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Testicular cancer and occupational exposures with a focus on xenoestrogens in polyvinyl chloride plastics 

Chemosphere 40 (2000) 1277-1282

Carl-Göran Ohlson a ,*, Lennart Hardell b

a Department o/ Occupational and Environmental Medicine, Orebro Medical Centre, SE-701 85 Orebro, Sweden
b Department of Oncology, Orebro, Medical Centre, SE-701 85 Orebro, Sweden
* Corresponding author. Fax : +46-19 120404.
E-mail address:
carl-goran.ohlson@orebroll.se (C.-G. Ohlson).

1. Introduction

The aetiology of testicular cancer is poorly understood and cryptorchidism, i.e., undescended testis, is the only established risk factor (Schottenfeldt et al., 1980). Prenatal factors have also been hypothesized to be of aetiological importance such as maternal hormonal levels (Bernstein et al., 1988). There is a growing interest in the possible role of xenoestrogens, i.e., substances in the environment with oestrogenic properties, but no mechanism has been proposed, which could explain their enhancement of the growth of a testis tumor (Toppari et al., 1995).

Impacts of increasing levels of xenoestrogens have been observed in aquatic systems (Staples et al., 1997). In humans concern has focused on the "endocrine disrupting chemicals" with either oestrogenic or antiandrogenic effects, which may be aetiologically related to an increase in the prevalence of hypospadia in newborn boys (Dolk, 1998). Indications of a decrease in sperm counts have been observed in recent years but the hypothesis of an association with exposure to xenoestrogens is still a controversial question (Jensen et al., 1995).

The agents most extensively tested for oestrogenic properties are phthalates, bisphenol A and nonylphenols. Phthalates are extensively used in polyvinyl chloride (PVC) as plasticizer and are widely spread in the environment. More than 30 different phthalates have been tested and some of them have oestrogenic properties in vitro. The phthalates reported to have the strongest oestrogenic potencies are butyl benzyl phthalate (BBP) and di-n-butyl phthalate (DBP), being 10"108 times less potent than the natural hormone 17-(3oestradiol (Jobling et al., 1995; Harris et al., 1997). The most commonly used phthalate, di-(2ethylhexyl)phthalate (DEHP), has an even weaker, if any, oestrogenic effect compared to the effect of 17-(3-oestradiol. Bisphenol A is used as an antioxidant and co-stabilizator in PVC-products. It has an oestrogenic potency estimated to be a few orders of magnitude stronger than that of phthalates but still 10'-10° times weaker than that of 17P-oestradiol (Steinmetz et al., 1997; Colerangle and Roy, 1997).

Testicular cancer has usually not been regarded as an occupational disease although increased risks have been reported for various agents and occupations. However the reports taken together do not form a consistent pattern. For more details, see Hardell et al. (1998).

In a case-control study on testicular cancer and various occupational exposures we observed a six-fold increase in the risk for seminoma, one type of testicular cancer, among men exposed to PVC (Hardell et al., 1997, 1998). The aim of this report is to summarize the findings and to discuss the aetiological relationship to xenoestrogens.

2. Material and methods

A detailed report on the recruitment and ascertainment of the cases and the controls is given in a previous publication (Hardell et al., 1997).

Cases with testicular cancer 30-75 yr old and reported to the Swedish Cancer Registry during the time period 1989-1992 were identified. The study encompassed 163 cases, 109 with seminoma testis and 54 with embryonal cancer.

Twice as many male controls as cases were used. They were sampled from the Swedish Population Registry by selecting the next subject in birth registration number (born the same year) as the cases, without any further matching such as to socioeconomic status.

2.1. Assessment of exposure

A 22-page questionnaire was mailed to each case and control. Life-time working history and specific exposures were asked for. The questionnaires were scrutinized by a trained nurse and supplemented over the phone if necessary. These interviews, as well as coding of the questionnaires, were made without knowing if it was a case or a control.

In all, 44 subjects reported exposure to plastics, mostly to styrene. Exposure to PVC plastics were confirmed by contact with the employers or the production managers. Nine subjects reported exposure to PVC and eight were confirmed. For one subject, a case, the company could not be contacted. However, he clearly stated PVC exposure in 1957-1960 in the production of plastic carpets and was included among the exposed subjects. Also jobs with potential exposure to PVC were checked. No additional case or control with such exposure could be identified thereby.

Cumulative exposure to PVC was calculated by multiplying exposure level, part of day (half day= 0.5, whole day= 1) and number of years of exposure. The exposure level was arbitrarily taken as 0 = no exposure, I = low grade exposure and 2 = high grade exposure.

2.2. Statistical methods

Conditional logistic regression model for matched studies was employed to obtain odds ratios (OR) and 95°/ confidence intervals (CI) (SAS Institute, Cary, NC). Analyses were made for different exposures. Exposure variables were dichotomized by the median value into a low and a high exposure category. The analyses were made both with latency times of one and five year. Calculations were performed for variables with at least 10 exposed subjects or if the exposure was of special aetiologic interest. In all, 30 occupations were analysed but only relevant findings are displayed in the tables. In the following results are presented using one year latency period.

3. Results

The questionnaire was answered by 148 cases (91'Y(,) and 314 (87°/) of the enrolled 363 controls. The mean age was similar, 41 yr, range 30-75 yr, for both cases and controls.

3.1. Risks for specific occupations

An increased risk was found for plastics workers, corresponding to an OR of 2.9 (1.3-6.5), Table I.

Increased risks, however not statistically significant, were also observed for engineers in electronic work or telecommunication, OR 2.3, for amateur radio operators, OR 2.2, and for radar equipment workers, OR 2.0 (based on only two exposed cases, both with seminoma).

Table 1 Conditional logistic regression OR and 95'% CI for selected occupations'

Occupation

Exp cases/controls

OR

CI

Amateur radio operator

7/7

2.2

0.7-6.6

Electrician

7/14

1.0

0.4 2.6

Engineer

 

 

 

Electronics/

8/9

2.3

0.8 6.7

telecommunication

 

 

 

Mechanics

4/11

0.8

0.3 2.6

Plastics worker

18/17

2.9

1.3 6.5

Radar worker

2/3

2.0

0.3- 14.2

Road worker

7/8

1.9

0.7 5.5

Telephone

5/11

1.0

0.3--2.8

assembler

 

 

 

Welder

15/37

0.9

0.5- 1.6

Video display unit work

53/84

1.5

0.98- 2.3

a Numbers of exposed cases and controls are given

A somewhat increased risk was found for work with a video display unit. The OR for low exposure (i.e., <480 days) was 1.4 (CI 0.8-2.5; n=24 cases), and for high exposure 1.8 (CI 1.1-3.2; n=29 cases) indicating a dose-response relationship (Table 5). For embryonal cancer OR 2.0 (CI 0.9-4.5; n =16 cases) was obtained, but with no dose-response effect. For seminoma OR was 1.4 (CI 0.8-2.3; n=37 cases). Low exposure gave OR 1.2 (CI 0.6-2.3) and high exposure OR 1.8 (CI 0.9-3.6) (not in table).

3.2. Risks for various plastics

A statistically significant increase in risk for testicular cancer was observed after exposure to PVC corresponding to an OR of 6.6, CI 1.4-32, Table 2. For other types of plastics no significantly increased risks were found.

A summary of exposure to PVC is displayed in Table 3. Six of the seven exposed cases had seminoma.

If subjects with self-reported cryptorchidism were excluded, the risk increased further. Thus, exposure to PVC yielded OR 14.0, CI 1.7-114, for all testicular cancer. One case with exposure to PVC reported that he had orchitis. Even if orchitis is not regarded as an established risk factor for testicular cancer all cases with self-reported orchitis were excluded yielding an OR 10.0, CI 1.2-87, for exposure to PVC. The ORs for exposure to other types of plastics were not significantly changed in similar calculations.

For cumulative exposure to PVC, cases and controls were divided in two groups with three cases and two controls in the lowest exposure group yielding OR 2.6, CI 0.3-32. In the highest exposure group four cases and no control were found indicating a dose-response relationship, although an OR could not be calculated. For the other plastic exposures dose-response relationships were absent or could not be calculated due to low numbers of exposed subjects. The results were similar both with one or five year latency periods.

3.3. Risks for various agents

Asphalt work yielded an unexpectedly high OR of 3.9 (1.1-15), not shown in table. This probably explains the weak overrisk observed in road workers, Table 1. Six of the seven exposed cases had seminoma.

For use of insect repellents an increased OR of 1.7 (CI 1.03-2.8) was found. Seminoma had OR 1.8 (CI 1.0-3.3; n = 26 cases) and embryonal cancer OR 1.4 (CI 0.6-3.6; n = 13 cases). Low exposure (i.e., < 1 15 days) gave OR 1.3 (CI 0.6-2.5; n = 15 cases) and high exposure OR 2.3 (CI 1.2-4.4; n=24 cases) for all testicular cancer.

Contact with transformer oil gave a somewhat increased risk, OR 1.7 (1.4-6.8), based on only four exposed cases. All exposed cases had seminoma.

Table 2 Exposure to plastic in cases and controls

Agent

All cancer

Seminoma

Embryonal carcinoma

 

No.

OR

CI

No.

OR

CI

No. 

OR

CI

Polyvinyl chloride

7/2

6.6

1.4-32

6/2

5.6

1.1-196

1/2

--

--

Styrene

4/15

0.6

0.2-2.0

2/15

0.5

0.1-2.3

2/15

1.0

0.2- 6.4

Urethane

4/5

1.5

0.4-5.6

2/5

1.0

0.2-5.5

2/5

3.2

0.3-37

Acrylate

2/1

3.2

0.3-37

0/1

--

--

2/1

3.2

0.3-37

Plastic, unspecified

4/3

4.3

0.8-24

1/3

2.5

0.2-40

3/3

6.0

0.6-58

a Number of exposed cases/controls, OR and 95% CI are given.

Table 3 Exposure to PVC for cases and controls

Birth year

Cumulative exposure

Year of first exposure

Year of diagnosis

Type of cancer

1930

6

1957

1992

Seminoma

1931

4

1967

1989

Seminoma

1939

12

1977

1989

Seminoma

1945

8

1965

1991

Seminoma

1947

5

1969

1991

Seminoma

1953

0.01

1978

1989

Embryonal

1956

2

1974

1992

Seminoma

1952

0.5

1964

Control

 

1958

2

1979

Control

 

3.4. Non-occupational exposures

Living in urban compared with rural area during childhood and adulthood was assessed, Table 4. A slightly increased risk was found for urban living both during childhood and as an adult. Living within 1000 m distance to a paper or pulp plant, steelworks or waste incinerator, or within a distance of 800 m to a high power line, as well as leisure time contact with any animal, smoking or use of oral snuff were not risk factors for testicular cancer.

In a multivariate analysis exposure to a video display unit, insect repellents and occupational plastics work were thereby identified as independent risk factors, Table 5. Also exposure to PVC was an independent risk factor in the multivariate analysis. Joint effects of these exposures were also analyzed. Significant interaction was found only for exposure to video display unit and insect repellents with OR 2.5 (CI 1.1-5.4). Calculations were also performed using five year latency period for the different exposures. Similar results as for one year latency period (as presented above) were thereby obtained.

Table 4 Conditional logistic OR and 95'% CI for residence a

 

Cases/controls

OR

CI

Maximum of 3000 m:

      Paper or pulp plant

15/23

1.4

0.7-3.0

      Steelworks

13/27

0.8

0.4-1.7

      Waste incinerator

11/19

1.3

0.6-2.8

Maximum of 800 m:

      High power line

15/35

1.0

0.5-1.9

Dwelling, adulthood

      Urban vs. rural

118/233

1.5

0.9-2.4

Dwelling, childhood

      Urban vs. rural

104/210

1.3

0.8-2.0

a Number of exposed cases and controls is given.

Table 5 Multivariate analysis of exposure to video display unit, insect repellents and plastics workers a

Agent Univariate Multivariate
OR  CI OR  CI
Video Display Unit
<480 days 1.4 0.8-2.5 1.4 0.8-2.5
480 days 1.8 1.1-3.2 2.1 1.1-3.7
Insect repellents
<115 days 1.2 0.6-2.5 1.1 0.8-2.5
115 days 2.3 1.2-4.4 2.1 1.1-3.7
Plastics worker
Occupational 2.9 1.3-6.5 3.3 1.4-7.7

a Conditional OR and 95'% CI are given.

4. Discussion

Only living cases and controls were included in the study in order to facilitate the exposure assessment. Bias might have been introduced if a risk factor is associated with poor prognosis for patients with testicular cancer. However, there is no information to support that notion.

4.1. Associations with xenoestrogens

Significantly increased risk was found for exposure to PVC. The induction latency period varied between 11 and 35 years with a median time of 22 years. Six of the seven exposed cases had seminoma. Further, the case with embryonal cancer had a low cumulative exposure. It is unclear why the increased risk was seen only for seminomas, but this tumour type occurs at somewhat older age than embryonal cancer which may increase the probability of an occupational association, although seminoma is not regarded in general as an occupational disease.

The chemical composition of PVC has two features. First, PVC is the only type of plastic which contains chlorine, about 56°/o of the molecular weight. Second, plasticizers, are used in PVC, mostly DEHP, from 0% to almost 50'% of the weight. Almost all phthalates are used in PVC, mostly DEHP, from 0% to almost 50% of the weight. Almost all phthalates are used in PVC production and the oestrogenic effects of some of them are well documented (Jobling et al., 1995; Harris et al., 1997).

The additives bisphenol A and nonylphenol are used as antioxidants in plastics. They are also of interest due to their oestrogenic potency as reported in experimental studies (Steinmetz et al., 1997; Colerangle and Roy, 1996). However, they are used in several types of plastics whereas we found increased risk only for exposure to PVC. It might be added that in a study of cases of stillbirths or infant deaths, some malformations and low birth weight, increased risk was found for mother's exposure during pregnancy to PVC but not for other plastics (Ahlborg et al., 1987).

Exposure to transformer oil was somewhat more frequent among cases, all seminoma, then among controls. Although based on only four cases, the finding is of potential interest since transformer oils used to contain polychlorinated biphenyls (PCBs). Experimental studies have shown that PCBs are not genotoxic but promote cancer development (Dobson and van Esch, 1993) and an association with non-Hodgkin's lymphoma was recently suggested (Hardell et al., 1996; Rothman et al., 1997).

A surprising result was the increased risk found for insect repellents, most pronounced for seminoma. Insect repellents are mostly used in rural areas and might be associated with farming. However, farming and rural dwelling were not associated with seminoma in this study. The majority of insect repellents in Sweden contain N,N-diethyl-m-toluamide (DEET) as the active ingredient. DEET has been associated with neurotoxic symptoms as described in Gulf War veterans (Haley and Kurt, 1997). No reports exist on an association with testicular cancer although atrophy of testis (Anon., 1989) and reduced sperm count have been indicated in experimental animals (Anon., 1980). Furthermore, phthalates may also be used in the manufacture of various consumer products including repellents (Wine et al., 1997).

4.2. Associations with electromagnetic fields

We found a non-significantly increased risk associated with radar work based on only two exposed cases, both with seminoma. This finding might be of interest in relation to the increased risk reported for policemen using hand held radar equipment (Davis and Mostofi, 1993; Finkelstein, 1998).

An association between occupational exposure to electromagnetic fields and testicular cancer has been suggested (Stenlund and Floderus, 1997). We found no increased risk for electricians, but engineers in electronics and telecommunication had just over double risk. Our finding of an increased risk for work with a video display unit might be of some interest in this context and the observed dose-response effect should encourage further research in this area. It might also be mentioned that additives in plastics and in electronic equipment, e.g., polybrominated diphenylethers (PBDE) with hormonal properties may migrate to the air (Bockler et al., 1996; Bergman et al., 1997).

4.3. An hypothesis

Clearly, "endocrine disruptors", e.g., xenoestrogens, may exert an effect on oestrogen receptors on cells, for instance in the testis. There are however at least three problems in interpreting the findings in this study. First, it is not obvious how an oestrogenic substance can promote a tumour in a tissue that is stimulated by hormones with an opposite action, i.e., androgens like testosterone. The weak oestrogenic activity of some xenoestrogens does not explain their profound effects on cell-proliferation in vivo (Colerangle and Roy, 1996, 1997). The interplay between a xenoestrogen, its metabolites, 17-Roestradiol, the oestrogen receptors and tumour induced testis cells seems to be very complex. Synergy between oestrogenic and other possible effects of a xenoestrogen has been proposed (Soto et al., 1997) as well as between different xenoestrogens (Arnold et al., 1996). Weak oestrogens may be antioestrogenic as well, causing a competitive inhibition of the receptor, and both parent compounds and their metabolites may cause both nongenotoxic cell-proliferative effects and genotoxic effects (Yager and Liehr, 1996). Furthermore, an antiandrogenic effect of high doses of di-n-butyl phthalate was demonstrated in rats (Mylchreest et al., 1998) which adds to the complexity of this problem.

The second problem relates to the weak oestrogenic potency of the xenoestrogens compared to the natural hormone 17-[3oestradiol. Even if the oestrogenic potency of DEHP can be estimated to be about one million times weaker than 17-(3oestradiol, the accumulation of DEHP in human tissues may well be many orders of magnitude higher than the concentration of 17-(3-oestradiol - the normal concentration of this hormone in men being only around 100 pmol/l. The concentrations of phthalates in human tissues are, to the best of our knowledge, not known. Still the accumulation of these "endocrine disruptors" may be sufficiently high to have an impact on endocrine sensitive tumours. Furthermore, xenoestrogen may combine a weak oestrogenic potency with a relatively high efficacy in inducing, for instance, hyperprolactinemia (Steinmetz et al., 1997).

The third problem in interpreting the findings is due to the bimodal incidence of testicular cancer. Embryonal cancer occurs mainly in younger men and seems to be influenced by hormonal factors in early infancy while the incidence of seminoma peaks at an older age, indicating a possible role of occupational exposures, adding to the process of ageing.

To conclude, in this case-control study of testicular cancer a surprisingly high risk was observed for exposure to PVC plastics. The shortcomings of retrospective assessment of exposure by a self-administered questionnaire are evident and spurious associations between PVC exposure and seminoma cannot be ruled out. Therefore, the results must be regarded as hypothesis generating and warrant further studies. The findings lend some support to the "endocrine disruptors" hypothesis which, however, must be evaluated in experimental models.

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