Intraindividual Variability in Arsenic Methylation in a U.S. Population

Abstract

Several recent investigations have reported associations between a reduced capacity to fully methylate inorganic arsenic and increased susceptibility to arsenic-caused cancer. In these studies, methylation patterns were based on a single assessment of urinary arsenic metabolites collected at the time of cancer diagnosis. However, the latency of arsenic-caused cancer may be several decades, and the extent to which a recent measurement can be used to estimate a person's past methylation pattern is unknown. In this investigation, the distribution of urinary inorganic arsenic, monomethylarsonate, and dimethylarsinate was used to assess intraindividual variation in methylation capacity in 81 subjects with low to moderate arsenic exposures. Multiple urine samples were collected from each subject over a 1-year period. Duplicate analyses done on 27 samples were used to assess laboratory measurement imprecision. The intraclass correlation coefficients (ICC) for the proportion of urinary arsenic as inorganic arsenic, monomethylarsonate, and dimethylarsinate in samples taken an average of 258 days apart, were 0.45 [95% confidence interval (95% CI), 0.23-0.63] 0.46 (95% CI, 0.24-0.64), and 0.49 (95% CI, 0.28-0.66). In analyses of duplicate samples, ICCs for the concentration of arsenic species ranged from 0.87 to 0.93, whereas ICCs for species proportions ranged from 0.63 to 0.76. These data suggest that individual methylation patterns remain fairly stable over time, although variability due to measurement imprecision or intraindividual changes over time does occur. This variability could lead to misclassification of methylation patterns and could bias relative risk estimates in studies of methylation and cancer towards the null.

Arsenic Metabolism, Genetic Susceptibility, and Risk of Premalignant Skin Lesions in Bangladesh

“…Several studies have indicated that the proportion of MMA in urine is positively associated whereas the proportion of DMA is inversely associated with the risk of skin and bladder cancer (7)(8)(9). Several smaller studies have indicated that arsenic metabolic process is influenced by demographic (sex and age) characteristics (13,32,33). The present study of arsenic-related skin lesions confirms these inferences in arsenic toxicity.…”

Arsenic exposure, urinary arsenic speciation, and the incidence of urothelial carcinoma: a twelve-year follow-up study

“…These profiles are good markers reflecting the metabolism of InAs ingested from drinking water [25,26]. The study showed that urinary arsenic methylation indices were fairly stable for 8-10 months for subjects who drank water with a 20 lg/l arsenic level [36]. Subjects that discontinued drinking high arsenic-containing water and changed to consuming low-level arsenic-containing water sequentially had a decreased urinary %MMA V and an increased %DMA V [37].…”

“…The relative risks should be interpreted cautiously due to the low incidence of cases of UC, resulting in inadequate statistical power. The arsenic methylation profiles were found to be constant over time, reflecting a uniform exposure via drinking water [54]. Reports about whether the arsenic methylation profile has or does not have long-term consistency are lacking.…”

“…The residents in that area had used artesian well water for more than 30 years when they were recruited to participate in the current study, and the duration of arsenic exposure may have been long enough to induce cancer. However, urinary arsenic profiles remain fairly stable over time [24], and the urinary arsenic species marker is a good index to predict the risk of arsenic-related disease [25,26]. This is the first cohort study to document the relationship between the urinary arsenic profile and the incidence of urothelial carcinoma (UC) in the area of southwestern Taiwan endemic for arseniasis.…”

Arsenic Methylation Capability, Heme Oxygenase-1 and NADPH Quinone Oxidoreductase-1 Genetic Polymorphisms and the Stage and Grade of Urothelial Carcinomas

“…An individual's methylation capacity plays an important role in determining the susceptibility to the adverse health effects of arsenic, especially MMA% or the MMA/DMA ratio and arsenic-related skin cancer and bladder cancer [11,12] . A recent report indicated that individual methylation patterns remain fairly stable over time [45] , suggesting that the predominant factors controlling this process are either genetically influenced or related to environmental factors such as long-term dietary patterns or smoking habits that also remain stable over time. Several studies have shown that inherited genetic traits might play important roles in determining individual arsenic methylation capabilities [46,47] .…”