Overall, air cadmium exposure was significantly associated with high tumor grade and metastatic PC at diagnosis (Table 2) among a large national cohort in the US. In RUCC 3 and 4, these odds ratios tended not to be statistically significant, and for RUCC 1 they were not very large (Fig. 2 and Fig. 3). In RUCC 2, among the three metals, odds ratios were observed to be the largest among cadmium which suggests exposure to air cadmium is more important than exposure to arsenic and lead (Fig. 2 and Fig. 3). In RUCC 1, 3, and 4, the results suggest that the adjusted odds ratios are similar among the three metals (Fig. 2 and Fig. 3).
Previous literature on the topic of association between cadmium overburden and PC aggressiveness fall into two categories: mortality as endpoint and biomarkers of aggressiveness at diagnosis.
For the first category (mortality as endpoint), meta-analyses literature surveys showed no statistically significant evidence of an association between cadmium exposure and PC mortality in the general population . However, mortality by itself, may not be a sufficient method to evaluate tumor aggressiveness for at least three reasons: (1) inaccuracy of death certificates and other methods of quantifying cause-related mortality, (2) differences in treatments, and (3) attenuation of the potential effect of environmental toxicants such as cadmium when the large majority of patients has an indolent disease such as PC.
Only a few papers addressed the second category (signs of aggressiveness at diagnosis). In an aged-matched study in four hospitals in Taiwan with 234 PC cases, patients with higher serum and urinary cadmium levels had significantly higher stage and Gleason grade, suggesting that high cadmium body burden could affect tumor aggressiveness . Among a large Danish cohort of 26,778 men (1,567 cases) followed prospectively for 13 years, there was no comparison between cases with high dietary cadmium vs. low dietary cadmium for the ratio of aggressive to non-aggressive cases, but the incidence of either of these two types of PC cases was not increased in men with high cadmium dietary exposure when analyzing these subtypes separately . In Sweden, another large prospective study that also used food frequency questionnaires to estimate the amount of cadmium daily ingestion discovered a rate ratio (RR) of 1.29 (CI: 1.08–1.53) for localized cases and RR of 1.14 (CI: 0.86–1.51) for advanced cases when comparing tertiles of dietary cadmium after 10.8 years of follow up. However, there was no cross-comparison of aggressive with non-aggressive PC cases . An earlier population-based study of 358 patients showed a tendency for higher incidence of aggressive PC in men in the upper quartile of dietary cadmium when compared to men in the lower quartile of the patient population: OR = 1.8 (CI: 0.7–4.7) for men < 68 years old, and OR = 1.5 (CI: 0.6–3.7) for men 68 years old and above . The strongest association was found for the entire (non-aggressive, intermediate aggressiveness and aggressive PC tumors) patient population that was > 67 years old, OR = 1.8 (CI: 1.1–3.1).
Unlike other studies of dietary cadmium that were interested in comparing the incidence of PC of varying aggressiveness separately , we calculated the odds ratio comparing the probability of aggressive to nonaggressive PC to understand the role cadmium may play in PC progression as this is an important measure of outcomes. In addition, our results support the findings that PC patients with higher cadmium levels have higher stage and Gleason grade . Lastly, since the absorption of dietary cadmium is relatively low compared to the absorption of cadmium inhaled into the body, our results may provide a more comprehensive assessment of environmental exposure to cadmium.
One of the many difficulties in assessing the risk imposed by excess cadmium in the diet is to separate cadmium intake (which is heavily dependent on the ingestion of bread and potatoes) from adiposity, which is a well-known risk factor for PC aggressiveness and mortality . Our findings support the idea that it is important to consider the relationship between environmental factors and the stage of cancer. Since we found the strongest associations to be in RUCC category 2 counties, follow-up studies should be conducted in these areas to further investigate the relationship of environmental exposure to air cadmium and PC. This could lead to future studies to identify modifiable sources of high cadmium emission. RUCC 2 counties are especially important because approximately 40 million Americans  live in these areas with a substantial portion of them subject to high cadmium exposure.
Since the ATSDR has indicated that air exposure to cadmium is only substantial near cadmium-emitting facilities, our hypothesis is that many cadmium-emitting facilities such as factories and mines tend to be in RUCC 2 counties which have populations of 20,000 to 250,000. Individuals in RUCC 2 counties might be closer to sources of cadmium pollution in the air than individuals living in other categories of RUCC counties. We hypothesize that these cadmium-emitting facilities are present in RUCC 1, 3 and 4 counties, but their effect is diluted. Since RUCC 3 and 4 counties consist of mostly rural areas, it is possible that residents tend to live in more spread-out areas away from urban activity and air pollution, so most individuals would not be impacted. On the other hand, RUCC 1 counties are metropolitan counties with a high number of residing individuals. Because facilities that emit air cadmium might only exist in some neighborhoods, overall negative effects among the RUCC 1 cohort might not be observed because only a portion of the population would be exposed.
To identify the sources of high air cadmium exposure for each of the counties with high incidence of metastatic and high grade cancer at diagnosis is beyond the scope of this paper, but an important task. Every year, the US Census Bureau obtains industry size by number employed at the county-level through the American Community Survey. This data is available publicly through an interactive website called Data USA, as a collaboration between Deloitte and MIT Learning Group . By comparing known sources of cadmium from the ATSDR to the list of all industries in each county in the upper two quintiles of air cadmium concentration in RUCC2 counties, some possible sources of cadmium exposure could be identified. Putative sources include smelters, mining and quarrying, waste incinerators, coal and fossil fuel power plants, and factories for manufacturing equipment and nickel-cadmium batteries.
The association between environmental cadmium exposure and diseases can be traced to contamination of drinking water, food sources and/or by inhalation of airborne cadmium in the work environment, cigarettes, and ambient air. In areas where city water cadmium levels are regulated and food is shipped from other areas, disease associations may be more accurately traced to dangerous air cadmium levels than in local water and soil. A previous study analyzing air quality and advanced PC stage prompted us on this investigation. Future studies that look at the link between cadmium or other environmental agents and PC should also consider the stage and grade of PC at diagnosis. The effect of cadmium on aggressiveness of PC is of particular interest since PC has high incidence, but by comparison with most other types of cancer, PC has a relatively low rate of progression to more aggressive disease .
Also of interest would be to understand the biological mechanisms of action of cadmium on cancer progression. Most of the literature addresses the effect of cadmium on the initiation and promotion of PC, with little attention to progression of already established malignancy (an increase in genomic instability, tumor growth and metastasis).
The few articles that do focus on low, nanomolar cadmium concentrations suggest that cadmium may act as a hormone disruptive agent and activator of signal transduction pathways that promote cell growth , but other possible mechanism(s) may also contribute. Most of the mechanism-driven studies in the literature utilize micromolar range in vitro concentrations of free, unbound cadmium salts that may not be relevant to PC as such concentrations of free cadmium rarely, if ever reach the prostate.
Studying the stage and grade score of PC at diagnosis eliminated any confounding factors that may be related to differences in treatment. Possible limitations include that the SEER database only contains data from 11 states, and it does not record if PC patients relocated from one county to another. Previous epidemiological studies have shown it is very challenging to estimate an individual’s amount of cadmium intake, absorption, and retention in the prostate. In this study, using county-level cadmium exposure concentrations, it is impossible to assess a specific individual’s exposure to air cadmium and its absorption. In addition, cadmium exposure concentration could vary throughout the county as well, which means that different individuals living in the same county could be exposed to different amounts of air cadmium. Lastly, it is also possible that our calculated odds ratios are affected by other factors in addition to the presence of cadmium that are not accounted for in our model, such as body mass index (BMI), waist-to-hip ratio, and physical activity. The main limitation of our study, in common with most epidemiological studies, is its observational nature.
For these reasons, follow-up studies should be conducted using state and local registries to use more precise concentrations of air cadmium exposure. The EPA publishes air toxic concentration data for census blocks and tracts, areas that are smaller than counties. These exposure concentrations might provide more information about the link between the distance of a patient’s address of residence to a cadmium-emitting source and PC aggressiveness at diagnosis. Lastly, studies should consider accounting for an individual’s occupation as well, as these might affect the amount of an individual’s exposure to air cadmium.