Lennart HARDELL1*, Carl-Goran OHLSON 2 and Mats FREDRLKSON3
1Department of Oncology Orebro Medical Center, Orebro Sweden
2 Department of Occupational and Environmental Medicine, Örebro Medical Center, Örebro, Sweden
3 Department of Occupational and Environmental Medicine, University Hospital, Linköping, Sweden
Contract grant sponsors: Telehjälpen, the Swedish Cancer Society and the
Orebro County Council Research Committee.
*Correspondence to: Department of Oncology, Orebro Medical Center, S-701 85 Orebro Sweden. Fax: + 46 19 18 35 10. E-mail: email@example.com
Received 20 May 1997; Revised 31 July 1997
Occupational exposures were assessed in a case-control study on testicular cancer using self-administered questionnaires. In total, answers were obtained for 148 (91 %) cases and 315 (87%) controls. Of the cases, 101 had seminoma and 47 had embryonal testicular cancer. An increased odds ratio (OR) was found for exposure to polyvinyl chloride (PVC) yielding an OR of 6.6 (95% confidence interval, 1.4-32). The risk increased further if cases with self-reported cryptorchidism or orchitis were excluded. Six of the 7 exposed cases had seminoma. Exposure to other types of plastics did not significantly increase the risk of testicular cancer. Int. J. Cancer 73:828-830, 1997.
The Swedish age-adjusted incidence of testicular cancer increased by 2.8% annually during the time period 1974-93, with a significant 98% confidence interval (National Board of Health and Welfare, 1997). This is the most common cancer among young men. The etiology is poorly understood. Cryptorchidism is the only established risk factor, and the risk has been reported to be increased also for the descendent testis (Henderson et al., 1979; Schottenfeld et al., 1980). Common risk factors for both cryptorchidism and testicular cancer have thus been suggested (Henderson et al., 1979). Furthermore, some prenatal risk factors seem to be common for both cryptorchidism and testicular cancer such as high levels of estrogens in the first trimester (Cosgrove et al., 1977; Bernstein et al., 1988), high body weight of the mother and low birth weight (Depue, 1984; Berkowitz et al., 1995), premature birth (Depue, 1988), hypospadia (Anonymous, 1992) and inguinal hernia (Swerdlow et al., 1983; Mori et al., 1992).
Prenatal exposures have been discussed to be of etiological significance. Exposure to some environmental pollutants with estrogenic potency have been of special concern during recent years (Toppari et al., 1995).
Testicular cancer has been associated with employment in agriculture and oil and natural gas extraction (Mills et al., 1984), in professionals and administrators (Hayes et al., 1990; Swerdlow et al., 1991; Van den Eeden et al., 1991). Exposure to the solvent dimethylformamide has been suggested to be one risk factor (Ducatman, 1989).
We have performed a case-control study on testicular cancer and lifetime occupational histories with associated exposures. We report here our results relating to job histories in the plastics industry. Results for other occupations and exposures will be reported separately.
MATERIAL AND METHODS
Patients with testicular cancer 30-75 years old and reported to the Swedish Cancer Registry during the time period 1989-1992 were identified. Since the aim of the investigation was to assess occupations and occupational exposures, younger subjects were not included. The cases were living in the middle and northern parts of Sweden. The physicians of 170 incident cases were contacted and asked for permission to include the patient in the study. Seven patients were judged not to be eligible, and the study thus encompassed 163 cases, 109 with testis seminoma and 54 with embryonal cancer. In addition to the 170 cases, 18 patients treated at these hospitals were deceased and were thus not included.
TABLE I - EXPOSURE TO PVC FOR CASES AND CONTROLS
|Birth year||Cumulative exposure||Year of first exposure||Year of diagnosis||Type of cancer|
Twice as many male controls as cases were studied. They were sampled from the Swedish Population Registry by selecting the next subject in birth registration order (born the same year) as the cases. We were not able to establish contact with 37 of the 326 control subjects and therefore the next subjects in the Population Registry fulfilling the inclusion criteria, i.e., birth registration number and sex, were used.
Assessment of exposure
A 22 page questionnaire was mailed to each case and control. Lifetime working histories were requested, as well as specific occupations and occupational histories. Thereafter, the questionnaires were scrutinized by a trained nurse, who completed the answers if these were unclear or if the question was misunderstood, using a standardized protocol. These interviews, as well as coding of the questionnaires, were made without knowing whether the subject was a case or a control.
In all, 44 subjects reported exposure to plastics, mostly to styrene. Exposures to polyvinyl chloride (PVC) plastics were confirmed by contact with the employers or the production managers. Nine subjects reported exposure to PVC and 8 were confirmed. For 1 subject, a case, the company could not be contacted. However, the subject clearly reported PVC exposure in 1957-60 in the production of plastic carpets, and he was thus included among the exposed subjects. Jobs with potential exposure to PVC were also checked. No additional case or control with such exposure could be identified.
Cumulative exposure was calculated by multiplying the extent of exposure, part of day (half day = 0.5, whole day = 1) by the number of years of exposure. The exposure extent was arbitrarily defined as 0 = no exposure, 1 = low-grade exposure and 2 = high-grade exposure.
TABLE II - EXPOSURE TO PLASTIC IN CASES AND CONTROLS
|Agent||All cancer||Seminoma||Embryonal carcinoma|
1Number of exposed cases/controls.- OR, odds ratio; CI, 95% confidence intervals.
A conditional logistic regression model for matched studies was employed to obtain exact odds ratios (OR) and 95% confidence intervals (CI) (EGRET, Statistics and Epidemiology Research Corporation, Seattle, WA, 1990). Separate analyses were performed for different measures of exposure. The analyses were made with latency times of 1 year and of 5 years.
Of the 163 cases, 148 (91 %) answered the questionnaire compared with 315 (87%) of the 363 controls finally enrolled. Thus, of the 170 incident living cases, 87%o participated in the study.
The mean age for both cases and controls was 41 years (range 30-75). For cases with seminoma (n = 101) the mean age was 43 years (range 30-75), compared with 38 years (range 30-57) for cases with embryonal cancer (n = 47).
A summary of exposure to PVC is shown in Table I. An OR of 6.6 (CI 1.4-32) was obtained for this exposure (Table II). Six of the 7 exposed cases had seminoma. For other types of plastics no significantly increased risk was found.
Only 1 case with exposure to plastic (polystyrene) reported cryptorchidism at a young age. If subjects with self-reported cryptorchidism were excluded, the risk increased further. Thus, exposure to PVC yielded an OR of 14.0 (CI 1.7-114) for all cases of testicular cancer. One case with exposure to PVC reported that he had had orchitis. If all cases with self-reported orchitis were excluded, exposure to PVC yielded an OR of 10.0 (CI 1.2-87). The ORS for exposure to other types of plastics were not significantly changed using similar calculations.
For cumulative exposure to PVC, cases and controls were divided into 2 groups with 3 cases and 2 controls in the lowest exposure group, yielding an OR of 2.6 (CI 0.3-32). In the highest exposure group, with cumulative exposure ?5, 4 cases and no controls were found and no OR could be calculated. For polystyrene. ORs of 0.5 (CI 0.0-5.5) and 0.7 (CI 0.1-3.1) were calculated in the lowest and the highest exposure groups, respectively. For the other plastic exposures dose-response calculations were not carried out due to low numbers of exposed subjects. The results were similar, both with 1 or 5 year latency periods.
Only living cases and controls were included in the study to facilitate the assessment of exposure. Bias might have been introduced if a risk factor would be associated with poor prognosis for patients with testicular cancer. However, there are no data to support this notion.
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 7 exposed cases had seminoma. Furthermore, the case with embryonal cancer had a low cumulative exposure. It is unclear why the increased risk was seen for seminomas only.
The chemical composition of PVC includes 2 features. First, PVC is the only plastic that contains chlorine, i.e., about 56%n of the molecular weight (KemI, 1995). Second, plasticizers, i.e., additives, are used in PVC, mostly diethyl hexyl phthalate (DEHP), from 0 to almost 50% of the weight. Almost all phthalates are used in PVC production. Estrogenic effects have been reported for phthalates (Joblin et al., 1995).
The additives bisphenol A and nonylphenol are used as antioxidants in plastics. They are of interest since estrogenic potency has been reported in experimental studies for both bisphenol A (Krishnan et al., 1993) and nonylphenol (Soto et al., 1991). However, these are used in several types of plastics whereas we found increased risk for exposure to PVC only. 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).
In conclusion, in our case-control study of testicular cancer, a somewhat surprisingly high risk was observed for exposure to PVC plastics. The shortcomings of retrospective assessment of exposure by a self-administered questionnaire are obvious, and spurious association between PVC exposure and seminoma cannot be ruled out. Therefore, our results must be regarded as hypothesis generating, and they warrant further studies.
This work was supported by grants from Telehjälpen, the Swedish Cancer Society and the Orebro County Council Research Committee. The assistance of Miss 1. Larsson in data collection is acknowledged.
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