This study aimed to determine whether there was an association between blood chloroform and cognitive function in the general elderly population. In this cross-sectional study of US elderly, we found that blood chloroform levels were negatively associated with cognitive function measured using the DSST. These results suggest that chloroform exposure in the general population may contribute to cognitive impairment as measured by the DSST.
Cognitive function refers to multiple mental processes including attention, learning, decision making, language, and memory and is an integral component of a healthy and independent lifestyle . Cognitive impairment in the elderly may have a profound impact on an individual’s activities of daily living including meal preparation and ability to manage medication regimens, resulting in poor health outcomes . Identifying and reducing modifiable risk factors of cognitive impairment is essential to minimizing the poor health outcomes associated with cognitive impairment and improving the health and well-being of the elderly .
Chloroform is a water disinfection by-product widely dispersed in the environment which has been formerly used as an anesthetic in the past . Its narcotic effects have been well documented; however studies on occupational or environmental exposures to chloroform and its relationship with cognitive function remain limited . In addition, previous studies have evaluated chloroform exposure in terms of inhaled or ingested concentrations instead of blood concentrations. In line with the results of our study, previous studies have reported a relationship between chloroform and cognitive function. In a case series of 29 cases of chloroform addiction, one case reported symptoms of slowing of intellect and weakness of memory . Other common symptoms included irritability, anxiety, depression, hallucinations, and hand tremor . In a study conducted at a medicinal lozenge producing factory in the UK, 8 out of 7 women exposed to chronic inhalation exposure to chloroform concentrations ranging from 77 to 237 ppm reported feelings of a lack of concentration, depression, and irritability . In a study of 61 workers exposed to long-term chloroform concentrations ranging from 0.87-28.9 ppm, workers experienced symptoms such as fatigue, dizziness, insomnia, and palpitations and significant changes were found in neurologic tests including the Simple Visual Reaction Time, Digital Symbol Substitution, and Digit Span test for some workers .
The molecular mechanism behind the association between chloroform and cognitive function is unclear; however, there are several possible mechanisms which may serve as an explanation . Glutamate is a neurotransmitter which plays a key role in cognitive function . In an in vitro study using mouse cortical wedges, chloroform concentrations of 3-6 mM antagonized responses of the glutamate receptor N-methyl-D-aspartate . Decreased serotonin neurotransmission is known to negatively influence cognitive function . Another study in mice investigating the effects of oral administration of chloroform showed decreased levels of 5-hydroxyindoleacetic acid, the main metabolite of serotonin, in the midbrain . In addition, chloroform may be associated with the changes in the calcium-dependent potassium conductance in neurons, which may play a role in cognition [22, 23].
After stratification by obesity status statistically significant associations were observed among the obese, indicating that the obese may be more susceptible. Chloroform is lipophilic and concentrates mainly in tissues with high lipid content . In an animal study, after 2.5 hours of deep anesthesia with chloroform, relative concentrations of chloroform were highest in adipose tissue followed by the brain, liver, kidney, and blood .
Chloroform is lipophilic and distributes to areas with high lipid density and therefore has a relatively high volume of distribution (Vd) . In addition, because total body weight is correlated with Vd for lipophilic drugs and a drug with a high Vd has a longer elimination half-life, individuals with higher BMIs may be more susceptible to the effects of chloroform .
Environmental routes of exposure to chloroform include inhalation to air polluted with chloroform, and oral and dermal routes from water contaminated water sources. A recent study investigating factors associated with chloroform exposure from the NHANES 2001-2011 cycles reported that elevated blood levels of chloroform were associated with taking a shower or bath within 6 hours of blood collection or being in a pool or hot tub or sauna within 24 hours, suggesting that contaminated water sources could be the source of chloroform exposure in the study population . Median chloroform concentrations in tap water collected from the homes of NHANES 2001-2011 participants aged 12 and older ranged from 7.52 to 12.3 µg/L, levels which are well below the WHO benchmark levels for drinking water quality (300 µg/l) and the US Environmental Protection Agency’s maximum contaminant level goal of 70 µg/L [27–29]. These results suggest that the NHANES sample was exposed to low levels of chloroform well below the recommended levels. Although our findings require confirmation, low levels of chloroform exposure seem to have an effect on cognitive function.
To the best of our knowledge, this is the first population-based study to examine the relationship between blood chloroform levels and cognitive function measured by the DSST in the general elderly population. Despite this fact, our study has several limitations. Due to the cross-sectional nature of the study, we cannot assess any casual or temporal relationships. Although we cannot assess temporality, the presence of a dose-response relationship between blood chloroform levels and DSST scores could provide evidence for a causal relationship. Secondly, due to the cross-sectional nature of the data, we were unable to differentiate between acute and chronic exposure. Blood trihalomethane levels are known to increase and decrease within minutes to hours after exposure to daily activities including showering, bathing, and dishwashing; however, blood trihalomethane concentrations are thought to reflect steady-state blood concentrations due to the frequency of water use activities and slow partitioning out of physiological compartments like adipose tissue [30–32]. Thirdly, several covariates were self-reported and as a result are not free from bias. Lastly, although basic sociodemographic confounding variables were considered, we cannot exclude the possibility of residual confounding due to unmeasured confounders.