Minimization and management of wastes from biomedical research.

Several committees were established by the National Association of Physicians for the Environment to investigate and report on various topics at the National Leadership Conference on Biomedical Research and the Environment held at the 1--2 November 1999 at the National Institutes of Health in Bethesda, Maryland. This is the report of the Committee on Minimization and Management of Wastes from Biomedical Research. Biomedical research facilities contribute a small fraction of the total amount of wastes generated in the United States, and the rate of generation appears to be decreasing. Significant reductions in generation of hazardous, radioactive, and mixed wastes have recently been reported, even at facilities with rapidly expanding research programs. Changes in the focus of research, improvements in laboratory techniques, and greater emphasis on waste minimization (volume and toxicity reduction) explain the declining trend in generation. The potential for uncontrolled releases of wastes from biomedical research facilities and adverse impacts on the general environment from these wastes appears to be low. Wastes are subject to numerous regulatory requirements and are contained and managed in a manner protective of the environment. Most biohazardous agents, chemicals, and radionuclides that find significant use in research are not likely to be persistent, bioaccumulative, or toxic if they are released. Today, the primary motivations for the ongoing efforts by facilities to improve minimization and management of wastes are regulatory compliance and avoidance of the high disposal costs and liabilities associated with generation of regulated wastes. The committee concluded that there was no evidence suggesting that the anticipated increases in biomedical research will significantly increase generation of hazardous wastes or have adverse impacts on the general environment. This conclusion assumes the positive, countervailing trends of enhanced pollution prevention efforts by facilities and reductions in waste generation resulting from improvements in research methods will continue.

The reliability of a self-reported measure of disease, impairment, and function in persons with spinal cord dysfunction.

OBJECTIVE: To develop a self-report instrument that would provide information about the different levels of the disablement process, and that (1) was suitable for persons with spinal cord disease (SCD), (2) could be completed quickly, (3) could be mailed, (4) had acceptable reliability, and (5) would be clinically useful. STUDY DESIGN: Test-retest using a convenience sample. METHODS: Review of the literature and an expert panel were used to develop the instrument. It was mailed to 49,458 individuals in June 1995 and a second mailing was done in August 1995. A subset of 725 individuals who responded to both mailings was used to examine the instrument's test-retest reliability. RESULTS: The instrument has a 4th grade reading level and has questions on causal disease, disease severity, impairment, activities of daily living (including a self-reported version of the Functional Independence Measure, the SRFM), and resource utilization. Individual item test-retest reliability was high for a mailed questionnaire; all kappa coefficients were near or above .60 and most were over .70. Intraclass correlation coefficient for the SRFM was .90 and internal consistency (Chronbach's alpha) was .96. CONCLUSION: This instrument provides a new, rapid way to obtain information relative to the differing levels of the disablement process.

Is use of mechanical ventilation a reasonable proxy indicator for coma among Medicare patients hospitalized for acute stroke?

OBJECTIVE: To ascertain whether use of mechanical ventilation on admission to the hospital is a proxy indicator of coma (i.e., very severe stroke) among acute stroke patients. METHODS: A secondary analysis of data from a medical record review on a nationally representative sample of 2,824 Medicare patients, ages 65 years or older, who were hospitalized for stroke in 1982-1983 or 1985-1986 in 297 acute care hospitals in 30 areas within five geographically dispersed states. RESULTS: Use of mechanical ventilation on the first day of hospitalization was significantly associated with level of consciousness on admission: < 2 percent of noncomatose patients versus 17.5 percent of comatose (p < .001). With a high specificity and high likelihood ratio for a positive test, use of mechanical ventilation on the first day of hospitalization ruled-in coma. It was also significantly associated with severity of illness, prognostic indicators (i.e., admission through the emergency room, admission to intensive care, and having a "do-not-resuscitate" order written during the hospital stay), and with in-hospital death. Adjusting for patient demographics, stroke type, comorbidity, and process of care, early initiation of mechanical ventilation remained significantly associated with both coma and in-hospital death. CONCLUSIONS: A stroke patient's use of mechanical ventilation on the first day of hospitalization is a valid proxy indicator of level of consciousness.

The relationships among reproductive endpoints in Swiss mice, using the reproductive assessment by Continuous Breeding database.

The database of Continuous Breeding mouse studies was evaluated to determine the relationships between the functional indicators of reproduction (pup measures) and the various necropsy endpoints collected for males and females. Of 72 chemicals studied, both males and females were affected in 33 studies, while females and/or conceptuses were affected in 7. Two compounds affected only males, 17 studies were negative, and in 13 studies with effects it was not possible to clearly determine the affected gender(s). Greater F0 dam weight was correlated with increased pup mass per litter; this relationship was strongest for the first litter, and weakest for the fifth litter. For both generations of treated females (F0 and F1), longer estrous cycles correlated with reduced numbers of pups; the relationship was stronger in F0 than in F1 females and was not seen in controls. Sperm parameters had different distributions in treated mice than in control mice. Fertility (total live pups/number of pairs cohabited) was reduced if there were > approximately 15% sperm abnormalities or if sperm motility (moving/not moving) was < approximately 37%. Both of these relationships appeared to have thresholds. Epididymal sperm count in treated animals, however, was linearly related to fertility, even within the control range, suggesting strongly that other factors are important. Using both treated and control data together, combining sperm count with motility could explain much (r = 0.77) of the variation in fertility; adding morphology did not significantly improve the correlation. The model was almost as strong using count and morphology, in which case adding motility did not strengthen the model. This analysis of these studies shows that while some endpoints (e.g., random-estrous-cycle-point ovary weight) correlate poorly with fertility, other necropsy endpoints (epididymal sperm count and motility, estrous cycle length, and testis and epididymal weights) can be useful (though not complete) surrogates of overall reproductive function. Indeed, over many studies, epididymal sperm count in treated animals correlates with fertility so well that even small reductions (approximately 20%) in count result in reduced fertility, suggesting that mice may be better models of human fertility than was previously believed.

Reproductive assessment by continuous breeding: evolving study design and summaries of ninety studies.

The Reproductive Assessment by Continuous Breeding (RACB) design has been used by the National Toxicology Program for approximately 15 years. This article details the evolutions in the thinking behind the design and the end points used in the identification of hazards to reproduction. Means of nominating chemicals are provided, and both early and current designs are described as well as some proposed changes for the future. This introduction is followed by a text and tabular summary of each study performed to date. We hope that this will not only be an explicit presentation of the findings of this testing program to date, but will help stimulate thinking about new ways to detect and measure reproductive toxicity in rodents, and help identify new relationships among the end points that are measured in such studies.

Racial differences in the utilization of inpatient rehabilitation services among elderly stroke patients.

BACKGROUND AND PURPOSE: We undertook this study to ascertain whether elderly black and white patients who are hospitalized for stroke utilize inpatient physical and occupational therapy (PT/OT) services differently, adjusting for characteristics associated with use of these services. METHODS: We retrospectively reviewed medical records regarding the care received by a nationally representative sample of 2497 black and white Medicare patients, aged 65 years of older, who were hospitalized at any of 297 acute-care hospitals located in 30 communities within five states. RESULTS: Compared with whites, black stroke patients were younger and more likely to have Medicaid coverage, have an ischemic stroke, and have a motor deficit noted at the time of admission. There was no difference in either sex or level of consciousness on admission. Overall, a larger proportion of black stroke patients used inpatient PT/OT at some point during the hospitalization (66.3% versus 55.8%; P < .01). However, after adjustment for characteristics associated with use of PT/OT, there was no racial difference in either the likelihood of inpatient PT/OT use (adjusted relative risk, 1.06; 95% confidence limits, 0.89 to 1.27; P = .42) or time to initial contact (median: blacks, 6.6 days; whites, 7.4 days; P = .42). Adjusted analyses also indicated a similarity between the racial groups in the number of inpatient PT/OT days overall or as a proportion of the hospital stay. CONCLUSIONS: Elderly black and white stroke patients who have Medicare coverage have similar patterns of use of inpatient PT/OT services.

PBPK modeling/Monte Carlo simulation of methylene chloride kinetic changes in mice in relation to age and acute, subchronic, and chronic inhalation exposure.

During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokinetic (PBPK) modeling coupled with Monte Carlo simulation and bootstrap resampling for data analyses, a significant induction in the mixed function oxidase (MFO) rate constant (Vmaxc) was observed at the 1-day and 1-month exposure points when compared to concurrent control mice while decreases in glutathione S-transferase (GST) rate constant (Kfc) were observed in the 1-day and 1-month exposed mice. Within exposure groups, the apparent Vmaxc maintained significant increases in the 1-month and 2-year control groups. Although the same initial increase exists in the exposed group, the 2-year Vmaxc is significantly smaller than the 1-month group (p < 0.001). Within group differences in median Kfc values show a significant decrease in both 1-month and 2-year groups among control and exposed mice (p < 0.001). Although no changes in methylene chloride solubility as a result of prior exposure were observed in blood, muscle, liver, or lung, a marginal decrease in the fat:air partition coefficient was found in the exposed mice at p = 0.053. Age related solubility differences were found in muscle:air, liver:air, lung:air, and fat:air partition coefficients at p < 0.001, while the solubility of methylene chloride in blood was not affected by age (p = 0.461). As a result of this study, we conclude that age and prior exposure to methylene chloride can produce notable changes in disposition and metabolism and may represent important factors in the interpretation for toxicologic data and its application to risk assessment.

Sonographic measurement of renal enlargement in children with acute pyelonephritis and time needed for resolution: implications for renal growth assessment.

OBJECTIVE: Failure of a kidney to grow satisfactorily in childhood is evidence of renal disease. Because kidneys may enlarge during an episode of acute pyelonephritis, concomitant renal length measurements cannot be used as baselines for growth assessment. This study was designed to determine the degree of renal enlargement in children with acute pyelonephritis and the time the enlargement takes to resolve after treatment is started to find the optimum time for obtaining baseline measurements. SUBJECTS AND METHODS: In a cohort study, 180 children younger than 5 years old with their first proven acute urinary tract infection, with or without pyelonephritis, had renal scintigraphy and sonography within 15 days of starting treatment. The presence of cortical defects on scintigrams indicated pyelonephritis. The lengths of kidneys with and without scintigraphic defects (i.e., with and without pyelonephritis) were compared, adjusting for age and sex, and the length of kidneys with defects was related to time elapsed between the start of treatment and sonography. RESULTS: Ninety-nine kidneys (28%) in 77 children (43%) had scintigraphic defects. Kidneys with defects were an average of 3.2 mm longer than kidneys without defects. Length and time interval between treatment and sonography in kidneys with defects correlated negatively, with mean length approaching that of kidneys without defects by 10-11 days. CONCLUSION: Kidneys with acute pyelonephritis initially increase in length but return to normal on average by the 11th day of treatment. If poor renal growth is used as an indication of renal disease, sonography should be delayed or repeated at least 2 weeks after the start of treatment to determine the length of the uninflamed kidney.

Hemispheric dysfunction in schizophrenia: assessment by visual perception tasks.

Before and after a double-blind trial of haloperidol vs. mesoridazine, 24 hospitalized schizophrenics performed visual perception tasks designed to assess function of the cerebral hemispheres. Tasks involved identifying as "same" or "different" two images (either letters, digits, or unfamiliar shapes) projected tachistoscopically to the right or left visual field or to both together. Multivariate analysis of variance related response latency and accuracy to task type, hemisphere stimulated, and pre- vs. posttreatment testing. Both before and after treatment, subjects responded most slowly and least accurately to letter-matching. Bilateral presentation of stimuli resulted in faster and more accurate responses, except on shape-matching. Neuroleptic treatment improved speed and accuracy overall, though not under certain task conditions. Results accorded more with an impairment in verbal processing and interhemispheric coordination than with a specific left-hemispheric deficit in schizophrenia.