristic

Patients (n ⫽ 623) Controls (n ⫽ 671)

ⴱ

No./Total No. % No./Total No. %

Median age, years 66.2 60.6 ⬍ .01

Interquartile range 60.5-71.5 54.0-67.1

Caribbean origin ⬍ .01

French West Indies (Guadeloupe or Martinique) 96.5 91.4

Haiti or Dominica 3.5 8.6

Education .03

High school and higher 13.3 10.7

Secondary 25.4 31.9

Primary 61.4 57.4

Body mass index† .49

Normal (⬍ 25) 44.0 47.0

Overweight (25-29.9) 44.3 41.0

Obese (ⱖ 30) 11.7 12.0

Waist-to-hip ratio ⬎ 0.95 45.4 30.1 ⬍ .01

Current or past alcohol use 86.8 82.9 .05

Current or past smoking 38.3 37.1 .69

Past urogenital infection 16.1 17.2 .65

Type 2 diabetes 18.1 12.3 ⬍ .01

Viral infection 23.5 24.1 .66

Prostate cancer screening history‡ 50.7 13.4 ⬍ .01

Family history of prostate cancer

No 55.9 78.0 ⬍ .01

Yes 24.4 10.2

Do not know 19.7 11.8

Banana farming 11.9 10.0 .27

Past residence in Western countries, ⬎ 1 year§ 29.9 23.9 .02

Median duration of residence in Western countries§ 15.1 13.2 .04

Interquartile range 7.0-26.3 6.5-24.8

Median years of residence in French West Indies from 1973 to reference date 32.8 32.7 .43

Interquartile range 31.5-33.8 30.0-33.3

Median plasma chlordecone,

␮

g/L 0.44 0.40 .39

Interquartile range ⬍ 0.25-1.00 ⬍ 0.25-0.86

Chlordecone reductase SNP (No./total No. with data)

rs3829192

Wild-type C 1,137/1,182 96.2 1,161/1,208 96.1 .91

Variant allele G 45/1,182 3.8 47/1,208 3.9

rs17134592

Wild-type C 1,137/1,182 96.2 1,161/1,208 96.1 .91

Variant allele G 45/1,182 3.8 47/1,208 3.9

Median PSA levels, ng/mL 8.75

Interquartile range 6.00-14.30

Gleason score

ⱕ 7(3⫹ 4) 82.0 —

4 ⫹ 3 and ⬎ 7 18.0 —

TNM

T1c or T2 and N0 and M0 13.8 —

T3 or T4, or N⫹ or M⫹ 86.2 —

Abbreviations: SNP, single nucleotide polymorphism; PSA, prostate-speciﬁc antigen.

ⴱ

P values for continuous variables are those for non parametric Mann-Whitney rank tests; for plasma chlordecone concentration values equal to or below the limit

of detection, we assigned rank values corresponding to the value of the limit of detection divided by 2; for categorical variables, P values were obtained in tests for

heterogeneity across levels and for SNPs, in tests for Hardy–Weinberg equilibrium among controls.

†The body mass index is the weight of the subject in kilograms divided by the square of the height in meters.

‡Within the 5-year period before the PSA test preceding the histological diagnosis of cases or allowing the selection of controls.

§All but four of the migrants had lived in mainland France. The remaining four migrants had lived in Germany.

Chlordecone Exposure and Prostate Cancer

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1.16 to 4.34; P for trend ⫽ .018). However, using the composite

index of aggressiveness, a signiﬁcantly higher risk was found only

for high aggressive forms (OR, 2.16; 95% CI, 1.33 to 3.51; P for

trend ⫽ .004), with the OR for low aggressive forms being only 1.45

(95% CI, 0.96 to 2.19; P for trend ⫽ .04).

Both SNPs, rs3829125 and rs17134592, were in Hardy-Weinberg

equilibrium in the controls (P ⬎ .05). These variants were in complete

linkage disequilibrium with D’ and r

of 1, and were present at identi-

cal frequencies in cases and controls. The frequencies of the allele

variants were low (0.04). We therefore stratiﬁed the analysis according

to genotype, using chlordecone concentrations at or below the LD as

the reference category and concentrations above the LD as the expo-

sure category. For carriers of variant alleles, a non signiﬁcant increase

in prostate cancer risk was observed (OR, 5.23; 95% CI, 0.82 to 33.32),

whereas the OR for wild-type allele homozygotes was 1.30 (95% CI,

0.91 to 1.85).

DISCUSSION

This study reveals that chlordecone exposure, evaluated by determin-

ing plasma chlordecone concentration, is consistently associated with

an increase in the risk of prostate cancer, and with a signiﬁcant

exposure-response relationship. This is the largest study to have inves-

tigated the effects of organochlorine compounds on prostate cancer

risk through the evaluation of exposure by biologic measurement.

Previous studies have been exploratory and based on less than 80

incident or prevalent prostate cancer cases.

18-21

A signiﬁcant increase in risk was observed after adjustment for

covariates. This unusual ﬁnding is explained by the contribution of

waist-to-hip ratio (abdominal obesity) and prostate cancer screening,

which act as negative confounding factors. In our population study,

both abdominal obesity and prostate cancer screening were associated

with a signiﬁcant increase in the risk of prostate cancer (data not

shown), as reported for abdominal obesity in other populations,

22,23

and for prostate cancer screening. We also found that these two co-

variates were associated with lower plasma chlordecone concentra-

tions in our study. In the case of abdominal obesity, peripheral fat may

sequester organochlorine lipophilic compounds, leading to an inverse

association between peripheral fat levels and circulating concentra-

tions of organochlorine compounds.

Many factors may account for

the observed inverse relationship between prostate cancer screening

and plasma chlordecone concentration. For example, we found that

individuals with a history of prostate cancer screening were more

likely to have lived in Western countries, and were less likely to have

worked on banana plantations, these factors in turn being associated

with lower plasma chlordecone concentration. In addition, screening

procedures may introduce distortions in the associations between

exposures of interest and cancer outcomes if the study would have

included fewer cases in the absence of screening.

This is particularly

true for Guadeloupe, where the recorded incidence of prostate cancer

Table 2. Plasma Chlordecone Concentration and Risk of Prostate Cancer

Chlordecone No. of Patients No. of Controls

Age Adjusted Multivariable

ⴱ

OR 95% CI OR 95% CI

Plasma concentration,

␮

g/L

ⱕ 0.25 (LD) 195 223 1.00 1.00

⬎ 0.25-0.47 128 150 0.95 0.69 to 1.31 1.11 0.75 to 1.65

⬎ 0.47-0.96 139 149 1.16 0.84 to 1.59 1.22 0.82 to 1.83

⬎ 0.96 161 149 1.27 0.93 to 1.72 1.77 1.21 to 2.58

Cumulative exposure index by quartile,

␮

g/L ⫻ No. of years†

1 (lowest) 88 112 1.00 1.00

2 101 112 1.05 0.69 to 1.58 1.06 0.62 to 1.82

3 101 112 1.15 0.76 to 1.74 1.23 0.72 to 2.11

4 134 112 1.33 0.89 to 1.99 1.73 1.04 to 2.88

Abbreviations: OR, odds ratio; LD, limit of detection.

ⴱ

The multivariable logistic model includes age (5-year intervals), total plasma lipid concentration (continuous), waist-to-hip ratio (ⱕ 0.95, ⬎ 0.95) and history of

prostate cancer screening (no, yes).

†For subjects with values above LD.

Table 3. Plasma Chlordecone Concentration and Interaction With Family History of Prostate Cancer, and Past Residence in Western Countries

Chlordecone Plasma

Concentration (

␮

g/L)

Without Family History of Prostate

Cancer

ⴱ

With Family History of Prostate Cancer

ⴱ

Interaction

Without Past Residence in Western

Countries

ⴱ

With Past Residence in Western

Countries

ⴱ

Interaction

ⴱ

No. of

Patients

No. of

Controls OR 95% CI

No. of

Patients

No. of

Controls OR 95% CI

No. of

Patients

No. of

Controls OR 95% CI

No. of

Patients

No. of

Controls OR 95% CI

ⱕ 0.25 (LD) 116 161 1.00 45 26 1.00 137 165 1.00 58 56 1.00

⬎ 0.25 to 0.47 78 111 1.35 0.80 to 20.26 26 19 0.97 0.33 to 2.83 87 116 1.09 0.68 to 1.74 41 34 1.15 0.53 to 2.48

⬎ 0.47 to 0.96 81 115 1.13 0.66 to 1.95 34 8 3.22 1.03 to 10.05 103 110 1.12 0.69 to 1.82 36 39 1.33 0.62 to 2.86

⬎ 0.96 68 123 1.27 0.76 to 2.13 45 14 3.00 1.12 to 8.07 ⬍ .001 110 118 1.53 0.98 to 2.39 51 31 2.71 1.26 to 5.83 ⬍ .001

Abbreviations: OR, odds ratio; LD, limit of detection.

ⴱ

The multivariable logistic model includes age (ﬁve-year intervals), total plasma lipid concentration (continuous), waist-to-hip ratio (ⱕ 0.95, ⬎ 0.95) and history of

prostate cancer screening (no, yes).

Multigner et al

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increased dramatically during the study period,

mostly due to the

development of PSA testing in the population. Consistent with this, it

should be borne in mind that one of the potential negative conse-

quences of prostate cancer screening is an increase in the diagnosis of

indolent or latent tumors that will never be a problem to the patient

and would not have been detected without screening. Such tumors,

like those found in autopsy series,

may reﬂect the natural aging

process rather than the consequences of exposure to chemicals, such as

chlordecone, in the environment.

Cancer is generally thought to occur a long time after the ﬁrst

exposure and after long periods of continuous exposure. Our study

population ﬁts this requirement, with the median exposure period

being almost 33 years. Moreover, given that chlordecone exposure in

our study population began in adulthood, at a median age of 30.2 years

(the youngest subject being 13 years old at the start of exposure), our

study did not include cases of exposure during critical periods for

carcinogenesis, such as the fetal or neonatal periods.

The prostate cancer risk associated with chlordecone exposure

was higher in subjects with a family history of prostate cancer. Similar

ﬁndings were reported for pesticide exposure in the Agricultural

Health Study.

27-30

Study subjects and their ﬁrst-degree relatives may

have similar patterns of exposure, and this might lead to a statistical

interaction between chlordecone exposure and family history of pros-

tate cancer; alternatively, the observed interaction may be indicative of

an inherited genetic trait, such as a polymorphism in a metabolic

enzyme that alters the balance between bioactivation and detoxiﬁca-

tion in the body.

The prostate cancer risk associated with chlordecone exposure

was particularly marked in subjects who had spent some time living in

a Western country. Most such subjects in our study migrated to a

Western country at the beginning of adulthood, remaining there for a

mean duration of 14 years. Most of these subjects returned to the

French West Indies at the time at which chlordecone use began. Many

intervening factors may explain the interaction observed and any

potential causal relationship should be interpreted with caution. Mi-

gration constitutes a period of exposure to speciﬁc environmental risk

factors, including hazardous chemicals or nutritional agents. Residing

in Western countries may induce signiﬁcant changes in an individual,

due, for example, to the adoption of a Western lifestyle, including, in

particular, eating habits that may be risk factors for prostate cancer.

Such changes in lifestyle may then be maintained by these individuals

after their return to the French West Indies.

Previous studies have shown differences in the interindividual

activity of chlordecone reductase in the liver between white and Japa-

nese individuals.

16,32

Such variability has been associated with a pro-

tein variant that arises from two nucleotide (C to G) substitutions at

positions 434 and 931 of the cDNA.

We show here that these two

mutations are in complete linkage disequilibrium and that the fre-

quency of the variant allele (0.04) is lower than that previously re-

ported in whites (0.10).

Although limited by the small number of

subjects, the observed high risk associated with carrying at least one

variant allele, for individuals with chlordecone concentrations above

the LD, is consistent with the mutated enzyme being less efﬁcient. This

may lead to lower levels of biliary excretion and of chlordecone clear-

ance from the circulation.

Chlordecone may act as a tumor promoter, through hormone-

mediated effects. Chlordecone binds the estrogen receptors

␣

(ER

␣

)

and

␤

(ER

␤

), acting as an agonist of ER

␣

and an antagonist of

␤

6,34,35

␣

mediates the adverse effects of estrogen on the pros-

tate, such as aberrant proliferation, inﬂammation, and malignancy.

␤

exerts opposite and beneﬁcial effects, such as antiproliferative,

anti-inﬂammatory, and, potentially, anticarcinogenic effects.

The

human prostate expresses both ER

␣

and ER

␤

, with ER

␣

expressed

primarily on stromal cells and ER

␤

found in the differentiated epithe-

lium.

37,38

The interplay between the agonistic effects on ER

␣

and the

antagonistic effects on ER

␤

of chlordecone may increase proliferation

of estrogen-sensitive tissues, increasing the risk of cancer. In addition

to its interaction with nuclear ER, chlordecone may activate alterna-

tive estrogen signaling pathways or other enzymes and receptors in-

volved in steroidal homeostasis.

39-43

It remains unclear whether such

mechanisms actually take place in human prostate and whether they

trigger prostate cancer.

We are aware of the inherent limitations of patient-control

studies. Several factors potentially generating bias must be consid-

ered, particularly those relating to differential errors in the mea-

surement of disease or exposure. Patient identiﬁcation was based

on unequivocal histologic criteria and controls were selected on the

basis of strict criteria, such as normal ﬁndings on digital rectal

examination and PSA in the normal range for age, taking into

account the ethnic origin of the population. We recruited incident

rather than prevalent patients, and controls were selected from a

representative sample of the male Guadeloupean population dur-

ing the study period. Exposure was evaluated on the basis of objec-

tive determinations of plasma chlordecone concentration, rather

than on questionnaires, which might generate recall bias. Single

determinations of plasma chlordecone concentration have been

shown to provide an accurate reﬂection of the load of this com-

pound in the body.

44,45

Classical organochlorine compounds (de-

termined in blood or fat tissues) have been found at lower

concentrations in French West Indies populations than in most

other populations and are not correlated with chlordecone levels.

The quantitative evaluation of chlordecone exposure-response is

therefore unlikely to have been confounded by the presence of

other organochlorine compounds in our study. However, we can-

not exclude the possibility that some unknown confounding fac-

tors remain that may account for the associations observed.

In conclusion, our results suggest that there is a causal relation-

ship between chlordecone exposure and prostate cancer risk. Our

study also suggests that this association may be affected by genetic

background, together with environmental agents related to diet or

lifestyle. These ﬁndings require further investigation.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS

OF INTEREST

The author(s) indicated no potential conﬂicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Luc Multigner, Pascal Blanchet

Financial support: Luc Multigner, Marc Romana, Bernard Je´gou,

Pascal Blanchet

Provision of study materials or patients: Helene Delacroix-Maillard,

Pascal Blanchet

Chlordecone Exposure and Prostate Cancer

Downloaded from ascopubs.org by 37.58.186.129 on February 8, 2017 from 037.058.186.129

Collection and assembly of data: Luc Multigner, Jean Rodrigue Ndong,

Arnaud Giusti, Marc Romana, Helene Delacroix-Maillard,

Pascal Blanchet

Data analysis and interpretation: Luc Multigner, Jean Rodrigue Ndong,

Arnaud Giusti, Marc Romana, Sylvaine Cordier, Bernard Je´gou, Jean

Pierre Thome, Pascal Blanchet

Manuscript writing: Luc Multigner, Jean Rodrigue Ndong, Arnaud

Giusti, Marc Romana, Helene Delacroix-Maillard, Sylvaine Cordier,

Bernard Je´gou, Jean Pierre Thome, Pascal Blanchet

Final approval of manuscript: Luc Multigner, Jean Rodrigue Ndong,

Arnaud Giusti, Marc Romana, Helene Delacroix-Maillard, Sylvaine

Cordier, Bernard Je´gou, Jean Pierre Thome, Pascal Blanchet

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OURNAL OF CLINICAL ONCOLOGY

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