Low-to-moderate arsenic exposure and urothelial tract cancers: A sixty-year latency analysis

doi:10.21203/rs.3.rs-1536386/v1

Download PDF

Research Article

Low-to-moderate arsenic exposure and urothelial tract cancers: A sixty-year latency analysis

https://doi.org/10.21203/rs.3.rs-1536386/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

Arsenic exposure can cause adverse health effects. The effects of long-term low-to-moderate arsenic concentrations and methylations remain unclear.

Objectives

This study aims to examine the association between low-to-moderate arsenic exposure and urothelial tract cancers while considering the effects of methylation capacity.

Methods

In this study, 5,811 participants were recruited from an arseniasis area in Taiwan for inorganic arsenic metabolite analysis. This follow-up study was conducted between August 1995 and December 2017, with an average 60-year latency period after exposure inception. We identified 85 urothelial tract cancers in these participants, including 49 bladder and 36 upper urothelial tract cancer cases. A Cox proportional hazards model was employed.

Results

The analyses revealed a significant association between concentrations of inorganic arsenic in water > 100 ppb and bladder cancer occurrence, with a hazard ratio (HR) of 4.88 (95% CI, 1.35–17.61). A statistically significant monotonic trend was observed between concentrations of inorganic arsenic in water (from 0 to >100 ppb) and the incidence of urothelial tract cancer, including bladder cancer (P < 0.05) and upper urothelial tract cancers (P < 0.05). Participants with a lower primary methylation index had a dose–response relationship with concentrations of inorganic arsenic (in water) of 0–10.00, 10.01–50.00, 50.01–100.00, and >100.00 ppb and developing urothelial tract cancers, with HRs of 1.00, 2.17, 3.11, and 4.60, respectively. Participants with a higher secondary methylation index had a dose–response relationship with concentrations of inorganic arsenic of 0–10.00, 10.01–50.00, 50.01–100.00, and >100.00 ppb and developing urothelial tract cancers, with HRs of 1.00, 1.20, 2.03, and 3.73, respectively.

Conclusions

A dose–response relationship was observed between low-to-moderate inorganic arsenic exposure and urothelial tract cancers among susceptible individuals with primary hypomethylation responses. Rigorous regulations and active interventions should be considered for populations with high-risk characteristics.

Low-to-moderate arsenic exposure

urothelial tract cancers

methylation capacity

dose–response relationship

The element arsenic is an environmental contaminant found in soil, air, food, and water. Chronic exposure to high levels of inorganic arsenic (iAs) is associated with numerous adverse effects, such as skin lesions, vascular diseases, cancers, reproductive toxicity, and neurological effects. Cancers of the skin and other internal organs, including the lungs, liver, bladder, and kidneys, are associated with iAs exposure[1]. In some areas of the world, such as Bangladesh, India, China, Chile, Argentina, and Mexico, there are high levels of iAs at > 100 ppb in their drinking water[1–3]. According to the literature, bladder and kidney cancer mortality resulting from arsenic exposure has a long latency, with increased risks not manifesting until 40 years after exposure to arsenic[3]. The International Agency for Research on Cancer (IARC), based on compelling evidences, indicate that arsenic increases the risk of urinary bladder cancer. Studies have demonstrated that the association between exposure to iAs in drinking water and bladder cancer is detectable only after exposure to iAs concentrations exceeding 100 µg/L. A prospective cohort study in northeastern Taiwan reported that the multivariate-adjusted relative risk of urinary tract cancer was statistically significant for residents who drank well water containing arsenic at levels > 100 µg/L[4, 5]. Results from different geographical areas have indicated a threshold for the association between iAs exposure at concentrations of 100 µg/L or higher and bladder cancer[6–8]. An increase in cancer mortality among cohorts exposed to extremely high levels at beyond 500 ppb of arsenic has been reported in Japan and Chile [9, 10]. The risks related to exposure to arsenic in the 10–100 µg/L range remain unclear[11, 12]. In studies on lower arsenic exposure conducted in the United States, no increase in bladder cancer incidence was found in populations consuming drinking water containing iAs at concentrations lower than 100 µg/L[12–14]. Multiple epidemiological studies have supported that exposure to low concentrations of iAs may not increase the risk of bladder cancer[8, 15].

On the other hand, a study demonstrated an association between low-to-moderate levels of arsenic in drinking water and bladder cancer risk in New England[16]. In addition, a review article characterizing the risks in populations exposed to low concentrations of arsenic identified a potential association between bladder cancer risk and exposure to arsenic at concentrations of less than 100 µg/L in drinking water[17]. An ecological study demonstrated that a low concentration arsenic may be associated with lung and bladder cancers[18]. However, evidence in the form of individual data with dose-response relationship remains lacking.

Most previous epidemiological reports have focused on the relationship between arsenic exposure and bladder cancer, whereas only a few studies have addressed the relationship between arsenic exposure and upper urinary tract urothelial carcinoma (UUT-UC). Furthermore, a clear association between arsenic exposure and higher UUT-UC mortality rates has not been reported[19–22]. In a study in Chile, exposure to arsenic was reportedly related to a critical need for UUT-UC health care and to high mortality rates, even after arsenic levels in drinking water had been controlled for 25 years[23]. An unusually high incidence of UUT-UC has been reported in southwestern and northeastern Taiwan[4, 24]. For renal pelvis and ureter cancers, the adjusted odds ratios (ORs) based on average intakes of arsenic at the high concentrations of < 400, 400–1,000, and > 1,000 µg/day (median water concentrations of 60, 300, and 860 µg/L) were 1.00, 5.71 (95% confidence interval [CI]: 1.65, 19.82), and 11.09 (95% CI: 3.60, 34.16; Ptrend < 0.001), respectively. Although the IARC has indicated that the evidence that ingested arsenic causes lung, bladder, and skin cancer is sufficient, a similar statement has not been made for kidney cancer or other UUT-UC because “no studies have reported dose–response relationships on the basis of individual exposure data.”[25] However, a study presented a latency pattern of increased mortality from kidney cancer among young adults exposed to arsenic and indicated that early life exposure may result in markedly higher kidney cancer mortality[26]. Therefore, investigations of the association between iAs exposure and UUT-UC under low-to-moderate exposure necessitates a relatively long period of observation.

Methylation is the central issue concerning inorganic arsenic carcinogenesis in humans. Studies have suggested that a higher ratio of methylarsonic acid (MMA) to dimethylarsinic acid (DMA) in urine is associated with an increased risk of developing bladder cancer[27, 28]. Studies have demonstrated that the risk of developing skin and bladder cancer increases with the percentage of methylated arsenic in urine[29, 30]. Furthermore, the overall risk of bladder (OR = 1.79; 95% CI: 1.42–2.26, n = 4 studies) and lung (OR = 2.44; 95% CI: 1.57–3.80, n = 2 studies) cancer increased significantly with the increase in %MMA without statistical heterogeneity[31]. In addition, a Taiwanese study demonstrated that subjects with a lower methylation capacity were more likely to develop a dose–response relationship between iAs exposure below the low-to-moderate range and lung cancer[32]. However, the effects of low-to-moderate arsenic exposure and its methylation on urothelial tract cancers occurrence are awaiting for investigations. Therefore, this study also aims to examine the moderating effects of iAs methylation capacity on the relationship between low-to-moderate iAs exposure and urothelial tract cancers.

Study participants

This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital in Taoyuan, Taiwan (100-2839C). On the basis of our previously established cohort in areas experiencing arseniasis, 5811 residents who were exposed to arsenic-contaminated well water and were eligible for a urinary iAs speciation analysis were defined as the study cohort. Residents of the arseniasis area in northeast Taiwan were recruited for this study between 1992 and 1995. This prospective follow-up study was conducted between August 1995 and December 2017, and the average follow-up period was 19 years, with an average observation period of 60 years following initial exposure. In the years following data collection, the local government implemented a tap water supply program, which was providing nearly 100% of all tap water in the study area by the late 1990s. Accordingly, the residents were exposed to arsenic-contaminated drinking water at a mean arsenic concentration of 136.43 ppb (0–3842.61 ppb) for an average of 41 years at recruitment.

Data Collection

Basic demographic characteristics, including age, sex, marital status, education level, occupation, cigarette smoking habit, alcohol drinking habit, coffee drinking habit, tea drinking habit, other chemical exposure and medical drug use, and duration of well-water exposure were collected using a questionnaire. Urothelial tract cancer diagnosis data were obtained from the National Cancer Registration Database and were verified against insurance claims data. International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes C67 and C64–66 and C68 were used to define bladder cancer and upper urothelial tract cancers, respectively. By the end of 2017, 85 incident cases of urothelial tract cancer had been identified. Underground water and urine samples were collected only at the time of recruitment and were stored at − 20°C until assays were performed. The arsenic concentration in the water was determined immediately after sample collection. Urinary arsenic speciation was performed through high-performance liquid chromatography to separate the arsenic species. This was followed by inductively coupled plasma mass spectrophotometry (NexION 350X, PerkinElmer, USA) to determine the concentrations of the separated arsenic species. The detection limits of the urinary iAs metabolites were 0.4, 1.4, 1.4, and 1.0 ppb for Asi^+ 3, Asi^+ 5, MMA, and DMA, respectively. A spiking analysis yielded an average recovery rate of 95.18–100.03%. SRM 2670a, a standard reference material, was used for validation, and the values were calculated within the suggested range. According to our review of the literature, the iAs metabolism pattern was further revealed through the primary methylation index (PMI), calculated as MMA/(Asi^+ 3 + Asi^+ 5), and the, calculated as DMA/MMA[33].

Statistical Analyses

Numerical variables with apparent skewness were presented as the median value (first and third quartiles), and logarithmic transformation before analysis of variance (ANOVA) and Scheffe’s multiple comparison procedure was used to compare the differences between the study groups. The Cox proportional hazards model was used to determine the strength of the association between the study variables and the occurrence of urothelial tract cancers during follow-up and for adjustment of the effects from other selected variables. To account for the collinearity among arsenic concentrations, duration of arsenic exposure, and cumulative arsenic exposure, we constructed various regression models for each arsenic exposure metric assessment. The results were expressed as multivariate-adjusted hazard ratios (HRs) and corresponding 95% CIs. The iAs metabolism patterns were further categorized on the basis of the medians of the PMI and SMI into four groups: low PMI/low SMI, low PMI/high SMI, high PMI/low SMI, and high PMI/high SMI. To estimate the arsenic exposure doses, water arsenic concentrations were categorized according to a review of the literature (0–10, 10.01–50, 50.1–100, and > 100 ppb). The cumulative arsenic exposure was categorized into tertiles (0–0.550, 0.551–2.548, > 2.548 ppm-years for T1, T2, and T3, respectively). The water arsenic concentrations at schools, away-from-home jobs, and at other lifetime residences were unknown among the study participants. Therefore, the urinary iAs metabolites, namely Asi^+ 3, Asi^+ 5, MMA, and DMA, were summed to calculate the biological dose of exposure. The urinary iAs metabolites were categorized into tertiles (\(<\)46.832, 46.832–95.342, and > 95.342 ppb for T1, T2, and T3, respectively). Accordingly, the low methylation capacity group contained metabolites whose PMIs or SMIs were lower than their respective median values, and the high methylation capacity group contained those whose PMIs and SMIs were higher than their respective median values. Data were analyzed using SAS 9.4.

The average age at recruitment was 59 years (35–93 years), with an average age of 78 years after 19 years of follow-up. The incidence density of urothelial tract cancers was 78.21 × 10^− 5/year and was significantly higher in the older age group (HR: 1.92; 95% CI, 1.24–2.98) than it was in the younger age group (Table 1). Water arsenic concentrations and cumulative arsenic exposure were significantly higher in the bladder cancer (350.45 ppb and 10.08 ppm-years, respectively) and upper urothelial tract cancers (346.23 ppb and 13.11 ppm-years, respectively) groups than they were in the noncancer control group (133.28 ppb and 4.44 ppm-years, respectively; P < 0.001 and P < 0.001, respectively). The total urinary iAs metabolites, urinary iAs, and DMA were higher in the bladder cancer group (192.48 ppb, 27.94 ppb, and 146.77 ppb, respectively) than they were in the noncancer control group (99.10 ppb, 9.32 ppb, and 79.07 ppb, respectively; 0.05 < P < 0.10; Table 2).

Table 1

Descriptive statistics of arseniasis cohort in association with urothelial tract cancers (*ICD10* = C64–68)
	person-years		Incidence density	Univariate analysis
			(10^− 5/year)	HR (95% CI)
Sociodemographic variables
Overall (n = 5811)	108683.65	85	78.21
Age at recruitment
< 58	63428.12	38	59.91	1.00
\(\ge\)58	45255.53	47	103.85	1.919	(1.237,	2.977)
Sex
Female	56006.77	42	74.99	1.00
Male	52676.88	43	81.63	1.11	(0.718,	1.708)
Marry Status
Married	105968.97	84	79.27	1.00
Single	1888.49	1	52.95	0.723	(0.101,	5.188)
Education
Elementary and lower	100234.16	80	79.81	1.00
Junior high and higher	8147.34	4	49.10	0.61	(0.222,	1.655)
Occupation
Soldiers/government employees	1255.63	1	79.64	1.26	(0.546,	4.51)
Labor workers and business person	15518.46	13	83.77	1.33	(0.549,	2.699)
Agriculture, and fisherman	46068.25	42	91.17	1.45	(0.859,	2.336)
Housekeeping and others	39675.00	25	63.01	1.00
Lifestyle Variables
Cigarette smoking
No	66706.98	45	67.46	1.00
Yes	41976.68	40	95.29	1.45	(0.94,	2.243)
Alcohol drinking
No	88977.83	70	78.67	1.00
Yes	19573.7	15	76.63	0.98	(0.551,	1.742)
Tea
No	82541.27	62	75.11	1.00
Yes	25842.75	23	88.99	1.24	(0.766,	2.007)
Exercise
No	84732.74	62	73.17	1.00
Yes	23614.93	23	97.40	1.304	(0.794,	2.143)

Table 2

Association of arsenic exposure metrics among study groups
	Non-cancer controls (n = 5726)		Bladder cancer cases (ICD10 = 67) (n = 49)			Upper urothelial tract cancers (ICD10 = 64 ~ 66, 68) (n = 36)			ANOVA^**
	Means	\(\pm\)SD	Means	\(\pm\)SD	HR	Median	\(\pm\)SD	HR	p-value
Arsenic Exposure
Concentration in well water (ppb)	133.28	\(\pm\)302.24	350.45	\(\pm\)696.36	1.00*	346.23	\(\pm\)643.20	1.00*	< .0001^ab
Years of exposure	41.54	\(\pm\)16.13	44.33	\(\pm\)15.10	1.02	41.14	\(\pm\)14.76	1.00	0.585
Cumulative arsenic exposure (ppm-years)	4.44	\(\pm\)10.58	10.08	\(\pm\)17.35	1.02	13.11	\(\pm\)24.19	1.03*	< .0001^ab
Urinary Inorganic Arsenic Metabolites
Total (ppb)	99.10	\(\pm\)130.43	192.48	\(\pm\)244.32	1.00*	95.95	\(\pm\)76.45	1.00	0.078
Inorganic arsenic (ppb)	9.32	\(\pm\)13.11	27.94	\(\pm\)65.29	1.02*	13.16	\(\pm\)17.77	1.01	0.064
MMA (ppb)	10.72	\(\pm\)18.64	17.77	\(\pm\)26.68	1.01	11.45	\(\pm\)13.68	1.00	0.508
DMA	79.07	\(\pm\)110.51	146.77	\(\pm\)174.49	1.00*	71.34	\(\pm\)56.83	1.00	0.098
Asi%	11.90	\(\pm\)9.74	12.58	\(\pm\)8.71	1.01	15.44	\(\pm\)14.34	1.02	0.598
MMA%	9.94	\(\pm\)6.66	9.09	\(\pm\)5.90	0.98	10.61	\(\pm\)7.76	1.01	0.577
DMA%	78.15	\(\pm\)11.60	78.33	\(\pm\)11.10	1.00	73.95	\(\pm\)14.50	0.98	0.200
PMI	1.95	\(\pm\)7.17	1.55	\(\pm\)2.86	0.98	4.50	\(\pm\)15.63	1.01	0.633
SMI	14.80	\(\pm\)62.39	19.41	\(\pm\)36.65	1.00	10.71	\(\pm\)6.57	0.99	0.506
P < 0.05, performed by univariate Cox regression model *Logarithmic transformation before ANOVA and Scheffe’s multiple comparison procedure ^aStatistical significance when comparing bladder cancer cases and noncancer controls ^bStatistical significance when comparing upper urothelial tract cancer cases and noncancer controls ^cStatistical significance when comparing upper urothelial tract cancer cases and bladder cancer cases

After adjustment for age, sex, marital status, education level, occupation, cigarette smoking habit, alcohol drinking habit, and iAs metabolism patterns (PMI and SMI), the Cox regression analyses revealed a significant association between water iAs concentrations > 100 ppb and the occurrence of bladder cancer at a HR of 4.88 (95% CI, 1.35–17.61). In addition, a statistically significantly monotonic trend was observed between water iAs concentrations and upper urothelial tract cancers (P < 0.05), although no significance was observed at any single level of exposure. A dose–response relationship was observed between cumulative arsenic exposure and bladder cancer but not between cumulative arsenic exposure and upper urothelial tract cancers. A significant monotonic trend was observed between total urinary iAs metabolite tertiles and bladder cancer, although no statistical significance was observed between tertiles and upper urothelial tract cancers. A significant association was observed between the second tertile of urinary iAs metabolites and upper urothelial tract cancers at a HR of 7.55 (95% CI, 1.65–34.53; Table 3).

Table 3

Multiple Cox regression analyses for arsenic exposure metrics and urothelial tract cancers
Bladder cancer (ICD10 = C67)										Upper urothelial tract cancers (ICD10 = C64 ~ 66, 68)
	Model I			Model II			Model III			Model I			Model II			Model III
	HR*	(95% CI)		HR*	(95% CI)		HR*	(95% CI)		HR*	(95% CI)		HR*	(95% CI)		HR*	(95% CI)
Arsenic exposure Concentration in well water (ppb)
\(\le\)10.00	1*	-	-							1*	-	-
10.01 ~ 50.00	1.86	(0.49	,7.04)							0.40	(0.10	,1.68)
50.01 ~ 100.00	1.61	(0.27	,9.67)							2.08	(0.60	,7.26)
> 100.00	4.88	(1.35	,17.61)							1.63	(0.51	,5.20)
Cumulative arsenic exposure (ppm-years; in tertile)
\(\le\)0.555				1*	-	-							1	-	-
0.555 ~ 2.548				5.06	(1.09	,23.49)							0.50	(0.13	,1.93)
> 2.548				10.22	(2.30	,45.47)							2.13	(0.80	,5.64)
Urinary inorganic arsenic metabolites (ppb)
\(\le\)46.832							1*	-	-							1	-	-
46.832 ~ 95.342							2.64	(0.80	,8.75)							7.55	(1.65	,34.53)
> 95.342							3.79	(1.15	,12.47)							4.28	(0.83	,22.11)
Arsenic methylation capacity
PMI(median low/high)
High	1	-	-	1	-	-	1	-	-	1	-	-	1	-	-	1	-	-
Low	0.60	(0.26	,1.39)	0.61	(0.26	,1.43)	0.45	(0.19	,1.09)	0.57	(0.23	,1.43)	0.56	(0.22	,1.40)	0.48	0.18	,1.24)
SMI(median low/high)
High	1	-	-	1	-	-	1	-	-	1	-	-	1	-	-	1	-	-
Low	1.18	(0.46	,3.02)	1.14	(0.44	,2.92)	1.00	(0.39	,2.59)	0.75	(0.28	,1.97)	0.75	(0.29	,1.98)	0.61	0.23	,1.63)
*P < 0.05, test for monotonic trend performed by multiple Cox regression analysis adjusted by age, sex, marital status, education, occupation, cigarette smoking, and alcohol drinking

To investigate the dose–response relationship between low-to-moderate iAs concentrations in water and urothelial tract cancers, a stratified analysis by the median (high and low) PMI and SMI groups was performed. Participants with exposure to water iAs concentrations of 0–10.00, 10.01–50.00, 50.01–100.00, and >100.00 ppb had HRs of 1.00, 2.17, 3.11, and 4.60 of developing urothelial tract cancers, respectively, in a dose–response relationship among participants with lower PMIs (Fig.1–1). Participants with exposure to iAs concentrations in water of 0–10.00, 10.01–50.00, 50.01–100.00, and >100.00 ppb had HRs of 1.00, 1.20, 2.03, and 3.73 of developing urothelial tract cancers, respectively, in a dose–response relationship among participants with higher SMIs (Fig.1–2). The tertile of cumulative arsenic exposure exhibited the same pattern of association between iAs concentrations and of developing urothelial tract cancers (Fig. 1–3, 1–4).

This study demonstrated the occurrence of urothelial cancers, including those at upper urothelial tract and bladder sites, in an arseniasis community cohort after a 25-year cessation of drinking well water. The analyses revealed a dose–response relationship between low-to-moderate arsenic exposure and urothelial tract cancers among residents with lower PMIs or higher SMIs. However, the strength of the association between arsenic exposure and different sites of urothelial tract cancers, namely bladder and upper urothelial tract cancers, varied. The reasons for this varying carcinogenic potency remain unclear. The underlying mechanisms of arsenic carcinogenesis at organ sites, such as the lungs, skin, bladder, and upper urothelial tract, may differ with the dose in target cells, the molecular response to toxins, and local metabolism. According to the literature, these differences are primarily associated with concentrations of oxygen, arsenic species in the tissues, chemicals involving arsenic metabolism, and other endogenous cellular factors[32]. In addition, this study demonstrated that individuals with lower primary methylation or higher secondary methylation exhibited a dose–response relationship between low-to-moderate arsenic exposure, ˂100 ppb, and urothelial tract cancers. This observation echoes those of advocates of the hazard of low-to-moderate arsenic exposure and indicates the key factors for assessing susceptibility. Accordingly, this finding provides a reference for future estimations of the risk of carcinogenesis due to low-to-moderate iAs exposure and a revision of the maximum allowance of arsenic in drinking water for susceptible populations.

Most epidemiological reports have focused on the association between arsenic exposure and bladder cancer, and only a few studies have discussed the effects of such exposure on upper urothelial tract cancers. In addition, a clear association between arsenic exposure, particularly low-to-moderate-level exposure, with higher upper urothelial tract cancers still requires validation[19–21]. Establishing an association between low arsenic exposure and a relatively lower incidence of cancer at organ sites is hindered by relative risks of nearly 1.0, insufficient statistical power, the necessity of managing confounding, exposure misclassification, and observation latency[34]. Therefore, although the IARC considers the evidence to date sufficient to support arsenic as increasing the risk of urinary bladder cancer, risks related to exposure in the 10–100 µg/L arsenic range remain unclear[12]. The patterns identified in this study were similar to those of a Chilean study, which demonstrated a considerable need for health care related to upper tract urothelial cancer and high mortality rates among residents who had been exposed to arsenic 25 years after the arsenic levels in drinking water had been controlled[22]. In addition, the present study contributes evidence of an association between exposure to low-to-moderate arsenic concentrations and the incidence of urothelial tract cancers in an exposure cohort. Our findings have supplemented the ecological literature on the effects of low-to-moderate arsenic concentrations, which includes a study demonstrating an association between low arsenic concentrations in drinking water (1.5–15.4 µg/L) and bladder cancer incidence in the United States[18] and a case–control study investigating the association between lifetime cumulative arsenic levels consumed through drinking water at a low-to-moderate arsenic exposure level and the incidence of bladder cancer[35]. This study has expanded on the understanding of this association by including an extended observation period and the participants’ methylation capacity to demonstrate the presence of a dose–response relationship between low-to-moderate iAs exposure and the risk of developing urothelial tract cancers.

Studies have demonstrated that a higher percentage of methylated arsenic in urine indicates a higher risk of skin and bladder cancer[29, 30]. Our previous cohort study demonstrated a dose–response relationship between arsenic exposure levels of 2–200 ppb and lung cancer under conditions of lower methylation capacity. The present study demonstrated that the association between low-to-moderate arsenic exposure and urothelial tract cancers was noticeable among participants with lower PMIs or higher SMIs. The methylation capacity of exposed individuals was a key moderator of the risk of developing urothelial tract cancers. This observation supports the proposition that differing iAs methylation capacities is a main factor causing variability in arsenic carcinogenesis. Researchers have proposed that high methylation capacity is a protective mechanism against cancer development at skin, lung, and urothelial tract sites[20, 36, 37]. However, frequently high levels of methylation in cells are hazardous. In an animal model with urothelial carcinogenesis, arsenic was reported to be more hazardous in hosts with a methyl donor or glutathione depletion[38]. Accordingly, experiments in human cells have demonstrated that arsenic depletes cellular S-adenosylmethionine concentrations and causes DNA hypomethylation. Low methylation capacity and high methylation demands may cause the accumulation of toxic arsenicals and in turn result in genotoxic events, such as the induction of oxidative stress, interference with signal transduction, and gene expression[39]. Furthermore, an animal model demonstrated that genome-wide DNA hypomethylation caused by relentless iAs methylation may provide the basis for improving the understanding of human carcinogenesis[40]. These mechanisms explain why a higher risk of developing urothelial tract cancers was observed among individuals with lower PMIs or higher SMIs in this study; relatively lower MMA metabolites may be a key indicator in iAs carcinogenesis of urothelial tract cancers. The epidemiological data with a sufficient follow-up period in this study offer a valuable opportunity for verifying these mechanisms.

The strength of this study is its cohort design with a sufficient follow-up period and its low detection bias, with verification through health insurance claims. In addition, the length of observation (> 60 years after exposure inception), which continued after 25 years of drinking well water cessation, offered a valuable opportunity to investigate the association between cancers and early life exposure to arsenic. Although these findings are novel and noteworthy, the study contains limitations that necessitate caution in interpreting the results. First, the specimens used to identify urinary arsenic metabolites were collected upon the participants’ recruitment. Although studies have demonstrated the soundness of repeated measurements, verification by using a population subset may improve the reliability of the dosimetry. Second, iAs metabolism profiles may vary across ethnicities; therefore, generalizations of these results to individuals in other countries should be cautiously made. Third, due to the length of follow-up and the investigation being conducted 25 years after cessation of exposure, various confounding factors may be present among participants with respect to lifestyle changes, medical treatment/seeking behaviors, and other interventions.

iAs

Inorganic arsenic

IARC

International Agency for Research on Cancer

MMA

Methylarsonic acid

DMA

Dimethylarsinic acid

PMI

Primary methylation index

SMI

Secondary methylation index

HRs

Hazard ratios.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital in Taoyuan, Taiwan (100-2839C). Informed consent was obtained from all individual participants included in the study.

Consent for publication

All authors of this research paper have directly participated in the planning, execution, or analysis of the study. All authors of this paper have read and approved the final version submitted.

Availability of data and materials

The dataset used for this study is available through a request to the National Cancer Registration Database and were verified against national health insurance claims database.

Competing interests

All authors claimed no competing financial interests.

Funding

This work was supported by the Ministry of Science and Technology, Taiwan (110-2410-H-182-013-MY3) and a Health Aging Research Center of Chang Gung University (EMRPD1L0401, EMRPD1L0451). This work was also supported by the Chang Gung Medical Foundation (CMRPD3L0021, CMRPD3L0022) and the Wang Jhan-Yang Charitable Trust Fund (WJY 2020-HR-01, WJY 2021-HR-01). Authors also acknowledged the supports of data linkage by Health and Welfare Data Center, Ministry of Health and Welfare in Taiwan.

Authors’ contributions

PJL performed data collection, data analysis and interpretation, and drafting the manuscript. CHL, SLW, HYC, and CJC conducted data interpretation, and intellectual discussion. KHH performed study design, data analysis and interpretation, and drafting and revising the manuscript.

Acknowledgements

Not applicable.

Humans, I.W.G.o.t.E.o.C.R.t. (2012). Arsenic, metals, fibres, and dusts. IARC Monogr Eval Carcinog Risks Hum, 100(Pt C), 11–465.
Sankpal, U.T., et al. (2012). Environmental factors in causing human cancers: emphasis on tumorigenesis. Tumour Biol, 33(5), 1265–74. https://doi.org/10.1007/s13277-012-0413-4
Cohen, S.M., et al. (2013). Evaluation of the carcinogenicity of inorganic arsenic. Crit Rev Toxicol, 43(9), 711–52. https://doi.org/10.3109/10408444.2013.827152
Chiou, H.Y., et al. (2001). Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan. Am J Epidemiol, 153(5), 411–8. https://doi.org/10.1093/aje/153.5.411
Chen, C.L., et al. (2010). Arsenic in drinking water and risk of urinary tract cancer: a follow-up study from northeastern Taiwan. Cancer Epidemiol Biomarkers Prev, 19(1), 101–10. https://doi.org/10.1158/1055-9965.Epi-09-0333
Mink, P.J., et al. (2008). Low-level arsenic exposure in drinking water and bladder cancer: a review and meta-analysis. Regul Toxicol Pharmacol, 52(3), 299–310. https://doi.org/10.1016/j.yrtph.2008.08.010
Chen, C.L., et al. (2010). Ingested arsenic, characteristics of well water consumption and risk of different histological types of lung cancer in northeastern Taiwan. Environ Res, 110(5), 455–62. https://doi.org/10.1016/j.envres.2009.08.010
Tsuji, J.S., et al. (2014). Arsenic exposure and bladder cancer: quantitative assessment of studies in human populations to detect risks at low doses. Toxicology, 317, 17–30. https://doi.org/10.1016/j.tox.2014.01.004
Tsuda, T., et al. (1995). Ingested Arsenic and Internal Cancer: A Historical Cohort Study Followed for 33 Years. American Journal of Epidemiology, 141(3), 198–209. https://doi.org/10.1093/oxfordjournals.aje.a117421%J American Journal of Epidemiology
Marshall, G., et al. (2007). Fifty-year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water. J Natl Cancer Inst, 99(12), 920–8. https://doi.org/10.1093/jnci/djm004
Humans, I.W.G.o.t.E.o.C.R.t. (2004). Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr Eval Carcinog Risks Hum, 85, 1–334.
Meliker, J.R., et al. (2010). Lifetime exposure to arsenic in drinking water and bladder cancer: a population-based case-control study in Michigan, USA. Cancer Causes Control, 21(5), 745–57. https://doi.org/10.1007/s10552-010-9503-z
Meliker, J.R., et al. (2007). Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in Michigan: a standardized mortality ratio analysis. Environ Health, 6, 4. https://doi.org/10.1186/1476-069x-6-4
Lamm, S.H., et al. (2004). Arsenic in drinking water and bladder cancer mortality in the United States: an analysis based on 133 U.S. counties and 30 years of observation. J Occup Environ Med, 46(3), 298–306. https://doi.org/10.1097/01.jom.0000116801.67556.8f
Zhou, Q. and S. Xi. (2018). A review on arsenic carcinogenesis: Epidemiology, metabolism, genotoxicity and epigenetic changes. Regul Toxicol Pharmacol, 99, 78–88. https://doi.org/10.1016/j.yrtph.2018.09.010
Baris, D., et al. (2016). Elevated Bladder Cancer in Northern New England: The Role of Drinking Water and Arsenic. J Natl Cancer Inst, 108(9). https://doi.org/10.1093/jnci/djw099
Gibb, H., et al. (2011). Utility of recent studies to assess the National Research Council 2001 estimates of cancer risk from ingested arsenic. Environ Health Perspect, 119(3), 284–90. https://doi.org/10.1289/ehp.1002427
Mendez, W.M., Jr., et al. (2017). Relationships between arsenic concentrations in drinking water and lung and bladder cancer incidence in U.S. counties. J Expo Sci Environ Epidemiol, 27(3), 235–243. https://doi.org/10.1038/jes.2016.58
Tan, L.B., K.T. Chen, and H.R. Guo. (2008). Clinical and epidemiological features of patients with genitourinary tract tumour in a blackfoot disease endemic area of Taiwan. BJU International, 102(1), 48–54. https://doi.org/10.1111/j.1464-410X.2008.07565.x
Ferreccio, C., et al. (2013). Case-control study of arsenic in drinking water and kidney cancer in uniquely exposed Northern Chile. Am J Epidemiol, 178(5), 813–8. https://doi.org/10.1093/aje/kwt059
Yang, M.H., et al. (2002). Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology, 59(5), 681–7. https://doi.org/10.1016/s0090-4295(02)01529-7
López, J.F., M.I. Fernández, and L.F. Coz. (2020). Arsenic exposure is associated with significant upper tract urothelial carcinoma health care needs and elevated mortality rates. Urol Oncol, 38(7), 638
.e7-638.e13
. https://doi.org/10.1016/j.urolonc.2020.01.014
Smith, A.H., et al. (2018). Lung, Bladder, and Kidney Cancer Mortality 40 Years After Arsenic Exposure Reduction. J Natl Cancer Inst, 110(3), 241–249. https://doi.org/10.1093/jnci/djx201
Chou, Y.H. and C.H. Huang. (1999). Unusual clinical presentation of upper urothelial carcinoma in Taiwan. Cancer, 85(6), 1342–4.
(2004). Some drinking-water disinfectants and contaminants, including arsenic. IARC Monogr Eval Carcinog Risks Hum, 84, 1–477.
Yuan, Y., et al. (2010). Kidney cancer mortality: fifty-year latency patterns related to arsenic exposure. Epidemiology, 21(1), 103–8. https://doi.org/10.1097/EDE.0b013e3181c21e46
Chen, Y.C., et al. (2003). Arsenic methylation and skin cancer risk in southwestern Taiwan. J Occup Environ Med, 45(3), 241–8. https://doi.org/10.1097/01.jom.0000058336.05741.e8
Chen, C.L., et al. (2004). Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan. Jama, 292(24), 2984–90. https://doi.org/10.1001/jama.292.24.2984
Moe, B., et al. (2016). Comparative cytotoxicity of fourteen trivalent and pentavalent arsenic species determined using real-time cell sensing. J Environ Sci (China), 49, 113–124. https://doi.org/10.1016/j.jes.2016.10.004
Khairul, I., et al. (2017). Metabolism, toxicity and anticancer activities of arsenic compounds. Oncotarget, 8(14), 23905–23926. https://doi.org/10.18632/oncotarget.14733
Gamboa-Loira, B., et al. (2017). Arsenic metabolism and cancer risk: A meta-analysis. Environ Res, 156, 551–558. https://doi.org/10.1016/j.envres.2017.04.016
Hsu, K.H., et al. (2017). Dose-Response Relationship between Inorganic Arsenic Exposure and Lung Cancer among Arseniasis Residents with Low Methylation Capacity. Cancer Epidemiol Biomarkers Prev, 26(5), 756–761. https://doi.org/10.1158/1055-9965.Epi-16-0281
Tseng, C.H. (2009). A review on environmental factors regulating arsenic methylation in humans. Toxicol Appl Pharmacol, 235(3), 338–50. https://doi.org/10.1016/j.taap.2008.12.016
Buehler, J., K. Rothman, and S. Greenland. (1998). Modern epidemiology. Philadelphia, PA: Lippencott-Raven.
Steinmaus, C., et al. (2003). Case-control study of bladder cancer and drinking water arsenic in the western United States. Am J Epidemiol, 158(12), 1193–201. https://doi.org/10.1093/aje/kwg281
Yu, R.C., et al. (2000). Arsenic methylation capacity and skin cancer. Cancer Epidemiol Biomarkers Prev, 9(11), 1259–62.
Pu, Y.S., et al. (2007). Urinary arsenic profile affects the risk of urothelial carcinoma even at low arsenic exposure. Toxicol Appl Pharmacol, 218(2), 99–106. https://doi.org/10.1016/j.taap.2006.09.021
Drobná, Z., et al. (2005). Metabolism and toxicity of arsenic in human urothelial cells expressing rat arsenic (+ 3 oxidation state)-methyltransferase. Toxicol Appl Pharmacol, 207(2), 147–59. https://doi.org/10.1016/j.taap.2004.12.007
Reichard, J.F., M. Schnekenburger, and A. Puga. (2007). Long term low-dose arsenic exposure induces loss of DNA methylation. Biochem Biophys Res Commun, 352(1), 188–92. https://doi.org/10.1016/j.bbrc.2006.11.001
Okoji, R.S., et al. (2002). Sodium arsenite administration via drinking water increases genome-wide and Ha-ras DNA hypomethylation in methyl-deficient C57BL/6J mice. Carcinogenesis, 23(5), 777–85. https://doi.org/10.1093/carcin/23.5.777

No competing interests reported.

tableEHJ.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

Low-to-moderate arsenic exposure and urothelial tract cancers: A sixty-year latency analysis

Status:

Version 1

Abstract

Figures

Background

Methods

Study participants

Data Collection

Statistical Analyses

Results

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1