The detrimental impact of acute high-level exposure to arsenic on health is well established; however, prior work has also documented adverse consequences of prolonged exposure to groundwater arsenic at levels below the current U.S. standard of 10 μg/L. Chronic exposure to low-levels of arsenic through drinking water is common in the U.S. where 13.6% of sampled public water-supply systems exceeded 5 μg/L and 25% exceeded 2 μg/L [1
]. Such exposure has been found to increase risk for a range of diseases including hypertension, diabetes, coronary artery disease, skin melanosis, cancer, and poorer cognition [2
]. Therefore, over 40 million Americans are at an increased risk for negative health consequences resulting from being exposed to low-levels of arsenic over the course of their lifetime [1
]. In fact, it has been proposed that exposure to environmental toxins, including arsenic, has caused a “silent pandemic” in modern society that has gone undetected [9
]. This circumstance has likely remained unnoticed because the neurodevelopmental and neurotoxic consequences of in utero
exposure (along with chronic lifetime exposure) may not become evident until neuronal attrition associated with aging occurs [9
]. To date, however, no prior work has been published looking at the potential impact of long-term low-level arsenic exposure on cognitive functioning among adults and elders. The purpose of this study was to take a first-step towards addressing this gap in the public health literature.
There is ample reason to hypothesize an association between chronic arsenic exposure at low levels and neuropsychological dysfunction. Inorganic arsenic at high doses is a known neurotoxin with both neurodevelopmental and neurocognitive consequences. From a neuropathological standpoint, arsenic exposure has been associated with an increase in the production of β amyloid [10
], hyperphosphorylation of tau protein [11
], oxidative stress [12
], inflammation [13
], endothelial cell dysfunction [15
] and angiogenesis [16
], all of which have been linked to cognitive dysfunction and are proposed mechanisms underlying Alzheimer’s disease [3
]. In animal models, arsenic exposure has been shown to cause morphologic and neurochemical alterations in the hippocampus and other memory-related neuronal structures and expected learning and memory deficits have been noted [15
]. However, the direct link between chronic low-level arsenic exposure and detailed neuropsychological status remains untested.
Despite the National Research Council’s call for epidemiological studies of the non-cancer health consequences of long-term low-level arsenic exposure [7
], little research has been conducted to date. This is not for lack of interest; however, the methods for conducting such investigations have yet to be established. The ideal situation is one where a biomarker of chronic exposure is available, which is the case when considering lead. Bone lead level measurement via K-shell-x-ray fluorescence has been used as a biomarker of long-term exposure [22
] and the correlation between such exposure and cognitive functioning has been studied [23
]. However, a valid biomarker for long-term arsenic exposure is lacking. One method that has been utilized is to reconstruct chronic exposures according to retrospective report of the level as well as the duration of exposure. In the PHYTHONER study, Baldi and colleagues [25
] have documented a detrimental impact of long-term pesticide exposures on neurocognitive functioning among French vineyard workers using this approach. In countries where high levels of arsenic exposure have been documented for decades (e.g., areas of China, Bangladesh, and Mexico), researchers have historical data regarding exposure levels that can be utilized to create models of chronic exposure. In the U.S., the state of Texas offers a very unique situation given that the Texas Water Development Board (TWDB) has been monitoring well-water levels of a large number of chemicals including arsenic, for over 15 years across the state. Additionally, we have been conducting an epidemiological study of rural health, Project FRONTIER, for several years in two West Texas counties with mean groundwater arsenic levels that are below the U.S. standard. As part of this protocol, we have collected subjects’ (1) exact residential location and (2) number of years living at that location. Therefore, combining data from the TWDB and Project FRONTIER can create estimates of current and long-term arsenic exposure. Groundwater arsenic concentration at each subject’s home can be estimated with Geographic Information System (GIS) approach (the ArcGIS program) based on the residential location’s distances to surrounding wells with known groundwater arsenic concentrations provided by TWDB. The purpose of the current study was to examine the potential association between current and long-term arsenic exposure estimated by the GIS methods and detailed neuropsychological functioning in a sample of rural-dwelling adults and elders. Based on our prior work, as well as work with children and adolescents, we hypothesized that increased low-level arsenic exposure would be significantly correlated with poorer scores in the domains of global cognition, executive functioning, memory, and language.
3. Results and Discussions
The mean age and education of the 434 participants was 62.12 (sd = 12.81; range = 40–96) and 10.84 (sd = 4.46; range = 0–20), respectively. Seventy-nine percent (n = 344) of the sample was tested in English, with the remainder completing the assessment in Spanish. Ninety-seven percent of the sample self-reported their racial status as White and 42% (n = 180) reported their ethnicity as Hispanic, with the majority (n = 171) being of Mexican American origin. Of those participants genotyped (n = 440), 329 (75%) were APOE4 negative and 111 (25%) were APOE4 positive. Demographic characteristics of the sample are presented in Table 2
. Estimated mean current arsenic level was 6.33 μg/L (sd = 3.03, range = 2.19–15.26). The 15-year mean arsenic concentrations in Parmer and Cochran County, TX were 3.06 μg/L and 7.39 μg/L, respectively. In both counties, there was less than 2 μg/L variability over any given time period with results remaining very stable over this time period. There were 301 participants with all requisite data for calculation of long-term arsenic exposure at current household; mean long-term exposure was 240.15 μg/L-years (sd = 182.96; range = 2.87–972.83). On average, participants resided in their current residence for 34.12 years (sd = 20.01 years, range = 1–80 years).
Current estimated groundwater arsenic exposure level was significantly associated with poorer scores in language (RBANS Language scores, B(SE) = −0.458 (0.171), p = 0.008), visuospatial skills (CLOX2, B(SE) = −0.118 (0.060), p = 0.048), and executive functioning (CLOX 1 B(SE) = −0.225 (0.080), p = 0.005) (see Table 3
). Current arsenic exposure significantly classified cognitive dysfunction (AUC = 0.58, 95% CI = 0.51–0.65, p = 0.03).
Long-term low-level exposure to arsenic was significantly associated with poorer scores in global cognition (MMSE B(SE) = −0.003 (0.001), p = 0.004), visuospatial skills (CLOX 2 B(SE) = −0.001 (0.001), p = 0.038), language (FAS B(SE) = −0.012 (0.004), p = 0.002; RBANS Language B(SE) = −0.005 (0.002), p = 0.017), processing speed (TMTA B(SE) = 0.034 (0.014), p = 0.016), executive functioning (EXIT B(SE) = 0.006 (0.002), p < 0.001), and immediate memory (RBANS Immediate Memory B(SE) = −0.010 (0.003), p = 0.003). Long-term low-level arsenic exposure significantly classified cognitive impairment (AUC = 0 .62, 95% CI = 0.55–0.69, p = 0.001).
With the rapidly growing number of elders world-wide, there is a great need for research examining factors that impact cognition among adults and elders. Prior work has consistently demonstrated the adverse health consequences of high levels of arsenic exposure. As a result, the U.S. acceptable standard of arsenic concentration was reduced in 2001 from 50 μg/L to 10 μg/L. However, as pointed out by the National Research Council, there remains a need for research examining the non-cancer health effects of low-level arsenic exposure [7
] using longitudinal methodologies. Our current findings suggest that long-term low-level arsenic exposure is detrimental for the cognitive status of adults and elders. Our findings are consistent with prior work linking environmental exposure to arsenic to poorer neuropsychological functioning. Bolla-Wilson and Bleeker [44
] evaluated the neurocognitive functioning of a 50-year-old adult following acute exposure to arsenic and documented deficits in learning and memory, which improved over time with no subsequent exposures. Similarly, Wright and colleagues [45
] examined the neuropsychological profile of 31 school-aged children residing in Ottawa County, Oklahoma, which contains the Tar Creek Superfund site, and found higher hair arsenic levels to be significantly associated with poorer scores on tests of intelligence and memory. Tsai and colleagues [46
] evaluated 49 junior school students and found that higher chronic groundwater arsenic exposure was significantly related to poorer memory and executive functioning (i.e.
, switching attention). In a sample of 602 school children age 6–8 years, Rosado and colleagues [47
] found that higher urinary arsenic levels were significantly associated with poorer visuospatial skills, intelligence, attention and executive functioning. In our study, higher levels of current groundwater arsenic exposure (though still low-level exposure) was related to poorer visuospatial skills, language, and executive functioning. Increased levels of long-term low-level exposure were related to significantly poorer performance in the domains of global cognition, language, executive functioning, as well as memory. The current study is, however, different from all of the previously conducted work in several ways. First, the mean and median values of groundwater exposures in the communities evaluated in this study are below the current U.S. acceptable standard and are therefore reflective of low-level exposure. Second, we examined the impact of exposure on neuropsychological functioning in a community-based sample of rural-dwelling adults and elders rather than school children. Lastly, ours is the first to study the impact of estimated long-term low-level
arsenic exposure on detailed neuropsychological functioning. Our results are consistent with and extend prior work to adults and elders exposed at lower levels of groundwater arsenic [3
The consistent finding of arsenic being related to the domains of executive functioning and memory is of critical importance as these are cognitive domains that may change as part of the normal aging process and may even be the earliest manifestations of Alzheimer’s disease [48
]. This is particularly important for the long-term estimates, which as can be seen from Table 3
, are more strongly related with cognitive status. Therefore, it is possible that the impact of low-level arsenic exposure on neuropsychological functioning happens over time, which fits with the developmental course of Alzheimer’s disease. Alzheimer’s disease is a disease of insidious onset with slow progression that begins decades before clinical manifestation. While it has been suggested that research should focus on preventative strategies for Alzheimer’s disease [50
], the recent NIH consensus panel suggested that there are no preventative strategies currently available for Alzheimer’s disease, albeit dietary factors were suggested as having promise. The notion of groundwater exposure to arsenic as a risk factor for late-life Alzheimer’s disease offers potential for the first ever population-wide preventative effort aimed at preventing and/or delaying onset of this disease, which could be accomplished by revision of the Safe Drinking Water Act (SDWA).
There are limitations to the current study. One limitation is the cross-sectional nature of the data, which does not allow for inference of causality. Longitudinal assessment of this topic will be conducted through Project FRONTIER as follow-up waves are completed. The key limitation to the current study is the lack of either a biomarker of arsenic exposure (i.e., blood, hair, or nail levels) or direct measurement of the actual water arsenic levels at participant homes. However, the existence of the TWDB data provides an exceptional opportunity to model chronic arsenic exposure and the state can serve as a naturalistic setting for future studies. This is due to the fact that there are several “hot beds” of high arsenic levels across the state, even though the majority of the state is well below the current EPA standard. It is shown that GIS-estimated arsenic concentrations are very close to the measured values, particularly in terms of rank. Future Project FRONTIER studies will examine serum arsenic levels along with current household water levels. We cannot at this point conclude that long-term low-level arsenic consumption through water is causally related to poorer cognition from the current data. However, we can assert that those individuals who have resided for long periods of time in regions that have historically low levels of arsenic in groundwater supplies are at increased risk for cognitive dysfunction. This finding is certainly novel and warrants further investigation.