Carbon monoxide and the nervous system.

Carbon monoxide (CO) is a colorless, tasteless, odorless, and non-irritating gas formed when carbon in fuel is not burned completely. It enters the bloodstream through the lungs and attaches to hemoglobin (Hb), the body's oxygen carrier, forming carboxyhemoglobin (COHb) and thereby reducing oxygen (O(2)) delivery to the body's organs and tissues. High COHb concentrations are poisonous. Central nervous system (CNS) effects in individuals suffering acute CO poisoning cover a wide range, depending on severity of exposure: headache, dizziness, weakness, nausea, vomiting, disorientation, confusion, collapse, and coma. At lower concentrations, CNS effects include reduction in visual perception, manual dexterity, learning, driving performance, and attention level. Earlier work is frequently cited to justify the statement that CO exposure sufficient to produce COHb levels of ca. 5% would be sufficient to produce visual sensitivity reduction and various neurobehavioral performance deficits. In a recent literature re-evaluation, however, the best estimate was that [COHb] would have to rise to 15-20% before a 10% reduction in any behavioral or visual measurement could be observed. This conclusion was based on (1) critical review of the literature on behavioral and sensory effects, (2) review and interpretation of the physiological effects of COHb on the CNS, (3) extrapolation from the effects of hypoxic hypoxia to the effects of CO hypoxia, and (4) extrapolation from rat behavioral effects of CO to humans. Also covered in this review article are effects of chronic CO exposure, the discovery of neuroglobin, a summary of the relatively new role for endogenous CO in neurotransmission and vascular homeostasis, groups which might be especially sensitive to CO, and recommendations on further research. The interested reader is directed to other published reviews of the literature on CO and historically seminal references that form our understanding of this ubiquitous gas.

Can animal pulmonary function testing provide data for regulatory decision making?

The process of setting health standards requires rigorous, scientifically sound data that relate to man's interaction with his environment. Tests of pulmonary function are especially useful, since they may permit some direct comparisons between animals and man. The development of tests to measure pulmonary function in small animals has been important, and research into the health effects of air pollution may be greatly strengthened with the use of data from such measurements.

Pulmonary function testing in small laboratory mammals.

The lung is the primary organ likely to be exposed by inhalation studies and, therefore, measurement of changes in lung function are of particular interest to the pulmonary physiologist and toxicologist. Tests of pulmonary function have been developed which can be used with small animals to measure spirometry (lung volumes), mechanics, distribution of ventilation, gas exchange or control of ventilation. These tests were designed on the basis of similar tests which are used in humans to diagnose and manage patients with lung disease. A major difference is that many of the measurements are performed in anesthetized animals, while human pulmonary function is usually measured in awake cooperating individuals. In addition, the measurement of respiratory events in small animals requires sensitive and rapidly responding equipment, because signals may be small and events can occur quickly. In general, the measurements described provide information on the change in normal lung function which results primarily from structural changes. These tests of pulmonary function can be repetitively and routinely accomplished and the results appear to be highly reproducible. Although some are quite sophisticated, many can be undertaken with relatively inexpensive equipment and provide useful information for toxicological testing.

Carbon monoxide poisoning--a public health perspective.

Carbon monoxide (CO) may be the cause of more than one-half of the fatal poisonings reported in many countries; fatal cases also are grossly under-reported or misdiagnosed by medical professionals. Therefore, the precise number of individuals who have suffered from CO intoxication is not known. The health effects associated with exposure to CO range from the more subtle cardiovascular and neurobehavioral effects at low concentrations to unconsciousness and death after acute or chronic exposure to higher concentrations of CO. The morbidity and mortality resulting from the latter exposures are described briefly to complete the picture of CO exposure in present-day society. The symptoms, signs, and prognosis of acute CO poisoning correlate poorly with the level of carboxyhemoglobin (COHb) measured at the time of hospital admission; however, because CO poisoning is a diagnosis frequently overlooked, the importance of measuring COHb in suspicious settings cannot be overstated. The early symptoms (headache, dizziness, weakness, nausea, confusion, disorientation, and visual disturbances) also have to be emphasized, especially if they recur with a regular periodicity or in the same environment. Complications occur frequently in CO poisoning. Immediate death is most likely cardiac in origin because myocardial tissues are most sensitive to the hypoxic effects of CO. Severe poisoning results in marked hypotension, lethal arrhythmias, and electrocardiographic changes. Pulmonary edema may occur. Neurological manifestation of acute CO poisoning includes disorientation, confusion, and coma. Perhaps the most insidious effect of CO poisoning is the development of delayed neuropsychiatric impairment within 2-28 days after poisoning and the slow resolution of neurobehavioral consequences. Carbon monoxide poisoning during pregnancy results in high risk for the mother by increasing the short-term complication rate and for the fetus by causing fetal death, developmental disorders, and chronic cerebral lesions. In conclusion, CO poisoning occurs frequently; has severe consequences, including immediate death; involves complications and late sequelae; and often is overlooked. Efforts in prevention and in public and medical education should be encouraged.

Functional and biochemical indicators of pneumoconiosis in mice: comparison with rats.

Mice were injected intratracheally with silica or Mt. St. Helens volcanic ash (0.2 mg/g body weight) and examined 6 mo later for changes in pulmonary function, histology, and hydroxyproline content. Results were compared with a similar study using rats. Mice injected with volcanic ash showed significant changes only in wet lung weights. Those injected with silica showed an approximate doubling of lung wet weight and dry weight and hydroxyproline content. Larger increases in lung weight were seen if lymph nodes were left attached. Lung compliance, total lung capacity, and the shape of the pressure-volume curve of the lung were changed as much as 22% in the silica-treated mice. A mild degree of fibrosis with no dense lung consolidation was noted microscopically in silica-treated mice. In contrast, silica-treated rats showed dense lung consolidation, threefold to fivefold increases in both wet and dry lung weights and hydroxyproline content, and up to 40% reductions in pulmonary function measurements. It is concluded that Swiss albino mice develop a milder degree of fibrosis than similarly treated Sprague-Dawley rats and that both biochemical and functional indicators are effective in detecting pneumoconiosis in these species.

Effects of prenatal nitrofen exposure on postnatal lung function in the rat.

The herbicide Nitrofen was administered by gavage to pregnant F-344 rats during Days 10 through 13 of gestation. Postnatal lung function was measured in male progeny at 3 and 6 weeks of age. There were no differences in body weight or wet and dry lung weights between control and Nitrofen-exposed rats in either age group. Nitrofen produced no observable effects on lung function at 3 weeks of age. However, by 6 weeks of age the Nitrofen-exposed animals had significant decreases in tidal volume (p less than 0.01), vital capacity (p less than 0.01), total lung capacity (p less than 0.05), and quasi-static lung compliance (p less than 0.01). There was also a mild ventilation inhomogeneity, as indicated by significant increases in the nitrogen washout slope (p less than 0.01) and the moment ratio (p less than 0.05). Histopathology of lung, liver, kidney, and testes was not significantly altered by Nitrofen exposure. These data suggest that prenatal Nitrofen exposure may have an effect on postnatal lung maturation in the rat and could potentially be useful as a model of pulmonary hypoplasia.

Inhalation studies of Mt. St. Helens volcanic ash in animals. II. Lung function, biochemistry, and histology.

Rats were exposed by inhalation to 9.4 mg/m3 size-fractionated volcanic ash for 5 days (2 hr/day) and examined for changes in pulmonary function and histology for periods of up to 1 year. Fine-mode volcanic ash, SO2, and a combination of ash and SO2 produced no observable effects in normal rats and rats with elastase-induced emphysema. However, there was a mild irritant response to SO2 which was not influenced by the volcanic ash. Rats injected intratracheally with fine-mode volcanic ash or saline showed no evidence of pulmonary alterations after 6 months. Those injected with coarse-mode volcanic ash showed minor pulmonary functional changes, histologically detectable alveolitis, and small increases in lung weight. In contrast, quartz-injected rats showed large alterations in pulmonary function, lung weight, hydroxyproline levels, and large areas of lung consolidation and fibrosis.

Pulmonary function in normal and elastase-treated hamsters exposed to a complex mixture of olefin-ozone-sulfur dioxide reaction products.

An elastase-induced emphysema model was utilized to determine if hamsters with preexisting lung disease were more susceptible to lung damage from air pollutant exposure. Male golden hamsters, divided into two treatment groups, were given a single intratracheal injection of either 6 units of porcine pancreatic elastase (EMP) or buffer (CNT). After a 4-week recovery period, equal numbers of each group were exposed 23 hr/day X 28 day to filtered air (AIR) or to the complex by-products from a dark phase reaction mixture of trans-2-butene, ozone, and sulfur dioxide (MIX). Lung function measurements on the elastase-treated groups showed changes consistent with mild emphysema. There were no significant differences in lung volumes or lung compliance between the AIR- and MIX-exposed animals. However, the nitrogen washout slope decreased (P less than 0.05), and the diffusing capacity for carbon monoxide increased (P less than 0.05) in both the CNT and EMP hamsters exposed to the MIX. The change in diffusing capacity was greater (P less than 0.05) in normal hamsters than in hamsters with emphysema, and it is hypothesized that animals with impaired lung function had a decreased ability to respond to a pulmonary insult from the mix.

Dose response of elastase-induced emphysema in hamsters.

Elastase-induced emphysema in hamsters was studied using pulmonary function tests in an effort to develop techniques for determining the effects of air pollutants on the progression of this disease. Single intratracheal injections of 6, 12, or 24 units of porcine pancreatic elastase produced dose-related changes in pulmonary function after 4 wk when compared with sham-injected control animals. Boyle's law end-expiratory volume and residual volume, measured by gas dilution, increased (p less than 0.05) at 12 and 24 units, respectively, whereas vital capacity, determined plethysmographically, and total lung capacity wee increased (p less than 0.05) at all 3 elastase doses. Respiratory system compliance, calculated by a nonlinear least squares regression fit of the deflation pressure-volume curve, increased (p less than 0.05) at 24 units only. The multiple-breath nitrogen washout slope (N2 slope) and the single-breath diffusing capacity for carbon monoxide (DLCO) decreased (p less than 0.05) at all 3 doses of elastase. Both histologic and physiologic evaluation showed dose-related pulmonary impairment. It appears, therefore, that as little as 6 units of elastase produces mild emphysema in hamsters, which is detectable by pulmonary function testing. Of these tests, the DLCO and N2 slope were the most effective in detecting the degree of impairment.

Evaluating the toxicity of urban patterns of oxidant gases. II. Effects in mice from chronic exposure to nitrogen dioxide.

The study reported herein evaluates the influence of a chronic exposure to an urban pattern of NO2 (continuous baseline exposure of 0.2 ppm, on which were superimposed two 1-h spikes of 0.8 ppm NO2, 5 d/wk) as compared to the baseline exposure to determine the contribution of the spikes to toxicity. Mice were exposed for up to 52 wk with interim examinations. Multivariate analysis of variance revealed a statistically significant treatment effect on infectivity (p = 0.05) and pulmonary function (p = 0.03) parameters. Infectivity mortality of mice in the spiked exposure regimen was significantly greater than that in either the NO2-background-exposed mice or in control mice. Four of the pulmonary function variables exhibited the greatest differences among the treatment groups: end expiratory volume, vital capacity, respiratory-system compliance, and multiple-breath nitrogen washout. Results from the pulmonary-function analyses indicate that the spiked exposures to 0.8 ppm NO2 may have induced a subtle lesion. The chronic study results indicate that the presence of spikes of NO2 is contributing significantly to effects on antibacterial lung defenses and pulmonary function of mice.

Morphologic changes in the lung during the lifespan of Fischer 344 rats.

Pulmonary structure and function were quantitatively investigated over the lifespan of the Fischer 344 rat by morphometric and physiologic techniques. Male animals 1 week, 6 weeks, 5 months, 14 months, and 26 months of age and female animals 5 months, 14 months, and 26 months of age were studied. All alveolar tissue compartments demonstrated significant increases in volume, surface area, and cell number during the first 5 months of life. From 5 to 26 months of age, remodelling in the epithelial and interstitial compartments continued to take place while the endothelial compartment remained relatively unchanged. In the epithelial compartment the ratio of type II cells to type I cells lining the alveolar surface decreased as age increased. In the interstitial compartment the volume of the noncellular components of the interstitium increased by 39% in males and by 89% in females from 5 to 26 months of age. Physiologic measurements of lung volumes in males at 6 weeks, 14 months, and 26 months demonstrated progressive increases in vital capacity (VC) and total lung capacity (TLC). Morphometric pulmonary-diffusion capacity (DLO2) increased in males from 1 week to 5 months of age and remained relatively unchanged from 5 to 26 months of age in both sexes.