4.1. Cd Exposure and Cancer Mortality
In Cd-exposed women, the hazard ratio for deaths from colorectal cancer differed significantly from that of controls, although no dose–response relationship was found between Cd exposure level and hazard ratio for deaths from any malignant neoplasms. This lack of relationship suggests that women living in the Cd-polluted Jinzu River basin area are not at a greater risk of dying of cancer.
In men, the adjusted hazard ratios for stomach cancer deaths were significantly higher for subjects exposed to mild, moderate, and high levels of Cd. No dose–response relationship, however, was found between Cd exposure levels and risk of stomach cancer deaths. The hazard ratio for lung cancer deaths was significantly lower in men exposed to high levels of Cd who had a historical record of proteinuria, glucosuria, and glucoproteinuria, suggesting a possible inverse association between Cd exposure or Cd-induced renal damage and lung cancer.
In our previous 22-year follow-up study in residents of another Cd-polluted area, the Kakehashi River basin in Japan, no association was found between Cd exposure levels, as indicated by urinary Cd content, and deaths from stomach and lung cancer in men. In women, however, hazard ratios for lung cancer deaths were significantly lower in the subjects with urinary Cd ≥10 μg/g Cr than in subjects with Cd <10 μg/g Cr [15
]. These findings suggest an inverse association between Cd exposure and lung cancer mortality, although the findings differed by sex.
Two meta-analyses of lung cancer risks associated with Cd exposure have been published, but their findings were inconsistent. Nawrot et al. (2015) analyzed three cohort studies and reported a significantly higher risk for lung cancer with environmental Cd exposure [16
]. Chen et al. (2016) included environmental and occupational exposures, and could not find significant associations between Cd exposure and an increased risk of lung cancer [17
4.2. Cd-Induced Renal Damage and Cancer Mortality
Renal tubular dysfunction is a characteristic symptom of chronic Cd poisoning and is indicated by glucoproteinuria (both proteinuria and glucosuria). We previously found increased cancer mortality in women with glucoproteinuria in the same cohort in the Jinzu river basin (Maruzeni et al. 2014). In the present analysis, we used proteinuria and/or glucosuria as a marker of Cd-induced renal effects. Their Cd exposure levels were remarkably high, with the 95th percentile urinary Cd ≥20 μg/L, suggesting Cd exposure from environmental pollution. Because the 95th percentile of urinary Cd was reported to be 3.50 μg/L in smokers aged ≥50 years old [18
], this suggested that smoking alone, a major cause of Cd exposure in the general population, cannot increase Cd exposure levels. The prevalence of proteinuria, glucosuria, and glucoproteinuria increased as Cd exposure levels increased, suggesting that either proteinuria or glucosuria can also serve as indicators of Cd-induced renal damage. However, type 2 diabetes is a risk factor for developing cancers, and subjects with only glucosuria might include patients with type 2 diabetes. Therefore, we deleted subjects at a risk of diabetes who showed fasted blood sugar ≥125 (mg/dL) from the subjects with proteinuria, glucosuria, and glucoproteinuria and analyzed their mortality risk ratios compared with the subjects without urinary findings.
In the present analysis, the mortality risk from malignant neoplasms in women was significantly higher in Cd-exposed subjects who had a history of urinary findings of proteinuria, glucosuria, and glucoproteinuria. Deaths from kidney and urinary tract cancers, including renal cancer, uterine cancer, and pancreatic cancer, were observed in this cohort. These findings were not detected in our previous analysis, which used glucoproteinuria as a biomarker of renal effects [10
]. The different results between our present and previous analysis suggest that in Cd-polluted areas, women who present with proteinuria, glucosuria, and glucoproteinuria may be at higher risk of death from kidney and urinary tract cancers, particularly renal cancer. In addition, we analyzed adjusted hazard ratios for deaths from renal and urinary tract cancer in a model including two factors—renal damage and exposure levels—in women. We found that only the renal damage factor was significantly associated with mortality risk. This finding suggests that Cd-induced renal damage may be a risk factor for death from renal cancer in women living in the Cd-polluted area.
Il’yasova and Schwartz (2005) performed a systematic review of studies on Cd exposure and renal cancer, and reported an increased risk in large-scale epidemiological studies with data from four countries [9
]. Cd content in the kidney cortex is not an effective marker of Cd accumulation following renal cellular damage [19
], and other markers should be used to evaluate exposure levels in cancer patients. Therefore, an association between Cd exposure and renal cancer could not be concluded from the findings in these clinical studies.
We reported an increased risk of mortality from uterine cancer in women with renal damage in our previous study [10
], confirming the positive association between Cd exposure and death from uterine cancer observed in the present analysis. In the USA, increased mortality from uterine cancer was reported to be associated with increasing urinary Cd levels in a study using data from the Third National Health and Nutrition Examination Survey (NHANES III) [8
]. These results suggest an increased mortality risk from uterine cancer is associated with increasing Cd exposure.
In the same mortality study by Adams et al. (2012), significantly increased mortality from pancreatic cancer associated with urinary Cd was reported in men [8
]. In the meta-analysis of cohorts with highly Cd-exposed workers, Schwartz and Reis (2000) indicated there was an increased risk of pancreatic cancer with borderline significance (standardized mortality ratio = 166; p
= 0.059) in both sexes [20
]. In the present study, increased mortality from prostatic cancer was also of borderline significance, but only in women. A further follow-up study may be required to determine whether Cd exposure influences the development of pancreatic cancers.
In men with historical records of proteinuria, glucosuria, and glucoproteinuria, the adjusted hazard ratios for mortality from kidney and urinary tract cancers were higher, with borderline significance. However, no death from kidney cancer was found in men with urinary findings; thus, the effects of Cd-induced renal damage on renal cancer mortality may be limited in men. In addition, the adjusted hazard ratio for prostate cancer deaths was higher, but its increase was not significant. An increased prostate cancer risk has been reported in several follow-up surveys in industrial workers in Europe [3
]. In our study in the Kakehashi River basin as well as in the present study, no association between renal damage and prostate cancer deaths was found [22
]. This lack of association may be because the European studies measured the incidence of prostate cancer, while we only measured mortality and because their cohorts had occupational exposure, while the exposure in our study was environmental.
Mortality from lung cancer was significantly lower in Cd-exposed men with a historical record of urinary findings. Since a lower risk of mortality from lung cancer was found in the dose–response analysis, we performed additional calculations with an exposure factor and a renal-effect factor and found that both factors were independently associated, with borderline significance, with decreased mortality from lung cancer in men. In our previous study [10
], we did not find differences in risk of mortality from lung cancer in Cd-exposed men with glucoproteinuria. Therefore, we cannot conclude that Cd-induced renal damage decreases the mortality risk from lung cancer.
Our present study has several limitations that should be considered. Follow-up data from the subjects included mortality from cancers but not their incidence. Therefore, we could not estimate cancer risk, particularly for cancers with high survival rates, such as prostate, uterine, and breast cancers. Stomach cancer can be found and treated at early stages, suggesting that its incidence may be a more important indicator of risk than mortality. For renal cancer, however, mortality may be an adequate risk indicator, because renal cancer is difficult to diagnose at an early stage, and most cases are fatal.
Another limitation is that environmental Cd exposure levels were based on the contribution of contaminated Jinzu River water [13
], and not biological markers of Cd body burden, such as urinary levels in each subject, which are more closely related to renal effects. In addition, we used historical exposure levels from the baseline survey, and did not measure Cd exposure during the follow-up period. Cd body burden, however, may not have significantly increased during the follow-up period, because ingestion of Cd-polluted rice and river water was prohibited in the Jinzu River basin, and residents are presumed to have had no additional Cd exposure during that period.
We used proteinuria, glucosuria, and glucoproteinuria as markers of renal damage in this analysis, but these urinary findings are not specific to renal tubular dysfunction. We first analyzed the dose–response relationship between Cd exposure levels and the prevalence of proteinuria and/or glucosuria to confirm that this marker indicated renal effects associated with Cd exposure. Urinary Cd levels and urinary β2-MG positive rates of the subjects with proteinuria, glucosuria, and glucoproteinuria were high enough to develop renal effects. Moreover, the subjects who showed glucosuria (without proteinuria) and diabetic elevation of blood sugar in the second step of the baseline health screening test were excluded from the mortality analysis to avoid confounding by the presence of type 2 diabetes. After these modifications, we believe that proteinuria, glucosuria, and glucoproteinuria can be used as markers of renal damage in these subjects living in a heavily contaminated area to Cd in Japan.