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Systematic Review

Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review

[version 1; peer review: 2 approved with reservations]
PUBLISHED 01 Apr 2021
Author details Author details
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Abstract

Background: There is an increasing body of evidence linking the exposure of an individual to pesticides such as organochlorine pesticides (OPCs) and an increased risk of developing diseases such as cancer. Exposure to OPCs has been suggested to increase the risk of developing hormone-dependant cancers such as prostate cancer (PCa). However, there is a relative paucity of information about the influence of exposure to these pesticides on the evolution of PCa, including risk of tumour development, progression to metastasis, and disease recurrence following therapy.
Methods: We used several databases such as PubMed MEDLINE Database, Web of Science, and Scopus, in order to conduct a systematic review of the available epidemiological data implicating an association between exposure to OCPs and biochemical recurrence (BCR) of PCa. We searched all peer-reviewed articles published up to July 31st 2020. Pre-defined eligibility criteria for the inclusion of studies were that they be original studies, reviews, previous meta-analyses, or case–control or cohort studies.
Results: Agent Orange is the most widely-studied OCP in the context of any possible causal role in the recurrence of PCa following radical prostatectomy, or in the progression to advanced disease. Only two studies didn’t demonstrate a significant association between exposure to OCPs and subsequent BCR following radical prostatectomy. Another study identified a significant association between exposure to Oxychlordane and PCB44 and progression to advanced PCa.
Conclusion: This review confirmed a relative lack of high-quality evidence regarding this topic. However, the available evidence to date suggests the presence of a potential causal relationship between exposure to OPCs and PCa development and progression.

Keywords

Organochlorine pesticides, prostate cancer, biochemical recurrence, advanced disease

Abbreviations

AO: Agent Orange; BCR: Biochemical Recurrence; OCs: Organochlorines; OCPs: Organochlorine Pesticides; PCa: Prostate Cancer

Introduction

Prostate cancer (PCa) is the second most common non-cutaneous malignancy diagnosed among men worldwide, and the most common cancer type detected in men in developed countries1. Several risk factors for the development of PCa have been established, including increasing age, positive family history, and accumulated environmental exposure to several hormones2,3. Some pesticides can influence the hormonal milieu in vivo by functioning to mimic the effect of hormones, regulate enzyme systems involved in hormone metabolism, and affect androgenic stimulation of the prostate gland, potentially leading to increased cellular proliferation and progression to malignancy46. Organochlorines (OCs) comprise a large number of pesticides, and these have been used extensively throughout the world for several decades. Whilst their use has been banned or severely restricted in many countries, they remain in use in many areas of the world, and this has the potential to adversely affect the health of individuals in countries where OCs are still in use. OCs are highly-persistent organic pollutants, with a high serum level being reported in several distinct populations710. The International Agency of Research on Cancer (IARC) has classified many OCPs as being Class 2B agents, implicating them as being possible carcinogens11. Moreover, a large number of OCPs have been demonstrated to have the potential to disrupt endocrine function12,13, suggesting that exposure to these specific types of pesticides may increase the risk of developing hormone-dependant cancers such as PCa14. Several OCPs including chlordecone, DDE, DDT and Lindane have been implicated as potential independent risk factors for PCa development1518. However, to date there is a relative lack of information about the impact of exposure to OCPs upon on the development of aggressive metastatic PCa, or influences on PCa disease-free survival, and potential BCR following radical treatment. The aim of this review article is to provide a contemporary update of the epidemiologic evidence implicating exposure to OCPs upon the recurrence of PCa following radical therapy.

Methods

Design and inclusion criteria

We conducted a systematic review of the available epidemiological data investigating a potential relationship between exposure to OCPs and the development of recurrent PCa following radical therapy. We searched all peer-reviewed articles published up to July 31st 2020. Pre-defined eligibility criteria for the inclusion of studies were that they be original studies, reviews, previous meta-analyses, or case–control or cohort studies. Moreover, it was mandatory that they contain information about association measures, including odds ratios (OR), relative risks (RR), and confidence intervals (CI) in order to facilitate an analysis of possible relationships between exposure to specific OCPs and development of recurrent PCa following treatment. Finally, it was necessary for the included studies to provide sufficient data and be written in English, French, or Spanish. Exclusion criteria included in vitro experimental and mechanistic studies, editorials, or letters, and as such these reports were not included in this review.

Search strategy and selection of articles

The initial search strategy included PubMed MEDLINE Database, Web of Science, and Scopus, utilising different “key words” to order identify studies investigating potential associations between exposure to OCPs and development of recurrent PCa following treatment (Figure 1).

e20a8d0e-cdc9-437b-ba8f-0ff1bf11757d_figure1.gif

Figure 1. Flowchart summarising the selection process of the articles included in this review.

MeSH controlled vocabulary was utilised, including combinations of the following key words: ‘‘organochlorine pesticides’’, ‘‘exposure’’, ‘‘DDT’’, ‘‘DDE’’, ‘‘hexachlorocyclobenzene’’, ‘‘lindane’’, ‘‘chlordecone’’, ‘‘kepone’’, ‘‘chlordan’’, ‘‘dicofol’’, ‘‘mirex’’, ‘‘dieldrin’’, ‘‘endrine’’, ‘‘aldrine’’, ‘‘PCB’’, ‘‘dioxine’’, ‘‘endosulfan’’, ‘‘heptachlor’’, ‘‘methoxychlor’’, ‘‘toxaphene’’, ‘‘prostate cancer’’, ‘‘biochemical recurrence’’, ‘‘biochemical failure’’, ‘‘prostatic carcinoma’’, ‘‘prostatic neoplasm’’, ‘‘prostatic adenocarcinoma’’, ‘‘case – control studies’’ and ‘‘cohort studies.’’

Extracted domains included sttudy design, demographics, findings

Results

An overview of five available studies investigating a potential relationship between exposure to OCPs and development of recurrent PCa following radical treatment is provided in Table 1. Two studies did not observe any significant relationship between the exposure of American Veterans to Agent Orange (AO) and subsequent BCR following radical prostatectomy19,20. Li et al. reported that exposure to AO significantly increased the Dioxin-TEQ level in blood samples (p < 0.001), but high dioxin-TEQ levels were not associated with an increased risk of subsequent BCR (p=0.23). A study by Ovadia et al. found that men exposed to AO did not have an increased risk of BCR following radical prostatectomy in both a univariate analysis (HR 1.03; 95% CI 0.84 – 1.25; p=0.80) and a multivariate analysis (HR 1.21; 95% CI 0.99–1.49; p=0.07). However, a study by Shah et al. reported a significant positive association between exposure to AO and BCR following radical prostatectomy. In this study of 206 men, those with documented exposure to AO had a significantly increased risk of subsequent BCR following radical prostatectomy (RR 1.55; 95% CI 1.15 – 2.09; p=0.004 when adjusted for clinical characteristics, and RR: 1.47; 95% CI 1.08 – 2.00; p=0.02 when adjusted for clinical plus pathological characteristics)21. Another study by Brureau et al. revealed a significant positive association between exposure to Chlordecone and BCR following radical prostatectomy and no associations for DDE or PCB-135. In this study of 326 men, those with documented exposure to Chlordecone had a significantly increased risk of subsequent BCR following radical prostatectomy (adjusted HR = 2.51; 95% CI: 1.39 – 4.56; for the highest versus lowest quartile of exposure; p trend = 0.002). In addition, sensitivity analysis revealed that Chlordecone exposure was still significantly associated with a risk of BCR after excluding patients with positive surgical margins or prostatectomy ISUP Gleason grade 3 or higher, or advanced pathological stage22.

Table 1. Details of available studies investigating potential relationship between exposure to OCPs and progression of PCa.

AuthorPopulation studyExposure characteristicsDefinition of BCRAssociation with BCR
Li et al.
Prostate cancer and prostatic
diseases (2013)19
93 men (37 with pesticides exposure
and 56 without) from American Veterans
administration treated by radical
prostatectomy for prostate cancer between
April 2005 and September 2009 with a
median follow-up of 5.3 years
37 men were exposed to Agent O
during the Vietnam War.
Exposure evaluation by measurement
Dioxin-TEQ level in blood.
Not definedNo significant
association
Ovadia et al. Urologic
Oncology: Seminars and
Original Investigation (2015)20
1882 men (333 with pesticides exposure
and 1549 without) from American
Veterans administration treated by radical
prostatectomy for prostate cancer between
1998 and 2011 with a median follow-up of
85 months
333 men were exposed to agent O
during the Vietnam War.
Agent O exposure was determined
by veteran self-reported verified by
Veterans Affairs committee in order to
determine Veterans exposure according
to his location during the war.
1 PSA level > 0.2 ng/ml, 2 levels of
0.2 ng/ml or secondary treatment
for a detectable PSA after radical
prostatectomy
No significant
association
Shah et al.
British Journal of Urology
International (2009)21
1495 men (206 with pesticides exposure and
1289 without) from the Shared Equal Access
Research Cancer Hospital database Veterans
Affairs treated by radical prostatectomy for
prostate cancer between 1988 and 2007 with
a median follow-up of 49 months.
206 men were exposed to agent O
during the Vietnam War.
Agent O exposure was determined by
veteran self-reported
Biochemical progression was
defined as one PSA level of
> 0.2 ng/mL, two of 0.2 ng/mL, or secondary treatment for an
elevated PSA level after radical
prostatectomy.
Significant
association
Brureau et al.
International Joural of Cancer
(2020)22
326 men with pesticides exposure from
University Hospital of Guadeloupe (FWI)
treated by radical prostatectomy for prostate
cancer between 2004 and 2007 with a
median follow-up of 73 months.
326 men were exposed to Chlordecone,
PCB 135 and DDE
Biochemical progression was
defined as one PSA level of
> 0.2 ng/mL, two of 0.2 ng/mL
Significant
association for
Chlordecone
No significant
association for DDE
and PCB 135.
AuthorStudy populationExposure characteristicsAdvanced diseaseAssociation
with metastatic
disease
Koutros et al.
Environmental Health
Perspectives (2015)22
Case control study included 150 cases and
314 controls in a population-based cohort
in Norway, who were diagnosed from
enrolment through 31 December 1999 and
were diagnosed at least 2 years after serum
collection.
150 men with metastatic prostate cancer
from Janus Serum Bank cohort in Norway.
11 organochlorine pesticides and their
metabolites and 34 PCB congeners
were analysed
Metastasis and histologic grade
were caracterized according to
the American Cancer Society’s.
All 184 incident metastatic
prostate cancer cases didn’t have
history of cancer (except non
melanoma skin cancer)
Significant
association for:
Oxychlordane.

PCB44 (inverse
association)

A report by Koutros et al. suggests that other pesticides, such as Oxychlordane and PCB44, may be implicated in modifying the risk of developing advanced PCa. For example, the development of metastatic PCa was twice as likely among men with a serum concentration of Oxychlordane in the highest quartile when compared against those in the lowest quartile (OR 2.03; 95% CI 1.03 – 4.03; p-trend=0.05). Findings for specific PCB-related chemicals showed a significant inverse association between natural log–transformed lipid-adjusted PCB44 and metastatic PCa (OR 0.74; 95% CI 0.56–0.97; p-trend=0.02)23. All characteristics of OCPs involved in BCR or metastatic PCa are summarised in Table 2.

Table 2. Organochlorine pesticide characteristics involved in BCR and metastatic prostate cancer.

NameMolecular structureComments
Agent Orange contaminated by
TCDD (2,3,7,8-tétrachlorodibenzo-
para-dioxine)
e20a8d0e-cdc9-437b-ba8f-0ff1bf11757d_T1.gifLipophilic molecule hence its stability when it’s in a living organism.
It’s resistant to the mechanisms of detoxification and remain stored in
the adipose tissue of animals. It’s chemically very stable molecule and is
therefore bio-accumulated.
His half-life is 5–10 years in human body25.
Oxychlordanee20a8d0e-cdc9-437b-ba8f-0ff1bf11757d_T2.gifBecause of their lipophilic properties and their persistence in the
environment, chlordane and related compounds bioaccumulate and
biomagnify along the food chain26.
PCB44
2,2′,3,5′-Tetrachlorobiphenyl
e20a8d0e-cdc9-437b-ba8f-0ff1bf11757d_T3.gifPCBs appeared to early twentieth century chemists interesting for their
dielectric properties. These are ubiquitous and persistent pollutants. Highly
fat soluble, they are part of the bioaccumulative contaminants commonly
found in fatty tissue in humans. Food is the primary source of PCB
exposure. They have endocrine disruptor properties27.
Chlordeconee20a8d0e-cdc9-437b-ba8f-0ff1bf11757d_T4.gifChlordecone interferes with estradiol signaling through binding to the
nuclear estrogen receptors α (ERα) and β (ERβ), eliciting agonistic and
antagonistic effects, respectively28.

Discussion

This systematic review confirms that there is a relative lack of high-quality evidence implicating a potential association between exposure to OCPs and BCR of PCa. However, the available evidence suggests that there may be a potential causal relationship between exposure to OCPs and development and progression of this malignancy. Agent Orange is the most widely-studied OCP in the context of any possible causal role in the recurrence of PCa following radical prostatectomy, or in the progression to advanced disease24. However, only two studies demonstrated a significant association between exposure to OCPs and subsequent BCR following radical prostatectomy. Two pesticides were involved: Chlordecone and Agent Orange21,22. Another study by Koutros et al. identified a significant association between exposure to Oxychlordane and PCB44 and progression to advanced PCa23. However, each of these studies are limited by their inclusion of a relatively small number of cases. Larger prospective clinical studies would be necessary to confirm these potential associations, however it is recognised that such studies would be very difficult to conduct, and are not presently feasible.

This review highlights the relative lack of evidence on the potential causal role of OCPs in PCa development and progression, despite the observation that a large number of pesticides exist and continue to be in use in many countries worldwide (Table 3). As such, this topic has potential impacts in aspects of global healthcare, and there is widespread public concern regarding pesticide exposure and negative impacts on health29. There is a well-documented causative relationship between exposure to pesticides and increased risk of development of many types of malignancy. It is therefore important to understand in greater detail the potential influence of OCP exposure upon aspects of PCa risk, and to identify the molecular pathways and mechanisms implicit in this increased risk (Figure 2).

Table 3. Organochlorine pesticides involved in prostate cancer risk.

ReferencesStudy designPesticidesOR (95% CI)Intensity of exposure
Alavanja et al. American Journal of
Epidemiology (2003)27
Cases-Controls
566 cases and 54766
controls
Chlorinated pesticidesa1.3 (1.0 – 1.6)
1.5 (1.2 – 2.0)
T2
T3L
Mills et al. Journal of occupational
and environmental medicine
(2003)15
Cases-Controls
222 cases and 1110
controls
Lindane


Heptachlor
1.9 (1.1 – 3.2)
2.4 (1.2 – 4.6)

2.1 (1.2 – 3.5)
2.0 (1.1 – 3.6)
Level 3
Level 4

Level 3
Level 4
Settimi et al. International journal of
cancer (2003)28
Cases-Controls
124 cases and 659
controls
DDT


Dicofol
2.2 (1.1 – 4.8)
2.8 (1.5 – 5.0)

2.8 (1.5 – 5.0)
2.4 (1.2 – 5.3)
3.0 (1.3 – 7.0)
Ever
≤ 15 years

Ever
≤ 15 years
> 15 years
Xu et al. Environmental Health
Perspectives (2010)24
Cases-Controls
1153 cases and 3999
controls
beta-Hexachlorocyclohexane3.4 (1.2 – 2.9)T3U
Band et al. The Prostate (2011)16Cases-Controls
65 cases and 1920
controls
DDT

Lindane
1.7 (1.0 – 2.7)

2.0 (1.2 – 3.6)
High

High
Cockburn et al. American Journal of
Epidemiology (2011)29
Cases-Controls
173 cases and 162
controls
Organochlrorine pesticidesb 1.6 (1.0 – 2.6)
2.0 (1.2 – 3.5)
Ever
High
Multigner et al. Journal of Clinical
Oncology (2011)17
Cases-Controls
623 cases and 671
controls
Chlordecone1.8 (1.2 – 2.6)Qu4
Emeville et al. Environmental Health
Perspectives (2015)18
Cases-Controls
576 cases and 655
controls
DDE1.5 (1.0 – 2.3)Qu5

T3L = lower tertile 3, T3U = uppertertile3, Q1, Q2, Q3, Q4 = Quartiles, Qu1, Qu2, Qu3, Qu4, Qu5 = Quintiles

a Included aldrin, chlordane, DDT, dieldrin, heptachlorandtoxaphene

b Dicofol, dieldrin, dienochlor, endosulfan, heptachlor, lindane, methoxychlor, and toxaphene

e20a8d0e-cdc9-437b-ba8f-0ff1bf11757d_figure2.gif

Figure 2. Putative molecular effects of organochlorine pesticides.

Some OCPs, such as PCBs and Chlordecone, have functional properties that disrupt various endocrine pathways, including the synthesis, secretion, transport, and binding of hormonal ligands to their cognate receptors, whilst in addition they may result in the elimination of natural human hormones30. Phthalte pesticides are endocrine disruptor molecules with demonstrable estrogenic effects in breast and PCa cells, and these may also be implicit in the etiology of hormone-independent PCa cancer31. Given that phthalates are estrogen-like substances, they can positively regulate the proliferation of human hormone dependent PCa cells by acting on the crosstalk between TGF-β and oestrogen receptor signaling pathways32. In addition, some studies suggest that estrogen and xenobiotic carcinogens may play an important role in PCa progression via oxidative estrogen metabolism. For example, the CYP1B1 enzyme is involved in the hydroxylation of estrogens, and this reaction is of key relevance to the regulation of estrogen metabolism33. The over-production of estrogen-like E2, or the bioconversion of E2 into genotoxic metabolites such as estradiol-3,4-quinone or 4-hydroxyestradiol by CYP1B1, may lead to the generation of reactive oxygen species which subsequently cause DNA damage and enhance PCa progression34. In support of this hypothesis, Gu et al. observed that men with the CY1B1 rs1056836 CC genotype had an increased risk of PCa recurrence following radical prostatectomy when compared against a combined CG and GG genotype35.

Conclusion

In conclusion, this review highlights the relative lack of studies regarding the potential influence of OCPs on the recurrence and progression of PCa following radical therapy. An increased understanding of the pathways and mechanisms through which pesticides may influence the natural history of PCa progression could influence the clinical management of men with this ubiquitous and common malignancy. It is important that the current relatively small body of evidence demonstrating a negative influence of OCPs on PCa risk should be added to in as timely a fashion as possible so that knowledge of this important health topic can increase, with a resultant positive health benefit for a significant number of individuals worldwide.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Figshare: PRISMA checklist for ‘Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review’, https://doi.org/10.6084/m9.figshare.14245694.v136.

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

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Brureau L, Multigner L, Hamdy F et al. Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review [version 1; peer review: 2 approved with reservations]. F1000Research 2021, 10:262 (https://doi.org/10.12688/f1000research.29990.1)
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
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Reviewer Report 22 May 2023
Pradeep Kumar Sharma, CSIR-Indian Institute of Toxicology Research, Lucknow, India 
Approved with Reservations
VIEWS 10
Brureau et al, in their work titled "Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review" have attempted to provide an evidence for causality between OCPs exposure and prostate cancer development, which is really pertinent ... Continue reading
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Sharma PK. Reviewer Report For: Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review [version 1; peer review: 2 approved with reservations]. F1000Research 2021, 10:262 (https://doi.org/10.5256/f1000research.33040.r172373)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 28 Feb 2022
Matthew J Roberts, Department of Urology, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia 
Approved with Reservations
VIEWS 6
Thank you for asking me to review this systematic review. The topic is interesting, especially as many men are exposed to OCPs that may be implicated in PC pathogenesis. The literature is limited, which is acknowledged. For the most part, ... Continue reading
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Roberts MJ. Reviewer Report For: Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review [version 1; peer review: 2 approved with reservations]. F1000Research 2021, 10:262 (https://doi.org/10.5256/f1000research.33040.r125204)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 01 Mar 2022
    Laurent BRUREAU, CHU de Pointe-à-Pitre, Univ Antilles, Univ Rennes, Inserm, EHESP, CHU de la Guadeloupe, Pointe-à-Pitre, France
    01 Mar 2022
    Author Response
    Thank you for reviewing this work. The objective of this review is to warn against the risk of exposure to pesticides and in particular organochlorines on prostate cancer. Indeed, most ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 01 Mar 2022
    Laurent BRUREAU, CHU de Pointe-à-Pitre, Univ Antilles, Univ Rennes, Inserm, EHESP, CHU de la Guadeloupe, Pointe-à-Pitre, France
    01 Mar 2022
    Author Response
    Thank you for reviewing this work. The objective of this review is to warn against the risk of exposure to pesticides and in particular organochlorines on prostate cancer. Indeed, most ... Continue reading

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Alongside their report, reviewers assign a status to the article:
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Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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