CDER risk assessment exercise to evaluate potential risks from the use of nanomaterials in drug products.

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example.

Managing future Gulf War Syndromes: international lessons and new models of care.

After the 1991 Gulf War, veterans of the conflict from the United States, United Kingdom, Canada, Australia and other nations described chronic idiopathic symptoms that became popularly known as 'Gulf War Syndrome'. Nearly 15 years later, some 250 million dollars in United States medical research has failed to confirm a novel war-related syndrome and controversy over the existence and causes of idiopathic physical symptoms has persisted. Wartime exposures implicated as possible causes of subsequent symptoms include oil well fire smoke, infectious diseases, vaccines, chemical and biological warfare agents, depleted uranium munitions and post-traumatic stress disorder. Recent historical analyses have identified controversial idiopathic symptom syndromes associated with nearly every modern war, suggesting that war typically sets into motion interrelated physical, emotional and fiscal consequences for veterans and for society. We anticipate future controversial war syndromes and maintain that a population-based approach to care can mitigate their impact. This paper delineates essential features of the model, describes its public health and scientific underpinnings and details how several countries are trying to implement it. With troops returning from combat in Afghanistan, Iraq and elsewhere, the model is already getting put to the test.

Resolving disputes about toxicological risks during military conflict : the US Gulf War experience.

In the last 15 years, the US and UK have fought two major wars in the Persian Gulf region. Controversy has arisen over the nature and causes of health problems among military veterans of these two wars. Toxic exposures have been hypothesised to cause the majority of the long-term health problems experienced by veterans of the 1991 Gulf War. The assessment of these toxic exposures and the resolution of controversy about their health effects provide a unique case study for understanding how toxicological disputes are settled in the US. Neither clinical examination of ill war veterans nor scientific research studies have been sufficient to answer contentious questions about toxic exposures. Numerous expert review panels have also been unable to resolve these controversies except for the US National Academy of Sciences Institute of Medicine (IOM). The IOM has conducted exhaustive and independent investigations based on peer-reviewed scientific literature related to potential health risks during the two Gulf Wars. In four recent studies, IOM committees identified a wide range of previously documented illnesses associated with common occupational and environmental exposures after considering thousands of relevant publications; however, they did not identify a new medical syndrome or a specific toxic exposure that caused widespread health problems among Gulf War veterans. These IOM studies have, therefore, added little to our basic knowledge of environmental hazards because most of the health effects were well known. Nevertheless, this expert review process, which is on-going, has been generally acceptable to a wide range of competing interests because the findings of the IOM have been perceived as scientifically credible and independent, and because none of the postulated toxicological risks have been completely ruled-out as possible causes of ill health among veterans.

The postwar hospitalization experience of Gulf War veterans participating in U.S. health registries.

In response to concerns that Gulf War veterans were experiencing increased morbidity resulting from wartime exposures in the Gulf War, the Department of Veterans Affairs and the Department of Defense (DoD) initiated clinical registries to provide systematic health evaluations for self-referred Gulf War veterans. The authors used Cox's proportional hazard modeling with data from all DoD hospitals to estimate the probability of hospitalization resulting from any cause, resulting from diagnosis in a major diagnostic category, and resulting from a specific diagnosis of interest. After adjusting for other risk factors, registry participants were 1.43 times more likely to have a postwar hospitalization than registry nonparticipants (95% confidence interval, 1.40-1.46). These findings support the hypothesis that registry participants were more likely to experience postwar morbidity than veterans who chose not to enroll in the health registries.

Risk factors for hepatitis C virus infection among patients receiving health care in a Department of Veterans Affairs hospital.

A cross-sectional, seroepidemiological study was conducted to determine the prevalence and risk factors for hepatitis C virus (HCV) infection among veterans receiving health care from the VA. Among 274 evaluated outpatients, anti-HCV was found in 27 (9.9%). The prevalence of anti-HCV was 3.7% among 190 individuals who reported no illicit drug use compared to 24.7% among 81 subjects who had used drugs (P < 0.001). The prevalence of anti-HCV was 4.8% among 208 veterans who had never been incarcerated compared to 27.9% among 61 veterans who had been incarcerated (P < 0.001). A multivariate model found the following factors to be independently associated with anti-HCV; having used illicit drugs [odds ratio (OR) = 3.7, 95% CI 1.3-11.8; P = 0.001), having been incarcerated (OR = 4.4, 95% CI 1.7-10.9; P = 0.001), and a yearly income less than 10,000 US dollars (OR = 3.5, 95% CI 1.3-9.4; P = 0.002). Because HCV infection was most strongly associated with illicit drug use, incarceration, and low income, these risk factors should be utilized to develop screening strategies among VA patients.

The investigation of chronic fatigue syndrome: a case-study of the limitations of inductive inferences and non-falsifiable hypotheses in medical research.

Karl Popper's argument that deductive logic and falsifiable hypotheses are necessary for the growth of scientific knowledge has been controversial. One approach to assess the relevance of his ideas to medical science has been to evaluate examples of successful research. Another approach is to analyze an unsuccessful investigation. The inconclusive search for a unique 'chronic fatigue syndrome' offers a well-documented case-study for this analysis. Over the past 130 years, numerous studies have provided clinical and epidemiological data, which have supported competing hypotheses about the etiology of chronic fatigue. However, few hypotheses have been refuted because it has not been possible to establish objective standards of inquiry for a subjective symptom like fatigue. As a result, intensive research efforts have not converged on correct explanations by eliminating erroneous ideas. This unsuccessful investigation illustrates how non-falsifiable hypotheses are insufficient to advance medical knowledge, even when there is an abundance of empirical data.

Self-reported health of Persian Gulf War veterans: a comparison of help-seeking and randomly ascertained cases.

The objective of this study was to compare self-selected Persian Gulf War veterans attending a health assessment program with veterans ascertained in an epidemiological study to determine why Gulf War veterans do, or do not, present for clinical assessment. A postal survey was sent to randomly selected United Kingdom Armed Forces personnel who served in the Persian Gulf conflict. Outcome measures included a symptom checklist, health perception, physical functioning, psychological distress, post-traumatic stress symptoms, and health attributions. A total of 173 survey respondents had also attended the Medical Assessment Program (MAP). MAP attendees were more likely to be female, older, and working part time or not working at all. They had poorer health perception and reported higher levels of illness, and they differed in terms of their health attributions. The belief that one had Gulf War syndrome and attributing health problems to Gulf War service were the most powerful predictors of MAP attendance, even when controlling for the level of physical functioning. The findings suggest that health beliefs rather than symptoms are more important predictors of attendance of an assessment program and that Gulf War veterans who attended the MAP have different characteristics than those who did not. This suggests that MAP patients are unrepresentative of the wider deployment to the Persian Gulf.

New perspectives on hepatitis E.

The infectious agent causing epidemic non-A, non-B hepatitis was identified in 1983 from a human challenge experiment. The novel hepatitis E virus (HEV) subsequently was cloned in 1990 and the genome sequenced. HEV transmission is highly endemic in Asia, the Middle East, and Africa. Fecal contamination of drinking water is the most common mode of spread. Although usually asymptomatic, HEV infection can cause fulminant hepatitis. Recent studies indicate that hepatitis E may be a zoonotic disease, with pigs and possibly rats serving as reservoirs for human infection. A recombinant HEV vaccine is currently in phase III clinical trials. The characterization of the major types of viral hepatitis during the last 20 years illustrates how modern genetic technology has revolutionized research in infectious diseases. Within less than two decades of the discovery of HEV, its epidemiology has been described, serologic tests have been developed, and a candidate vaccine has been evaluated in clinical trials.

Responding to chemical, biological, or nuclear terrorism: the indirect and long-term health effects may present the greatest challenge.

The possibility of terrorists employing chemical, biological, or nuclear/ radiological (CBN) materials has been a concern since 1995 when sarin gas was dispersed in a Tokyo subway. Contingency planning almost exclusively involved detection. containment, and emergency health care for mass casualties. However, it is clear that even small-scale CBN incidents--like the recent spread of anthrax spores through the mail--can cause widespread confusion, fear, and psychological stress that have lasting effects on the health of affected communities and on a nation's sense of well-being. More emphasis therefore needs to be placed on indirect effects and on the medical, social, economic, and legal consequences that follow months to years afterward. To respond effectively to CBN attacks, a comprehensive strategy needs to be developed that includes not only emergency response, but also long-term health care, risk communication, research, and economic assistance. Organizing an effective response challenges government institutions because the issues involved--eligibility for health care, the effects of low-level exposure to toxic agents. stress-related illnesses, unlicensed therapeutics. financial compensation--are complex and controversial.

Protecting the health of United States military forces in Afghanistan: applying lessons learned since the Gulf War.

Four weeks after the terrorist attacks on the World Trade Center and the Pentagon, US combat troops began bombing missions over Afghanistan in Operation Enduring Freedom. Additional Reserve and National Guard personnel were called to active duty to support the war effort and to ensure security throughout the United States. All of these troops will require health care and assistance during and after this war on terrorism. They will benefit from recent federal legislation that has increased access to health care and from the changes implemented by the Departments of Defense and Veterans Affairs since the Gulf War. An innovative Defense Department "Force Health Protection" strategy places greater emphasis on helping service members and families stay healthy and fit and on preventing injury and illness. The two agencies also have developed new post-deployment clinical practice guidelines, established deployment research centers, and made further improvements in preventive medicine, health surveillance, and risk communication and are thus better prepared for this newest generation of war veterans.

Endemic infectious diseases of Afghanistan.

The current crisis in Afghanistan has resulted in an influx of Western military personnel, peacekeepers, humanitarian workers, and journalists. At the same time, unprecedented numbers of internally displaced persons and refugees have overwhelmed much of the already fragile infrastructure, setting the stage for outbreaks of infectious diseases among both foreigners and local populations. This review surveys the literature concerning the infectious diseases of Afghanistan and south-central Asia, with particular emphasis on diseases not typically seen in the Western world.

Force health protection: 10 years of lessons learned by the Department of Defense.

The Department of Defense has applied lessons learned since the Persian Gulf War to develop the force health protection (FHP) strategy. The goal of this new, unified strategy is to protect the health of military members from medical and environmental hazards associated with military service to the maximum extent possible. FHP is an evolving strategy that seeks to balance the military health system's responsibilities to promote and sustain health and wellness throughout each person's military service; prevent acute and chronic illnesses and injuries during training and deployment; and rapidly stabilize, treat, and evacuate casualties. In addition, FHP demands a continuous assessment of the current and future health of military members through medical surveillance, longitudinal health studies, adequate medical record documentation, and clinical follow-up. Effective communication with military members, leaders, veterans, families, and the public regarding military members' health status and the health risks of military service is a key element of the FHP strategy.

The Recruit assessment Program: a program to collect comprehensive baseline health data from U.S. military personnel.

Pilot testing has begun on the Recruit Assessment Program (RAP). The RAP is a proposed Department of Defense (DoD) program for the routine collection of baseline demographic, medical, psychosocial, occupational, and health risk factor data from all U.S. military personnel at entry into the armed forces. The RAP currently uses an optically scannable paper questionnaire, which will provide data for the first building block of an electronic medical record within the DoD and the Department of Veterans Affairs. The RAP will serve several important functions, including automating enrollment into the military health care system, improving patient care and preventive medicine efforts, and providing critical data for investigations of health problems among military personnel and veterans. If the feasibility of the RAP is demonstrated and the program is fully implemented throughout the DoD, it could provide a substantial improvement in health care delivery. For the first time, DoD and Department of Veterans Affairs physicians, public health officers, and researchers will have access to comprehensive baseline health status data.