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Biomedical subjects

T R Lewis

Publications and source records attributed to T R Lewis.

At least 19 recordsLinked to original sources
PubMed1989

Sister chromatid exchange in chronic ethylene oxide-exposed primates: unexpected effects of in vitro culture duration, incubation temperature, and serum supplementation.

Ethylene oxide (EtO), a potent monofunctional DNA alkylating agent, has been shown to induce sister chromatid exchanges (SCE) in the peripheral blood lymphocytes of animals and workers exposed to it in vivo. We have previously reported that elevations of SCE persist for 6 years after cessation of EtO exposure in cynomolgus monkeys chronically exposed to EtO; the elevation in mean SCE was entirely attributable to a subpopulation of high SCE frequency cells (HFCs). We now report that the detection of persistent HFCs is dependent on the conditions of cell growth, and that EtO exposure increases the replication indices of lymphocytes from the exposed animals when these cells are examined at early cytogenetic harvest times. Culture of lymphocytes in differing serum supplements, changes in cytogenetic harvest times, and alterations in in vitro incubation temperature all markedly affected mean SCE frequency by influencing the detection of HFCs. The frequency of EtO-induced HFCs was independent of 5-bromodeoxyuridine concentration, used for differential staining of sister chromatids. These observations indicate that the detection of persistent alkylation-induced chromosomal changes, observed long after cessation of in vivo chronic exposure of these animals, is highly dependent upon factors affecting cell growth.

Animals↗
PubMed1989

Establishing aerosol exposure concentrations for inhalation toxicity studies.

Criteria for the selection of aerosol concentrations to be used in inhalation studies assessing the toxicity and carcinogenicity of chemical substances were discussed by the authors in a meeting sponsored by the National Toxicology Program. Concepts in the design of aerosol inhalation studies emerged from that meeting and are being communicated through this publication. Inhalation studies assessing the toxicity and carcinogenicity of aerosols have often used maximum exposure levels on the basis of technological feasibility. Evidence has now accumulated that the amount of pulmonary burden of deposited particles impacts on particle clearance above some as yet not well-defined exposure concentration. The sequelae are such that lung clearance decreases with increased particulate burden to the point of approaching complete cessation. This paper focuses on the major determinants in establishing maximal aerosol concentrations for use in inhalation toxicity studies with special emphasis on experimental design features to assess lung retention. The subject matter of this paper is a rapidly developing area in terms of knowledge. Accordingly, the contents of this article are intended as guidelines and not as absolute rules for the conduct and interpretation of inhalation exposure studies.

Administration, Inhalation↗
PubMed1988

Persistently elevated sister chromatid exchanges in ethylene oxide-exposed primates: the role of a subpopulation of high frequency cells.

Ethylene oxide (EtO) is a potent DNA-alkylating agent which has been shown to induce sister chromatid exchanges (SCE) in the peripheral blood lymphocytes of exposed workers. To study further the persistence of EtO-induced SCE, we have examined lymphocytes from a group of cynomolgus monkeys exposed to EtO in control, 50-ppm, and 100-ppm concentrations for 7 h/day, 5 days/week over the years 1979-1981. The data collected in 1987 were compared with those generated immediately prior to the cessation of exposure in 1981. EtO-induced SCE persisted at levels significantly above those of the nonexposed controls. Comparison of the distributions of SCE between 1979 and 1987 shows that, although mean SCE decreased from 1981 to 1987, the mean SCE in the top 10% of the distribution has not diminished over time. Consequently, the increased level of SCE is entirely attributable to a subpopulation of cells with high frequencies of SCE. These findings suggest that long-lived lymphocytes may inefficiently repair EtO-induced lesions which produce SCE. The results also have important implications for the proper use of SCE analytical techniques in the epidemiological study of cytogenetic damage after chronic exposure to DNA-alkylating agents.

Animals↗
PubMed1986

Subchronic inhalation of diethylamine vapor in Fischer-344 rats: organ system toxicity.

Male and female Fischer 344 (F-344) rats were exposed at 0,25 or 250 ppm diethylamine (DEA) vapor, 6.5 hr per day, 5 days per week, for 24 weeks in order to assess cardiac and other organ system toxicity. Scheduled sacrifices were performed following 30, 60, and 120 days of exposure. During the first 2 weeks of exposure, the rats exposed at 250 ppm DEA did not gain weight. After 2 weeks, however, the rate of weight gain of these rats was greater than that of controls. Nevertheless, mean body weights for both sexes of rats exposed at 250 ppm DEA remained depressed compared to controls throughout the study. Sneezing, tearing, and reddened noses were seen in rats exposed at 250 ppm DEA. Histopathologic examinations revealed lesions of the nasal mucosa of rats exposed at 250 ppm DEA (rats exposed at 25 ppm were not evaluated). These lesions of the respiratory epithelium consisted of squamous metaplasia, suppurative rhinitis, and lymphoid hyperplasia. There were no pronounced treatment-related effects on organ weights, hematology, or clinical chemistry indices except for blood urea nitrogen which was evaluated in rats of both sexes exposed at 250 ppm DEA for 24 weeks. In contrast to the high-dose animals, no treatment-related effects were observed in rats intermittently exposed at 25 ppm DEA for up to 24 weeks. No evidence of cardiotoxicity was seen in rats exposed to either DEA concentration for up to 24 weeks.

Animals↗
PubMed1986

Ozone enhancement of platinum asthma in a primate model.

Three groups of adult male cynomolgus monkeys (Macaca fascicularis) were exposed to either 200 micrograms/m3 ammonium hexachloroplatinate [(NH4)2PtCl6], 200 micrograms (NH4)2PtCl6 concurrently with 1 ppm ozone (O3), or to 1 ppm O3 only. The animals were exposed by inhalation for 6 h per day, 5 days per week for 12 wk. The experimental design included methacholine preexposure and Na2PtCl6 bronchoprovocation challenge evaluations, Na2PtCl6 threshold skin tests, and sera for analyses of antibodies. Two weeks after the 12-wk exposures, these same indices were reevaluated. Baseline pulmonary function was not significantly affected by the exposure regimens; however, the combination of exposure to O3 and (NH4)2PtCl6 significantly reduced the concentration of platinum (Pt) salt and methacholine necessary to increase average pulmonary flow resistance (RL) 200% (EC200 RL). Ozone or Pt exposure alone had no significant effect on these parameters. Platinum and methacholine EC200 RL values were highly correlated for both Pt-exposed groups after exposure. These data indicated that combined O3 and Pt exposure significantly increased specific (Pt) and nonspecific (methacholine) bronchial hyperreactivity more often than did exposure to either O3 or the Pt salt alone. Combined O3 plus Pt exposure also significantly increases the incidence of positive Pt skin tests when compared with the other exposure groups. Similar to the human experience, radioallergosorbent testing (RAST) for Pt-specific antibodies was not as sensitive as direct skin testing in identifying allergic persons.

Animals↗
PubMed1985

Pulmonary responsiveness to methacholine and disodium hexachloroplatinate (Na2PtCl6) aerosols in cynomolgus monkeys (Macaca fascicularis).

Hyperreactivity of the airways is a common finding in human asthma, and responsiveness to inhaled methacholine aerosols is routinely used for assessing airway irritability. Workers in precious metal refineries demonstrate pulmonary signs suggestive of asthma, presumably related to exposure to soluble platinum salts. In these workers, evidence of physiologic dysfunction precedes immunologic evidence (skin test) of disease, suggesting an initial pharmacologic mechanism. With a primate animal model for the screening of occupational asthmogens, 24 Cynomolgus monkeys were evaluated for their comparative pulmonary responsiveness to inhaled aerosols of methacholine and sodium hexachloroplatinate (Na2PtCl6). Average pulmonary flow resistance (RL), dynamic compliance (CLdyn), maximum expiratory flow volume (MEFV), and respiratory frequency changes were evaluated after bronchoprovocation challenge. Both agents produced dose-dependent increases in RL, dose-dependent decreases in CLdyn and MEFV, and no effect on respiratory rates. Analyses of the correlation between concentration effects of the two agents showed no association between cholinergic airway irritability status and Na2PtCl6-induced bronchoconstriction. Na2PtCl6 bronchoprovocation produced significantly greater flow impairment at lower lung volumes when compared to methacholine concentrations with equipotent effects on RL and CLdyn. These compounds have differential effects on peripheral airway function. The lack of respiratory rate change seen on bronchoprovocation with these compounds, in comparison to the rapid shallow breathing in anesthetized monkeys following irritant or histamine challenge, indicates that neither aerosol stimulated pulmonary irritant receptors.

Airway Resistance↗
PubMed1985

Influenza virus infection in mice after exposure to coal dust and diesel engine emissions.

Influenza virus infection initiated after aerosol exposure of CD-1, white Swiss mice for durations of 1, 3, and 6 months to respirable particulates maintained at 2 mg/m3 of either coal dust (CD), diesel engine emissions (DEE), a combination of both (CD/DEE), or to filtered air (control) was studied. The course of infection in mice previously exposed for 1 month to various particulates did not differ appreciably among the four animal groups with respect to mortality, virus growth in lungs, interferon levels, or hemagglutinin antibody response. In mice exposed for 3 and 6 months to different particulates, the mortality response was similar among all animal groups. However, the percentage of animals showing lung consolidation was significantly higher in the 3-month groups exposed to DEE (96.5%) and CD/DEE (97%) than in the control (61.2%); in the 6-month groups, the percentages were twice that of the control for both DEE- and CD/DEE-exposed animals. Complementing these observations of both 3- and 6-month-exposed animals was the higher virus growth levels attained in the DEE and CD/DEE animals with concomitant depressed interferon levels which were the inverse of findings noted in the control group. Hemagglutinin-antibody levels in particulate-exposed animals, especially at the 6-month interval, were fourfold less than the control. Histopathologic examination of lungs revealed no qualitative differences in the inflammatory response at any one specified time interval of exposure to influenza virus among the control and particulate-exposed animal groups. However, there were differences in severity of reaction in relation to the particulate component of the exposures. Focal macular collections of pigment-laden macrophages were seen only in DEE and CD/DEE but not in CD animals after 3- and 6-month exposures. The findings of this study indicated that the severity of influenza virus infection is more pronounced in mice exposed to diesel engine emissions than in control animals and it is not appreciably accentuated by coal dust.

Animals↗
PubMed1985

Subchronic inhalation toxicity of isobutyl nitrite in BALB/c mice. I. Systemic toxicity.

The effects of subchronic inhalation exposure to isobutyl nitrite (IBN) on body weight, selected organ weights, hematology, and gross pathology and histopathology of BALB/c mice were evaluated. Mice of both sexes were exposed at 0, 20, 50, or 300 ppm IBN for 6.5 h/d, 5 d/wk for up to 18 wk. Most changes in measured indices occurred in mice exposed at 300 ppm IBN and included decreased thymus weight (females); decreased liver weight (males); decreased white blood cell counts (males); mild focal hyperplasia and vacuolization of the epithelium lining bronchi and bronchioles of the lungs (males and females). Organ weight and hematologic changes, however, were not accompanied by any observed histologic changes. In addition, elevated methemoglobin concentrations were detected in mice of both sexes exposed at 50 and 300 ppm IBN. Body weights were not adversely affected by exposure. These data suggest that mild tissue injury, restricted to the lung, and methemoglobinemia are the major toxic effects observed following exposures of mice to IBN at concentrations up to 300 ppm for 18 wk. No treatment-related effects were noted in mice exposed at 20 or 50 ppm IBN, except for slight elevations in methemoglobin concentrations in mice exposed at 50 ppm.

Animals↗
PubMed1985

Effects of a two-year inhalation exposure of rats to coal dust and/or diesel exhaust on tension responses of isolated airway smooth muscle.

This study was performed to determine whether chronic inhalation exposure of rats to levels of coal dust (CD) and/or diesel exhaust (DE) similar to those experienced by underground miners affects the pharmacologic characteristics of the animal's airway smooth muscle. Animals were exposed for 2 yr to CD alone (2 mg/m3 of respirable particulates), DE alone (2 mg/m3 of respirable particulates), or CD and DE (CD + DE) in combination (1 mg/m3 CD plus 1 mg/m3 DE). Concentration-response relationships for tension changes induced with acetylcholine, 5-hydroxytryptamine, potassium chloride, and isoproterenol were assessed in vitro on isolated preparations of rat airway smooth muscle (trachealis). Compared with control animals, the maximal contractile responses to acetylcholine of tissues from CD-, DE-, and CD + DE-exposed animals were significantly increased; the effects of CD and DE exposure were additive. The CD + DE exposure, but not the individual treatments, resulted in a significant increase in the maximal relaxation response elicited by isoproterenol; this interaction may have resulted from the addition of, or the synergism between, the nonsignificant effects of CD and DE alone. No treatment altered the sensitivity (EC50 values) of the muscles to the agonists used. The results indicate that chronic exposure to CD, DE, and CD + DE produces differential modifications in the behavior of rat airway smooth muscle. These findings may have some bearing on humans exposed to these substances.

Administration, Intranasal↗
PubMed1985

Pulmonary effects of acute vanadium pentoxide inhalation in monkeys.

An experimental study was conducted to investigate the hypothesis that changes in pulmonary function induced by vanadium pentoxide (V2O5) inhalation would be accompanied by evidence of pulmonary inflammation. Sixteen adult, male cynomolgus monkeys were acutely exposed by whole-body inhalation of V2O5 dust at aerosol concentrations of 0.5 mg V2O5/m3 and 5.0 mg V2O5/m3, conducted at a 1-wk interval. Comprehensive pulmonary function tests were performed 1 day after each inhalation exposure to detect functional changes in the airways and pulmonary parenchyma. Pulmonary inflammation was assessed by cytologic analysis of respiratory cells recovered from the lower respiratory tract by bronchoalveolar lavage (BAL). Postexposure values for pulmonary function and BAL were compared with the baseline values determined for each monkey prior to V2O5 exposure. Acute V2O5 dust inhalation produced significant air-flow limitation in both central and peripheral airways without producing any detectable changes in parenchymal function. These functional changes were accompanied by a significant increase in the total cell counts recovered from the lungs by BAL. The increase in total cell count occurred through a dramatic increase in absolute number and relative percentage of polymorphonuclear leukocytes (PMN). These findings suggest that pulmonary inflammatory changes involving PMN may play an important role in the occurrence of air-flow limitation after acute inhalation of V2O5 dust.

Air Pollutants, Occupational↗
PubMed1985

Fibrogenic potential of intratracheally instilled quartz, ferric oxide, fibrous glass, and hydrated alumina in hamsters.

As a first step in the development of an animal model for determining the role of pulmonary fibrosis in the etiology and pathogenesis of lung cancer, the fibrogenic potential of quartz, quartz and ferric oxide administered together, fibrous glass, and hydrated alumina were studied by multiple intratracheal instillation in groups of male Lak:LVG Syrian golden hamsters. Dose-related decreases in survival were evident for the groups instilled with the two highest doses of quartz or quartz and ferric oxide. Instillation of quartz or quartz and ferric oxide induced the greatest pulmonary fibrosis in response to the materials tested. However, the dense fibrous tissue present in the lungs in classical human silicosis and in experimental silicosis of rats was not observed in this study. The results of this study indicate that the Syrian golden hamster is not a suitable species for studying the role of quartz-induced pulmonary fibrosis in pulmonary carcinogenesis.

Aluminum↗
PubMed1984

Ethylene oxide: an overview of toxicologic and epidemiologic research.

Ethylene oxide (EtO) is a reactive epoxide and potent biocide. It is used widely in gas sterilization of hospital equipment. An estimated 75,000 health care workers in the United States have potential exposure. EtO binds covalently to deoxyribonucleic acid (DNA) and has been shown in 13 species to cause point mutations. Apparently, as a consequence of its alkylating ability, EtO exposure can result in chromosomal damage. In monkeys EtO exposure produces increased frequencies of sister chromatid exchanges (SCEs) and chromosomal aberrations. In man, five cytogenetic studies have shown dose-related increased frequencies of either SCE or chromosomal aberrations; in one study SCEs developed after regular exposures lasting less than five minutes per day. EtO is a reproductive toxin. In adult male rats, exposure produces decreased fertility, increased fetal deaths, and heritable chromosomal translocations. In pregnant female rats and rabbits, exposure causes increased fetal losses, and in one study in pregnant mice exposure was associated with increased numbers of malformed fetuses. In male monkeys EtO causes dose-related reductions in sperm count and sperm motility. In pregnant women, one study suggests that brief occupational exposure twice daily in concentrations of 20 ppm or above was associated with increased spontaneous abortions. EtO is carcinogenic to animals. In rats it causes dose-related increases in mononuclear cell leukemias, peritoneal mesotheliomas, and cerebral gliomas. In man, exposure has been associated in two epidemiologic studies with increased leukemias: 3 leukemias observed versus 0.2 expected in one study, and 2 observed versus 0.14 expected in the other; two additional small studies of limited power found no excess leukemias. Quantitative risk assessment indicates that from 634 to 1,093 excess deaths from cancer will occur per 10,000 workers exposed to EtO at 50 ppm over a working lifetime, and that 12 to 23 excess cancer deaths will occur per 10,000 workers exposed at 1 ppm. The National Institute for Occupational Safety and Health (NIOSH) recommends that EtO be regarded as a potential human carcinogen. NIOSH has recommended that eight-hour time-weighted average exposure to EtO be less than 0.1 ppm and that short-term peak exposure not exceed 5 ppm for more than ten minutes per working day.

Abnormalities, Drug-Induced↗
PubMed1984

Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats.

The chronic inhalation toxicity and carcinogenicity of ethylene oxide (EO) and propylene oxide (PO) were evaluated in a 2-year inhalation bioassay. Five groups of male weanling Fischer 344 rats, 80 per group, were exposed at 0 ppm (shared control; filtered air), 50 ppm EO, 100 ppm EO, 100 ppm PO, or 300 ppm PO (7 hr/day, 5 days/week) for 104 weeks. Body weights from rats exposed to EO and PO at all exposure concentrations were significantly reduced compared to controls. A statistically significant increase in mortality was observed in all groups of exposed rats compared to controls. Skeletal muscle atrophy in the absence of any sciatic nerve neuropathology was found in rats exposed at 100 ppm EO and 300 ppm PO. Statistically significant associations between EO exposure and an increased incidence of the following rat neoplasms were observed: mononuclear cell leukemia, peritoneal mesothelioma, and mixed cell brain glioma. Among rats exposed to PO there was a dose-dependent increase in the incidence of complex epithelial hyperplasia in the nasal passages, and two adenomas were detected in the nasal passages of rats exposed at 300 ppm PO. The incidence of adrenal pheochromocytomas was elevated in both PO exposure groups, but not in a dose-related manner. All rat groups were affected by an outbreak of Mycoplasma pulmonis infection which occurred about 16 months into the study. This infection alone and in combination with the epoxide exposures affected the survival of rats in this study, and influenced the development of the proliferative lesions in the nasal mucosa of the PO-exposed rats. No treatment-related changes in any clinical chemistry or urinalysis indices were detected. PO exposure did not increase the incidence of the three neoplasms associated with EO exposure; however, adrenal pheochromocytomas and proliferative lesions of the nasal cavity were increased in rats exposed to PO.

Animals↗
PubMed1984

Sister-chromatid exchanges and chromosome aberrations in lymphocytes from monkeys exposed to ethylene oxide and propylene oxide by inhalation.

The ability of long-term exposures to inhaled ethylene oxide (EO) and propylene oxide (PO) to induce sister-chromatid exchanges (SCEs) and chromosome aberrations in peripheral lymphocytes of monkeys was investigated. Five groups of adult male cynomolgus monkeys were exposed at 0 (shared control), 50, or 100 ppm EO, and at 100 or 300 ppm PO (7 hr/day, 5 days/week) for 2 years. EO exposures at 50 and 100 ppm resulted in statistically significant increases in sister-chromatid exchange rates and in the incidence of chromosome aberrations in monkey lymphocytes. Both EO-exposed groups had increased numbers of SCEs/metaphase compared to controls, with the SCEs/metaphase of the EO 100 ppm group also significantly elevated versus the EO 50 ppm group. Variability of SCEs/metaphase within each monkey increased even more than the increase in total SCEs/metaphase group with increasing EO exposure. Chromatid-type aberrations were also significantly increased for both EO 50 and EO 100 ppm groups compared to controls. Statistically significant increases in the number of chromosome-type aberrations (excluding gaps) were found only in the EO 100 ppm group. Combined chromatid- and chromosome-type aberrations were increased in both EO 50 and EO 100 ppm groups. No group differences in the number of gaps were found. In lymphocytes from monkeys exposed at 100 and 300 ppm PO, there were no group differences compared to controls for any variable-chromatid or chromosome-type aberrations, gaps, or SCEs/metaphase. These results indicate that EO is a more potent clastogen than PO and demonstrate, for the first time, statistically significant effects of EO on both SCEs and chromosome aberrations in lymphocytes of nonhuman primates.

Animals↗
PubMed1984

Effects of coal dust and diesel exhaust on immune competence in rats.

The effects on the immune system of rats that had been exposed to a 2-mg/m3 dose of either respirable coal dust, diesel exhaust fumes and particulates, or the combination of these were studied. Animals that were housed similarly but exposed only to filtered air served as controls. After 12 and 24 mo of exposure, the rats were tested for immunocompetency by enumerating antibody-producing cells in the spleen 4 d after immunization with sheep erythrocytes and by monitoring the proliferative response of splenic T-lymphocytes to the mitogens concanavalin A and phytohemagglutinin. The results of this study indicate that no major alterations occurred in the immunologic functions measured as a result of exposure to either coal dust, diesel exhaust fumes and particulates, or their combination.

Animals↗
PubMed1984

Chronic inhalation of diesel exhaust and coal dust: effect of age and exposure on selected enzyme activities associated with microsomal cytochrome P-450 in rat lung and liver.

Male Fisher-344 rats were exposed by inhalation to low levels of diesel exhaust and coal dust, alone or in combination, or to filtered air, 7 h/d, 5 d/wk for 24 mo. Cytochrome P-450-associated benzo[a]pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were assayed in lung and liver microsomes after 3, 6, and 24 mo. Age-related changes in enzyme activities were observed, but they were not altered by the exposures. When the data were adjusted for age, only one difference was observed. Lung benzo[a]pyrene hydroxylase activity in rats exposed to diesel exhaust and coal dust in combination was lower than that in animals exposed to coal dust alone (2.8 versus 4.4 pmol/min X mg protein). Neither value, however, differed significantly from the filtered-air controls, and no differences were observed in the other lung and liver activities. The data suggest exposure of the rats to diesel exhaust and/or coal dust had little or no effect on the selected lung and liver cytochrome P-450 activities under the conditions of the experiment.

Age Factors↗
PubMed1984

Low-dose chronic inhalation of diesel exhaust and/or coal dust by rats: effect of age and exposure on lung and liver cytochrome P-450.

Rats were exposed by inhalation to low levels of diesel exhaust and/or coal dust, seven hours/day, five days/week for 24 months. Cytochrome P-450-associated benzo[a]pyrene hydroxylase and 7-ethoxycoumarin deethylase activities were assayed in lung and liver microsomes after 3, 6, and 24 months. When data were analysed across all time intervals and adjusted for age, lower benzo[a]pyrene hydroxylase activity was observed in lung microsomes from rats exposed to diesel exhaust plus coal dust than in those exposed to coal dust alone. Data are discussed in terms of interaction between diesel exhaust and coal dust and effect of infectious agents.

7-Alkoxycoumarin O-Dealkylase↗