Neurologic Symptoms, Motor Function, and Sensory Deficits

The NRC report found that most human studies indicate effects on visuomotor and motor function, fatigue, headache, and deficits in concentration, primarily resulting from acute exposures to solvents. Acute inhalation and oral exposure to PCE can induce symptoms of CNS depression (dizziness and drowsiness), electroencephalograpic changes, and neurobehavioral changes such as alterations in flash-evoked visual potentials, deficits in vigilance, and deficits in eye–hand coordination. The effects of long-term occupational exposure to TCE include memory loss, mood swings, the impairment of cognitive function, and olfactory and trigeminal neuropathy (NRC, 2009). Oral doses of PCE given as an anthelminthic (de-wormer) resulted in narcotic effects and various associated changes, such as inebriation, perceptual distortion, and exhilaration (ATSDR, 1997). The NRC report also cited a study (Reif et al., 2003) that evaluated neurobehavioral function in 184 adults who had been exposed to TCE-contaminated drinking water many years before testing. Higher exposures were associated with poorer performance on several tests (such as digit symbol substitution test, contrast sensitivity C test, and contrast sensitivity D test) and with increased neurobehavioral symptoms (such as confusion, depression, and tension).

Amyotrophic Lateral Sclerosis, Alzheimer's Disease, and Multiple Sclerosis

In the NRC report, several neurologic diseases and endpoints were assessed to determine if they were associated with exposure to TCE, PCE, or solvent mixtures. Specifically, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis (MS), and Alzheimer's disease were considered. The report concluded that there was inadequate/insufficient evidence to determine whether an association exists between exposure to solvents and ALS, MS, or Alzheimer's disease (NRC, 2009).

Parkinson's Disease

The NRC report concluded that there was inadequate/insufficient evidence to determine whether an association exists between solvent exposure and Parkinson's disease (NRC, 2009). Two case-control studies (Dick et al., 2007; McDonnell et al., 2003) and one occupational cohort (Gash et al., 2008) were evaluated by the NRC committee to assess the relationship between exposure to solvents and Parkinson's disease. The first case-control study showed a trend of increasing odds of developing the disease with increasing duration of occupational exposure; however, the study did not account for other possible risk factors or confounders. The second study did not show any association between solvent exposure and the risk of developing Parkinson's disease, but this study relied on individual recall regarding occupational and hobby-related exposures to solvents. The final study was an occupational cluster investigation that showed that three workers diagnosed with Parkinson's disease had workstations adjacent to a TCE source.

Neurologic Symptoms, Motor Function, and Sensory Deficits

This committee's updated literature search identified one new study that addressed neurologic effects resulting from solvent exposure. Static postural sway and hand tremor parameters were evaluated in 57 workers occupationally exposed to TCE for 0.1 to 37 years (mean 10.9 years); 60 unexposed workers served as controls (Murata et al., 2010). A cumulative exposure index was calculated by multiplying total urinary trichloro-compound levels by work duration. Neuromotor function tests were conducted on a Friday after the work shift. Maximum ambient TCE was estimated at less than 22 ppm, but air measurements were not taken. Sway area, transversal sways, and sagittal sways with eyes open were all significantly greater in the exposed workers than in the controls (p = < 0.001, 0.012, and 0.029, respectively). Hand tremor intensities in the dominant hand were significantly larger in exposed workers than in the controls (p = 0.038), but there was no significant difference for the non-dominant hand. A trend of greater sway and increased tremor intensity was seen with increasing exposure (as measured by a cumulative exposure index), but the effect was not statistically significant, probably because of the small number of individuals in each exposure category.

This committee concluded, based on the 2009 NRC report and the updated literature, that the best characterized neurologic effects associated with solvent exposure, in particular exposure to TCE and PCE, were deficits in visuomotor function, motor function, memory, and concentration. Based on the evidence, the committee is interpreting “deficits in concentration” to mean attentional disorders.

Amyotrophic Lateral Sclerosis, Alzheimer's Disease, and Multiple Sclerosis

In the 2009 NRC report, several neurologic diseases and endpoints were assessed to determine if they were associated with exposure to TCE, PCE, and solvent mixtures. Specifically, the report considered ALS, Parkinson's disease, MS, and Alzheimer's disease. This committee considers each of these diseases to have neurobehavioral effects that could lead to their diagnosis and therefore looked at any new literature since the 2009 report on exposure to solvents and the development of these neurologic diseases.

No new evidence provided additional support for a relationship between exposure to solvents and the development of ALS, Alzheimer's disease, or MS. However, two investigations of Camp Lejeune military personnel and civilians compared mortality from ALS and MS with that of military personnel and civilians stationed at U.S. Marine Corps Camp Pendleton in California.

In two retrospective cohort studies (Bove et al., 2014a,b), both civilian employees and military personnel stationed at Camp Lejeune were evaluated for exposure to contaminated drinking water and risk of mortality from cancers and other chronic diseases. It should be noted that only mortality resulting from a disease was examined, not the development or prevalence of the disease itself. Both populations were matched to control cohorts from Camp Pendleton. The exposures of Camp Lejeune employees and military personnel were estimated using average monthly contaminant concentrations in the drinking water during the period of their employment or residence on base. All cohorts were identified through the Defense Manpower Data Center files, with vital status at follow up obtained through the Social Security Administration Death Master File and the National Death Index.

Among military personnel, there were 27 and 21 deaths from ALS at Camp Lejeune and Camp Pendleton, respectively, and 10 and 12 deaths from MS at the two camps. These results are elevated compared to the general population but do not reach statistical significance (Bove et al., 2014a). Among civilians who worked at Camp Lejeune or at Camp Pendleton there were one and four deaths from ALS, respectively, and there was one death from MS at each camp. Because there were so few cases, the authors could not compute a hazard ratio comparing the two camps for either disease (Bove et al., 2014b). Thus, no increase in mortality from ALS or MS was observed in these study populations.

Parkinson's Disease

The committee identified four new studies that address solvent exposure and Parkinson's disease that have been published since the NRC report.

In a case-control study to determine the association between occupational exposure to specific solvents—including TCE and PCE—and the development of Parkinson's disease, 99 all-male twin pairs discordant for Parkinson's disease were identified from the National Academy of Sciences/NRC World War II Veteran Twins Registry (Goldman et al., 2012). Occupational solvent exposure was assessed through a questionnaire. Exposure to TCE was associated with a significantly increased risk of Parkinson's disease (OR [odds ratio] = 6.1, 95% CI [confidence interval] 1.2–33) and tended toward significance for PCE (OR = 10.5, 95% CI 0.97–113). The risk was also significantly increased for the combined variable of TCE or PCE exposure (OR = 8.9, 95% CI 1.7–47). In 48% of the pairs, at least one twin was exposed to one or more of the six solvents studied. The mean duration of exposure to TCE or PCE was 9.0 years in the control twin compared with 18.5 years in the twin diagnosed with Parkinson's disease (p = 0.009), suggesting that the duration of exposure was a factor in the development of the disease.

In the retrospective cohort studies of mortality in the Camp Lejeune and Camp Pendleton populations, the civilian cohort included 4,647 full-time civilian employees with a median age of 58 years who were employed at Camp Lejeune during 1973–1985 (Bove et al., 2014b). Controls were 4,690 full-time civilian employees (median age 60 years) at Camp Pendleton. The standardized mortality ratio (SMR) for Parkinson's disease in the Camp Lejeune cohort was 2.91 (95% CI 0.71–5.11) versus an SMR of 0.88 (95% CI 0.24–2.26) for the Camp Pendleton cohort. There was a nonsignificant increase in the risk of mortality from Parkinson's disease among the Camp Lejeune cohort (HR = 3.13, 95% CI 0.76–12.86) compared with the Camp Pendleton cohort, adjusted for sex, race, occupation, and education. There were five cases of Parkinson's disease in the Camp Lejeune cohort, as compared with four cases from Camp Pendleton. Four of the five Camp Lejeune cases were associated with a cumulative exposure above the median for TCE and PCE as well as for vinyl chloride and benzene resulting in hazard ratios of greater than 2.50 (p ≤ 0.05).

The military cohort included 154,932 marine and Navy personnel with a median age of 49 years who began active-duty service between April 1975 and December 1985, and who were stationed at Camp Lejeune at some time during that period. The controls were 154,969 personnel stationed at Camp Pendleton at any time during the same active-duty interval. SMRs were not calculated for Parkinson's disease because there were fewer than five cases in each cohort. The committee notes that the military Camp Lejeune cohort is still too young to be informative about the risk of death from Parkinson's disease. At the end of the 2008 mortality follow up, the median age was 49, and only 2.7% of cohort members were 55 or older (Bove et al., 2014a). Because Parkinson's disease is a rare condition before age 50 (National Parkinson Foundation, 2014) and mortality occurs several years after diagnosis, a longer follow up is needed to provide meaningful results on this disease.

In a recent review, Lock et al. (2013) concluded that neither toxicologic nor epidemiologic studies present clear evidence that any specific solvent or class of solvents is an established cause of Parkinson's disease. However, based on the findings of Goldman et al. (2012) and Bove et al. (2014a,b), as well as limited data from the NRC (2009) and the U.S. Environmental Protection Agency (EPA) (2011) assessments, the committee finds that TCE and similar solvents may have potential etiologic relevance in the development of Parkinson's disease.

The committee concludes that Parkinson's disease is a neurobehavioral effect that may have resulted from the consumption of the contaminated drinking water at Camp Lejeune. This conclusion is based on the positive trends of increased risks from occupational and drinking water exposures reported by Goldman et al. (2012), NRC (2009), and Bove et al. (2014b). Despite the limitations of these studies, such as lack of statistical significance, the potential for recall bias, and the lack of incidence data pertaining to Parkinson's disease, the committee recommends including Parkinson's disease as an outcome associated with exposure to TCE and PCE. Because of the slow onset of Parkinson's disease, patients developing it years after their exposure, regardless of their age at exposure, may have not had symptoms at the time of exposure. Patients who have Parkinson's disease now or who develop it in the future and are otherwise eligible for the Camp Lejeune program should be covered by the guidance for neurobehavioral effects even if the symptoms were not apparent during their time at Camp Lejeune.

The committee recommends that VA consider adding Parkinson's disease in the clinical guidance and in algorithm B as a neurobehavioral effect that may result from exposure to contaminated drinking water at Camp Lejeune.

Birth Defects Affecting the Nervous System

A case-control study was conducted to determine whether children born to mothers with residential exposure to contaminated drinking water at Camp Lejeune during pregnancy were more likely to have childhood hematopoietic cancers, neural tube defects, or oral clefts (Ruckart et al., 2013). The exposed population included live births between 1968 and 1985 to mothers who resided on base at any time during their pregnancy. Parents of 12,598 children were asked during a telephone interview if their child had a birth defect. The risk for neural tube defects associated with average first-trimester exposures were increased nonsignificantly for TCE above 5 parts per billion (ppb) (OR = 2.4, 95% CI 0.6–9.6). A monotonic exposure response relationship was observed in those exposed to less than 5 ppb (OR = 1.1, 95% CI 0.3–3.5) and greater than 5 ppb (OR = 2.4, 95% CI 0.6–9.6) compared with those who were unexposed. (Five ppb is the maximum contaminant level; see Chapter 1 for a description.)

A Cape Cod population cohort of 1,658 children exposed prenatally to PCE and 2,999 unexposed children was also examined for risks of congenital anomalies (Aschengrau et al., 2009). No meaningful increases in ORs were seen for cardiac and musculoskeletal malformations, and there were too few exposed cases to estimate ORs for eye; ear, face, and neck; respiratory; and other anomalies. Among children with any prenatal exposure, there was a nonsignificant increase in the ORs for neural tube defects (OR = 3.5, 95% CI 0.8–14.0). The neural tube defects observed in the cohort included four cases of anencephaly among exposed children versus none in the unexposed children, one case of spina bifida among the exposed children versus three cases among unexposed children, and one case of Arnold-Chiari malformation among exposed versus none among unexposed children.

Risks of neural tube defects from a maternal occupational exposure to organic solvents were assessed using data from the population-based National Birth Defects Prevention Study (Desrosiers et al., 2012). The maternal occupational exposure period was restricted to 1 month prior to the estimated date of conception through the end of the first trimester; jobs were coded by occupation and industry and assessed for exposure to 10 organic solvents, including TCE and PCE. Regression analyses were used to determine associations between solvent class (chlorinated, Stoddard, aromatic) and outcome. A total of 511 neural tube defect cases with 2,972 controls were included in the analyses; exposure to chlorinated solvents was associated with a statistically significant increased risk of neural tube defects (OR = 1.96, 95% CI 1.34–2.87).

Risks of congenital anomalies in children born to mothers exposed to TCE, PCE, or other solvents during pregnancy have been evaluated in several studies. An association between neural tube defects and drinking water exposure (Aschengrau et al., 2009; Ruckart et al., 2013) or occupational exposure (Desrosiers et al., 2012) has been shown. The committee concludes that neural tube defects may have resulted from in utero exposures to these solvents in the contaminated drinking water at Camp Lejeune.

The committee recommends that VA consider including neurobehavioral effects as a result of neural tube defects to the Camp Lejeune clinical guidance and in algorithm B-1.

Neuropsychological Performance

Performance on a battery of neuropsychological tests was assessed in a small cohort of 35 adults who had been exposed to PCE at Cape Cod in utero or during early childhood between 1969 and 1983 and also in 28 unexposed subjects (Janulewicz et al., 2012). No associations were found between prenatal and early postnatal exposure to PCE and decrements on tests that assess abilities in the domains of omnibus intelligence, academic achievement, and language. Trends were found among exposed individuals both for mood alterations and for slightly worse performances in various domains, including visuospatial, learning and memory, attention, fine motor speed, and executive function, but the effects were not statistically significant, most likely because of the small sample size.

A sample of 1,349 exposed and 737 unexposed children was evaluated for risk of learning and behavioral disorders following prenatal and early postnatal exposure to PCE (Janulewicz et al., 2008). All the children were born between 1969 and 1983 to mothers who lived on Cape Cod at the time of birth; enrollment occurred during 2002–2003. The measures of learning, attention, and behavior used in the study included whether the child ever had a diagnosis of attention deficit disorder or hyperactive disorder, ever received tutoring for reading or math, ever had special class placement for academic or behavioral problems, ever had an individual education plan, or ever repeated a school grade, as well as the child's highest level of education achieved. No associations were found between exposures and the maternal reports of any measured outcome.

Psychiatric Disorders

Another cohort of the Cape Cod population with 831 exposed and 547 unexposed children enrolled during 2006–2008 was evaluated for an affinity for risky behaviors and for the occurrence of mental illness. Risky behaviors included in the study were smoking, drinking, or illicit drug use as a teen or adult (Aschengrau et al., 2011). Individuals with any level of exposure during gestation and early childhood were more likely than unexposed subjects to have used two or more major illicit drugs as a teenager (risk ratio [RR] = 1.4, 95% CI 1.0–1.8) or as an adult (RR = 1.3, 95% CI 1.0–1.6). Individuals in the highest tertile of exposure (that is, greater than the 67th percentile) during gestation and early childhood were 50 to 60% more likely to have used two or more major illicit drugs as a teenager (RR = 1.6, 95% CI 1.2–2.2) or as an adult (RR = 1.5, 95% CI 1.2–1.9). The specific drugs for which increased risks were observed included cocaine and crack cocaine, psychedelics and hallucinogens, and club and designer drugs, Ritalin without a prescription, and heroin (RRs = 1.4–2.1). Increases in the risk of certain drinking behaviors were seen only among highly exposed subjects, with no evidence of a dose–response relationship. For example, only individuals in the highest tertile of exposure during gestation and early childhood experienced increases in the risk of drinking more than 8 days/month as a teenager (RR = 1.6, 95% CI 1.1–2.3).

Mental illnesses (depression, bipolar disorder, PTSD, and schizophrenia) were also assessed in the Cape Cod cohort (Aschengrau et al., 2012). Subjects with any exposure during gestation and childhood were 1.8 times more likely to have developed bipolar disorder (95% CI 0.9–3.5), although the effect was not statistically significant. However, when the analysis was restricted to subjects in the highest tertile of exposure, a significantly increased risk for bipolar disorder was observed (RR = 2.7, 95% CI 1.3–5.6). The risk of PTSD was greater for subjects with any exposure during gestation and childhood (RR = 1.5, 95% CI 0.9–2.5), but the effect was not statistically significant. While there were too few cases of schizophrenia to examine a dose–response relationship, three of the four schizophrenia cases were in the exposed group (RR = 2.1, 95% CI 0.2–20.0 for any exposure). No associations were found between PCE exposure and an increased risk of depression among exposed subjects.

The available studies of the effects of solvents in children and adults who were exposed in utero or in childhood in Cape Cod found a number of neurobehavioral effects. The limitations of these studies include their retrospective nature, modeled exposure estimates, and self-reported mental illnesses. However, the major strengths of the studies were that exposed and unexposed groups were from the same geographic location, population characteristics were similar between the two groups, and similar proportions of participants and nonparticipants were exposed to PCE, which reduced selection bias. No other studies were identified that examined these psychological and psychosocial outcomes in association with in utero or childhood exposure to PCE, TCE, or other solvents. Thus, although the positive findings reported for the Cape Cod cohorts for illicit drug use and bipolar disorder associated with in utero and early childhood exposures to PCE have not been confirmed by research in other populations, the committee agreed that the studies provide important information on such exposures and warrant further research.

Committee members were not in agreement on whether the two studies on illicit drug use and bipolar disorder (Aschengrau et al., 2011, 2012) provided enough evidence to warrant a recommendation on the inclusion of these two neurobehavioral effects in the guidance and in the algorithms.

Nevertheless, in keeping with the VA policy that “in cases where there is reasonable doubt as to the diagnosis or primary cause for the diagnosis, clinicians should resolve in favor of the Camp Lejeune veteran or family member,” the committee recommends that VA consider including adolescent and adult illicit drug use and bipolar disorder as neurobehavioral effects in the Camp Lejeune clinical guidance and in algorithm B-1.