Review of VA Clinical Guidance for the Health Conditions Identified by the Camp Lejeune Legislation (2015)

Summary

U.S. Marine Corps Base Camp Lejeune covers about 156,000 acres in eastern North Carolina, and at any given time is home to about 170,000 active-duty personnel, family members, retirees, and civilian employees who live on base or in the surrounding community. Between 1957 and 1987, the groundwater at Camp Lejeune was inadvertently contaminated with chemicals, primarily industrial solvents. Many of these chemicals were later found to cause cancer and other health problems, although not all of them were recognized as toxic at the time of contamination. In 1980 trichloroethylene (TCE) and perchloroethylene (PCE, also called tetrachloroethylene), as well as other solvents, were first detected at Camp Lejeune in treated drinking water, and by 1987 the contaminated water wells were closed. In 1989, the U.S. Environmental Protection Agency (EPA) placed Camp Lejeune on the National Priorities List, also known as Superfund. It is estimated that between 500,000 and 1 million people may have used the contaminated water, and many of them continue to have concerns about the long-term health effects that might result from that exposure.

STUDIES ON THE CAMP LEJEUNE POPULATION

From 1991 to 1997 the Agency for Toxic Substances and Disease Registry (ATSDR), part of the Centers for Disease Control and Prevention, conducted a public health assessment that evaluated exposures and potential risks at Camp Lejeune. It also performed a historical reconstruction of the contamination based on water quality modeling and estimated that well contamination with PCE from an off-base dry cleaner began as early as the 1950s.

In 2009, the National Research Council (NRC) released its report Contaminated Water Supplies at Camp Lejeune: Assessing Potential Health Effects in response to a request from Congress. That report built on a 2003 Institute of Medicine (IOM) report that reviewed the toxicologic and epidemiologic literature on solvents that had been used in the 1990–1991 Gulf War and their potential health effects. The NRC report assessed studies published after the IOM report and focused on the potential health effects of the solvents on Camp Lejeune residents and similarly exposed populations.

In 2012, Congress passed the Honoring America’s Veterans and Caring for Camp Lejeune Families Act, also known as the Janey Ensminger Act (P.L. 112-154). The act provides health benefits to veterans and family mem-

bers who have any of 15 health conditions.¹ Eligible veterans must have served on active duty at Camp Lejeune for 30 days or longer between January 1, 1957, and December 31, 1987, and eligible family members must have resided (including being in utero to a mother in residence) at Camp Lejeune for 30 days or longer during the same time frame.

To assist in the implementation of the act, the Veterans Health Administration (VHA) has drafted clinical guidance, including five clinical algorithms, to help health care providers determine whether a veteran or family member has a medical condition that is covered by the act and whether an episode of care is related to a covered condition.

COMMITTEE’S STATEMENT OF TASK AND APPROACH

To ensure that the clinical guidance for the 15 covered medical conditions listed in Public Law 112-154 is “scientifically sound,” the U.S. Department of Veterans Affairs (VA) asked the IOM to convene an ad hoc committee to review the guidance for VHA staff and make recommendations for its improvement. In addition, the committee was asked to perform the following specific tasks:

1. Based on the latest scientific literature and the committee’s review, describe the medical conditions that result from “renal toxicity” due to solvent exposures.
2. Based on the latest scientific literature and the committee’s review, characterize the “neurobehavioral effects” as mandated for coverage in the law.

To conduct its task, the committee held two open sessions to learn about the guidance from VA health professionals. Literature searches were also performed to identify the recent epidemiologic and toxicologic studies and assessments of the contaminants of interest. The committee reviewed the available literature to identify possible renal and neurobehavioral endpoints; no endpoints were ruled out by the committee in advance.

The committee adopted a rule that a renal or neurobehavioral effect must be reported with statistical significance in at least one relatively well-designed study, or have sufficient strength of evidence to be considered a possible effect. In cases where the weight of the evidence was sparse but showed a positive association, or was equivocal and expert judgment was used to make the finding, the committee gave the benefit of the doubt to the veteran and family member.

The committee also recognized that many factors can affect the etiology and presentation of a health condition. This is of particular concern because many of the health conditions in the VA clinical guidance require that the clinician determine whether the health condition was caused by something other than the patient’s residence at Camp Lejeune during the time of contamination. VA has made a policy decision that clinicians do not have to consider exclusionary factors for any of the cancers or for scleroderma, but these factors are considered for the other health conditions. Because these are policy decisions and not based on scientific evidence, the committee did not comment on the validity of these decisions.

RENAL TOXICITY

Toxicologic and Epidemiologic Evidence

Previous reviews have suggested that among the contaminants residents at Camp Lejeune were exposed to TCE and PCE were the most likely to be responsible for acute kidney injury and subsequent chronic renal disease. In general, human and animal studies demonstrate that high-dose exposures are required for acute renal effects to be observed and that such effects are variable among species. In animal studies, acute exposure to high doses of

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¹ The 15 conditions in the act are esophageal cancer, lung cancer, breast cancer, bladder cancer, adult leukemia, kidney cancer, multiple myeloma, myelodysplastic syndromes, female infertility, miscarriage, hepatic steatosis, scleroderma, renal toxicity, and neurobehavioral effects identified by the 2009 NRC report as having limited/suggestive evidence of an association with exposure to TCE, PCE, or solvent mixtures; and non-Hodgkin’s lymphoma.

TCE causes tubular necrosis, which results in a decreased glomerular filtration rate. In both humans and animals, chronic exposures to high doses of either TCE or PCE cause kidney pathology, such as cytomegaly, karyomegaly, and necrosis of the tubular epithelium.

Based on the cumulative data, there appears to be strong evidence for an association between acute exposure to high levels of TCE or PCE and acute tubular toxicity in both rodents and humans, although humans metabolize these chemicals to a lesser extent and are thus more resistant to their adverse effects. There is accumulating evidence that acute renal injury, as might occur soon after exposure, significantly increases the likelihood that chronic kidney disease will appear many years later; such an effect can occur even if the acute injury is subclinical and thus not detected at the time of exposure. Thus, a patient should not be ineligible for the VA program because of a lack of documented evidence of kidney disease during or shortly after residence at Camp Lejeune.

While there is some evidence for increased mortality from solvent-induced hypertensive end-stage renal disease (ESRD), the association between TCE and PCE and chronic kidney disease is less clear, although there does appear to be an association between exposures to high levels of these solvents and ESRD. However, the documented levels of PCE and TCE in the drinking water at Camp Lejeune were much lower than those in the human and animal studies reviewed in this report, and the exposure duration would likely have been much shorter for Camp Lejeune residents. There is no evidence for an increased incidence of chronic kidney disease in those who resided at Camp Lejeune during the time of the contaminated drinking water. Nevertheless, although the evidence indicates that chronic kidney disease in Camp Lejeune residents is likely due to other causes, the role for solvent exposure cannot entirely be ruled out. This is a common problem when seeking causes of kidney disease where there is no specific diagnostic histopathology.

Clinical Guidance and Algorithm for Renal Toxicity

The VA guidance asks first whether the patient has evidence of renal injury, when the onset of chronic kidney disease occurred, and if the patient has other comorbid conditions. The clinician then assesses whether it is probable that the chronic kidney disease is attributable to a known cause other than solvent toxicity. If there is no evidence for another cause, chronic kidney disease could be due to toxic exposure. The committee finds that VA’s general approach to renal toxicity in the guidance and in algorithm K is appropriate and in cases of uncertainty with regard to the etiology of the renal injury, the case should be resolved in favor of the veteran or family member.

There may be a lack of evidence of acute renal nephrotoxicity at the time of exposure because it did not occur, because a patient was asymptomatic and there was no indication to conduct the necessary laboratory tests, or because the tests were not sensitive enough to detect mild disease. Neither the guidance nor the algorithm includes other indicators of acute renal injury, such as abnormal urinalysis results, serum creatinine, or blood urea nitrogen which, if assessed at about the time of exposure and documented in medical records, may help a clinician establish that acute effects had occurred, which later might result in or contribute to chronic kidney disease. The committee finds that these types of tests, conducted while the patient was in residence at Camp Lejeune, should be considered when determining whether or not the patient’s chronic kidney disease is related to exposure to contaminated drinking water while at Camp Lejeune. If the evaluation shows that the patient’s kidney disease is compatible with another etiology, such as diabetic nephropathy or hypertensive nephrosclerosis, it is unlikely that solvent exposure at Camp Lejeune was the causative agent. If the evaluation does not suggest another etiology, or if the clinical course is atypical for the identified etiology, the patient should be included in the Camp Lejeune program.

NEUROBEHAVIORAL EFFECTS

All Age Exposures

The 2009 NRC report found that there was limited/suggestive evidence of an association between solvent exposure and neurobehavioral effects including abnormal results on neurobehavioral test batteries; symptoms such as fatigue, lack of coordination, sensory disturbances, confusion, depression, tension, trouble concentrating, and headache; deficits in attention, reaction time, visuomotor coordination, motor function, digit symbol, and contrast sensitivity; and certain neuropsychological disorders such as learning or behavioral disorders. The 2009 NRC report found that most of the neurobehavioral effects in the epidemiologic studies were concurrent with exposure and that few studies assessed long-term effects after the exposure ended. That report further concluded that there is inadequate/insufficient evidence to determine whether an association exists between an exposure to solvents and amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease, or Parkinson’s disease.

The NRC report separated neurologic diseases, such as Alzheimer’s disease and Parkinson’s disease, from neurobehavioral effects, which left unanswered what those signs and symptoms indicated in terms of diagnostic entities. Because neurobehavioral symptoms or testing can be indicative of neurologic or behavioral problems, in an effort to be complete, this committee chose to define neurobehavioral effects broadly to include all neurologic and behavioral effects (diseases, disorders, symptoms, and deficits). Toxicologic studies were not specifically described because the studies published since 2008 did not describe clinical outcomes that a physician might encounter in patients.

New studies assessed by this committee suggest that deficits in visuomotor function, motor function, and concentration (that is, attentional deficits) best characterize the long-term neurobehavioral symptoms and deficits associated with solvent exposure. No new evidence provided additional support for a relationship between an exposure to solvents and the development of ALS, multiple sclerosis, or Alzheimer’s disease. However, the committee reviewed four new studies on Parkinson’s disease and solvent exposure that led it to conclude that Parkinson’s disease is a neurobehavioral effect that may result from exposure to TCE and/or PCE. Because of the slow onset of Parkinson’s disease, patients who develop it years after their exposure, regardless of their age at Camp Lejeune, may not have had symptoms at the time of exposure.

In Utero and Childhood Exposures

At Camp Lejeune, pregnant women may have inadvertently exposed their fetuses to the contaminated water, and children may also have been exposed. The committee believes that the health impacts of contaminated Camp Lejeune water on fetuses, infants, and children needs to be considered in the VA guidance. The 2009 NRC report concluded “that there continues to be inadequate/insufficient evidence to determine whether an association exists between chronic exposure to TCE or PCE and congenital malformations” such as congenital heart defects, neural tube defects, and oral clefts. However, recent studies of congenital anomalies in children born to mothers exposed to TCE, PCE, or other solvents during pregnancy show a clear association with neural tube defects.

Most of the new literature identified by the committee was the product of epidemiologic studies of a Cape Cod, Massachusetts, population that had been exposed to PCE in drinking water, from 1968 through 1980. The committee found that, in general, the Cape Cod community studies of PCE exposure had appropriate controls, appropriate adjustment for confounders, and large enough samples to allow for the detection of elevated risks.

They are the only studies that have examined 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 have not been confirmed by research in other populations, they have good scientific plausibility and a demonstrate a dose–response.

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

The committee acknowledges that the visual deficits found in the Cape Cod population and other studies are subclinical, that several studies had small sample sizes, and that evidence is lacking by which to assess whether the effects are short term or long term. Although prior reports found that there was inadequate/insufficient evidence to determine whether an association exists between exposure to solvents and long-term reduction in color discrimination, this committee finds that the weight of evidence indicates that deficits in contrast sensitivity and color discrimination may occur from such exposures.

Revising the Guidance and Algorithm

The guidance currently has a short section for clinicians on what is meant by neurobehavioral effects, what would be a covered condition, and what signs or symptoms should be determined to have been present when a veteran or family member was exposed to contaminated drinking water during or shortly after residence at Camp Lejeune. It is unclear how VA selected the neurobehavioral effects given in the guidance and algorithm B, why the effects do not reflect the 2009 NRC report, or why neurotoxic endpoints from a 1987 National Institute for Occupational Safety and Health Current Intelligence Bulletin on occupational exposure to organic solvents are included. The committee notes that more recent reviews are available from organizations such as EPA.

The guidance does not currently address conditions associated with in utero or childhood exposures at Camp Lejeune. The committee believes it is important that the guidance address these exposures because those outcomes differ from those for adults and are not captured in the current guidance or in algorithm B.

OTHER HEALTH OUTCOMES

Cancer and Neoplastic Diagnoses

The guidance is unclear or fails to address four issues regarding how or what cancers are covered by the Camp Lejeune program.

Eight cancers (esophageal cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, leukemia, multiple myeloma, and non-Hodgkin’s lymphoma) and myelodysplastic syndromes are listed in the 2012 Janey Ensminger Act. VA has stated that following the precedent it set in response to Agent Orange exposures for Vietnam veterans it will cover listed cancers regardless of latency because this policy provides the benefit of the doubt to veterans and family members.

VA may wish to clarify whether it will cover secondary or recurrent/metastatic cancers if the first primary (which was one of the eight neoplasms covered) occurred before the exposure at Camp Lejeune.

The guidance and algorithm do not address whether precancerous lesions of the eight cancers and myelodysplastic syndromes (such as ductal carcinoma in situ, Barrett’s esophagus, and monoclonal gammopathy of undetermined significance) are also covered. VA has indicated that it plans to cover precancerous lesions, and the committee finds this approach to be reasonable.

Finally, the guidance defines active treatment for cancer as surgery, chemotherapy, or radiation therapy, or some combination of the three, but it does not specifically include immunotherapy and hormone therapy.

Scleroderma (Systemic Sclerosis)

Scleroderma is a rare autoimmune condition characterized by the presence of thickened, sclerotic skin lesions. The 2009 NRC report concluded that there was limited/suggestive evidence of an association between mixed solvent exposures and scleroderma. New reviews conducted by other authoritative entities have confirmed the association between scleroderma and TCE. In 2013, the American College of Rheumatology updated its diagnostic criteria for scleroderma.

Because scleroderma onset can occur at any time after exposure to a solvent, any exposed veterans and family members are eligible for health benefits and are accepted to the Camp Lejeune program regardless of when their disease was diagnosed. The committee finds that the guidance and algorithm for scleroderma are reasonable and appropriate.

Miscarriage and Infertility

Miscarriage refers to a spontaneous abortion. Factors that may increase the risk of miscarriage include maternal hormone problems or infections, trauma, age greater than 45 years, smoking, drug use, excessive caffeine, and exposure to the solvents such as those found at Camp Lejeune. Infertility—that is, failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse—may be caused by several factors that affect different aspects of female reproduction. One such factor is exposure to environmental contaminants such as TCE and PCE, which can also affect fertility by reducing fecundity and altering menstrual cycles.

There is no evidence for an increased risk of miscarriage remaining after an exposure to solvents has ended, but a miscarriage may have long-term psychologic and medical consequences, such as depression, anxiety, and posttraumatic stress disorder (PTSD), which themselves may persist and result in long-lasting psychological, social, and health changes. Infertility may also have an impact on quality of life and mental health. Some studies indicate, for instance, that infertility is associated with depression and loneliness.

VA guidance on female infertility and miscarriage specifies time of onset. Exposed veterans and family members who experienced or were diagnosed with these problems during their time at Camp Lejeune are eligible for health benefits if they require ongoing medical treatment. Later or current infertility or miscarriage in a woman who was a child, adolescent, or young adult while at Camp Lejeune is not covered.

Algorithm W requires documentation that infertility or miscarriage occurred during residence on Camp Lejeune. The committee notes that medical records from that time may not be available, so it is important that VA encourage informed clinical judgment to identify veterans or family members who have persistent health problems that may have resulted from miscarriage or infertility that occurred at the time of exposure. The committee finds the guidance and algorithm for miscarriage and infertility to be generally appropriate.

Hepatic Steatosis

Hepatic steatosis, also referred to as fatty liver, is associated with a variety of conditions, including type 2 diabetes, obesity, alcohol use, hepatitis, hyperlipidemia, and other liver diseases; the use of some medications (e.g., chemotherapeutic agents, antibiotics); and exposure to organic chemicals such as TCE, PCE, and chloroform. Most patients who have hepatic steatosis have elevated liver enzyme levels, but they may be asymptomatic. A probable diagnosis can be established by ultrasound, computed tomography, and magnetic resonance imaging. Hepatic steatosis is generally benign, and the condition is reversible, but if it persists more severe pathologies such as fibrosis, cirrhosis, and liver cancer may develop.

Application of the guidance and algorithm H for hepatic steatosis is challenging because of the high prevalence of other potential causes of hepatic steatosis in the general population. Informed clinical judgment can help identify veterans or family members whose hepatic steatosis may have resulted from exposure to drinking water at Camp Lejeune on the basis of its persistence since residing at Camp Lejeune and the absence of other more likely causes.

The guidance states “[M]oreover if a patient’s clinical course is atypical or progresses faster than expected, then exacerbation by TCE, PCE or other organic solvents from Camp Lejeune should be considered.” However, there is no evidence that solvent exposure would result in an atypical presentation or rapid progression of hepatic steatosis at a later date. Chronic alcohol consumption of 16 g of alcohol or more per day is strongly associated with steatosis.

Finally, there are several commonly used medications that are known to cause steatosis, including chemotherapeutic agents and corticosteroids.

USE OF THE GUIDANCE

The committee was asked to assess the scientific soundness of the guidance for the covered health outcomes. The committee was not asked to comment on the implementation of, administration of, training for, or evaluation of the Camp Lejeune Health Program itself. It is important to remember that the guidance is based not only on scientific evidence, but also on VA policies and congressional legislation as well.

The guidance specifies that VA will reimburse eligible family members for screenings related to the 15 covered conditions if clinically indicated or if recommended by the U.S. Preventative Services Task Force only if the outcome of that screening leads to the diagnosis of a covered condition. The diagnosis of a covered condition may require screening as well as a diagnostic evaluation at the discretion of the clinician, but the guidance does not indicate whether a diagnostic evaluation will be covered.

Decision Points

The committee considered the usefulness of the three decision points to assess whether a “medical illness, injury or condition is eligible for coverage under the Camp Lejeune Program.” It indicated where revisions to the guidance and the algorithms might improve clarity and consistency.

The committee considered three topics for this decision point: referrals, secondary conditions, and time of symptom onset and duration. The guidance does not indicate when referrals to specialists, such as psychiatrists or nephrologists, may be appropriate for the diagnosis of a covered condition.

The guidance states that VA has authority to reimburse family members for medical conditions that are secondary to a covered condition. However, the descriptions and algorithms for the covered conditions, other than for female infertility and miscarriage, do not acknowledge that secondary conditions and medical complications can result not only from the presence of the condition itself, but also from disease progression and from treatment for the condition.

In general, the committee notes that the time of onset and duration are not specified for every covered condition. For example, VA has made a policy decision that the time of onset matters for miscarriage and infertility, but

that it is not a consideration for cancer. This variation in criteria among outcomes may result in confusion on the part of the Camp Lejeune veterans, family members, and clinicians.

The guidance states, “[H]ospital care and medical services may not be furnished…for an illness or condition of a Camp Lejeune Veteran or family member that is found, in accordance with guidelines issued by the Under Secretary for Health, to have resulted from a cause other than the residence at Camp Lejeune.” The act requires other causes be assessed only for family members and not for veterans. The committee finds the language in the guidance regarding the need to consider other causes of covered conditions for veterans or family members to be inconsistent and unclear.

The guidance uses several terms to assist the clinician in determining whether the condition had another cause, such as “are as likely as not,” or “probable,” but no criteria are given for making such judgments. This is particularly problematic as the guidance states “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 finds that the language in the guidance is inconsistent with regard to the likelihood that exposure at Camp Lejeune resulted in a covered condition.

The guidance asks clinicians to “verify” or “certify” information pertaining to whether a specific visit, treatment, or secondary condition is related to a covered condition. It is unclear what health care providers, including non-VA clinicians, must do in order to certify or verify that a treatment or service is related to a covered condition and what documentation must be submitted.

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