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This paper presents the analysis of urine bioassay data, spanning four decades, from five workers who had wounds contaminated with plutonium at the Department of Energy Rocky Flats Plant during the period 1961-1967. The cases were selected from participants in the Department of Energy-sponsored Former Radiation Worker Medical Surveillance Program at Rocky Flats, which provided medical monitoring, modern bioassay measurements, and internal dose re-evaluations for former Rocky Flats workers. The cases include a variety of wound types, excision treatment regimes, and monitoring information. These wound cases illustrate the use of two multi-compartment wound models and three plutonium urine excretion models for retrospective calculation of internal plutonium depositions resulting from wounds for which no chelation therapy was administered. Wound model compartment fractions and half times are determined for each case and urine excretion model as are composite parameter values. The urine analysis and wound count measurements obtained under the program provide data with state-of-the art measurement sensitivity, as well as the opportunity to include long-term excretion and wound site data that exceed 10,000 d post-exposure for retrospective intake and dose evaluations. These data are provided to the radiation dosimetry community for use in developing and testing improved models for plutonium deposition in wounds.

Background: The beryllium lymphocyte proliferation test (Be-LPT) measures beryllium-specific cellular immune response, and is useful in medical surveillance of beryllium sensitivity and chronic beryllium disease (CBD)., Methods: Current and former employees (n = 12,194) of 18 United States Department of Energy (DOE) sites were tested for beryllium sensitization at four laboratories with Be-LPT expertise. Beryllium sensitized individuals were offered evaluations for CBD. The sensitivity, specificity, and positive predictive value (PPV) of the Be-LPT were determined, as was inter- and intra-laboratory agreement., Results: False positives were calculated to be 1.09%, with a laboratory range of 0.00-3.35% for the 10-year investigation. Be-LPTs performed on inter-laboratory split blood specimens from sensitized individuals showed a false negative rate of 31.7%. The intra-laboratory repeatability of abnormal Be-LPT results ranged from 80.4-91.9%. The sensitivity of the Be-LPT was determined to be 0.683, with a specificity of 0.969. The PPV of one abnormal Be-LPT was 0.253., Conclusions: The Be-LPT is efficacious in medical surveillance of beryllium-exposed individuals. The PPV of the Be-LPT is comparable to other widely accepted medical tests. Confirmation of an abnormal result is recommended to assure appropriate referral for CBD medical evaluation., (Copyright 2004 Wiley-Liss, Inc.)

The United States Department of Energy (DOE), Office of Occupational Medicine and Medical Surveillance, has supported an ongoing Former Radiation Worker Medical Surveillance Program at the DOE Rocky Flats site since 1992. The program currently is managed for DOE by Oak Ridge Institute for Science and Education through a contract with Oak Ridge Associated Universities. Participation in the program is entirely voluntary and provides former Rocky Flats workers who were exposed to radiation with long-term medical monitoring and an update to the assessment of their radiation dose. Program participants receive medical examinations and in vivo and in vitro bioassay measurements of residual radioactivity. Radiation doses to participants are largely a result of internal depositions of plutonium and its radioactive decay products. The causes of many of the higher internal doses were accidents that generally are well documented. Former radiation workers are invited to participate in the program if they meet specific criteria for radiation exposure. Informed consent is documented using a consent form approved by an Institutional Review Board. Demographic, medical, and dosimetric information is maintained in a computer database and will be evaluated for any trends or correlations between exposure and health outcome.

The prevalence of beryllium sensitization and chronic beryllium disease by job category was examined among individuals tested in the Rocky Flats Beryllium Health Surveillance Program. The program offered ongoing beryllium health surveillance for any current or former employee who believed they may have been exposed to beryllium at the Rocky Flats Environmental Technology Site. Of the 18,589 living individuals contacted, 7,573 requested participation and 6,614 (87.3%) eventually participated. Of this group, 78.2 percent were found to have verifiable job and building histories. The beryllium lymphocyte proliferation test was used to identify beryllium-sensitized individuals. Sensitization and chronic beryllium disease rates were analyzed with respect to gender, building work location(s), and length of employment at Rocky Flats. Several job categories and buildings were strongly associated with the 81 cases of chronic beryllium disease and the additional 154 cases of beryllium sensitization in this population. Beryllium sensitization was highest among beryllium machinists, 11.4 percent (odds ratio = 3.04, compared to the remainder of those tested, 95 % confidence interval = 1.48, 3.97) and health physics technicians, 11.9 percent (odds ratio = 2.87, 95% confidence interval = 1.12, 7.36). However, odds ratios were also increased among custodial employees, 5.64 percent (odds ratio = 1.30, 95% confidence interval = 0.92, 1.85) and other job titles that were thought to have only minimal potential for exposure to beryllium.

The Rocky Flats Beryllium Health Surveillance Program (BHSP), initiated in June 1991, was designed to provide medical surveillance for current and former employees exposed to beryllium. The BHSP identifies individuals who have developed beryllium sensitivity using the beryllium lymphocyte proliferation test (BeLPT). A detailed medical evaluation to determine the prevalence of chronic beryllium disease (CBD) is offered to individuals identified as beryllium sensitized or to those who have chest X-ray changes suggestive of CBD. The BHSP has identified 27 cases of CBD and another 74 cases of beryllium sensitization out of 4268 individuals tested. The distribution of BeLPT values for normal, sensitized, and CBD-identified individuals is described. Based on the information collected during the first 3 1/3 years of the BHSP, the BeLPT is the most effective means for the early identification of beryllium-sensitized individuals and to identify individuals who may have CBD. The need for BeLPT retesting is demonstrated through the identification of beryllium sensitization in individuals who previously tested normal. Posterior/anterior chest X-rays were not effective in the identification of CBD.

The first case of chronic beryllium disease (CBD) at the Rocky Flats Environmental Technology Site (Rocky Flats) was diagnosed in a machinist in 1984. Rocky Flats, located 16 miles northwest of Denver, Colorado, is part of the United States Department of Energy (DOE) nuclear weapons complex. Research and development operations using beryllium began at Rocky Flats in 1953, and beryllium production operations began in 1957. Exposures could have occurred during foundry operations, casting, shearing, rolling, cutting, welding, machining, sanding, polishing, assembly, and chemical analysis operations. The Beryllium Health Surveillance Program (BHSP) was established in June 1991 at Rocky Flats to provide health surveillance for beryllium exposed employees using the Lymphocyte Proliferation Test (LPT) to identify sensitized individuals. Of the 29 cases of CBD and 76 cases of beryllium sensitization identified since 1991, several cases appear to have had only minimal opportunistic exposures to beryllium, since they were employed in administrative functions rather than primary beryllium operations. In conjunction with other health surveillance programs, a questionnaire and interview are administered to obtain detailed work and health histories. These histories, along with other data, are utilized to estimate the extent of an individual's exposure. Additional surveillance is in progress to attempt to characterize the possible risks from intermittent or brief exposures to beryllium in the workplace.

This paper demonstrates that current standards used by the Occupational Safety and Health Administration (OSHA) to establish an area free from potential beryllium contamination may be inadequate. Using the Beryllium Antibody Assay, it was shown that workers exposed to former beryllium work areas, thought to be sanitized and to meet OSHA standards, experienced statistically significant rises in blood beryllium antibody titers. This finding raises the question of whether the equipment currently required to protect workers in beryllium-laden environments is sufficient. The project mission of decommissioning/decontaminating the former nuclear weapons plant at Rocky Flats Environmental Technology Site (RFETS), instituted in 1992, has necessitated development of new technology directed toward safe and responsible cleanup. Challenges have been posed not only by the need to dispose of radioactive and chemical waste, but also by the problem of cleaning up hazardous metals such as the element beryllium. Beryllium was used extensively in research and the manufacture of nuclear weapons components at Rocky Flats for over 40 years. Since inhalation of this element can induce chronic beryllium disease (Eisenbud and Lisson, 1983), an antibody assay was developed to screen workers for internal exposure to beryllium. Exposure is indicated by a titer of antibodies greater than two standard deviations above a normal population control (defined as the mean titer of pooled samples from 51 individuals with no known exposure to beryllium) and a p-value of < 0.05. This paper describes two new applications for the assay: risk assessment and health surveillance. Case study 1 involves a team of three workers who cleaned a beryllium plenum and whose beryllium antibody titers provided a quantitative assessment of their exposure. Case study 2 describes the use of the antibody assay to determine the probable manner in which one worker was exposed to beryllium while performing his duties as an architectural engineer.

Chair-restrained rhesus monkeys (Macaca mulatta) were inoculated subcutaneously with 10(2)--10(3) plaque-forming units of virulent Rickettsia rickettsii. The latent period for fever and rickettsemia was three to four days; death occurred six to eight days after infection. Total circulatory electrolyte levels and fluid volumes, including plasma, red blood cell, true circulatory blood, and extracellular fluid, increased. The expansion of the extracellular and plasma volumes resembled findings reported during severe Rocky Mountain spotted fever in humans, guinea pigs, and rabbits. Total water content of the liver also increased. Intracellular concentrations of K+, as well as total Na+ and K+, decreased in the diaphragm. Both the lung and medulla oblongata showed increased levels of intracellular Na+ and water with simultaneously decreased levels of extracellular Na+ and water. Such an intracellular overhydration of the medulla oblongata could contribute to death as a result of depression of the cardiovascular and respiratory centers. On the basis of the findings in monkeys, the intravenous infusion of fluids and electrolytes during clinical therapy of severe rickettsial infections should be considered extremely dangerous.

Polyriboinosinic-polyribocytidylic acid, stabilized with poly-L-lysine and carboxymethylcellulose (poly ICLC), favorably alters the pathogenesis of Venezuelan equine encephalomyelitis virus infection in rhesus monkeys by decreasing the number of infected monkey that become detectably viremic and by delaying the onset of viremia in the remaining monkeys. Poly ICLC is known to induce high circulating levels of interferon in primates, and the interferon system is assumed to be the mechanism by which poly ICLC exerts its antiviral effect. Poly ICLC treatment was associated with a few deaths, but only under certain conditions of infection and handling. The death of some infected, treated monkeys in the absence of death in monkeys that were either infected and untreated or treated and uninfected suggests a synergistic toxicity resulting from the combination of infection, handling, and poly ICLC treatment, although other explanations are possible.

The clinical records and follow-up data obtained over 13 years on the results of radiotherapy of spontaneous fibrous connective-tissue sarcomas in dogs, cats, and horses were reviewed. The results obtained from the treatment of fibrosarcomas and sarcoids of horses indicated that radiation administered with 60Co is important in the medical and surgical management of these tumors. Fibrous connective-tissue sarcomas in horses were radioresponsive. When radiotherapy was applied postoperatively, the probability of a 2-year cure approached 50% for all prescribed radiation doses of less than 2,000 to greater than 4,000 rads. If radiation doses of 4,500-6,000 rads were used, a 2-year cure rate may approach or exceed 60%.

Serum interferon activity was determined in 12 cynomolgus and 12 rhesus monkeys injected intravenously once daily for 10 days with from 0.1 to 6.0 mg of a stabilized polyriboinosinic acid . polyribocytidylic acid complex per kg, composed of polyriboinosinic acid . polyribocytidylic acid, poly-1-lysine, and carboxymethylcellulose [poly(ICLC)]. Interferon activity was detected 2 h after the first injection, with maximum activity occurring 8 h after the second injection. A period of hyporesponsiveness occurred after the third injection of poly(ICLC) in all monkeys and lasted until the sixth injection in the rhesus monkeys, when interferon activity again became more elevated. The delayed rebound was not as apparent in cynomolgus monkeys. Rhesus monkeys injected with 6 mg/kg did not exhibit serious side effects.

Polyriboinosinic-polyribocytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose [poly(ICLC)] enhances the antibody response in rhesus monkeys immunized with swine influenza virus subunit vaccine. Monkeys given the vaccine-adjuvant combination had earlier and significantly (P less than .05) higher titers by 14 days compared to those that received vaccine alone. The potentiation of the antibody response of young monkeys given a split-virus vaccine in combination with poly(ICLC) suggests that this vaccine-adjuvant combination may similarly provide a potentially useful alternative approach to the immunization of pediatric and young adult age groups against swine influenza.

Groups of guinea pigs were injected with a range of dosages for sarin (0, 140, 279, 557 micrograms/kg) followed by pralidoxime (2-PAM) and atropine sulfate (16 mg/kg). Poisoning by sarin in these animals elevated plasma pralidoxime content in a dose-dependent manner within 10 min of intoxication. Plasma levels after administration of 3.12 mg/kg of 2-PAM were elevated from a control mean of 6.18 micrograms/ml to a maximum of 13.78 micrograms/ml in animals given 557 micrograms/kg of sarin at 2 min after the injection of the therapeutic compounds. This suggests that pathophysiological changes following intoxication by potent inhibitors of cholinesterase result in a decrease in the rate and extent of distribution of therapeutic compounds. This effect is most likely a consequence of changes in cardiovascular functions influencing blood flow to various organs.

A highly virulent strain of Venezuelan equine encephalomyelitis (VEE) virus produced less severe histopathologic changes in brain tissues of mice previously exposed to sublethal total-body x-irradiation than it caused in nonirradiated mice. Prior exposure to 600 R of x-irradiation virtually eliminated the lesions of vasculitis and encephalitis that were found in the infected nonirradiated control mice. Mean peak brain lesion scores generally decreased as radiation exposure dose was increased. Irradiation of mice before inoculation often decreased median time to death, whereas the severity of pathologic changes in brain tissues from inoculated irradiated mice was often reduced, without significantly altering ultimate host survival. The inflammatory response did not appear to have a significant role in clearance of this virus from the brain. There was no evidence that participation of the immune response contributed to total mortality from VEE virus encephalitis, as indicated by the failure of radiation immunosuppression to reduce mortality. Death apparently was caused by the direct cytocidal effects of VEE virus replication.

Serum lactate dehydrogenase enzyme (sLDH) was studied in both healthy and yellow fever virus (YFV)-infected young adult rhesus monkeys (Macaca mulatta). In healthy monkeys, significant variation (p less than 0.001) was observed for both total activity and isoenzyme distribution among the following comparisons: individual monkeys, different days, different times of day, and caged versus chair-restrained monkeys (until 7 da after chair restraint). However, variability of baseline values was reduced by the use of samples obtained from resting subjects at 9:00 am on at least 3 consecutive days. Normal total activity and isoenzyme distribution values were based on 148 determinations obtained from 73 healthy, caged monkeys. Both total activity and the proportion of the 5th isoenzyme fraction increased significantly (p less than 0.001) in the YFV-infected monkeys, beginning 90 hr postinfection, consistent with hepatocellular necrosis and release of isoenzymes into the serum. The assay for sLDH appears to be of value as a diagnostic indicator during the course of YFV infection in the rhesus monkey.

Temporal effects of exposure to sublethal, total-body X radiation (400 R) on responses to vaccination with attenuated Venezuelan equine encephalomyelitis vaccine virus. TC-83, were examined in rhesus monkeys. Viremia, often with delayed onset, was prolonged even when irradiation preceded vaccination by 28 days. Virus titers were increased, articularly in groups irradiated 4 or 7 days before vaccination. Delay in appearance of hemagglutination-inhibition and serum-neutralizing antibody correlated closely with persistence of viremia in irradiated-vaccinated monkeys. The temporal course of antibody response was markedly affected by the intervals between irradiation and injection of this replicating antigen. With longer intervals between irradiation and vaccination, the somewhat depressed antibody responses approached normal or surpassed those of nonirradiated monkeys. Vaccination 14 days after radiation exposure resulted in lethality to 8 of 12 monkeys, apparently as a result of secondary infection. The additional lymphopenic stress due to the effect of TC-83, superimposed on the severly depressed hematopoietic competence at 14 days, undoubtedly contributed to this increased susceptibility to latent infection.

Repetitive blood sampling of miniature swine was accomplished by percutaneous puncture of the femoral vein. Swine were restrained manually in dorsal recumbency. The skin was penetrated in the inguinal area approximately 2.5 cm laterally to the most posterior mammary gland with a 21-gauge, 3 cm (1.5 inch) needle. Ten milliliters of blood were withdrawn of frequent intervals for 4 months without apparent harm to the animals.

The respiratory pathophysiology of A2 influenza infection was studied in mice treated with small-particle aerosols (SPA) of rimantadine or ribavirin. Untreated infections in mice resulted in survival rates of 15% or less and were characterized by (i) severe hypoventilation (decreased P(O2) and increased P(CO2)), (ii) compensated respiratory acidosis (increased P(CO2) and HCO(3) (-), with normal pH), (iii) pneumonia with increased ratio of wet/dry lung weight, and (iv) hypothermia. Treatment with SPA of rimantadine (21 mg/kg per day for 4 days) beginning 72 h after virus challenge significantly improved survival rate (80%) but failed to alter lung pathology from that found in infected, untreated mice. Rimantadine treatment decreased somewhat the severity of hypoventilation, respiratory acidosis, lung wet weight, hypothermia, and lung virus titers from that observed in infected, untreated mice. SPA of ribavirin (26 mg/kg per day for 4 days) initiated 6 h after SPA exposure of mice to virus significantly improved survival rate (95%) and reduced lung virus titers and lung pathology. Gas exchange and pulmonary edema in ribavirin-treated, infected mice were significantly improved over those of infected, untreated controls. The mechanisms for increased survival rates induced by SPA of rimantadine remain uncertain, since increased survival rates could not be ascribed entirely to improvements in lung functions. In contrast, however, ribavirin treatment appeared to improve survival rates by reducing major lung pathology and pulmonary dysfunction. This was probably mediated through the antiviral effects of ribavirin.

The microvasculature of C3H/Bi mouse mammary carcinomas 8 mm in average diameter was evaluated using morphometric methods following six consecutive daily exposures of 500 R of x radiation. Tumor volume did not change significantly during the intervals between treatments. Tumors began to grow again 72 hours after the sixth 550-R fraction, with mean vessel length and surface area reaching maximum values and vessel diameters and volumes becoming minimal at this time. These changes were attributed to improved colloidal-carbon filling of previously existing nonfunctional vessles. When anatomically derived estimates of vascular dimensions were related to a metabolically useful blood supply, improved capability for exchange of essential nutrients occurred 72 hours after the sixth 500-R fraction.

Studies were conducted to determine the effects of sublethal, acute, total-body irradiation (600 R) on the immune response of mice to a replicating antigen. Irradiation was performed at varying times (0 to 21 days) prior to immunization with attenuated Venezuelan equine encephalomyelitis virus, TC-83. Development of protective immunity was studied by inoculating subgroups of irradiated mice with virulent Venezuelan equine encephalomyelitis virus on days 1 through 28 after immunization. Irradiation failed to affect the overt clinical response of mice inoculated with the attenuated strain, but antibody responses and the onset of protective immunity was delayed, particularly in mice irradiated 2 h to 3 days prior to vaccination. Immunity afforded by TC-83 developed more rapidly as the interval between irradiation and vaccination increased: when this interval was 14 or more days, the temporal course of immune response in irradiated mice was similar to that of nonirradiated vaccines. Persistence of TC-83 viremia was greatly prolonged in irradiated mice through the irradiation recovery period and probably provided the antigenic stimulus responsible for delayed development of effective immunity.

The epizootic Trinidad donkey strain of Venezuelan equime encephalomyelitis virus (VEE) was cleared slowly from the circulation of rhesus monkeys following intravenous inoculation, while the live, attenuated vaccine strain, TC-83, was cleared rapidly. The efficent clearance of TC-83 vaccine may be a factor in the lower viremia and benign course of TC-83 virus infection in rhesus monkeys.

Polyriboinosinic.polyribocytidylic acid [poly(I).poly(C)] stabilized with poly-l-lysine and carboxymethylcellulose [poly(ICLC)] has been previously shown to be a compound with marked adjuvant activity when given in high doses with inactivated Venezuelan equine encephalomyelitis (VEE) virus vaccine. This study investigated the effects of much lower doses of poly(ICLC) on the magnitude and kinetics of the primary and secondary humoral antibody responses of rhesus monkeys to inactivated VEE virus vaccine. Monkeys given a single injection of vaccine developed very low neutralizing antibody titers, whereas those given adjuvant plus vaccine had 30- to 100-fold-higher titers which remained elevated for longer than 6 months. Low doses of poly(ICLC) given with VEE virus vaccine resulted in a profound but transient increase in priming of secondary antibody responses to the antigen. In contrast, the administration of poly-l-lysine and carboxymethylcellulose alone without the poly(I).poly(C) component of the complex had no adjuvant effect on antibody responses of monkeys to VEE virus vaccine. The temporal development of antibody by class (immunoglobulin M-immunoglobulin G) in monkeys given two injections of adjuvant-vaccine was not different from that with vaccine alone. Serial hematological and clinical chemistry determinations on monkeys given single or multiple doses of poly(ICLC) with vaccine were not different from values in monkeys given vaccine alone.

Pretreatment of rhesus macaques with nonlethal total-body x-irradiation (400 R) prolonged survival time from an average of 15 hours to 101 hours after intravenous (IV) inoculation of 50 microgram of staphylococcal enterotoxin B (SEB)/kg of body weight. Radiation exposure per se did not produce detectable cardiorenal changes; however, the longer survival after SEB challenge exposure in x-irradiated rhesus macaques was associated with improved cardiorenal functions if compared with that of nonirradiated macaques given the same dose of SEB. Total-body radiation exposure 4 days prior to IV SEB inoculation prevented typical SEB-induced decreases (where measured at 5 hours) in cardiac output, stroke volume, TcH2O, CPAH, Cosm, and urine flow, as well as increases in total peripheral and renal resistance. A theory concerning the significance of radiation-induced leukopenia on modification of SEB-induced cardiorenal functions is postulated.

A pen to hold individual miniature pigs during long-term radiation exposure studies has been designed and used. Wooden construction results in low cost and minimizes radiation scatter problems associated with higher density materials. An automatic water system is provided.