Review of the U.S. Naval Medical Research Institute's Toxicology Program (1994)

The Naval Medical Research Institute's Toxicology Detachment (NMRITD) is collocated with the toxicology programs of the Air Force and the Army at Wright-Patterson Air Force Base (WPAFB). NMRITD employs 34 persons and has an annual budget of approximately 3 million dollars.

The mission of NMRITD is to (1) develop the biomedical data necessary to characterize the toxicity of materials of interest to the Navy; (2) use these data to formulate occupational and environmental health-hazard evaluations and risk assessments, including appropriate personnel exposure limits, which address specific Navy circumstances of exposure; and (3) develop and maintain a cadre of naval personnel skilled in the discipline of toxicology and its application to health-hazard evaluation and risk assessment. This mission is amplified in the functions and tasks statements in a Navy document (NMRI, 1991).

To review the current toxicology program of NMRITD and its preliminary Ten-Year Strategic Plan, the subcommittee members visited WPAFB, where NMRITD members and associated personnel gave tours of the facilities and made presentations on the ongoing research efforts.

The Navy requested answers to the following four questions pertaining to the current toxicology program:

1. Is the Navy getting the appropriate science to meet its needs?

2. Is current research effectively addressing actual problems?

3. Is there a proper balance between basic and applied research?

4. What constraints on executing the scientific program are imposed by the staffing and current facilities?

The subcommittee's responses to those questions are presented below. The responses are based on its on-site visit to NMRITD and the oral presentations of investigators from NMRITD.

It is not clear that some of the scientific studies being conducted are meeting the Navy's needs. The Navy's toxicology program can be improved by identifying more clearly the needs of the Navy and focusing the research activities on those needs. Efforts should continue to provide a focus for the present toxicology program by further developing its preliminary Ten-Year Strategic Plan (see Chapter 4).

The focus of Navy's current toxicology program needs to be clearly defined to be consistent with NMRITD's mission. At present, research activities are based primarily on the interests of the individual investigator assigned to NMRITD rather than on specific research targets. In other words, toxicological research should be determined by the Navy's needs and not by the expertise of the Navy scientists assigned to NMRITD.

The subcommittee recognizes that the Navy's primary need is for “applied” toxicology—that is, the acquisition and application of data by experts to reach informed solutions to short- and long-term toxicological problems encountered in field operations. Much of the data used to formulate such solutions will result from “basic” research, generally defined as that done without a specific goal of application. That does not mean, however, that basic research should be conducted in a “vacuum”; rather, it should be focused in areas that address specific toxicological needs. For example, studies on the molecular effects of a class of chemicals could be used to identify biomarkers of exposure. Applied toxicology can also be aided by expert opinion. An example of the lack of basic

research hampering the resolution of a critical issue is in the area of the effect of continuous exposure (e.g., 90 days) to low levels of chemical contaminants. This lack of knowledge hampers the Navy 's ability to implement the National Research Council's recommendations on 90-day continuous exposure guidance levels (CEGLs) for submarine contaminants. An example of basic research facilitating the solution to a problem is the use of pharmacokinetic modeling in risk assessment. This research has been helpful not only for carcinogenic effects but also for noncarcinogenic end points, and is being used to guide research in evaluating toxicity in operational scenarios, such as deep-sea diving, ship engine rooms, and sustained operations. Expert opinions must be made by individuals who collectively can provide and evaluate current basic and applied data and who have field and laboratory experience in a number of toxicology subspecialties to make recommendations concerning the need for specific types of future research, both basic and applied.

A definitive focus for Navy's toxicology program should permit (1) recruiting the critical personnel needed to support basic and applied toxicology subspecialties; (2) formulating budget requests to supply the facilities and equipment necessary for achieving research goals; (3) planning that will provide a continuum of personnel who possess the appropriate academic disciplines requisite to obtaining sustained, high-quality results; and (4) reorienting research with a consistent goal of publishable results. Personnel issues are further discussed below in the section “Constraints on Executing Scientific Program.”

The subcommittee applauds incorporating triservice planning as part of NMRITD's toxicology program and encourages expansion of joint efforts in toxicological research on problems common to all branches of the armed services.

The subcommittee identified several other changes that would enhance the quality and quantity of the science needed to meet the Navy' s needs: (1) install a computer system that would permit use of advanced methods for data accumulation and analysis; (2) establish a computerized data base for known and suspected toxic chemicals of current (and possible future) interest to the Navy, which would aid in assessing risks in current studies and assist in decision-making regarding future research; (3) add personnel trained in risk analysis and risk assessment (an invaluable tool for determining risks and managing field exposure to toxic chemicals) and other toxicology specialties; (4) develop models for predicting hu-

man toxicity; (5) place additional emphasis on using molecular approaches to all disciplines of toxicology; and (6) increase publication of research in peer-reviewed journals.

The triservice combustion toxicology program and the pathology laboratory program were two areas in which the research was viewed as effective in addressing the Navy's problems in the area of toxicology. Both were judged capable of providing a wide range of support for toxicology and investigative efforts. Those areas could be established as core facilities for all three services. Other areas of NMRITD's toxicology program did not appear to be as effective in addressing actual problems.

As previously noted, efforts should continue to increase NMRITD's effectiveness in addressing actual Navy problems. Comparison of the science-based projects of NMRITD to its mission and its preliminary Ten-Year Strategic Plan should be helpful. Another useful exercise would be to review NMRITD along the lines described in the NRC report Review of the U.S. Army Environmental Hygiene Agency ToxicologyDivision (NRC, 1991, Chapter 2). This review will help define the integration of the toxicology program with other health, safety, and environmental programs of the Navy.

There is a need to expand the program to predict toxicity, to tailor exposure control recommendations, to evaluate degradation of field-personnel performance resulting from sublethal exposures, and to assess the impact of toxicity in mission execution. The subcommittee supports such an expansion but wishes to emphasize the need to coordinate it with a stronger focus on NMRITD programs designed to anticipate and resolve the problems unique to the Navy and its personnel.

The subcommittee believes that consideration should be given to increasing the amount of applied research done by NMRITD.

The strategic planning effort conducted by the Naval Medical Research and Development Command's corporate board led to a decision that the Navy needs its own toxicology program. NMRITD will have to work closely with Navy leadership to (1) attain a mutual understanding of the appropriate supporting role of basic research in fulfilling NMRITD's mission; (2) establish a flexible balance (determined periodically) of basic and applied toxicology research that is required to meet what the Navy perceives as its current and future needs; and (3) justify the commitment and funding necessary to carry basic and applied research projects through to completion.

Establishment of definitive goals for NMRITD's research is essential for determining the proper mix of basic and applied projects as well as the proper mix of classical toxicology (effects detected at the tissue, organ, and organism levels) and mechanistic toxicology (effects detected at the molecular, biochemical, and cellular levels). Periodic external peer review would be valuable in helping the Navy arrive at the appropriate mix of approaches and state-of-the-art methods.

The basis and need for a Navy toxicology program appear to be valid because of the unique toxicological problems (e.g., continuous exposure to toxicants for extended periods of time and exposure to toxicants in hyperbaric conditions) associated with Navy activities. Therefore, the emphasis of NMRITD should be on applied research with some long-range research efforts—basic and applied—that are targeted to solving the Navy's problems in the area of toxicology as defined in NMRITD's mission. Issues common to all branches of the armed services should be addressed by triservice-supported research. Pursuit of basic research projects designed to obtain fundamental knowledge would be enhanced by collaboration with academia, other government laboratories, and industry.

The subcommittee identified four constraints that affect the ability of NMRITD to execute its scientific program: staffing, space and facilities, equipment, and the funding cycle.

Major limitations on NMRITD result from the small size of the group and the constant rotation and, relatively short tenure of naval officers. Frequent rotation adversely affects program continuity and stability and also retards, if not impedes, completion of research projects. These limitations further contribute to the significant deficits in program structure and personnel staffing (as noted above).

Some of the military scientists demonstrate genuine understanding of specific areas of need and address them with appropriately focused toxicological studies. Others appear to simply apply their expertise rather than use the best available and most appropriate techniques to solve a given problem. The latter group of scientists and the Navy would benefit by pairing rotating officers with senior civilian scientists to improve research techniques on important projects.

The subcommittee recommends expansion of the core group of civilian scientists to provide the continuity necessary for long-term program execution, for staying abreast of trends in toxicology, and for producing high-quality scientific studies that can be applied to support the Navy's needs. An adjunct to this recommendation would be stabilization of Navy personnel assignment with appropriate rank-advancement opportunities —i.e., a technical career ladder within NMRITD and elsewhere as appropriate to meet the Navy's needs. To that end, the Navy could use existing personnel management tools to develop a more attractive technical career plan for officers with relevant training and experience. The career track should include assignments designed to foster (1) research skills in toxicology and allied sciences, (2) insight into the needs of the various user groups, (3) and methods of applying research results to health-hazard evaluation and risk assessment. This career track should lead into senior program management and technical expert applications, which would permit the Navy to take advantage of specialized capabilities to integrate the toxicology program into broader Navy strategic plans and programs.

These suggested policy changes would permit NMRITD, as directed in its mission statement (NMRI, 1991), to provide an exemplary “cadre of Navy personnel skilled in the discipline of toxicology and its application to health-hazard evaluation and risk assessment.”

The laboratories provided to the NMRITD at WPAFB are conveniently housed within a single facility and are located adjacent to the laboratory animal-holding facility, which is accredited by the American Association for the Accreditation of Laboratory Animal Care. However, the building is old and has a number of problems ranging from leaking pipes to ventilation and air-handling deficiencies, which, for example, prevent maintenance of clean room conditions required for state-of-the-art trace-level chemical analysis. Lack of adequate space makes experimentation difficult for certain types of research—e.g., cell and tissue culture and use of radiolabeled materials, both of which require dedicated space. The heating, ventilation, air conditioning, and temperature and humidity control systems are inadequate for inhalation and general toxicity studies, as are the chemical handling hoods, which are supported by a single exhaust system and which present potential safety problems. Space for storage of chemical samples and other archival materials is inadequate.

If the recommended changes in staffing are to be made, additional laboratory and office space will be needed.

There is a need to modernize the scientific equipment in many of the study areas. The subcommittee was pleased to learn at its July 13, 1993, meeting that a few pieces of equipment had been replaced with up-to-date instruments, but some glaring deficiencies remain —e.g., an outdated gas chromatography/mass spectrometer and the lack of modern nuclear magnetic resonance instrumentation.

The well-known inhalation exposure facilities at WPAFB appear to be in good condition. The pathology laboratory also appears capable of a wide range of support for toxicology and investigative efforts. There are electron microscopes (transmission and scanning), quantitative morphometry systems, and immunostaining facilities. Routine necropsy and histopathology services are available.

The current funding cycle is 1-2 years for most projects. It is extremely difficult, if not impossible, to build a quality research program with such a short funding cycle. In addition, funding comes from different areas within the Navy and is project-directed rather than program-directed.

Individual project proposals are submitted for approval. If the project is approved, the researcher is granted funding, but the funds might not be sufficient to support the critical personnel and the equipment needed to do state-of-the-art research in a program area. Consequently, the researcher is often forced to work under less than optimal funding, equipment, space, and personnel circumstances, which can lead to inferior results. The subcommittee recommends that serious consideration be given by the appropriate administrative office within the Navy to modify its funding procedures for research units.

The subcommittee recommends the following changes in NMRITD's current toxicology program:

• The toxicology program should be expanded to

  • Place greater emphasis on predicting toxicity of materials used in Navy operations.

  • Place greater emphasis on developing permissible exposure limits for exposure scenarios encountered by Navy personnel.

  • Evaluate degradation of field-personnel performance resulting from sublethal exposures.

  • Assess the impact of toxicity on field operations.

• The major emphasis of NMRITD should be on applied toxicology with some long-range basic research that is targeted to solving the Navy 's toxicological problems. Although the Navy's primary need is

for applied toxicology, support should be given to basic research on matters that are unique to the Navy.

• Staffing: Since the tours of duty of military personnel typically are of short duration, greater emphasis should be given to the core group of civilian scientists to provide the continuity necessary for long-term program execution, for staying abreast of current trends in toxicology, and for conducting high-quality scientific studies to support the Navy 's needs. In addition, assignments should be stabilized for Navy personnel at NMRITD, and rank-advancement opportunities should be provided within NMRITD.

• Space and Facilities: The current laboratory buildings are old and thus have potential problems with leaking pipes, ventilation, and air handling. Therefore, attention to adequate and suitable space is necessary to support state-of-the-art toxicological research.

• Equipment: Although a few pieces of equipment are state of the art, obvious deficiencies remain. For example, some of the equipment at NMRITD, such as gas chromatography/mass spectrometer and nuclear magnetic-resonance instrumentation, is outdated. Such equipment should be modernized.

• Funding: It is extremely difficult to build a quality research program with the current 1- to 2-year funding cycle. Therefore, serious consideration should be given by the appropriate administrative office within the Navy to coordinate and improve funding procedures for NMRITD. The funding in NMRITD is project-directed rather than program-directed, which leads to funding of projects that are not capable of supporting the critical personnel and the equipment to do state-of-the-art research.