These results suggest that there is a modest increase in the risk of meeting one or more criteria for drug use disorder among adults with any exposure to PCE-contaminated drinking water during gestation and early childhood. No dose-response relationships were observed with increasing levels of PCE exposure. Nevertheless, the present results are consistent with our previous finding that illicit drug use is increased among individuals with early life exposure to PCE-contaminated drinking water (27). In that study, specific increases in risk were seen for using crack/cocaine, psychedelics/hallucinogens, club/designer drugs and heroin. Because the use of these drugs may lead to further uncontrollable use (28, 29), it is plausible that early life PCE exposure also increases the risk of having one or more criteria for drug use disorder.
These findings should be interpreted in light of the study limitations. The first is likely exposure misclassification. Because historical PCE exposure measurements were impossible to obtain from subject residences, we estimated PCE exposure using water distribution modeling software that was modified to incorporate a leaching and transport model (41, 49). The model was applied to water distribution system conditions in 1980 and was assumed to be representative of the entire exposure period. This assumption was supported by observation that the distribution systems changed little between the late 1960s and the 1980s, except for adding water sources to accommodate population growth. Furthermore, the exposure assessment predicted the annual mass of PCE delivered to each subject’s residence during gestation and early childhood, and did not incorporate information on water consumption and bathing habits due to poor recall of these behaviors. While results from validation studies indicate reasonable correlation between our exposure estimates and PCE concentrations in historical water samples (50–51), non-differential exposure misclassification likely biased the findings from dichotomous comparisons (e.g., any exposure vs. none) towards the null (51). The expected direction of bias for comparisons involving three exposure levels (e.g., high, low, unexposed) is more difficult to predict. However, it is possible that the lack of a dose-response relationship according to PCE levels may reflect bidirectional misclassification between the low and high exposure levels.
Another limitation stems from the use of self-reports as the source of information on the criteria for drug use disorder and did not capture diagnoses made by clinicians who were trained in addiction medicine. While the prevalence of drug use among study subjects was similar or higher than reported in independent surveys of Cape Cod and other Massachusetts residents (52), some underreporting of the criteria was likely in this questionnaire format. However, since most subjects did not know their exposure status, underreporting was likely to be non-differential and so would not have affected the observed risk ratios (51).
Still another limitation stems from possible residual confounding because of missing data on risk factors for drug use disorder (such as family dynamics and peer pressure). However, in order to account for the associations observed in this study, these factors would need to be causally related to PCE exposure, an unlikely scenario given the irregular pattern of the PCE contamination across the neighborhoods of Cape Cod. In fact, our prior analyses of this cohort also found little or no confounding for the outcomes being investigated (27, 53).
A further limitation stems from the low response rate. Although this problem reduced the statistical power of the study, the following evidence suggests that it did not result in selection bias. First, many available characteristics of Phase 1 and 2 participants and non-participants were similar, including PCE exposure status. Second, while Phase 2 participants were more likely to be female, and have college-educated mothers, these differences were equally present for exposed and unexposed non-participants. Third, losses stemming from the death of potential subjects (N = 117) were small and unrelated to initial PCE exposure status. Our review of death records from the Massachusetts Registry of Vital Records and Statistics and the National Death Index suggested that seven of the 117 deaths were associated with substance use; four of these deaths occurred among exposed subjects and three occurred among unexposed subjects.
Both animal and human studies have found neurotoxic effects following PCE exposure (6). Because of its small size and lipid solubility, PCE easily crosses the blood brain barrier and selectively concentrates in the brain and other lipophilic tissue. Epidemiologic studies of adults with occupational exposure to PCE and related solvents have reported increases in anxiety and depression (8–9, 11, 16–18) and impairments in cognition, memory, attention, executive function and trigeminal nerve and vestibular function (8–15).
Studies of the neurotoxic effects among individuals with early life exposure to organic solvents have produced mixed results. Eskenazi et al. found no deficits in intellectual ability, motor skills or memory among pre-school children whose mothers had jobs involving solvent exposure during pregnancy (19). In addition, no meaningful differences were seen in two studies of cognitive and abnormal behavioral function among children attending a nursery school and day care center who were exposed to PCE from nearby dry cleaning facilities (20–21). Our prior cohort study on the reproductive and developmental effects of prenatal and early postnatal PCE exposure also did not observe any associations with disorders of attention, learning, and behavioral control throughout childhood (41). In contrast, Till et al. found that pre-school children whose mothers were exposed to organic solvents during pregnancy had lower scores on language tests, reduced graphomotor skills, and more behavioral problems than unexposed children (22). In addition, Laslo-Baker et al. found that preschool children with prenatal exposure to organic solvent mixtures scored lower on tests of general intelligence, language and motor skills (23). Pele et al. also found a greater frequency of behaviors indicative of attention deficits, hyperactivity, and aggression (24) and Costet et al. found increased externalizing behavior among children with prenatal exposure to solvents (25). These disparate findings may stem from varying exposure levels and the use of different measures of neurobehavioral measures as outcomes.
An important feature of these early life studies is their focus on short-term effects in young children. To the best of our knowledge, only three prior studies --ours and two others– have investigated the long-term neurotoxic impacts of early life exposure to solvents. An Israeli study found a 3.4-fold increased risk of schizophrenia among offspring of parents who worked in dry cleaning during their gestation and childhood (55), and a Danish study found a 3.2-fold increased risk of schizophrenia among individuals who were exposed to high levels of benzene air pollution during early life (56).
Our cohort study investigated a wider variety of neurotoxic effects, including drug use among individuals with prenatal and early childhood PCE exposure (26–27, 57). Moreover, our prior analyses found that individuals who were exposed to PCE-contaminated drinking water in early life experienced 30–40% increases in the risk of using multiple drugs as a teenager or as an adult (27). We also found that early life PCE exposure was associated with increased risks of mood disturbances and diminished performance on tests of learning, memory, attention, and executive functioning (26).
The mechanism by which PCE and related solvents may cause neurotoxic effects is presently unknown (6). Furthermore, to the best of our knowledge, no one has investigated how early life PCE exposure might contribute to the multifactorial etiology of drug use disorder (30, 31). However, available evidence suggests that PCE may exert neurotoxic actions via the peroxidation of cell membrane lipids (32), changes in the fatty acids in the brain (33), demyelination of nerve cells (34), and changes in ligand-gated ion channel activity involving the following receptors: GABAA, glycine, NMDA, glutamate kainite, and AMPA (e.g., 35–39). It has been postulated that exposure to agents such as ethanol during synaptogenesis can trigger substantial apoptotic neurodegeneration because these agents interfere with the action of neurotransmitters and GABAA receptors (58).
In summary, the results of this study suggest that the criteria associated with drug use disorder are modestly increased among adults exposed to PCE-contaminated drinking water during gestation and early childhood. Because this study has several limitations, these findings should be confirmed in follow-up investigations of other exposed populations with more diverse racial and socioeconomic characteristics. Because PCE remains a common contaminant of public drinking water supplies, it is important to determine its long-term impacts on behavioral health.