Toxicity of 2,6-Di-tert-butyl-4-Nitrophenol (DBNP).

U.S. Navy submarines reported a yellowing of metal surfaces on their internal surfaces. The yellowing was initially identified on the painted steel bulkheads but further examination indicated that it was not limited to steel surfaces and included bedding, thread tape, Formica, plastisol covered hand-wheels, and aluminum lockers. Crew members also reported to the medical department that their skin turned yellow when they came in contact with these contaminated surfaces and requested information on the effects of exposure. Studies conducted by General Dynamics' Electric Boat Division (EBD) determined that the agent was 2,6-Di-tertbutyl-4-Nitrophenol (DBNP). 2,6-Di-butylphenol (DBP) is an antioxidant additive used in lubricating oils and hydraulic fluids. In the enclosed atmosphere of a submarine, the oil mist could be spread throughout the boat by venting the lube oil to the atmosphere. Submarines use electrostatic precipitators (ESP) to clean the air of particulate materials. During passage through the ESP, oil mist containing DBP is nitrated to DBNP, which is then moved throughout the boat in the ventilation system. Analysis of the EBD data indicated 24-hour exposure concentrations to be in the range of <3.0 to 122 ppb in the laboratory and submarine settings. Submarine crews may be exposed to these concentrations for as many as 24 hours/ day for 90 days during underway periods. Toxicity studies regarding the oral and dermal uptake of DBNP were conducted. From the literature the lethal dose to 50 percent of the population (LD50) of DBNP (rat) was reported by Vesselinovitch et al. in 1961 to be 500 mg/kg. Our studies indicated that the LD50 is in the range of 80 mg/kg in the rat. Our work also includes dermal absorption studies, which indicated that DBNP is not well absorbed through intact skin. Within this study, no no-observable adverse effect level (NOAEL) or lowest observable adverse effect level (LOAEL) was identified. Calculation of a reference dose was completed using standard methods based on the LD50 as a numerator with several uncertainty and modifying factors. EBD's determination of airborne concentrations aboard submarines fall in the range of these anticipated allowable concentrations and could indicate significant chronic exposures. No adverse effects from DBNP exposures have been reported to date.

The establishment of good laboratory practices at the Naval Medical Research Institute Toxicology Detachment.

A quality-management program (QMP) has been launched at the Naval Medical Research Institute Toxicology Detachment to support the planning, assessment, interpreting, and reporting of toxicology study data. The QMP conforms to the intent of the Good Laboratory Practice established by the Food and Drug Administration and the Environmental Protection Agency for regulatory compliance. The biomedical data necessary to characterize the toxicity of materials of interest to the Navy are used to formulate occupational and environmental health-hazard evaluations and risk assessments, including appropriate exposure limits for personnel for Navy-specific circumstances of exposure. The goal of the QMP is to help management and investigators ensure the quality and integrity of the data collected in laboratory animal toxicology studies. These data are used to reduce or eliminate potential health risks from exposure to toxicants during Navy operations. The primary purpose of the risk-reduction program is to help ensure readiness to accomplish the military mission. This article briefly reviews the need for the QMP and the military relevance of the quality-assurance requirements. The pros and cons of establishing the QMP are discussed, and examples of specific research projects and programs that support the need for a quality management program are presented. Aspects of integrating the QMP program to ensure compliance with Good Laboratory Practice are reviewed, and the value of the improvements in the quality of data from the Naval Medical Research Institute/Toxicology Detachment is summarized.

Risk assessment policy for evaluating reproductive system toxicants and the impact of responses on sensitive populations.

Risk assessment policy for evaluating environmental chemicals for their potential to produce reproductive system failures is similar to policy for evaluating cancer-causing effects. The objective of reproductive system risk assessment is to expand on the test standards that primarily focus on fertility endpoints and birth defects by using mechanism-of-action studies and quantitative risk assessment methods. An understanding of the sensitivity of reproductive system insult between animal species and from animal models to man is critical to developing risk assessment policy and test standards. The reproductive process is complex and involves a number of maturation and sex cell development processes. Sensitivity to insult varies throughout this process, especially during, (1) the development of the conceptus, sperm and ova, (2) fertilization, (3) implantation, and (4) puberty. Reproductive failure has many causes and clinical effects. Risk assessment policy is directed toward reducing the uncertainty associated with the cause by providing a guide to understanding how dose, duration, and characteristics of the reproductive toxicant affect the reproductive process.