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

Concerns about the toxicity of the materials that Navy and Marine Corps personnel must work with can be traced to the latter part of the 19th century (Forman, 1988). From 1939 to 1941, as the nation prepared to drastically increase its industrial output, the Navy worked hard to enhance its capabilities in occupational medicine and industrial hygiene, an effort that was formalized with the establishment of the Navy's Industrial Health Program by the Secretary of the Navy in December 1941. That was the beginning of the Navy's Occupational Safety and Health Program (although it was not known by that name until more than 30 years later).

The Navy had a vigorous occupational medicine program during the first half of the century, but it relied heavily on a small cadre of physicians to evaluate military operational environments as well as civilian working environments. With the training of physicians and others to support the Navy's new Industrial Health Program at Harvard and Columbia universities came the beginning of a complementary industrial hygiene community, which made use of data from the general scientific literature to evaluate hazards resulting from various chemicals under varying exposure conditions. In an unrelated move, the Naval Medical Research Institute (NMRI) was founded in 1941; its mission was to investigate infectious diseases and other medically related matters that might affect the war effort.

When toxicological research was required to evaluate potential haz-

ards, it was supported on an ad hoc basis. Some work was performed in-house, primarily at NMRI, and additional work was funded at universities. For instance, inhalation and dermatotoxicological research of the explosives nitroglycerin and RDX, used in underwater demolition work, was funded by the Office of Scientific Research and Development as a set of cooperative projects between the Naval Underwater Explosives Laboratory in Betterton, Maryland, and the University of Pennsylvania Medical School.

Two events during the early to mid-1950s stimulated the Navy's interest in toxicology as a separate program. Explosions aboard the USS Leyte Gulf and the USS Bennington were traced to flammable and explosive hydraulic fluids. As replacement fluids were being developed, concerns were raised about their toxicity and the costs of selecting ones that could cause different and unanticipated problems (some, for instance, contained triaryl phosphates, e.g., Cellulube 220). During that time, the USS Nautilus was put to sea. Initial trials showed that its atmosphere control plant was contaminating the air with monoethanolamine from the scrubbers. That contamination threatened to curtail the duration of submerged operations. Further consideration of the operational environment that the submarine's crew would face revealed a lack of information regarding the health effects of continuous exposure to air contaminants for an extended period. Almost immediately, that issue was raised with regard to a new hydraulic fluid (Pydraul 150) for the submarine mast hoist system.

These problems were referred to the Navy's Bureau of Medicine and Surgery (BUMED), which lacked the means to conduct investigations and research in a rapid, responsive manner to support fleet requirements. Additional demands for toxicological data that could be applied to fleet conditions were anticipated and were expected to increase. Concerns were also growing regarding working conditions and the materials used in the Navy's shipyards and other industrial facilities (Lawton and Snyder, 1976). Some of the demands for data were being met on an ad

hoc basis by NMRI (e.g., data on Pydraul 150); such efforts, however, were inefficient and detrimental to NMRI's primary research areas. Other demands were being handled on a contractual basis by universities (data on monoethanolamine) or by the Army's Chemical Center. Still others were met by the establishment of a contract with the National Research Council (NRC) in 1958 to provide “best professional judgment ” for toxicological questions where data were lacking. However, the sum of these measures was recognized as filling only part of the need.

In early 1957, BUMED began planning for an operational toxicology and health engineering unit and, in October of that year, formally proposed such an activity to the other bureaus, to the chief of naval research, and to the Marine Corps. There was widespread perception of need for toxicological information and its application to Navy-specific requirements, as well as widespread support for an organization dedicated to meeting that need. The Secretary of the Navy formally established the U.S. Navy Toxicology Unit (NTU) in January 1959.

The NTU was assigned the mission of “providing technical and specialized services in the fields of operational toxicology and health engineering as related to toxicity problems encountered aboard ships and in the design and use of new weapons; and to develop and provide biological data necessary for determining permissible exposure limits so that precautionary measures, conducive to good health practices, may be prescribed.” The goal was not merely to conduct research to characterize the toxicity of materials, but to understand the specific circumstances of exposure and determine the expression of a material's intrinsic toxicity under those circumstances. In today's risk-assessment terminology (NRC, 1983), the NTU was given the task to perform toxicity characterization and toxicological research required for hazard identification and dose-response assessments, on-site air sampling required for exposure assessments (the exposed military population characterization was a given), and data integration necessary for risk characterization. Although no explicit mention of involvement is made in NMRITD's mis-

sion statement, the NTU was necessarily involved in the process of defining relative and comparative risks and in the cost-benefit analyses.

The NTU was located on the grounds of the National Naval Medical Center in Bethesda, Maryland, in a small office of 3,000 square feet. By 1965, the NTU was staffed by 22 personnel in six divisions: pharmacology, pathology, biochemistry, chemistry, behavior, and health engineering. It had already outgrown an earlier expansion. At that time, however, structural deficiencies in the building were identified, and it was condemned. Initial planning in January 1964 for a replacement building had identified a need for an additional 17,000 square feet, mostly for exposure and support facilities to handle increasing demands, particularly in hyperbaric toxicology. In 1966, a building plan for the Environmental Health Effects Laboratory (EHEL) was proposed by NMRI; it included 30,000 square feet for the NTU, which would increase its staff to 46 in 1973. This expansion was to accommodate additional capabilities to perform long-term studies in support of work required by the Strategic Systems Program Office (the Polaris missile program) and to obtain data needed to validate recommendations by NRC on continuous exposure limits. By 1972, however, the project had funding difficulties, and the projected increases in capability, programs, and staffing were never realized.

In May 1975, the NTU was disestablished, and its mission, staff, and facilities were incorporated into the NMRI as the Division of Toxicology in the Environmental Biosciences Department. With the loss of the laboratory space in the EHEL and with the imminent loss of their building to termites, new facilities had to be obtained quickly. Contacts with the U.S. Air Force's (USAF) equivalent laboratory, the Toxic Hazards Division of the Aerospace Medical Research Laboratory (AMRL) at Wright-Patterson Air Force Base (WPAFB) near Dayton, Ohio, led to a proposal in February 1976 to establish a detachment of the NMRI at WPAFB in facilities to be provided by the USAF. In addition to obtaining the needed laboratory space, this mechanism provided the advantages of coopera-

tive and collaborative work with USAF toxicologists. The Navy agreed to help fund (up to 25%) a contract to operate a large inhalation toxicology research facility, of the Toxic Hazards Research Unit, adjacent to the USAF's in-house laboratory. Approval was granted to establish the Naval Medical Research Institute's Toxicology Detachment (NMRITD) in June 1976. The first staff arrived at WPAFB in November 1976, and staffing reached about 10 in 1977; initial program funding (in-house plus contract) was about $850,000.

NMRITD has grown steadily in the subsequent 17 years, expanding from one floor to fill an entire building (about 12,000 square feet). Collaborative work is also conducted with Air Force and Army toxicology personnel in their facilities at WPAFB. In November 1993, there were 18 authorized staff members augmented by 16 on-site contractor personnel as well as student employees and reservists, with an annual budget of approximately 3 million dollars.

The concerns within the Navy that led to the development of a formal toxicology program focused on exposures occurring under Navy and Marine Corps operating conditions and the materials being developed for use under those conditions. The exposures were predominantly by inhalation, the duration of which ranged from intermittent to continuous for periods of minutes to months. The issues were limited to the nonstandard exposure durations and frequencies that altered the expression of toxicity and to the toxic effects of the materials used (complex mixtures) rather than the pure components. Exposure control limits were derived that were relevant to the exposure of concern (e.g., emergency or continuous exposures).

The emphasis gradually shifted over the years as a result of distinguishing between the process of characterizing toxicity for the immediate purpose of setting standards to control exposures and the need to improve the process of characterizing toxicity. Research was necessary to understand the underlying causes of toxicity to predict effects and to develop or adapt research methods to improve the toxicity-characterization process (Jenkins, 1992). The shift in emphasis within the research

program increased the focus on mechanistic and predictive studies. Another issue helping to shift the emphasis was the increasing concern about toxicity end points beyond classical descriptive pathology and the consequent need to develop methods for assessing the different end points. Operational concern was focusing on the impact of adverse health effects on mission performance. Although there was an increasing demand for the application of scientific expertise for health-hazard evaluations and risk assessments, NMRITD was limited by resources to providing assessments based on professional judgment only in those cases where significant data gaps existed and identifying the research needed to fill those gaps. Thus, the more straightforward assessments, along with the on-site evaluations, shifted to the Navy Environmental Health Center in Norfolk, Virginia, beginning in 1971. The division of labor between the two organizations was formalized in 1988.

The current research program of NMRITD emphasizes three fundamental areas of interest: (1) inhalation exposures, (2) the pulmonary system as route of entry and as target organ, and (3) performance deficits as the end points of neurobehavioral effects. These interests arise directly from the nature of the exposure conditions in the naval fleet and the concerns of operational commanders for the impact of chemical exposure on mission performance (or the impact of controls imposed to reduce adverse health effects). These areas of interest, in turn, rest on a foundation of (1) biochemical and metabolic studies for understanding the effects seen, (2) analytical chemistry for quantitation of exposure, dose, response, and the resultant effect, and (3) mathematical simulation modeling for predictive capability and risk assessment.