Environmental and Occupational Exposures and Prostate Cancer

Introduction

Prostate cancer is the most common solid organ malignancy diagnosed in men and the second leading cause of cancer deaths in American men. The etiology and risk factors for prostate cancer are largely unknown. Some theories suggest that environmental carcinogens or occupation-related exposures may be associated with prostate cancer. In particular, research efforts have focused on the interplay between environmental exposures and hormonal aspects of prostate growth and carcinogenesis. Chemicals, such as endocrine disruptors, have garnered attention in recent years. While no definitive associations between environmental or occupational exposures have been identified, this continues to be an active research area.

This review of the current literature of environmental/occupational exposures and prostate cancer will cover topics including Agent Orange (AO), endocrine disruptors, pesticides and farming, metal exposures, rubber manufacturing, whole body vibration, and air pollution.

Agent Orange

AO, named for the color of its storage containers, was used extensively as a defoliant in the Vietnam War. It was composed of a mixture of 2,4-dichloro-phenoxyacetic acid (2,4-D) and 2,4,5-trichloro-phenoxyacetic acid (2,4,5-T). The mixture was contaminated with 2,3,7,8- tetrachlorodibenzo- p -dioxin, a by-product and known carcinogen. Over the course of the conflict, eleven million gallons of AO were sprayed in southeast Asia. In 1998, the National Academy of Science reviewed the association between AO and prostate cancer and the committee found “limited/suggestive evidence.”

Various studies have examined the relationship between AO and prostate cancer with conflicting results. A study of cancers in veterans who participated in “Operation Ranch Hand,” an Air Force initiative for aerial AO spraying, found an increased incidence of prostate cancer in exposed veterans.

A case-control study looked at whether AO exposure is associated with prostate cancer diagnosis. The authors identified 47 prostate cancer cases and 142 randomly selected controls from the Ann Arbor Veterans Affairs (VA). After controlling for age and race, veterans reporting AO exposure were more likely to have a diagnosis of prostate cancer, though this result did not reach statistical significance (OR 2.06, 95% CI 0.81–5.23).

Chamie et al. assessed the incidence and characteristics of prostate cancer in AO-exposed veterans in the Northern California VA Health System. The cohort included a total of 13,144 veterans, 6214 exposed and 6930 unexposed based on the standard VA protocol for AO exposure determination. AO exposed veterans with prostate cancer were younger, had high-grade disease, and were more likely to present with metastases. After adjusting for other risk factors, the odds ratio for developing any prostate cancer after AO exposure was 4.83 (95% CI 3.42–6.81). High-grade cancer was independently associated with AO (OR 2.59, 95% CI 1.3–5.13). The authors conclude that AO exposure was the most important factor for predicting high-grade prostate cancer.

Another study corroborated these results in a 2720 veteran cohort. In multivariable logistic regression analysis, AO exposure was associated with higher odds of prostate cancer on biopsy (OR 1.52, 95% CI 1.07–2.13), high-grade prostate cancer (OR 1.74, 95% CI 1.14–2.63), and Gleason 8 or greater prostate cancer (OR 2.1, 95% CI 1.22–3.62). Exposed veterans in this study were diagnosed with prostate cancer 5 years earlier than their unexposed counterparts.

AO exposure may impact outcomes after prostate cancer treatment. A retrospective review of 1592 veterans from the West Los Angeles, Palo Alto, Augusta, and Durham VA hospitals found a higher risk of biochemical progression and shorter PSA doubling time after radical prostatectomy with AO exposure.

Despite conflicting evidence, the Department of Veterans Affairs recognizes an association between AO and prostate cancer and provides compensation and healthcare to veterans with documented exposure.

Pesticides and farming

Farming is associated with an increased risk of cancer, possibly due to on-the-job exposures to chemicals such as pesticides. In the Agricultural Health Study there was a slightly higher standardized incidence ratio (SIR) of cancer in private farmers as compared to controls (1.19, 95% CI 1.14–1.25). The SIR was even higher for commercial pesticide applicators in the study (1.28, 95% CI 1–1.61). A meta-analysis of 12 studies including 3978 prostate cancer cases and 7393 controls found an increased likelihood that cases were farmers by occupation when compared to controls (meta OR 1.38, 95% CI 1.16–1.64); however, there was an inverse relationship between pesticide exposure and prostate cancer (meta OR 0.68, 95% CI 0.49–0.96).

Other conflicting studies include the Netherlands Cohort Study that after 9.3 years of follow-up and controlling for multiple variables found no association between occupational exposure to pesticides and prostate cancer. Pesticide use is dominated by the United States and Europe who together consume 25–30% of pesticides worldwide.

A meta-analysis of 22 studies from the United States, Canada, and Europe found an elevated meta-rate ratio of 1.13 (95% CI 1.04–1.22) for prostate cancer in farmers and pesticide applicators. An expanded meta-analysis by the same authors included, in addition to farmers, occupations such as agricultural pesticide applicators, farmers licensed to use pesticides, farmers reporting exposures to pesticides, nursery and greenhouse workers, and employees of pesticide spraying companies. In the 22 studies analyzed, the meta-rate ratio for pesticide exposure and prostate cancer was 1.24 (95% CI 1.06–1.45), slightly higher than the smaller meta-analysis. When limited to pesticide manufacturing workers, they found a meta-rate ratio of 1.28 (95% CI 1.05–1.58). The main chemical class exposures associated with prostate cancer were herbicides contaminated with dioxin and/or furan.

Other studies have looked at specific agricultural chemicals and risk of prostate cancer. A case-control study based in the California Central Valley from 2005 to 2006 used the geographical information system (GIS) approach to quantify pesticide exposure and type and in 173 cancer registry cases and 162 control subjects. Methyl bromide and organochlorines were associated with an increased risk of prostate cancer. Similarly, a systematic review of three epidemiologic studies found that prostate cancer risk increased in a dose-dependent pattern to methyl bromide exposure. This finding was pronounced for men with a family history of prostate cancer (OR 3.47, 95% CI 1.37–8.76).

Methyl bromide binds covalently to DNA and creates DNA adducts that lead to sister chromatid exchange. The purported mechanism of prostate cancer carcinogenesis occurs via inactivation of two gene products (pi-class glutathione S-transferases (GSTP1) and glutathione S-transferase theta ) that protect cells from cytotoxic and carcinogenic agents. Methyl bromide has been used as a fumigant to strip soil off pathogens, though it has also been used to disinfect furniture, wood, barges, warehouses, buildings, cargo ships, and freight containers. Exposure is primarily through inhalation or direct skin contact. It was first recognized as a potential carcinogen in a cohort study of chemical plant workers who had long-term exposures and had higher mortality from testicular cancer than the general population.

The largest study of pesticides and a variety of diseases including prostate cancer is the Agricultural Health Study (AHS), a prospective cohort study of nearly 89,000 licensed pesticide applicators from North Carolina and Iowa. The study enrolled 82% of individuals applying for licenses for restricted use pesticides between December 1993 and December 1997. Participants completed detailed pesticide exposure, diet, and medical history questionnaires and cancer cases were identified from cancer registries. Follow-up of the cohort continues today.

An update of the AHS prostate cancer cohort identified 1962 cancers of which 919 were defined as aggressive based on Gleason score greater than 7, distant metastases or underlying cause of death being prostate cancer. Three organophosphate insecticides (fonofos, malathion, terbufos) and one organochlorine insecticide (aldrin) were associated with development of aggressive prostate cancer, especially in those with a family history ( Table 22.1 ). Organophosphate pesticides are metabolized to highly toxic intermediaries called oxons, which create reactive oxygen species that damage DNA. Organochlorines are endocrine disruptors and accumulate in fat to have a potentially continuous effect.

The hormonal and endocrine disrupting effects of pesticides may cause prostate carcinogenesis. Vinclozolin, a fungicide for crops, has antiandrogen activity and interferes with androgen receptor activity. Maternal exposures may cause epigenetic changes that result in premature acinar atrophy and aging-associated prostatitis. DDT and DDE are pesticides that function as 5-alpha-reductase inhibitors. In the Agricultural Health Study, chlorpyrifos, fonofos, and phorate inhibit P450 enzymes that metabolize sex hormones such as estradiol, estrone, and testosterone. These enzymes are found in the liver and the prostate.

Certain individuals may have a genetic predisposition to prostate cancer after pesticide exposure, explaining the link between family history of prostate cancer and pesticides. The AHS prostate cancer cohort has been further subdivided into nested case-control studies consisting of 776 prostate cancer cases and 1444 controls designed to examine genetic susceptibilities. One recent study identified an interaction between the base excision repair (BER) gene NEIL3 , increasing exposure to fonofos and prostate cancer. Men with a mutation-high fonofos use were 3.25 times more likely to develop prostate cancer than men reporting no use. Derangement in BER genes leads to deficits in oxidative damage repair and has been associated with carcinogenesis.

A genome-wide association study from the same nested cohort found that men with prostate cancer single nucleotide polymorphisms (SNPs) who were exposed to pesticides were more susceptible to developing prostate cancer. Men with two T alleles at the rs2710647 SNP in the EHBP1 gene and high exposure to the pesticide malathion had a 3.43 times higher risk of developing prostate cancer (95% CI 1.44–8.15). EHBP1 is located at chromosome 17q24 and participates in signal transduction and other cell membrane functions. Similarly, men with two A alleles at the rs7679673 SNP in the TET2 gene and high exposure to the pesticide aldrin had 3.67 times the risk of prostate cancer as unexposed men (95% CI 1.43–9.41). TET2 is a tumor suppressor gene located on chromosome 4 and involved in androgen regulation in prostate cancer cell lines.