The results presented here suggest that risky behaviors involving smoking, alcohol consumption and drug use are increased among individuals who were exposed to PCE-contaminated drinking water during gestation and early childhood. In particular, the most highly exposed subjects reported increases in the risk of using multiple major drugs both as a teenager and as an adult. Specific drugs for which elevated risks were observed included crack/cocaine, psychedelics/hallucinogens, club/designer drugs, Ritalin without a prescription, and heroin. Increases in the risk of certain smoking and drinking behaviors were also seen among the highest exposure group. Limiting the analyses to subjects without prenatal exposure to maternal cigarette smoking, marijuana use and alcohol consumption strengthened these associations.
Any causal interpretation of these findings should consider the following study limitations. First, the results are likely affected by exposure misclassification. Because historical exposure measurements were unavailable, we estimated PCE exposure during the study period using EPANET water distribution modeling software that was modified to incorporate a leaching and transport model [21
]. The model was applied to water distribution system conditions in 1980 and was assumed to be representative of the entire exposure period. Furthermore, the exposure assessment predicted the annual mass of PCE delivered to each subject's residence during gestation and early childhood and, because information on maternal water use was available for only 58% of the study population, we did not incorporate these data into our analyses. Results from validation studies indicate reasonable correlation between our exposure estimates and PCE concentrations in historical water samples [31
], but non-differential exposure misclassification likely biased the findings from dichotomous comparisons (e.g., any exposure vs. none) towards the null [33
]. The expected direction of bias for comparisons involving the exposure tertiles is more difficult to predict, but associations seen among subjects in the highest tertile are likely to be attenuated while those in the middle category could have either an upward or downward bias.
Another limitation stems from the use of self-reports as the source of information on the risky behaviors. While the prevalence of these behaviors among study subjects is similar or higher than reported in independent surveys of Cape Cod and other Massachusetts residents [34
], some faulty reporting was likely. However, since most subjects did not know their exposure status (see results section), inaccurate reporting was likely to be non-differential and so would not have affected the risk ratios from this cohort study [36
Still another limitation stems from possible residual confounding by some contextual feature of highly exposed communities. In fact, 52% of highly exposed residents came from the town of Falmouth. However, there was no association between town of birth/residence and the prevalence of risky behaviors. For example, risk ratios for multiple major drug use as a teen and as an adult were 1.1 and 1.0, respectively, when Falmouth residents were compared to residents of the other study towns.
Residual confounding is also possible from missing data on several risk factors for substance use during childhood and adolescence, including parental smoking, alcohol and drug use, poor parental supervision, peer influences, behavior problems, and adverse events [37
]. In order to account for the associations observed in this study, these factors would need to be highly correlated with PCE exposure, an unlikely scenario given the irregular pattern of the PCE contamination across the neighborhoods of Cape Cod. In fact, our prior studies of this cohort also found little or no confounding for the associations being investigated [42
]. Furthermore, the magnitude of most associations increased when the analysis was restricted to subjects whose mothers reported that they did not smoke cigarettes or marijuana, or drink alcoholic beverages during the subject's gestation, suggesting that residual confounding by other similar factors could have led to a downward bias.
A further limitation stems from the study's 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, most available characteristics of participants and non-participants were similar, including initial PCE exposure status. Second, while participants were more likely to be female (60.7% of participants vs. 43.5% of non-participants), and have mothers with some college education (61.0% for participants vs. 49.3% for non-participants), these differences were equally present for exposed and unexposed non-participants. Third, losses stemming from the death of potential participants were small and unrelated to initial PCE exposure status (n = 111, Table ). In addition, our review of death records from the Massachusetts Registry of Vital Records and Statistics and the National Death Index suggested that only four deaths were associated with substance use; two of these deaths occurred among exposed subjects and two occurred among unexposed subjects.
Intermediate factors that may have contributed to a subject's decision to engage in risky behaviors include early puberty [44
], learning disabilities [45
], and mental illness [46
]. Analyses of our study population do not indicate any association between high PCE exposure and either early puberty or learning disabilities [16
]. Analyses of the occurrence of mental illness in relation to early life exposure to PCE are currently underway.
PCE's potential to cause neurotoxic effects has been established through numerous animal and human studies [3
]. Because of its small size and fat solubility, PCE readily crosses the blood brain barrier and has a high affinity for the lipophilic tissues of the central nervous system. Most epidemiologic studies of adults with occupational exposure to PCE and related solvents have reported impairments in cognition, memory, attention, and executive function [4
]. Increases in anxiety and depression have also been reported in several of these studies [4
As noted in the Introduction, 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 [13
]. In addition, no meaningful differences were seen in two studies of cognitive and behavioral function among children attending a nursery school and day care center who were exposed to PCE from nearby dry cleaning facilities [14
]. 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 behavior throughout childhood [16
]. 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 [17
]. 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 [18
]. The inconsistent findings among these studies may stem from differences in the sensitivity of measures used to assess deficits in brain function [16
To the best of our knowledge, no prior study has investigated other lasting consequences of early life exposure to PCE and related solvents. However, because PCE and alcohol have similar neurotoxic effects [3
], two long-term birth cohort studies of prenatal alcohol exposure provide pertinent data for comparison. A prospective cohort study from Seattle, Washington found a significant association between prenatal alcohol exposure and drinking problems among offspring at age 14 and 21 years, even after controlling for family history of alcohol problems, prenatal maternal smoking, prenatal and postnatal parental drug use, postnatal parental alcohol use, and parenting style [19
]. Another prospective cohort study from Brisbane, Australia also found that prenatal alcohol exposure was associated with heavy alcohol consumption and alcohol disorders among offspring during adolescence and early adulthood [20
]. In particular, investigators observed a 2.74-fold increase in the risk of consuming three or more drinks per drinking occasion at age 14 years among offspring whose mothers consumed at least three drinks per drinking occasion during pregnancy (95% CI:1.70-4.22) [48
]. Additionally, they observed a 3.29-fold increased risk of developing alcohol disorders at ages 18-21 years among offspring whose mothers consumed at least three drinks per drinking occasion during early pregnancy (95% CI: 1.74-6.24) [20
]. These investigators also adjusted for numerous confounding variables, including gender, maternal smoking, education, age, anxiety, depression, and child behavior. While results from these two studies may be still be confounded by genetic predisposition and unmeasured environmental influences for alcohol consumption, they are supported by animal data suggesting that early life exposure to alcohol increases subsequent affinity, either by creating a preference for similar stimuli or by developing an association between alcohol's odor and taste and its pharmacological effect [49
The mode of action by which PCE and other organic solvents may cause neurological effects, including an affinity for risky behaviors, is currently unknown [3
]. There is evidence to support neurotoxic mechanisms involving the peroxidation of cell membrane lipids [50
], changes in the fatty acid profile of the brain [51
], and loss of myelin [52
]. In addition, experiments suggest that the neurotoxic mechanism may involve ligand-gated ion channel activity via the following receptors: GABAA
, glycine, NMDA, glutamate kainite, and AMPA [53
]. In fact, it has been suggested 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
In summary, the results of this study suggest that risky behaviors, particularly drug use, are increased among adults exposed to high levels of PCE during gestation and early childhood. Because this study has several limitations and is the first to report this association, these findings should be confirmed in follow-up investigations of similarly exposed populations. Because PCE remains a commonly used commercial solvent that exposes workers and consumers and causes frequent contamination of drinking water from groundwater sources, it is important to determine its long-term impact on behavior.