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Biomedical subjects

H Witschi

Publications and source records attributed to H Witschi.

At least 37 records · Page 2Linked to original sources
PubMed1998

The effects of phenethyl isothiocyanate, N-acetylcysteine and green tea on tobacco smoke-induced lung tumors in strain A/J mice.

Male and female strain A/J mice were exposed to a mixture of cigarette sidestream and mainstream smoke at a chamber concentration of total suspended particulates of 82.5 mg/m3. Exposure time was 6 h/day, 5 days/week for 5 months. The animals were allowed to recover for another 4 months in filtered air before sacrifice and lung tumor count. Male animals were fed either 0.2% N-acetylcysteine (NAC) or 0.05% phenethyl isothiocyanate (PEITC) in diet AIN-76A with 5% corn oil added. Female animals received normal laboratory chow and were given a 1.25% extract of green tea in the drinking water. Corresponding control groups were fed diets without NAC or PEITC or given plain tap water. Exposure to tobacco smoke increased lung tumor multiplicity to 1.1-1.6 tumors/lung, significantly higher than control values (0.5-1.0 tumors/lung). None of the putative chemopreventive agents (NAC, PEITC or green tea extract) had a protective effect. In positive control experiments, PEITC significantly reduced both lung tumor multiplicity and incidence in mice treated with the tobacco smoke-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In mice treated with three different doses of urethan and fed NAC in the diet, a significant reduction in lung tumor multiplicity was found only at one dose level. Green tea extract did not reduce lung tumor multiplicity in animals treated with a single dose of NNK. It was concluded that successful chemoprevention of tobacco smoke-induced lung tumorigenesis might require administration of several chemopreventive agents rather than just a single one.

Acetylcysteine↗
PubMed1998

Overexpression of CC10 modifies neoplastic potential in lung cancer cells.

CC10 is infrequently expressed in non-small cell lung cancer cell lines, despite being abundantly produced by progenitor cells for normal and neoplastic airway epithelium. We overexpressed CC10 cDNA in the non-small cell lung cancer cell line A549 to determine its effect on the neoplastic phenotype. A549 cells transfected with CC10 demonstrated a marked reduction in invasiveness that was paralleled by diminished 92-kDa and absent 72-kDa metalloproteinase activity by zymography. Western analysis revealed the near absence of the corresponding matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in the CC10-transfected cell lines, but not in the vector-transfected cell lines. The CC10-transfected cell lines also demonstrated decreased adhesiveness to fibronectin compared with the controls. CC10 expression was associated with decreased anchorage-independent growth but not with decreased anchorage-dependent growth. These data suggest that loss of CC10 may contribute to carcinogenesis, because CC10 antagonizes the neoplastic phenotype.

Adenocarcinoma↗
PubMed1997

A recommended occupational exposure limit for formaldehyde based on irritation.

In recent years, several regulatory agencies and professional societies have recommended an occupational exposure limit (OEL) for formaldehyde. This article presents the findings of a panel of experts, the Industrial Health Foundation panel, who were charged to identify an OEL that would prevent irritation. To accomplish this task, they critiqued approximately 150 scientific articles. Unlike many other chemicals, a large amount of data is available upon which to base a concentration-response relationship for human irritation. A mathematical model developed by Kane et al. (1979) for predicting safe levels of exposure to irritants based on animal data was also evaluated. The panel concluded that for most persons, eye irritation clearly due to formaldehyde does not occur until at least 1.0 ppm. Information from controlled studies involving volunteers indicated that moderate to severe eye, nose, and throat irritation does not occur for most persons until airborne concentrations exceed 2.0-3.0 ppm. The data indicated that below 1.0 ppm, if irritation occurs in some persons, the effects rapidly subside due to "accommodation." Based on the weight of evidence from published studies, the panel found that persons exposed to 0.3 ppm for 4-6 h in chamber studies generally reported eye irritation at a rate no different than that observed when persons were exposed to clean air. It was noted that at a concentration of 0.5 ppm (8-h TWA) eye irritation was not observed in the majority of workers (about 80%). Consequently, the panel recommended an OEL of 0.3 ppm as an 8-h time-weighted average (TWA) with a ceiling value (CV) of 1.0 ppm (a concentration not to be exceeded) to avoid irritation. The panel believes that the ACGIH TLV of 0.3 ppm as a ceiling value was unnecessarily restrictive and that this value may have been based on the TLV Committee's interpretation of the significance of studies involving self-reported responses at concentrations less than 0.5 ppm. The panel concluded that any occupational or environmental guideline for formaldehyde should be based primarily on controlled studies in humans, since nearly all other studies are compromised by the presence of other contaminants. The panel also concluded that if concentrations of formaldehyde are kept below 0.1 ppm in the indoor environment (where exposures might occur 24 h/d) this should prevent irritation in virtually all persons. The panel could not identify a group of persons who were hypersensitive, nor was there evidence that anyone could be sensitized (develop an allergy) following inhalation exposure to formaldehyde. The panel concluded that there was sufficient evidence to show that persons with asthma respond no differently than healthy individuals following exposure to concentrations up to 3.0 ppm. Although cancer risk was not a topic that received exhaustive evaluation, the panel agreed with other scientific groups who have concluded that the cancer risk of formaldehyde is negligible at airborne concentrations that do not produce chronic irritation.

Animals↗
PubMed1997

The carcinogenic potential of the gas phase of environmental tobacco smoke.

Female strain A/J mice were exposed to unfiltered or HEPA-filtered environmental tobacco smoke (ETS). Total suspended particulates (TSP) in the full smoke exposure chamber was 78.5 mg/m3 and in the filtered smoke chamber 0.1 mg/m3; nicotine concentrations in the full and filtered smoke chamber were 13.4 and 3.1 mg/m3, respectively. Animals exposed to filtered ETS (6 h a day, 5 days a week) and killed after 5 months had a higher lung tumor incidence and multiplicity than controls maintained in filtered air, although the differences were not statistically significant. Animals exposed to filtered and full ETS and allowed to recover in air for 4 months had an average of 1.2 +/- 0.3 tumors per lung and 1.3 +/- 0.3 tumors per lung, respectively. Air exposed control animals had an average tumor multiplicity 0.5 +/- 0.1 tumors per lung. Increased immunostaining for CYP 1A1 was not evident in the lung of animals exposed to filtered smoke. Based on the chamber concentrations of selected nitrosamines and polycyclic aromatic hydrocarbons, the possible maximum uptakes by the mice of NNK, NNN and benzo[a]pyrene during the 5 months exposure period were three to six orders of magnitude below doses reported in the literature to produce 1 lung tumor in strain A/J mice. It was concluded that the gas phase of ETS is as carcinogenic as is full ETS. The carcinogenicity of the gas phase may be due to some as yet unidentified, yet highly potent carcinogens or by placing a substantial, possibly free radical-mediated oxidative stress on the lung.

Animals↗
PubMed1997

The carcinogenicity of environmental tobacco smoke.

Male strain A/J mice were exposed for 6 h a day, 5 days a week to environmental tobacco smoke (ETS) generated from Kentucky 1R4F reference cigarettes. Chamber concentrations were 87 mg/m3 of total suspended particulate matter (TSP), 246 p.p.m. of CO and 16 mg/m3 of nicotine. After 5 months, 33% of the ETS exposed and 11% of the control animals had one or several lung tumors; the difference was statistically not significant. A second group of animals exposed for 5 months to ETS was allowed to recover for another 4 months in filtered air. When they were killed, 85% of the ETS animals had lung tumors (average number per lung: 1.4 +/- 0.2), whereas in the control group 38% had lung tumors (average number of lung tumors in all animals 0.5 +/- 0.2). The differences in tumor incidence and multiplicity were statistically significant. More than 80% of all tumors were adenomas, the rest adenocarcinomas. When animals were pretreated with a carcinogen, lung tumor multiplicity was lower in the ETS exposed animals after 5 months compared with controls injected with a carcinogen and kept in air. However, after an additional 4 month recovery period in air, lung tumor multiplicities were the same in ETS plus carcinogen exposed mice as in carcinogen-treated air-exposed controls. Histopathologic and morphometric analysis of the lung tissue failed to reveal any differences between ETS exposed and control animals. However, immediately after ETS exposure, immunohistochemistry revealed increased staining for CYP1A1 in airway epithelia and lung parenchyma; following recovery in air, the staining disappeared again. Analysis of cell kinetics showed an initial burst of increased DNA synthesis in the epithelial cells of the airways and a smaller early positive response in the parenchyma. Feeding of butylated hydroxytoluene during ETS exposure did not modulate lung tumor development. It was concluded that ETS is a pulmonary carcinogen in strain A/J mice.

Adenocarcinoma↗
PubMed1997

The toxicology of environmental tobacco smoke.

It has by now become obvious that environmental tobacco smoke (ETS) may pose a health risk to nonsmokers. Epidemiological data suggest that exposure to ETS may increase the risk of developing lung cancer, cardiovascular disease, intrauterine growth retardation, predisposition to chronic lung disease, and sudden infant death syndrome. The human populations most at risk from ETS exposure appear to be neonates, young children, and possibly the fetus while in utero. Experimental studies with cigarette sidestream smoke (SS) have successfully duplicated several of these disease conditions in laboratory animals, particularly the effects of SS on fetal growth, lung maturation, and altered airway reactivity. The availability of animal models may open the way to fruitful experimental studies on mechanisms that help us to better understand disease.

Adult↗
PubMed1997

Pulmonary cell kinetics and morphometry after ozone exposure: day versus night and dose response in rats.

Male Sprague-Dawley rats were exposed to increasing concentrations of ozone as follows: 0.12, 0.24, 0.36, 0.6, or 0.8 ppm. Controls were kept in chambers ventilated with filtered air. One-half of the animals in ozone was exposed for 12 h a day during daytime hours, and the other one-half of the animals was exposed for 12 h during nighttime. Cumulative labeling indexes were measured after 4 and 7 days in the terminal bronchioles, large intrapulmonary airways, trachea, and nasal epithelia. The penetration of the lesions from the bronchiole-alveolar junction into the alveolar zone was measured with quantitative morphometry. After 4 days of exposure, the extent of injury was dose dependent. Labeling indexes in the terminal bronchioles were 15-20% higher in animals exposed during nighttime compared with the animals exposed during daylight hours. On the other hand, depth of penetration of ozone lesions into the centriacinar region was not significantly different in animals exposed during the night compared with animals exposed during daytime. Labeling indexes in the large airways, trachea, or nasal cavity were not influenced by time of exposure. Between days 4 and 7, the lesions in the terminal bronchioles progressed only to a minimal degree (10%). It was concluded that the pattern of centriacinar tissue remodeling 1) followed a gradient based on ozone concentration and 2) was essentially complete after only 4 days of ozone exposure. Although a difference between daytime and nighttime exposure was observed, it was not considered to be large enough to invalidate conclusions drawn from studies in which animals are exposed to ozone during daylight hours.

Animals↗
PubMed1995

Mutations of the Ki-ras protooncogene in 3-methylcholanthrene and urethan-induced and butylated hydroxytoluene-promoted lung tumors of strain A/J and SWR mice.

Mutations of the Ki-ras protooncogene in 190 lung tumors initiated in male A/J and SWR mice by 3-methylcholanthrene(MCA) or urethan and promoted by butylated hydroxytoluene (BHT), were evaluated by utilizing polymerase chain reaction (PCR) and sequencing analysis. The most common mutation pattern was a GC to CG transversion at the first base of codon 12/13. The predominant mutation pattern at codon 61 was an AT to TA transversion and the next frequent one an AT to GC transition. Mutations of Ki-ras codon 12/13 were found in 44% (A/J) and 13% (SWR) of MCA-induced and in 94% (A/J) and 43% (SWR) of MCA plus BHT-induced lung tumors. Mutations of the Ki-ras codon 61 were found in 31% (A/J) and 13% (SWR) of urethan-induced and 69% (A/J) and 44% (SWR) of urethan plus BHT-induced lung tumors. These data suggest that in strain A/J mice the 2 carcinogens produce Ki-ras mutations and that BHT promotes the activations of Ki-ras protooncogenes in lung tumors.

Animals↗
PubMed1995

Environmental tobacco smoke: experimental facts and societal issues.

Involuntary exposure to environmental tobacco smoke (ETS) in public or in working places is considered to be a serious risk to human health. This symposium addressed several issues of toxicological interest that are associated with exposure to ETS. Epidemiologic evidence obtained in human studies suggests that "passive smoking" increases the risk of developing lung cancer in nonsmokers and favors the development of respiratory tract infections in children. Comparatively few data are available from animal studies that provide experimental support of the observations. Exposure of pregnant or neonate rats to cigarette sidestream smoke (SS) affects developmental patterns of drug metabolizing enzymes that may persist up to 90 days. In young roosters, SS accelerates the development of arteriosclerotic plaques. On the other hand, exposure of adult rats for up to 90 days induces only transient signs of damage in the nasal passages, but not in the deep lung, and this only at extremely high concentrations of ETS. So far, experimental toxicology has provided comparatively few data on the correlation between exposure to ETS and adverse health effects. yet, such data are needed, particularly since many conclusions drawn from the epidemiological studies remain open to criticism and questions.

Animals↗
PubMed1995

Six-month exposure of strain A/J mice to cigarette sidestream smoke: cell kinetics and lung tumor data.

Male strain A/J mice were exposed to sidestream smoke (SS) generated from burning Kentucky 1R4F reference cigarettes. Chamber concentrations were 4 mg/m3 of total suspended respirable particulate matter (TSP). Animals were exposed 6 hr a day, 5 days a week. One-week cumulative labeling indices were significantly increased in the large intrapulmonary airways during the 1st week and in the respiratory epithelium of the nasal and maxillar turbinates during the first 3 weeks of exposure and then returned to control values. Subsequently, signs of increased cell proliferation were again found in the nasal and maxillar turbinates during the 9th and 16th exposure weeks. The experiment was terminated after 6 months. The number of animals bearing lung tumors was the same in smoke-exposed as in filtered air-exposed animals as was the average number of tumors per lung. Analysis of the DNA of individual tumors obtained from exposed and control mice for K-ras mutations suggested that exon 2 might be a specific target for SS. It was concluded that (1) duration of exposure was too short or (2) concentration of TSP was too low to reveal a possible carcinogenic potential of SS in strain A/J mice or that (3) SS is not carcinogenic in strain A mice.

Administration, Inhalation↗
PubMed1995

Cumulative labeling indices in epithelial cell populations of the respiratory tract after exposure to ozone at low concentrations.

Male Sprague-Dawley and F344 rats were exposed to concentrations of 0.12 ppm of ozone for 12 hr a night or for 24 hr a day, to 0.24 ppm for 24 hr a day, and to 0.36 ppm for 8 hr a night. Cumulative labeling indices were measured during the first and the third week of exposure in the terminal bronchioles, the large intrapulmonary airways, the trachea, and the anterior nasal passages. The most sensitive indicator for exposure to ozone after a 1-week exposure was an increased labeling index in the epithelium lining the terminal bronchioles. Sprague-Dawley and F-344 rats were equally sensitive to ozone. In the large intrapulmonary airways and in the maxillar turbinates, an increased cumulative labeling index was observed only at the highest dose (concentration x time). During the third week of exposure, no increases in labeling index were found in the large intrapulmonary airways and terminal bronchioles, whereas in the nasal passages the highest ozone concentration continued to elicit a proliferative response. Animals were also exposed for 1 week to ozone and then allowed to recover in air for another week. Renewed exposure to ozone produced a smaller, but still significant, increase in the labeling index compared to that in animals exposed to ozone for the first time. It was concluded that the determination of the cumulative labeling index in the terminal bronchioles may serve as a method to explore dose and time effects of such concentrations of ozone as may be encountered in heavily polluted urban environments.

Air Pollutants↗
PubMed1995

Correlation between cumulative labeling indices measured in the terminal bronchioles and in the centriacinar region in the lungs of rats exposed to oxidant air pollutants.

Male Sprague-Dawley rats were exposed on 7 consecutive days for 8 h a night to 0.6 ppm ozone, 10.8 ppm NO2 or a mixture of the two gases. Cumulative labeling indices were measured in the epithelium of the terminal bronchioles and the adjacent centriacinar region. An excellent correlation in labeling indices between the two sites was found. It is concluded that the labeling index in the terminal bronchioles represents a sensitive measurement for ozone-induced lung injury.

Air Pollutants↗
PubMed1995

Histochemical characterization of non-neuroendocrine tumors and neuroendocrine cell hyperplasia induced in hamster lung by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone with or without hyperoxia.

Lung tumors induced by 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) with or without hyperoxia have frequent K-ras mutations but only rare p53 mutations, suggesting that this may be a model for non-small cell lung cancers. The goals of the present study were (1) to characterize the histopathology of lung tumors induced in hamsters by NNK with or without O2 and (2) as a corollary, to quantitate the pulmonary neuroendocrine cell hyperplasia in the different treatment groups early and late in the treatment period. Lung tumors induced by NNK with or without O2 were 71% adenomas, 22% adenocarcinomas, approximately 4% bronchoalveolar carcinomas, and approximately 4% squamous/adenosquamous carcinomas. One-half of all tumors were positive for the Clara cell antigen CC10 and 21% of NNK-induced tumors were mucin positive, compared with 2% of NNK/O2-induced tumors (P = 0.003). Immunostaining for PGP9.5 was positive in 5% of tumors induced by NNK alone, but in none of NNK/O2-induced tumors (P = 0.024). Abundant proliferating cell nuclear antigen occurred in 55% of NNK-induced tumors, compared with 19% of NNK/O2-induced tumors (P = 0.009). These data indicate that NNK with or without O2 induces non-neuroendocrine lung tumors. Hyperoxia appears to inhibit cell proliferation and suppress mucinous and partial neuroendocrine differentiation in some of these tumors.

Animals↗
PubMed1994

Decreased fetal weights in rats exposed to sidestream cigarette smoke.

Pregnant Sprague-Dawley rats were exposed to sidestream cigarette smoke (SS) for 6 hr a day, at a concentration of 1 mg/m3 of respirable total suspended particulate material (TSP) on Days 3, 6-10, and 13-17 of pregnancy. Controls were kept in an identical chamber without smoke exposure. The animals were killed on Day 20 of gestation. No differences were found in maternal body weight gain or average daily food consumption between the smoke-exposed and control groups. The numbers of fetuses and of implantation sites per litter were comparable among the groups. None of the pups showed any gross malformations and no difference was found between controls and SS-exposed pups when examined for reduced skeletal ossifications. However, there was a small but significant reduction in mean pup weight. We conclude that intermittent exposure of rats to sidestream cigarette smoke at concentrations severalfold greater than those encountered in smokey public indoor environments causes intrauterine growth retardation.

Abnormalities, Drug-Induced↗
PubMed1994

Short-term effects of sidestream smoke on respiratory epithelium in mice: cell kinetics.

Male strain A/J and C57BL/6 mice were exposed on five consecutive days, for 6 hr a day, to sidestream smoke generated from Kentucky 1R4F reference cigarettes. Chamber concentrations were 1 mg/m3 of total suspended particulate matter and 528 to 549 micrograms/m3 of nicotine. Cumulative labeling indices in the airways and in the pulmonary parenchyma were measured following 1, 3, or 5 days exposure to unfiltered or filtered sidestream smoke. A significantly increased labeling index was found in A/J mice in the epithelium lining large intrapulmonary airways and terminal bronchioles after 3 and 5 days exposure to unfiltered smoke, whereas following exposure to filtered smoke labeling indices remained normal. The alveolar labeling index was not increased following smoke exposure. In C57BL/6 mice, sidestream smoke did not produce signs of increased cell proliferation in the respiratory tract. It is concluded that the response to sidestream smoke inhalation in mice may depend upon the strain of mice examined.

Animals↗
PubMed1994

Effects of exposure to nicotine and to sidestream smoke on pregnancy outcome in rats.

Nicotine-delivering transdermal patches were applied to the back of timed-pregnant Sprague-Dawley rats. Pregnancy failure was 100% in animals exposed to 3.5 mg of nicotine per day during the entire pregnancy and 50% in animals exposed to the same amount during the first trimester. Application of 1.75 mg of nicotine per day resulted in a 50% pregnancy failure when exposure occurred during the entire pregnancy. In animals exposed for the first half of pregnancy to cigarette sidestream smoke, under conditions where plasma nicotine levels reached about 25% of those observed following exposure to 1.75 mg of nicotine per day, the average litter size was reduced by about 25%. It is concluded that continuous exposure to nicotine early during pregnancy may adversely affect pregnancy outcome in rats.

Administration, Cutaneous↗