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PubMed1988

Lung injury in guinea pigs caused by multiple exposures to ultrafine zinc oxide: changes in pulmonary lavage fluid.

Metal oxide particles with diameters of less than 0.1 micron (ultrafine particles) are important products of fossil fuel combustion. Pulmonary lavage fluid was obtained from guinea pigs given 1, 2, or 3 consecutive, daily, 3-h, nose-only exposures to 0, 2.3, 5.9, or 12.1 mg/m3 of freshly generated zinc oxide (ZnO) particles with a projected area diameter of 0.05 micron. Exposure to ZnO at 5.9 or 12.1 mg/m3 was associated with increased protein, neutrophils, and activities of angiotensin-converting enzyme, alkaline phosphatase, acid phosphatase and lactate dehydrogenase in lavage fluid, and with histologic evidence of pulmonary damage characterized by centriacinar inflammation. The severity of inflammation, graded by the number of inflammatory foci per square centimeter of lung, correlated with the amount of protein and the activity of angiotensin-converting enzyme and other enzymes in lavage fluid. These results indicate that analysis of pulmonary lavage fluid is a useful and sensitive method for quantitative evaluation of pulmonary damage caused by inhalation of low levels of ultrafine ZnO.

Animals↗
PubMed1989

Formation of DNA and hemoglobin adducts of fluoranthene after single and multiple exposures.

The dose-dependence of hemoglobin binding as well as distribution of fluoranthene and fluoranthene-DNA adducts in various tissues was characterized in male rats 24 h after a single i.p. injection of [3H]fluoranthene. Formation and distribution of DNA adducts after chronic administration of fluoranthene in the diet was also studied. Fluoranthene-derived radioactivity was widely distributed throughout the animal after a single dose, and excreta contained the greatest amounts of radioactivity at all dose levels. Fluoranthene binding to globin was proportional to dose over the range of 2 nmol/kg to 177 mumol/kg, and the adducted protein was cleared at the same rate as unmodified hemoglobin, indicating that the adducts are stable in vivo. In contrast, fluoranthene-DNA adducts were not present at detectable levels in liver or kidney 24 h after one dose; low levels of adducts were found only in the lung at the highest dose level. Chronic administration of fluoranthene in the diet, however, resulted in DNA adduct formation in most tissues examined, including liver, kidney, lung, small intestine, heart, spleen and lymphocytes; adducts were not detectable in testes DNA. The major fluoranthene-DNA adduct found in rat tissues was identified by its chromatographic similarity to the major fluoranthene adduct formed in vitro using microsomally-activated fluoranthene and calf thymus DNA, previously identified as a reaction product of anti-2,3-dihydroxy-1,10b-epoxy-1,2,3-trihydro-fluoranthene with N2-deoxyguanosine. The unusual stability of this diol epoxide at physiological pH may allow transport of this ultimate DNA-binding metabolite to virtually all tissues. These results demonstrate the applicability of the HPLC-32P-postlabelling procedure to detect and quantify fluoranthene-DNA adducts formed in vivo, and suggest that analysis of these adducts in accessible tissues such as lymphocytes may be a means of assessing chronic, high level exposure to fluoranthene. Our results also indicate that hemoglobin adducts of fluoranthene could be useful dosimeters for detecting short-term or chronic exposure to this compound if a suitable method for their detection were developed.

Administration, Oral↗
PubMed1997

Provocative appeals in anti-smoking mass media campaigns targeting adolescents--the accumulated effect of multiple exposures.

This paper reports findings from a longitudinal study that evaluated the accumulated effect of three consecutive mass media campaigns using provocative and dissonance arousing appeals to prevent cigarette smoking by adolescents. In the spring of 1992, all eligible adolescents aged 14 and 15 in one intervention county (N = 4898) and one control county (N = 5439) in Norway were included in the study, and were followed until they were 17 and 18 years of age in 1995. Only students who completed questionnaires both in 1992 and 1995 were included in the analyses. Among the non-smokers at baseline, a significantly lower proportion of adolescents of both genders had started to smoke in the intervention county compared to the proportion in the control county. Among those who were smokers at baseline, significantly more girls in the intervention county had stopped smoking than in the control county, while no significant difference between the counties was detected among boys. Our findings suggest that provocative and dissonance arousing appeals that create affective reactions and lead to interpersonal communication should be given more attention in campaigns designed to influence adolescent smoking. However, such appeals may easily produce negative reactions and the normative context should be thoroughly considered when using such appeals in future interventions.

Adolescent↗
PubMed2001

Elimination of cocaine by pregnant sheep following single or multiple exposures.

To test the hypothesis that chronic exposure to cocaine would alter drug elimination in pregnant and fetal sheep compared to a single exposure, we administered intravenous cocaine HCl to 8 pregnant sheep daily as a bolus, followed by a 2-h infusion beginning at gestational age 75 days. Eight additional animals received an equivalent volume of saline. Three days after maternal and fetal catheter placement on day 125, ewes in both groups received cocaine HCl, 2 mg/kg, as a bolus. Maternal and fetal plasma samples were serially obtained and analyzed for cocaine and benzoylecognine. Cocaine half-life in the ewes and fetuses exposed to cocaine was no different from that in animals exposed to saline. We conclude that cocaine is rapidly metabolized in pregnant sheep and that chronic administration does not alter drug clearance.

Animals↗
PubMed2002

Pulmonary and systemic effects of zinc-containing emission particles in three rat strains: multiple exposure scenarios.

As a common component of ambient particulate matter (PM), zinc has been proposed to play a role in PM-induced adverse health effects. Although occupational exposures to high levels of zinc-fume have been associated with metal-fume fever accompanied by pulmonary inflammation and injury, the effects of PM-associated zinc are unclear. We hypothesized that an oil combustion emission PM (EPM) containing bioavailable zinc would induce pulmonary injury and systemic hematological changes attributable to the leachable zinc following acute as well as longer-term exposures in a rat strain-specific manner. In order to initially characterize the pulmonary response to EPM, male Sprague-Dawley (SD) rats were intratracheally (IT) instilled with 0.0, 0.8, 3.3, or 8.3 mg/kg EPM in saline. To further determine if the pulmonary injury was associated with the EPM leachable zinc, subsequent studies included IT instillation of SD rats with either saline, whole EPM suspension, the saline leachable fraction of EPM, the particulate fraction of EPM (all at 8.3 mg/kg, soluble Zn = 14.5 microg/mg EPM), or ZnSO(4) (0.0, 33.0, or 66.0 microg/kg Zn). Finally, to ascertain the cumulative impact of inhaled EPM in the causation of acute pulmonary and systemic effects as well as long-term fibrotic responses, we exposed three rat strains of differential susceptibility to PM. Male SD, normotensive Wistar-Kyoto (WKY), and spontaneously hypertensive (SH) rats (90 days old) were exposed nose-only to either filtered air or EPM: 2, 5, or 10 mg/m(3) (6 h/day x 4 days/week x 1 week); or 10 mg/m(3) (6 h/day x 1 day/week for 1, 4, or 16 weeks) and assessed at 2 days postexposure. IT exposures to whole EPM suspensions were associated with a dose-dependent increase in protein/albumin permeability and neutrophilic inflammation. Pulmonary protein/albumin leakage and neutrophilic inflammation caused by the leachable fraction of EPM and ZnSO(4) were comparable to the effect of whole suspension. However, protein/albumin leakage was not associated with the particulate fraction, although significant neutrophilic inflammation did occur following instillation. With EPM nose-only inhalation, acute exposures (10 mg/m(3) only) for 4 days resulted in small increases in bronchoalveolar lavage fluid (BALF) protein and n-acetyl glucosaminidase activities (approximately 50% above control). Surprisingly, unlike IT exposures, no neutrophilic influx was detectable in BALF from any of the inhalation groups. The only major effect of acute and long-term EPM inhalation was a dose- and time-dependent increase in alveolar macrophages (AM) regardless of the rat strain. Histological evidence also showed dose- and time-dependent accumulations of particle-loaded AM. Particles were also evident in interstitial spaces, and in the lung-associated lymph nodes following the inhalation exposures (SH > WKY = SD). There were strain-related differences in peripheral white blood cell counts and plasma fibrinogen with no major EPM inhalation effect. The present study demonstrated the critical differences in pulmonary responsiveness to EPM between IT and inhalation exposures, probably attributable to the dose of bioavailable zinc. EPM IT exposures, but not acute and long-term inhalation of up to 10 mg/m(3), caused neutrophilic inflammation. Inhalation exposures may result in particle accumulation and macrophage recruitment with potential strain differences in EPM clearance.

Administration, Inhalation↗
PubMed1999

Semiparametric methods for multiple exposure mismeasurement and a bivariate outcome in HIV vaccine trials.

Exposure to infection information is important for estimating vaccine efficacy, but it is difficult to collect and prone to missingness and mismeasurement. We discuss study designs that collect detailed exposure information from only a small subset of participants while collecting crude exposure information from all participants and treat estimation of vaccine efficacy in the missing data/measurement error framework. We extend the discordant partner design for HIV vaccine trials of Golm, Halloran, and Longini (1998, Statistics in Medicine, 17, 2335-2352.) to the more complex augmented trial design of Longini, Datta, and Halloran (1996, Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 13, 440-447) and Datta, Halloran, and Longini (1998, Statistics in Medicine 17, 185-200). The model for this design includes three exposure covariates and both univariate and bivariate outcomes. We adapt recently developed semiparametric missing data methods of Reilly and Pepe (1995, Biometrika 82, 299 314), Carroll and Wand (1991, Journal of the Royal Statistical Society, Series B 53, 573-585), and Pepe and Fleming (1991, Journal of the American Statistical Association 86, 108-113) to the augmented vaccine trial design. We demonstrate with simulated HIV vaccine trial data the improvements in bias and efficiency when combining the different levels of exposure information to estimate vaccine efficacy for reducing both susceptibility and infectiousness. We show that the semiparametric methods estimate both efficacy parameters without bias when the good exposure information is either missing completely at random or missing at random. The pseudolikelihood method of Carroll and Wand (1991) and Pepe and Fleming (1991) was the more efficient of the two semiparametric methods.

AIDS Vaccines↗
PubMed1981

Cancer induction following single and multiple exposures to a constant amount of vinyl chloride monomer.

Vinyl chloride monomer (VCM), already identified as a human animal carcinogen, was selected as a model agent to explore an area of concern for single and intermittent low level exposure. In traditional cancer bioassay, animals are repeatedly exposed over their lifespan to a dose of suspected chemical. In the current studies rats and mice were exposed in an inhalation chamber to single one-hour doses of VCM ranging from 50 to 50,000 ppm. A second group was given 10 one-hour exposures to 500 ppm or 100 one-hour exposures to 50 ppm of the same chemical. All animals were then observed for the remainder of their lives, generally 18-24 months. Moribund animals were euthanized, and survivors were sacrificed on schedule and their tissues examined for pathological changes. Specifically, the oncogenic study demonstrated dose related effects for single one-hour exposure of VCM at high levels, i.e., 5,000 and 50,000 ppm. These concentrations increased the incidence of pulmonary adenomas and carcinomas in mice. Repeated exposure of A/J mice to the same chemical at 500 ppm X 10 one-hour exposures also increased the incidence of pulmonary adenomas and carcinomas which are considered highly one-hour exposure, no significant increase in tumors was observed. Rats exposed to identical concentrations of VCM failed to elicit a tumorigenic response.

Adenoma↗
PubMed1979

[Accumulation kinetics of trichloroethylene and its metabolites during multiple exposures. A theoretical study (author's transl)].

In attempting to establish an excretory TLV for trichloroethylene, the rates at which trichloroethylene and its metabolites accumulate in the body with increasing number of exposures and their plateau values attained after repetition of an infinite number of exposures were estimated theoretically with a mathematical model. After a single inhalation exposure to trichloroethylene is over, its concentration in the blood, x, and the amount of its urinary metabolites, [D]to, as a function of time t are expressed as a sum of three exponentials: (formula: see text). where A1-A3 and D1-D3 are constants depending on the inhaled air concentration of trichloroethylene, and alpha 1-alpha 2 and kA-K3 rate constants. When the same degree of exposure is repeated for n consecutive days, the blood concentration, t hours after the nth day's exposure, becomes (formula: see text). From the experimental results of a single human exposure reported previously, the concentration of trichloroethylene in the blood was predicted to change only to a negligible degree after repetition of an infinitive number of exposures, whereas the amount of total urinary metabolites was predicted to increase by twice as much as that excreted after the single exposure.

Environmental Exposure↗
PubMed1981

Adenosine and guanosine 3',5' cyclic monophosphate phosphodiesterase activities in rat small and large bowel following single and multiple exposure to 1,2-dimethylhydrazine.

The hydrolytic activities of adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterases (PDE) in rat large and small bowel tissue were determined after exposure to the colon carcinogen 1,2-dimethylhydrazine (DMH). Immediate increases in the cAMP-PDE activities were found in the tissues after a single exposure to the chemical which returned towards normal while chronic exposure resulted in no visible changes. The increased cAMP-PDE activities may be the factor responsible for the diminished intracellular cAMP concentrations found after exposure to the carcinogen. In contrast, the cGMP-PDE activities changed little in the colon and increased in the small bowel, suggesting that the determinant for the increases in the concentration cGMP was the activation of guanylate cyclase enzymes following exposure to DMH. Ratios of cAMP to cGMP and cAMP-PDE to cGMP-PDE in the colon showed major changes after carcinogenic insult by the DMH, suggesting that such measurements might serve as useful markers for exposure to environmental toxicants.

1,2-Dimethylhydrazine↗