Detecting subtle human CNS dysfunction: challenge for toxicologists in 1990's.
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Biomedical subjects
Publications and source records attributed to A Lash.
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Ethylene oxide is now frequently used to chemically sterilize heat-sensitive materials in the hospital setting. Previous reports of neurotoxic effects of ethylene oxide have been described in animals and humans. Recent reports suggest that cognitive deficits may be associated with chronic low-level ethylene oxide exposure. We undertook this study of hospital workers with chronic ethylene oxide exposure and compared them with a non-exposed control group in an attempt to detect neurological and neuropsychological abnormalities. Ethylene oxide breathing zone levels of up to 250 ppm in exposed subjects were reported. All evaluations were done without examiners' knowledge of exposure status of the subjects. The exposed group was found to have a statistically significant lower P300 amplitude, bilaterally hypoactive distal deep tendon reflexes and poorer performance on neuropsychological tests involving psychomotor speed. Exposed subjects acknowledged more symptoms and higher levels of depression and anxiety. Nerve conduction velocities and EEG spectral analysis were similar in both exposed and control groups as were scores on most psychological tests. Based upon this information and prior reports, ethylene oxide should be considered in a differential diagnosis of neuropsychological, peripheral and central nervous system dysfunction in workplace settings associated with ethylene oxide exposure.
Ethylene Oxide is widely used to sterilize heat-sensitive materials. Acute and chronic neurogenic effects to the central and peripheral nervous system in man and animals have been described. To assess the chronic, subtle neuropsychologic effects of ethylene oxide, we performed a cross-sectional study of 25 hospital central supply workers exposed to low levels of ethylene oxide and 24 unexposed control workers. Subjects were tested using a neuropsychological screening battery by examiners blinded to exposure status. Testing results were reviewed independently by two neuropsychologists without knowledge of exposure. Subject status was categorized as normal, "impaired," or disagreement (between the two neuropsychologists). There were significantly more subjects concordantly judged as impaired in the exposed group versus the control group (chi 2 (2) = 6.0861, p less than 0.05). Although limited by the cross-sectional study design and the global categorization, these findings suggest that CNS dysfunction and cognitive impairment may result from chronic ethylene oxide exposure in hospital central supply units.
Although the toxic effects of lead have been known for centuries, lead intoxication is still widespread in the United States. Without baseline tests of neuropsychological, neurobehavioral and neurophysiological testing it may be difficult to detect subtle changes in neurological function after lead exposure. This may be further confounded by partial chelation treatment and exposure to neurotoxic mixtures or inability to quantitate alcohol consumption. We undertook a cross-sectional study to address these problems in 24 exposed and 29 control subjects in a plant that manufactured electrical components using fritted leaded glass to coat capacitors and transistors. Potentially exposed workers had blood lead levels ranging between 3 micrograms/dL to 135 micrograms/dL. Industrial hygiene monitoring revealed the plant's air lead levels ranged from 61 micrograms/m3 to 1,700 micrograms/m3 in excess of OSHA permissible exposure limits of 40 micrograms/m3/10 hr day. Using a specially designed battery of neurophysiological, neurobehavioral and neuropsychological screening tests, we demonstrated a significant difference from controls in measures of psychomotor speed, motor strength and verbal memory. Although limited by the cross-sectional design, these findings support the hypothesis that the battery of neurophysiological, neuropsychological and neurobehavioral tests can detect a significant inter-group differences between lead-exposed and control subjects.
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Lymphocytes displaying iC3b (Type 3) complement receptors (CR3) were quantified by flow cytometry in patients with systemic lupus erythematosus. The percentages and absolute numbers were compared to age and sex matched controls. Total CR3+ lymphocytes identified by the monoclonal antibodies OKM1 or Leu 15 were significantly decreased in patients with symptomatic arthritis, serositis or vasculitis and those with lupus nephritis, whereas values for CR3+ lymphocytes in patients with inactive disease were similar to normal donors. The phenotype of CR3+ lymphocytes was markedly different in patients with active SLE. In normals granular lymphocytes bearing Fc receptors for IgG (L cells) comprised two-thirds of CR3+ lymphocytes. However, in SLE this subset was reduced to 20% and there was a corresponding increase in CR3+ lymphocytes co-expressing the T3 marker. Percentages of CR3 T4+ but not CR3+ T8+ lymphocytes were significantly increased in SLE. Although patients with active disease were lymphopenic, absolute numbers of CR3+ lymphocytes co-expressing T cell markers were similar to normal controls. Since L cells are non-specific suppressors of Ig production, the reduction of this subset along with the increase in CR3 T4+ cells could contribute to unregulated antibody production characteristic of SLE.
By using the OKM1 monoclonal antibody and the fluorescence-activated cell sorter to identify lymphocytes bearing iC3b (type 3) complement receptors, two principal populations of OKM1+ lymphocytes have been identified in human peripheral blood. One subset exhibited azurophilic granules and Fc receptors for IgG stained by Leu-11. The other population did not display FcR, but was enriched in cells reacting with OKT3 and OKT8 (low intensity). In healthy subjects, approximately 60% of CR3+ lymphocytes were granular FcR-bearing cells and only 18% co-expressed OKT3 determinants. In patients with systemic lupus erythematosus (SLE), CR3+ lymphocytes were predominantly FcR negative cells and 71% lacked granules. Only 33% reacted with Leu-11, but 50% co-expressed OKT3, 44% reacted with OKT8+, and 15% were OKT4+. We tested the hypothesis that agranular OKT3+ Leu-11- lymphocytes, such as those found in SLE patients, contained the precursors of natural killer (NK) cells. Leu-11+ cells were removed from normal lymphocytes by complement lysis, and the remaining cells were treated with recombinant IFN-alpha, IFN-gamma, or IL 2. These procedures were ineffective in generating typical NK effector cells. Our studies do not support the hypothesis that CR3+ Leu-11- lymphocytes are the precursors of granular Leu-11+ NK cells.
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Patients with chyluria, postoperative chylothorax, or surgical thoracic duct drainage are depleted of lymphocytes, IgA, and C3 as a result of the loss of lymphatic cellular and humoral elements, but the specific defects have not been well characterized. Therefore, we investigated the immunologic status of three patients with longstanding chyluria who were lymphopenic but did not have evidence of opportunistic infections. All patients had normal levels of immunoglobulins except for a moderate decrease in the IgA fraction, a normal antibody response to viral agents, and a normal hypersensitivity response to at least one of six recall antigens. Their complement levels were essentially normal. All were leukopenic because of decreased numbers of circulating lymphocytes. Two had depressed relative and absolute numbers of OKT4 (helper/inducer) T cells and normal or increased relative numbers of OKT8 (cytotoxic/suppressor) T cells, resulting in a marked reversal of the OKT4 to OKT8 ratio. The third was severely depleted of both OKT4 and OKT8 cells. The response of their peripheral blood mononuclear cells to mitogen stimulation was reduced, but they all had normal or increased absolute and relative numbers of natural killer (NK) cells as defined by HNK-1 or OKM-1. Their NK activity was less than that of normal controls unless stimulated by interferon, suggesting that many of the NK cells were immature. Normal delayed hypersensitivity, reduced but effective mitogen stimulation, and a normal NK response after interferon may be factors that protect these patients against opportunistic infections and neoplasms.
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