Incidence of oral cancer in relation to nickel and arsenic concentrations in farm soils of patients' residential areas in Taiwan

Heavy metals are trace elements in the environment. Their content and distribution in the air, water or soils are decided by both the nature and human activities. There is already an abundant literature addressing the effects on human health by exposures to these heavy metals [1]. Some of them are known to play a role in the development of human cancers [2]. A notorious example is the increased incidence of lung, skin and bladder cancer caused by exposures to arsenic via drinking well water for residents from the Black Foot Disease endemic area in Taiwan [3, 4]. Another example is the increased incidence of cancer in the lungs, nose, and larynx for workers exposed to nickel in the factory [1, 5].

Heavy metals in soils may exert their effects on human health via the food grown on them. Vegetable or fruit growing on soils containing a high amount of heavy metals were found to contain higher levels of heavy metals [6, 7], too, which may put people eating them under a higher risk of cancer development, if the metal is proved a carcinogen. The distribution of a certain kind of heavy metal in the environment is determined by both the nature and human activities. The advances in human technology may put the latter one a more important and decisive factor [8].

Oral cancer (OC) is one of the fastest growing malignancies in Taiwan [9]. In 1982, its incidence was at 5.12 per 10⁵ men and 1.54 per 10⁵ women per year. In 2001, these rates increased to 27.04 and 3.17 per 10⁵ for men and women, respectively, which were an alarming 5.3-fold increase for men and a two-fold increase for women in a span of only two decades. It is ranked as the fourth most common type of cancer in men, as well as the leading type of cancer that causes death in the same gender between the ages 25 and 44. In contrast, in the United states of America, the United Kingdom, Brazil and many other countries [10–12], the incidence and mortality of OC were either stable or in decline in the past 2 to 4 decades. It is therefore urgent for local scholars to understand the causes behind the opposite trend in Taiwan.

Our previous study [9] showed that the incidence rate of OC in Changhua, at 45.07 per 10⁵ people per year, was the highest among the 23 counties in Taiwan in 2001. In two decades, from 1982 to 2001, Changhua saw an alarming 6.3-fold increase in the incidence of OC among men. We plotted the incidence against the prevalence of cigarette smoking (CS) and betel quid chewing (BQC), and found that Changhua stood out as the only significant outlier, with an exceptionally high incidence but a mediocre prevalence of BQC and CS. These results suggest to us existence of a new risk factor in this area.

We also found that [13] the age at diagnosis and the prognosis of OC in Changhua were related to the patient's residential area. The mean age at diagnosis was 53.1 and 52.8 for patients living in the north and middle area of Changhua, while that for patients living in the south area was 55.1. Meanwhile, Kaplan-Meier survival curves and log-rank test show patients living in the north and middle area of Changhua have a poorer long-term prognosis. Moreover, the density of electroplating factories is significantly higher in the north and middle areas of Changhua. Since heavy metals are utilized in the industry, and many of these metals are known carcinogens [14, 15], it is important to know if exposures to heavy metals are a factor in the development of OC. We also found that OC at Changhua is not limited among factory workers. Most of the OC patients are not working in the electroplating factories. Therefore, a medium via which people can be exposed to heavy metals may be in existence.

Although an abundance of literatures have addressed the carcinogenic effects of various kinds of heavy metal [1], heavy metal and oral cancer has rarely been addressed. The purpose of this study is to explore the spatial relationship between OC and the heavy metal concentrations in soils. Our findings show that the OC incidences in Taiwan are geographically and statistically related to the arsenic and nickel concentrations in farm soils.

Exposures to hazardous materials in the home, the workplace, and the community can cause or exacerbate a multitude of diseases [31]. Physicians commonly treat the sequelae of these diseases; however, unless we start to recognize the connection between the occurrence of diseases and exposures to hazardous elements, treatment of the manifestations rather than the cause at best only ameliorate the condition. At worst, ignoring the effect of hazardous exposures may both lead to failure of treatment and failure to recognize a public health problem with widespread significance. Nowadays, environmental exposures are increasingly being associated with deterioration in health whose outcomes range from the subclinical to the clinically catastrophic [31].

Despite that many countries have observed a steady or declining OC incidence in the past decades, it is the fastest growing malignancy in Taiwan. We were interested to know that the State of Nevada has also witnessed a trend of increase in the OC incidence, opposite to most other states in the United States of America[10]. It is a surprising coincidence that experts in the University of Nevada, Las Vegas found that there was a severe environmental pollution with heavy metals resulted from widespread and massive landscaping [8].

For the Changhua County in Taiwan, OC is ranked as the third most common type of cancer in men [32]. We found that the prognoses of OC patients diagnosed and treated at the Changhua Christian Hospital[13] are associated with their residencies. Patients who live in areas with higher density of electroplating factories survive shorter, and in areas with lower density, longer.

As stated above, treatment of the manifestations rather than the cause at best can ameliorate the condition. BQC and CS are the established risk factors of oral cancer in Taiwan. A high association between these two habits is also reported [27]. The Government in Taiwan has long recognized the causal relationship between OC and BQC. In fact, a vigorous campaign has been waged to combat OC through public education. People are well informed of the risk accompanying BQC, and chewers are encouraged to abstain from the habit or at least undergo regular check-ups with the dentist for detection of early oral cancer. However, the incidence of OC keeps increasing in recent years.

If we simply look at the prevalence of BQC and CS and the incidence of OC on the map, it is hard to miss the discord. Where the prevalence of BQC and CS is high does not correspond to where the incidence of OC is high. Something may be amiss in the picture of our understanding of the pathogenesis of OC in Taiwan. Our previous studies [9, 13] make us suspect that local factors may be present and prompt us to identify the underlying connections with hazardous exposures.

Arsenic is a known carcinogen causing many types of cancer [14]. Hazardous exposures to arsenic present in artesian well water are considered a major cause of the Black Foot Disease (BFD) and other types of cancer on the southwest coast of Taiwan. As has shown in figure 4, concentrations of arsenic in farm soils in areas endemic for BFD are also higher than those in other areas on the island. The government in Taiwan has already completed the construction required to supply the area inflicted with BFD with tap water in the early 1980s. However, despite the disappearance of BFD, the incidence of cancer reported to be associated with hazardous exposures to arsenic remains very high [33, 34]. These facts made us wonder if arsenic in farm soils may be playing a role similar to that in artesian well water.

Nickel is also a well-recognized carcinogen, which is known to increase the incidence of nasal cancer and lung cancer among those with hazardous exposures during purification in the factory [35, 36]. However, most, if not all authors in the literature[1] described an association between exposures of factory workers and the incidence of a particular type of cancer among them. A widespread effect of this heavy metal on the public in the community, be it small or large, has not been described yet.

Here we present a strong association between concentrations of arsenic and nickel in farm soils, and the incidence of OC. Farm soils can be regarded as either an emitter or a receiver of the environmental toxin. As an emitter, the soil may release toxin to crops, to the groundwater, or to air; as a receiver, it does not matter whether the toxin was initially in the air or water; the residuals eventually settle onto the soil. Therefore the heavy metal concentration in farm soils can fairly reflect the amount of heavy metal present in the environment, and the risk that the residents in the vicinity are exposed to [37]. A question arises then: How do these known carcinogens in farm soils enter the human body? One possible route is via the food grown on them. Vegetable or fruit growing on soils with high contents of heavy metals were found to contain higher levels of heavy metals [6, 7], which may put the people eating them under a higher risk of cancer development, as a result. Note that in this study we excluded people living in the 3 major metropolitan areas; people in these areas are more likely to have access to farm products produced far away. To clarify the pathways via which heavy metal in the soils exerts it effects on human health, we are currently teaming up with experts in environmental engineering for further study.

A limitation of this study is that the residency does not necessarily reflect the lifetime exposure, migration may happen. However, the trend here is from the country to the city and the three big cities here are excluded in the analysis.

Another limitation is that the BQC/CS prevalence are available for only 177 townships and the prevalence for the rest townships were obtained by interpolating methods. To verify our results, we tried various interpolating methods as well as the non-interpolating data, and all led to the same conclusion that BQC, Ni and As are significantly associated with OC incidence. In addition to these 3 factors, we also noted the indicator variable of aboriginal residency is significant in some concise models. Areas classified as aboriginal residency have a higher OC incidence rate. However, this variable is strongly confounded with a few variables like age and income, and its effect needs further investigation. Here we focused mainly on the male OC, and the female OC is not addressed. Because only 12% of the 22,083 cases in study are women, the small number will make cases in each township/precinct too few for statistical analyses. On the other hand, a great disparity of BQC prevalence between the genders in Taiwan [38] also makes the estimation of the prevalence of BQC in women difficult. Though BQC is prevalent in men, women rarely practice it. This difference may be related to culture and the image a chewer creates in the public. The results here support our hypothesis: BQC is the inducer, while arsenic and nickel act as promoters in the carcinogenesis of OC. Of course, it is still a hypothesis; more work is needed to prove or disprove it, and we are currently working on it.

A past study had found an association between the density of electroplating factories and prognosis of oral cancer. This report further extended the finding: beside the two established risk factors, cigarette smoking and betel quid chewing, concentrations of nickel and arsenic in farm soils are also correlated with incidence of oral cancer in Taiwan. We are now studying serum levels of heavy metal in patients and controls to ascertain the evidence of the novel risk factors. Hopefully through the works, more efficient preventive procedures can implemented for public health.

I.C.D-O-FT T-140, 141.1-141.9, 143-144,145.0-145.2, 145.6, 145.8, 145.9, 149.8, and 149.9 [9].