Children's exposure to environmental pollutants and biomarkers of genetic damage. II. Results of a comprehensive literature search and meta-analysis

The present review is based on findings from 178 publications retrieved through an extensive search of the MedLine/PubMed database for a 25 years time period (1980-2004) and 10 manually identified papers. Among the cytogenetic biomarkers that are frequently used in field studies, chromosome aberrations (CA) and micronuclei (MN) but not sister chromatid exchanges (SCE) were found consistently increased in children exposed to environmental pollutants. Meta-analysis of the studies reporting SCE in cord blood showed similar levels of SCE in exposed and in non-exposed newborns. Exposure to airborne pollutants, soil and drinking water contaminants, mostly increased CA and, to a lesser extent, MN levels in children. The effect of exposure to airborne urban pollutants was consistently reported by field studies measuring DNA, albumin and hemoglobin adducts. Prenatal (in utero) and postnatal exposure (environmental tobacco smoke, ETS) to tobacco smoke compounds were associated with increased frequencies of DNA and hemoglobin adducts and CA. The limited number of field studies measuring DNA fragmentation (Comet assay), hypoxanthine-guanine phosphoribosyltransferase (HPRT) and the glycophorinA (GPA) mutation frequency in environmentally exposed children precluded a meaningful evaluation of the usefulness of these assays. Meta-analyses performed in children exposed to ETS and in newborns exposed in utero to their mothers' smoke showed 1.3 and 7 times higher levels of hemoglobin adducts compared to referent subjects, respectively. These increases are consistent with the epidemiological evidence of higher lung cancer risks reported in adults who had never smoked and were exposed to ETS during childhood and with 7-15 times higher lung cancer risks reported in smokers than in non-smokers. Higher levels of PAH-DNA adducts were found in fetal than in maternal tissue, suggesting a specific susceptibility of the fetus to this class of ubiquitous environmental pollutants. According to these findings, future research and biomonitoring programs on children would greatly benefit from the inclusion of selected biomarkers that could provide biologically based evidence for the identification of intervention priorities in environmental health.     

Enhancement of pre-existing DNA adducts in rodents exposed to cigarette smoke

Exposure to tobacco smoke has been implicated in the increased incidence of cancer and cardiovascular diseases. This report describes various experimental studies in animals that were carried out to determine the ability of cigarette smoke to form DNA adducts and to define chromatographic nature of the major adducts. Tissues from rodents exposed to mainstream or sidestream cigarette smoke in nose-only and whole-body exposure systems, respectively, for different durations were analyzed for DNA adducts by 32P-postlabeling assay. The results showed essentially similar qualitative patterns in various respiratory (lung, trachea, larynx) and non-respiratory (heart, bladder) tissues of smoke-exposed rats. However, adduct pattern in the nasal mucosa was different. The mean total DNA adducts in various tissues expressed as per 1010 nucleotides exhibited the following order: heart (700)>lung (420)>trachea (170)>larynx (150)>bladder (50). Some qualitatively identical adducts were routinely detected in tissues from sham-treated rats but at greatly reduced levels (5- to 25-fold). The levels of lung DNA adducts increased with the duration of exposure up to 23 weeks and returned to control levels 19 weeks after the cessation of exposure. Species-related differences in adduct magnitude and patterns were observed among rats, mice and guinea pigs; mouse being the most sensitive to DNA damage and guinea pig the least sensitive. Whole-body exposure of rats to sidestream cigarette smoke also enhanced the pre-existing DNA adducts by several fold in different tissues. Selective chromatography, and extractability in butanol suggested lipophilic nature of smoke-associated DNA adducts, which were, however, recovered significantly better in nuclease P1 than butanol enrichment procedure. The major smoke-associated adducts were chromatographically different from any of the reference adducts of polycyclic aromatic hydrocarbons (PAHs) co-chromatographed with the smoke DNA samples. Because PAH-DNA adducts are recovered with equal efficiency by the two enrichment procedures, the above observations suggested that smoke-associated adducts are not related to typical PAHs, like benzo[a]pyrene. It is concluded that cigarette smoke increased the levels of pre-existing endogenous DNA adducts (the so-called I-compounds) in animal models and that these adducts are unrelated to those formed by typical PAHs.     

Enhanced lung C-fiber responsiveness in sensitized adult guinea pigs exposed to chronic tobacco smoke.

Tobacco smoke (TS) exposure induces bronchoconstriction and increases airway secretions and plasma extravasation in certain sensitive individuals, particularly those with asthma. C-fiber activation also induces these effects. Although the mechanism by which chronic TS exposure induces airway dysfunction is not well understood, TS exposure may enhance C-fiber responsiveness. To investigate the effect of chronic TS exposure on C-fiber responsiveness to capsaicin and bradykinin, especially in atopic individuals, we exposed ovalbumin (OA)-sensitized guinea pigs to TS (5 mg/l air, 30 min/day for 7 days/wk) or to compressed air. Nonsensitized guinea pigs were also exposed to either compressed air or TS. Beginning after 120 days of exposure, C fibers and rapidly adapting receptors (RARs) were challenged with capsaicin and bradykinin. TS exposure enhanced sensory receptor and airway responsiveness to both intravenous capsaicin and bradykinin challenge. C-fiber, RAR, and airway responsiveness to capsaicin challenge was greatest in OA-sensitized guinea pigs exposed to TS. OA alone induced capsaicin hyperresponsiveness at 5 microg. Airway responsiveness to bradykinin was also greatest in OA-sensitized guinea pigs exposed to TS. OA alone enhanced C-fiber responsiveness to bradykinin at 5 and 10 microg. C-fiber activation by either agonist appeared direct, whereas RAR activation appeared indirect. Therefore, a mechanism of airway hyperirritability induced by the combination of OA sensitization and chronic TS exposure may include hyperirritability of lung C fibers.     

Dose-Response Model for Lassa Virus

This article develops dose-response models for Lassa fever virus using data sets found in the open literature. Dose-response data were drawn from two studies in which guinea pigs were given subcutaneous and aerosol exposure to Lassa virus. In one study, six groups of inbred guinea pigs were inoculated subcutaneously with doses of Lassa virus and five groups of out-bred guinea pigs were similarly treated. We found that the out-bred subcutaneously exposed guinea pig did not exhibit a dose-dependent trend in response. The inbred guinea pigs data were best fit by an exponential dose-response model. In a second study, four groups of out-bred guinea pigs were exposed to doses of Lassa virus via the aerosol route. In that study, aerosol diameter was less than 4.5 μ m and both mortality and morbidity were used as endpoints. The log-probit dose-response model provided a somewhat better fit than the Beta-Poisson model for data with mortality as the endpoint, but the Beta-Poisson is considered the best fit model because it can be derived using biological considerations. Morbidity data were best fit with an exponential dose-response model.     

Development of a new in vitro system for continuous in vitro exposure of lung tissue to complex atmospheres: Application to diesel exhaust toxicology

The purpose of this study was the development of a new incubation system that can allow continuous exposure of lung tissue to complex atmospheres as a tool for the assessment of aerial environmental lung toxicology. To assess the pertinence of this new exposure system, we studied the impact of diesel engine exhausts as a complex atmosphere containing both gaseous and particulate fractions and have been able to discriminate between the toxicological impacts of the gaseous phase and particulate matter from diesel exhausts. Continuous flow-through rotating chambers with controlled pO₂, pCO₂, and hygrometry have been designed in which lung slices are positioned in rolling inserts that allow free access of atmosphere to the exposed lung tissue. Under control conditions, cell viability was preserved for at least 48 h as assessed by intracellular ATP, GSH, and K⁺ levels and slice O₂ consumption levels. Short-term exposure (1 h) to diesel whole exhausts did not affect intracellular potassium or slice O₂ consumption, while intracellular ATP and GSH levels were markedly decreased. Exposure to filtered exhausts showed less marked effects on both ATP and GSH levels. Superoxide dismutase activity was decreased in a similar way by both total and filtered exhausts while Se⁺-dependent glutathione peroxidase activity was induced by filtered exhausts to a larger extent than after total exhaust exposure, showing different response patterns of lung tissue after exposure to whole or filtered exhausts. In conclusion, this newly designed model opens a promising area in in vitro environmental lung toxicology testing.     

Vitamin C prevents hyperbaric oxygen-induced growth retardation and lipid peroxidation and attenuates the oxidation-induced up-regulation of glutathione in guinea pigs

Hyperbaric oxygen therapy is used to treat various clinical conditions, but it also causes oxidative damage. The objectives of this study are to determine if increased vitamin C intake can prevent hyperbaric oxygen-induced damage and to determine interactions among vitamin C, glutathione and vitamin E in response to oxidative stress. The growth rates of unexposed guinea pigs fed 1.25 mg vitamin C/day were indistinguishable from that of guinea pigs fed 50 mg vitamin C/day. In contrast, hyperbaric oxygen exposure resulted in growth retardation in guinea pigs fed 1.25 mg vitamin C/day, but it had little effect on the growth rates of guinea pigs fed 50 mg vitamin C/day. Increased vitamin C intake also prevented hyperbaric oxygen-induced lipid peroxidation in the liver. In guinea pigs not exposed to hyperbaric oxygen, levels of vitamin C in tissues were closely related to vitamin C intake, but tissue levels of glutathione and vitamin E were not related to vitamin C intake. However, interactions between vitamin C and glutathione were observed upon chronic hyperbaric oxygen exposure. Chronic hyperbaric oxygen exposure resulted in >2-fold increases in the levels of glutathione in liver and lung of guinea pigs fed 1.25 mg vitamin C/day. In comparison, the oxidation-induced increases in glutathione were significantly attenuated in guinea pigs fed 50 mg vitamin C/day. These data show that increased intake of vitamin C can prevent or alleviate the hyperbaric oxygen-induced damage. The interactions between vitamin C and glutathione upon hyperbaric oxygen exposure indicate that there is a homeostatic regulation of antioxidant capacity in guinea pig tissues.     

Transmission of rat and guineapig Haemophilus spp. to mice and rats

Mice and rats, free from Pasteurellaceae, were exposed to Haemophilus spp. (V-factor dependent Pasteurellaceae) by housing in proximity to infected rats or guinea pigs, and monitored by culture and enzyme-linked immunosorbent assay (ELISA) for cross infection. A minority of mice became infected when exposed to Haemophilus-infected rats but none when exposed to guinea pigs. Rats were readily infected when exposed to Haemophilus-infected guinea pigs or rats. Although Pasteurellaceae infections are commonly considered as host specific, our data show that Haemophilus spp. can cross the species barrier from rats to mice and from guinea pigs to rats.     

The conditioning effect of large doses of ascorbic acid in guinea pigs

The influence of prolonged exposure of guinea pigs to excessive ascorbic acid (AA) on the outcome of pregnancy, as well as the adaptive effect of the vitamin either during preweanling life or following weaning, were examined. Continuous exposure to AA (1 mg/mL drinking water) from the time they were first mated up to the time of second pregnancy, had no significant effect on the number of offspring and on their weights at birth, when compared with that of the animals receiving 0.1 mg AA/mL drinking water. However, change in AA intake from 1 to 0.1 mg/mL drinking water, at the age of 21 days, resulted in a significant loss in body weight and reductions in the plasma, leukocyte, and adrenal concentrations of AA, as compared with those of the pair-fed animals receiving 0.1 mg/mL drinking water throughout. The present study also indicated that the conditioning effect is less pronounced in guinea pigs when exposed to the high AA following weanling age than in utero.     

Dose-response model for Burkholderia pseudomallei (melioidosis)

Aims: The objective of this study was development of a dose–response model for exposure to Burkholderia pseudomallei in different animal hosts and analysis of the results. The data sets with which the model was developed were taken from the open literature. Methods and Results: All data sets were initially tested for a trend between dose and outcome using the Cochran–Armitage test. Only data showing a statistically significant trend were subjected to further analysis (fitting with parametric dose–response relationships). Dose–response relationships (exponential, beta-Poisson and log-probit) were fit to data using the method of maximum likelihood estimation. Conclusions: Dose–response analysis of BALB/c mice, C57BL/6 mice, guinea pigs and diabetic rats showed that BALB/c mice exposed intranasally (i.n.) and guinea pigs exposed intraperitoneally (i.p.) are significantly more sensitive to B. pseudomallei than C57BL/6 mice exposed i.n. and diabetic rats exposed i.p. Significance and Impact of the Study: The results confirmed the findings of a study of outbreak data that the diabetic population is more susceptible to infection with B. pseudomallei than the general population. The low dose prediction from best fit dose–response models can be used to draw guidelines for public health decision making processes, including consideration of sensitive subpopulations.     

Chronic tobacco smoke exposure increases airway sensitivity to capsaicin in awake guinea pigs.

Tobacco smoke (TS) exposure induces airway hyperreactivity, particularly in sensitive individuals with asthma. However, the mechanism of this airway hyperreactivity is not well understood. To investigate the relative susceptibility of atopic and nonatopic individuals to TS-induced airway hyperreactivity, we exposed ovalbumin (OA)-sensitized and nonsensitized guinea pigs to TS exposure (5 mg/l air, 30-min exposure, 7 days/wk for 120-156 days). Two similar groups exposed to compressed air served as controls. Airway reactivity was assessed as an increase in enhanced pause (Penh) units using a plethysmograph that allowed free movement of the animals. After 90 days of exposure, airway reactivity increased in OA-TS guinea pigs challenged with capsaicin, bradykinin, and neurokinin A fragment 4--10 aerosols. In addition, substance P content increased in lung perfusate of OA-TS guinea pigs in response to acute TS challenge compared with that of the other groups. Airway hyperirritability was not enhanced by phosphoramidon but was attenuated by a cocktail of neurokinin antagonists, nor was airway hyperreactivity observed after either methacholine or histamine challenge in OA-TS guinea pigs. Chronic TS exposure enhanced neither airway reactivity to histamine or methacholine nor contractility of isolated tracheal rings. In conclusion, chronic TS exposure increased airway reactivity to capsaicin and bradykinin aerosol challenge, and OA-TS guinea pigs were most susceptible to airway dysfunction as the result of exposure to TS compared with the other groups. Increased airway reactivity to capsaicin suggests a mechanism involving neurogenic inflammation, such as increased activation of lung C fibers.     

Exposure-dependent accumulation of N-(2-hydroxypropyl)valine in hemoglobin of F344 rats exposed to propylene oxide by the inhalation route

The detection of hemoglobin adducts by mass spectrometry is a very sensitive and specific measurement of the extent of covalent binding of electrophilic chemicals. The exposure-dependent accumulation of N-(2-hydroxypropyl)valine (N-HPVal) in globin of rats exposed to propylene oxide (PO) (0, 5, 25, 50, 300 or 500 ppm) by the inhalation route was measured to assess the utility of Hb adducts as biomarkers of exposure. Analysis of N-HPVal by gas-chromatography tandem mass spectrometry showed a linear exposure-dependent response for adduct accumulation in globin of rats exposed to PO for 3 days (6 h/day). After 20 days of exposure (6 h/day; 5 days/week), the exposure-response curve was slightly sub-linear. DNA adducts had been measured in several organs of the same animals in a companion study. The dose-response for accumulation of DNA adducts was similar to that obtained for Hb adducts. However, the number of DNA adducts varied by 17-fold between different tissues. The highest number of DNA adducts was found in respiratory nasal tissue, followed by lung and then liver. These data demonstrate that hemoglobin adducts provide a sensitive dosimeter for systemic exposure, but cannot be used to predict the extent of DNA binding in individual tissues. Furthermore, the exposure-response curve for both hemoglobin and DNA adduct accumulation does not reflect the tumor incidence curve for PO, providing evidence that the assessment of risk to cancer is more complex than simple biomarker measurements. When the present rat data were compared with recent N-HPVal measurements in humans, similar binding was found.     

The red blood cells in growing guinea pigs. (Cavia cobaya). II. Communication: erythropoiesis and red blood cells in the postnatal development period

Bone-marrow smears of 175 guinea pigs aged 1-27 days and venous blood samples of 351 animals aged 1-25 days were prepared for cell counting. A significant increase of erythroblasts were found between life day 1 and 2; normoblasts increased in number synchronously with a decrease of erythroblasts after the 5th day. The percentage of the erythroid bone marrow increased from 10 to 14 during the developmental period. Beyond the perinatal period the red blood picture is characterized by the following changes: a decrease of erythrocyte count, hematocrit, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin; a constant mean corpuscular hemoglobin concentration; an increase of the reticulocyte count. The decrease of the red cell count is compensated by a decreasing oxygen affinity attained by an important increase of 2,3-DPG. Nevertheless, the stimulus for a raising erythropoiesis remains constant which can be shown by the growing percentage of erythroid cells and reticulocytes. The difference between the human postnatal development and that of the guinea pig becomes obvious. Cell counts in dependence of body masses in postnatally growing guinea pigs, veil the perinatal finding of the increase in erythrocytes up to the 5th day and the decrease of the mean corpuscular volume after the 3rd day.     

Specific antibodies to hemoglobin A1 (anti-Glu) and hemoglobin S (anti-Val) in the guinea pig: immunologic and structural correlations.

Like goats and sheep, guinea pigs can produce, in response to human sickle cell hemoglobin (beta6 Glu leads to Val), an antibody population (anti-Val) that will bind sickle cell hemoglobin but not normal hemoglobin HbA. Unlike goats and sheep, guinea pigs can produce in response to human hemoglobin A1 an antibody fraction, anti-Glu, that will not react with human sickle cell hemoglobin. These anti-Glu antibodies have been isolated by affinity chromatography and their specificity confirmed by fluorescence-quenching titrations. The sequence of the first 10 amino acids of the beta-chain of guinea pig hemoglobin has been determined. This sequence differs from those of both hemoglobin HbA and sickle cell hemoglobin by two residues, those at positions 5 and 6. This explains the similarity of the immunogenicity of this site on the two human hemoglobins when administered to guinea pigs. Both goats and sheep are identical to hemoglobin A1 at the beta-6 position.     

Subacute inhalation of cigarette smoke by pregnant and lactating rodents: AHH changes in perinatal tissues

To study the transplacental acquisition of tobacco smoke products and the effects on fetal tissue enzymes, pregnant rats, guinea pigs, and hamsters were exposed to freshly generated cigarette smoke via a nose-only inhalation system on a daily basis through the latter one-third (guinea pigs) or latter half (rats, hamsters) of the gestational period. Following euthanasia on the day of parturition, microsomal aryl hydrocarbon hydroxylase (AHH) activities were determined in the lungs, livers, and kidneys of both dams and fetuses. The possible acquisition of tobacco smoke products via the milk was studied by exposing lactating dams to cigarette smoke daily for either 4 or 14 days (rats), 4 or 7 days (guinea pigs), or 10 days (hamsters), with analysis of tissues from the euthanized pups for AHH. Pups were also exposed directly (nose only) to cigarette smoke. In the treated pregnant and lactating rat, maternal pulmonary, hepatic, and renal AHH was significantly increased but only fetal lung and the liver of 14-day-old pups showed a marked induction of AHH activity. In the pregnant and lactating guinea pig, only the pulmonary and renal AHH activities were increased following exposure, whereas in the fetuses and nursing pups, none of the tissue AHH activities was significantly altered by exposure. In the pregnant and lactating hamster, only the pulmonary AHH was increased following exposure to cigarette smoke, whereas the activity in fetal and pup tissues remained unchanged from the levels observed in control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tobacco smoke exposure and bombesin-like peptides in guinea pigs

Bombesin-like peptides (BLPs) are associated with tobacco smoke (TS)-induced diseases. We sought to determine if acute TS exposure releases BLPs into the pulmonary circulation. Sensitized and non-sensitized guinea pigs were chronically exposed to TS or compressed air. Thereafter, the lungs were acutely challenged with TS while perfused. Perfusates were analyzed for BLPs. TS increased BLPs in non-sensitized guinea pigs. A separate study determined daily bombesin exposure increased lung cell counts but not airway hyperresponsivensess. TS exposure releases BLPs into the pulmonary circulation but can be modified by host factors and bombesin itself does not induce airway hyperresponsiveness.     

Hydroxyl radical formation by UV-irradiated epidermal cells.

To elucidate the mechanism of sunlight-induced skin damage, guinea pigs were exposed to UV light (280-320 nm, UV B, 4 J/cm2) and a homogenate of the epidermis was examined by means of the thiobarbituric acid (TBA) test. Three hours after the exposure, TBA-malondialdehyde adducts had increased while glutathione reductase activity had decreased, indicating lipid peroxidation. To detect the initial species, spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was applied to a suspension of illuminated epidermal cells (0.5 J/cm2). An ESR signal obtained only with irradiation comprised a 1:2:2:1 quartet [a(N)= a(beta H) = 1.49 mT] attributable to a spin adduct of hydroxyl radicals. These results suggest that sunlight exposure of skin may lead to hydroxyl radical generation and simultaneous lipid peroxidation.     

Chronic exposure to sidestream tobacco smoke augments lung C-fiber responsiveness in young guinea pigs.

Children chronically exposed to environmental tobacco smoke (ETS) have more coughs, wheezes, and airway obstruction, which may result in part from stimulation of lung C fibers. We examined the effect of chronic exposure to sidestream tobacco smoke (SS, a surrogate for ETS) on lung C-fiber responsiveness in guinea pigs, in which dynamic compliance (Cdyn), lung resistance, tracheal pressure, arterial blood pressure, and heart rate were also monitored. Guinea pigs were exposed to SS (1 mg/mm(3) total suspended particulates) or filtered air 5 days/wk from 1 to 6 wk of age. They were then anesthetized, and lung C fibers (n = 55), identified by a conduction velocity of <2.0 m/s, were tested for responsiveness to chemical and mechanical stimuli. SS exposure doubled C-fiber responsiveness to left atrial capsaicin (P = 0.02) and lung hyperinflation (P = 0.03) but had no effect on responsiveness to inhaled capsaicin or bradykinin or on baseline activity. The data indicate that chronically exposing young guinea pigs to SS enhances C-fiber sensitivity to certain stimuli and may help explain respiratory symptoms in children exposed to ETS.     

Toluene diisocyanate-induced airway hyperreactivity in guinea pigs depleted of granulocytes

The influence of cyclophosphamide-induced granulocyte depletion on toluene diisocyanate (TDI)-related changes in airway reactivity and pathology was assessed in guinea pigs. Twelve cyclophosphamide-treated and 12 control animals comprising each group were studied physiologically before and 2 h after a single 10-min exposure to 3 ppm of TDI. Reactivity was determined in intact unanesthetized animals by measuring specific airway conductance before and during intravenous acetylcholine infusion. After testing, tracheal tissue for light microscopic examination was obtained from three hyperreactive guinea pigs in each exposed group and compared with tissue from treated and control animals (n = 3 each) that had not been TDI exposed. Cyclophosphamide treatment caused substantial decreases in both circulating and airway granulocyte counts. However, the incidence and degree of bronchial hyperreactivity that occurred 2 h post-TDI was similar in the untreated and treated groups. Our results indicate that TDI-induced bronchial hyperreactivity 1) occurs shortly after a brief high concentration exposure and 2) appears independent of circulating or airway granulocyte counts.     

Occupational exposure and respiratory health of workers at small scale industries

Certain occupations like welding, painting, and vehicle repairing are associated with regular exposure to dust, exhausts, fuels, fumes, PM, and vapors of welding, solvents, and paint. Many studies have proved a reduction in lung functions due to exposure to these agents. The present study aims to assess and compare respiratory symptoms and pulmonary functions among exposed and non-exposed persons as well as suggests controls respectively. A cross-sectional case study was carried out among small scale industry workers having matched demographic and anthropometric parameters. Medical Research Council (MRC) questionnaire and Micro Direct computerized automated spirometer were used for recording respiratory ailments and pulmonary function tests (PFT) respectively. The percentages of mechanics, welders and painters were 40.9, 31.8, and 27.3 respectively. The highest reported respiratory symptom was chest tightness and whistling among exposed (22.7%) and unexposed (10%). Among study exposed cases, the occupational exposure was found as often (22.7%), sometimes (68.2%) and never (9.1%) while the reported use of airway protection (masks) was very low. Overall respiratory health of the exposed versus controls was reported as excellent (54.5% vs 73.4%), good (27.3% vs 23.3%) and average (18.2% vs 3.3%) respectively. The exposed group on contrary to control one has decreased mean values for FEV1 (3.12 vs 3.50), FVC (4.12 vs 4.43), FEV1/ FVC % (79.60 vs 80.79) and PEF (414.77 vs 523.16). The present study reveals that exposed workers are at increased risk of developing respiratory symptoms and decreased pulmonary functions as compared to unexposed. Such exposure research studies are instrumental in health status evaluation of workers. However, this area has been neglected by the researchers in Saudi Arabia. It is, thus, strongly recommended to carry out prospective studies to substantiate the study results including large sample size, background pollutants concentrations and biological monitoring. Control strategies should be adopted to reduce the vapor concentration in the ambient air, protect and promote respiratory health of workers.     

Arachidonic acid metabolites do not mediate toluene diisocyanate-induced airway hyperresponsiveness in guinea pigs

Arachidonic acid metabolites have previously been demonstrated to mediate the airway hyperresponsiveness observed in guinea pigs and dogs after exposure to ozone. Guinea pigs were treated with indomethacin (a cyclooxygenase inhibitor), U-60,257 (piriprost, a 5-lipoxygenase inhibitor), or BW775c (a lipoxygenase and cyclooxygenase inhibitor) and exposed to air or 3 ppm TDI. Airway responsiveness to acetylcholine aerosol was examined 2 h after exposure. In control animals, the provocative concentration of acetylcholine which caused a 200% increase in pulmonary resistance over baseline (PC200) was significantly less (p less than 0.05) after exposure to TDI (8.6 +/- 2.0 mg/ml, geometric mean + geometric SE, n = 10) than after exposure to air (23.9 + 2.5 mg/ml, n = 14). The airway responsiveness to acetylcholine in animals treated with indomethacin or piriprost and exposed to TDI was not different from that of control animals exposed to TDI. Treatment with BW755c enhanced the airway hyperresponsiveness observed in animals exposed to TDI without altering the PC200 of animals exposed to air. The PC200 of animals treated with BW755c and exposed to TDI (2.3 + 0.8 mg/ml, n = 8) was significantly lower than the PC200 of control animals exposed to TDI (p less than 0.025). These results suggest that products of arachidonic acid metabolism are not responsible for TDI-induced airway hyperresponsiveness in guinea pigs. BW755c, however, appears to potentiate the TDI-induced airway hyperresponsiveness to acetylcholine by an as yet unidentified mechanism.