The incidence of TGCT has been increasing in the U.S. since prior to World War II (19
). Though few risk factors have been identified, a number of studies have reported that there is a pronounced birth-cohort effect on risk, suggesting that changes in exogenous exposures may be related to the trend (20
). One exogenous exposure, endocrine disrupting chemicals, including PCBs, has been the subject of much speculation as animal data suggested that they might be related to a variety of male reproductive disorders in humans (8
). The results of the current study, however, that PCBs are inversely related to risk of TGCT, do not support the hypothesis. In that the inverse association appeared more pronounced, although nonsignificantly so, among persons with high serum levels of p,p’-DDE, it is possible that the effect of PCBs will depend on the mix of other endocrine disruptors also present. Even at lower serum p,p’-DDE levels, however, there was no indication that PCBs served to increase risk.
PCBs are a group of related compounds composed of two carbon-linked benzene rings to which are attached between one and ten chlorine atoms. Between 1929 and 1977, PCBs were manufactured and used in the U.S. as insulators and coolants in electrical equipment, and in the production of numerous household products. Concerns about possible long-term health effects first surfaced in the 1960s when PCBs were reported to be prevalent in wildlife and persistent in the environment (21
). Subsequent animal studies reported that PCB exposure resulted in a number of outcomes, including neurobehavioral changes, hypothyroidism, reproductive disorders and tumors. Among humans, mass PCB food-poisonings in Japan (1968) and Taiwan (1979) resulted in chloracne, menstrual irregularities, altered immune responsiveness and general fatigue. In 1977, the sole manufacturer of PCBs in the U.S., the Monsanto Company, ceased production two years prior to the formal ban by U.S. Environmental Protection Agency. Based on the animal data and on occupational studies in humans, IARC has classified PCBs as being a probable carcinogen in humans (22
In humans, PCBs are stored in adipose tissue and levels tend to increase with age (12
). Thus, it is difficult to determine in the present study when the study participants were exposed. PCBs, however, can cross the placental barrier and are present in breast milk, thus some of the exposure may have occurred in utero
and/or via breast feeding. If significant exposure occurred in utero
, PCBs may also affect the risk of the male reproductive congenital anomalies that are associated with TGCT. To date, very few studies of either cryptorchism or hypospadias have examined PCB levels, however. Two studies of cryptorchism and PCBs have been reported and neither has found a relationship (23
). In contrast, a study of the prevalence of hypospadias in Greenland found an unexpectedly low rate despite high levels of PCBs in the population (25
), suggesting that PCBs might be inversely associated with risk of hypospadias.
Among the testicular dysgenesis syndrome disorders (9
) that become evident in adulthood (impaired spermatogenesis and TGCT), more studies have examined the relationship of PCBs with the former than the latter. In general, the results of the PCB-fertility studies are somewhat equivocal. Several studies have found statistically significant associations with impaired sperm parameters (26
), while others have found associations only in subsets of their populations (29
), or not all (32
). In contrast, several studies have reported direct associations between PCB levels and fertility (33
). The summary of the international INUENDO study of PCBs and fertility in four populations, however, concluded that a representative congener, PCB-153, did not appear to affect fertility or to have direct hormone-like activity (35
Only one prior study of TGCT and PCBs has been reported to date (13
). A case-control study of Swedish men found no association of TGCT with sum of PCBs, estrogenic PCBs, or enzyme-inducing PCBs. An examination of PCB levels in the mothers of the men, however, found that mothers of the cases had significantly higher levels of 21 of the 37 congeners tested. When the PCBs were examined by functional group, the analysis found that the case mothers had significantly higher levels of sum of PCBs and enzyme-inducing PCBs. Interpretation of the mothers’ results is rather difficult, however, as the mothers’ blood samples were obtained approximately 30 years after their sons were born. Body burdens of PCBs in women are affected by weight changes, child bearing and lactation over time, so it is unclear to what extent the mothers’ PCB levels were representative of their levels during pregnancy with their sons. It is uncertain why the sons’ results differed from the results of the current study, but the discrepancy may be related to the small size of the Swedish study (n=58 cases, 61 controls), differences in the PCB mixtures used in each country and timing of the collection of blood samples, as population PCB levels have declined since they were banned. The blood samples in the Swedish study were drawn at a later time (1997–2000) than the samples in the current study, suggesting that the PCB levels might be lower in the Swedish study. A comparison of median levels of estrogenic PCBs and enzyme-inducing PCBs, however, only partially supports this conjecture. The median level of estrogenic PCBs among the Swedish control men was 25 ng/g lipid in contrast with the median control level in the current study of 69.7 ng/g lipid. The median level of the enzyme-inducing PCBs, however, was 174 ng/g lipid among Swedish controls and 73.9 ng/g lipid among US controls. It is also possible that the level of risk or protection of PCBs is determined by the mixtures of congeners present in any location, or the presence of other compounds with endocrine disrupting properties. For example, p,p’-DDE was not related to TGCT in the Swedish study, but was related to risk in the STEED population (10
). This difference may be explained by the lower general level of p,p’-DDE in Sweden than in the U.S. (36
Why PCBs would be inversely associated with TGCT remains to be determined. p,p’-DDE, which has demonstrated antiandrogenic properties, was associated with increased risk in the same population. PCBs have a range of estrogenic, antiestrogenic, androgenic and antiandrogenic effects (12
). Examining the effect by the Wolff groupings (15
), only two (PCB-101, PCB-187) of the PCBs in Wolff Group-1 (potentially estrogenic) were examined in the current study. While PCB-101 had no relationship with risk, PCB-187 was inversely associated with both TGCT and nonseminoma. All of the Wolff Group 2 (potentially anti-estrogenic, dioxin-like) PCBs examined (PCB-118, PCB 156, PCB-138, PCB-170) were significantly inversely related to TGCT risk. Three of the four Wolff Group 3 (phenobarbitol, CYP1A, and CYP2B inducers) PCBs were significantly inversely related to risk (PCB-153, PCB-180, PCB-183) while there was no relationship with PCB-99. Given that there were inverse relations in all the groups, it is not clear what effect is most important in determining risk. In light of the DDE relationship, however, it seems unlikely that an antiandrogenic effect of PCBs would be inversely related to risk. An antiestrogenic effect, however, might be related, especially as the ratio of androgenic to estrogenic exposures has been postulated to be important in TGCT development. Although there was no statistically significant difference in the relationship of PCB levels to TGCT in low and high DDE strata, significant trends only in the high DDE strata may indicate that the presence of other endocrine disruptors is critical to determining the effect of PCBs.
A major advantage of the current study was that pre-diagnostic serum samples were analyzed. Other advantages were that participants were drawn from a well-defined population, the tumors were histologically confirmed and the participants were likely to be representative of a wide spectrum of the underlying population. Study limitations include that some potential participants could not be contacted due to deployment, the analysis adjusted for self-reported body size rather than measured body size and the study could not determine when and how the participants were exposed to PCBs. Inability to contact men due to deployment presents a potential bias in that deployed men might be different in some way that non-deployed men. As most young men in military service are healthy and fit, however, it would seem unlikely that that deployment would confer substantial bias.
In conclusion, the current study suggests that PCBs are inversely associated with the risk of TGCT, particularly with nonseminoma. The results argue for further examination of PCBs and TGCT in other populations as PCBs are detectable in a large proportion of the world’s population. It will be particularly instructive to examine PCB levels in concert with other endocrine disruptor levels in order to determine whether the inverse association detected in the current study is a result of exposure to other environmental chemicals.