Biomedical subjects

R W Setzer

Publications and source records attributed to R W Setzer.

32 records · Page 2Linked to original sources

PubMed1995

Ozone exposure has both a priming effect on allergen-induced responses and an intrinsic inflammatory action in the nasal airways of perennially allergic asthmatics.

Ozone may play a significant role in the exacerbation of airway disease in asthmatics, either by priming the airway mucosa such that cellular responses to allergen are enhanced or by exerting an intrinsic effect on airway inflammation. Previous investigations of nonasthmatic subjects revealed that ozone induces both nasal and bronchial inflammation, suggesting that nasal responses to ozone may be used as a surrogate marker for the effect of this pollutant on bronchial mucosal inflammation. In this study, the effect of exposure to 0.4 ppm ozone on nasal inflammation in 11 allergic asthmatics sensitive to Dermatophygoides farinae was examined. This study was designed such that the effect of ozone exposure on the late-phase reaction to allergen was emphasized, using eosinophil influx and changes in eosinophil cationic protein as principal endpoints. By employing a "split-nose" design, in which allergen was applied to only one side of the nose while saline was applied to the contralateral side, both the effect of ozone on nasal inflammation due to allergen challenge as well as its direct action on non-allergen-challenged nasal tissues was examined. The results reported herein indicate that ozone exposure has both a priming effect on allergen-induced responses as well as an intrinsic inflammatory action in the nasal airways of perennially allergic asthmatics.

Adolescent↗

PubMed1994

Biologically based dose-response modeling in developmental toxicology: biochemical and cellular sequelae of 5-fluorouracil exposure in the developing rat.

Mechanistically based dose-response models for developmental toxicity require elucidation of critical biological events that intervene between maternal exposure and adverse developmental outcome. We have examined some of the major events in the rat embryo/fetus following a subcutaneous injection of 5-fluorouracil (5-FU; 0-40 mg/kg) to the dam on Day 14 of gestation. This treatment resulted in reduced fetal weight that was significant at doses of 20 mg/kg and higher, generalized reduced ossification at doses above 25 mg/kg, and wavy ribs at doses of 30 mg/kg and higher. Numerous malformations including cleft palate and hindlimb defects were substantially increased at doses of 35 and 40 mg/kg. 5-FU inhibits thymidylate synthetase (TS), resulting in inhibited growth of rapidly proliferating tissues. To identify early events in the pathogenesis of hindlimb defects, we examined the effects of 5-FU on TS activity, cell cycle, growth, and morphology in the developing hindlimb as a function of dose and time. The rate of decline of TS activity following 5-FU exposure was dose related, although maximal inhibition and recovery were similar at doses within (20 and 40 mg/kg) and below (10 mg/kg) the range of detectable developmental toxicity. Flow cytometric analysis of nuclei from embryonic hindlimbs revealed a transient increase in the percentage of cells in S phase and decrease in G0/G1 phase 8 hr after maternal injection of 20-40 mg 5-FU/kg, but not at lower doses. Reduction in growth and morphometric changes of hindlimbs were observed only after maternal exposure to 40 mg/kg. The tissue specificity of these effects was examined by comparing the hindlimb with other embryonic tissues. There was also a dose-related decline of TS activity in the embryonic liver. However, the pattern of recovery of TS activity and cell cycle alterations were different in the liver than in the hindlimb, probably reflecting the higher cell proliferative rate in the liver at this stage. We have derived a quantitative, empirical model for induction of hindlimb defects based on TS inhibition and subsequent cellular events following 5-FU exposure. The model predicted a dose response similar to that of the observed data although the predicted curve was shifted toward lower doses. These results suggest that while this model may not capture all of the critical events involved in the induction of hindlimb defects following maternal exposure to 5-FU, it does reflect a central mechanism of its developmental toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Exposure to ionizing radiation and risk of cutaneous malignant melanoma. Search for error and bias.

In a 1984 case-control study of cutaneous malignant melanoma (CMM) among workers at the Lawrence Livermore National Laboratory, Austin and Reynolds found an association between reported employment in proximity to ionizing radiation and CMM (odds ratio (OR) = 5.4; 95% confidence interval (CI): 1.4, 20.7). But in a preliminary study in 1981, they found no association between individual radiation dosimetry readings and CMM. We reanalyzed the 1984 Austin-Reynolds case-control data to determine whether error or bias explain the inconsistency between reported employment in proximity to radiation and individual radiation dosimetry readings. Using individual radiation dosimetry readings, we developed an index of occupation-specific radiation. This index was associated with case status (OR = 10.8; 95% CI: 1.4, 85.1). No definitive evidence for influential matched sets, confounding, recall bias, or any other sources of bias was identified. These results suggest that the odds ratio for reported employment in proximity to radiation may be valid.

Bias↗

PubMed1994

Limitations of relative sensitivity in detecting differential misclassification in case-control studies.

Apparent relative sensitivity, based on an investigator's external standard, is the ratio of observed case to control exposure sensitivity. An apparent relative sensitivity different from 1.0 is usually interpreted as evidence for differential misclassification of exposure status. We undertook this investigation to determine the conditions under which an apparent relative sensitivity exceeding 1.0 is actually due to differential misclassification. We also consider whether apparent relative sensitivity correctly quantifies the degree of differential misclassification. To achieve these goals, we derived an algebraic relation involving apparent relative sensitivity, true sensitivities and specificities, true odds ratio, an index of how well the external standard classifies true exposure, and the incidence of the disease among the nonexposed. We found that an apparent relative sensitivity greater than 1.0 correctly indicates differential misclassification when either (1) the investigator's external standard classifies true exposure perfectly, or (2) the investigator's external standard is imperfect, but the true odds ratio equals 1.0, true relative sensitivity is greater than 1.0, and true relative specificity is less than 1.0. We also found that apparent relative sensitivity greater than 1.0 falsely suggests differential misclassification when true relative sensitivity equals 1.0, the investigator's external standard is imperfect, and the true odds ratio is greater than 1.0. Furthermore, even when apparent relative sensitivity correctly detects the presence of differential misclassification, it may misrepresent the degree.

Bias↗

PubMed1994

Dose-response relationship in multistage carcinogenesis: promoters.

Published dose-response curves of promoters of multistage carcinogenesis were selected that met the combined criteria of long study times, multiple doses, and low doses. In rat liver, 12 dose-response studies of 7 different promoters (phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], clophen A-50 (a polychlorinated biphenyl), alpha-, beta-, and gamma-hexachlorocyclohexane [HCH], and chloroform) were selected. These promoters were studied for 7-86 weeks and either altered hepatic foci or hepatic cancer were determined. The doses ranged from 1 ng (TCDD) to 400 mg (chloroform). In mouse skin, 10 dose-response studies of 4 promoters (12-O-tetradecanoylphorbol-13-acetate [TPA], anthralin, chrysarobin, and 2,6-di-tert-butyl-4-hydroperoxyl-2,5-cyclohexadienone [BHTOOH]) were selected. In these mouse skin studies the doses ranged from 0.425 nmole (TPA) to 20,000 nmole (BHTOOH) per mouse. The length of time promoters were applied to the skin varied between 15 and 60 weeks. Either skin papillomas or carcinomas were determined. The dose-response relationships are presented on the basis of moles of promoter, percentage of the fully effective promoting dose, or percentage of the acute oral rat LD50. The degree of concavity of the dose-response curves was determined. The available dose-response data are critiqued and discussed on the basis of future research needs for biologically based cancer risk assessment models.

Animals↗

PubMed1992

Analysis of X-ray-induced HPRT mutations in CHO cells: insertion and deletions.

Molecular alterations were examined in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene of 41 independent X-ray-induced thioguanine-resistant (TGR) Chinese hamster ovary (CHO) cell clones. Rapid screening of the clones by multiplex polymerase chain reaction (PCR) for the presence or absence of exons revealed that the causes of the mutant phenotype were total gene deletion (26/41), partial gene deletion (4/41), and an insertion (1/41). No alterations of exon number or sizes were apparent in 10 of the mutants. Southern blot analysis confirmed the deletion data and revealed an additional class of mutants that had a gene disruption but retained all hprt exons (2/41). Therefore, at least 80% of the ionizing radiation-induced mutations were due to mechanisms involving DNA breakage and rejoining. The distribution of deletion sizes suggests that the two DNA breaks required for a deletion are not independent events. A possible mechanism is presented. In addition, the DNA sequence of the insertion mutation was determined. The insertion (229 bp) is coupled with a deletion (31 bp). An imperfect inverted repeat with flanking hprt DNA was identified and may be involved in the insertion event.

Animals↗

PubMed1991

Assessing developmental hazard: the reliability of the A/D ratio.

The quantitative relationship between developmentally toxic exposure levels and adult toxic exposure levels has been used as an index of developmental hazard and has figured prominently in discussions of legal regulation of developmentally toxic agents. Perhaps the most frequently cited index of developmental hazard is the A/D ratio. This index, a ratio of marginally toxic adult and developmental dose levels (e.g., NOAELs or LOAELs), is attractive because it is easily calculated from published toxicity assays and because it has been argued that A/D is relatively constant across species for a given agent. We explored some quantitative aspects of the A/D ratio and of the concept of developmental hazard by simulating 661,500 mammalian developmental toxicity assays on 441 hypothetical compounds. In our simulations, A/D often varied substantially among replicate assays: the median ratio of the upper and lower limits of the distribution of A/D values that include about 95% of the observed A/D values is 16. In addition, A/D did a poor job of predicting the relative developmental and adult responses at dosages lower than those used to calculate the index: among simulated compounds with A/Ds of about 1.0, the developmental response at 1/100th of the NOAEL ranged from about 0.1% to 20,000% of the adult response. Finally, we measured the concordance between pairs of four different indices of developmental hazard, including A/D. Concordance was greatest when the indices were based on the same portion of the dose response, and was much weaker between indices that examined different portions of the dose response. Therefore, it seems likely that no single index can quantify "developmental hazard," as defined by relative adult and developmental susceptibility, and more effort needs to be expended in refining the concept if it is to be useful for hazard assessment.

Abnormalities, Drug-Induced↗

PubMed1991

Selection kinetics during serial cell culture passage of mixtures of wild-type Autographa californica nuclear polyhedrosis virus and its recombinant Ac360-beta-gal.

Detailed analysis of the selection process in serial co-infections of cell cultures by wild-type Autographa californica nuclear polyhedrosis virus (AcNPV) strain E2 (AcNPV/E2) and Ac360-beta-gal, a genetically engineered strain, shows that the unaltered strain was clearly dominant even when it initially constituted the minority component in the inoculum. A method of calculating a selection coefficient that quantifies the relative advantage of one strain of virus over the other under specific culture conditions is described. Calculated selection coefficients were relatively homogeneous and almost exclusively favoured the progenitor. Selection pressure was not influenced by the relative proportions of the two strains in the population. Selection coefficients, as determined in the present study, may be useful for evaluating the effect of a genetic alteration on viral fitness under specified conditions. Unexpected high frequencies of mixed phenotype plaques were observed during infectivity titrations of media from early serial passages of co-infected cultures. Statistical evaluation implicates some non-heritable combinational phenomenon. Virus plated from mixed phenotype plaques show high segregation of phenotypes implying that genetic recombination does not contribute in a major way to the high mixed phenotype frequencies. Electron microscopic examination of virion pellets from infected 72 h cell culture media similarly argue against co-envelopment as a major contributory factor to the high frequency of mixed phenotype plaques. The cause remains undetermined.

Baculoviridae↗

PubMed1990

Effects of chemically induced maternal toxicity on prenatal development in the rat.

The hypothesis that chemically induced overt maternal toxicity induces a characteristic syndrome of adverse developmental effects in the rat was investigated. Pregnant animals (Sprague-Dawley strain) were dosed by oral gavage with one of a series of compounds on days 6-15 of gestation. These chemicals were diquat (DIQ), ethylene-bis-isothiocyanate (EBIS), toxaphene (TOX), styrene (STY), 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenol (2,4,5-Tr), triphenyl tin hydroxide (TPTH), and cacodylic acid (CAC). The compounds were chosen because they exhibited little or no developmental toxicity in previous studies. Dosage levels producing maternal weight loss and/or lethality were determined from preliminary toxicity studies. Significant maternal weight reductions were noted during the course of treatment with all compounds except CAC and 2,4,5-Tr. Maternal lethality was produced by EBIS, TOX, 2,4,-D, and 2,4,5-Tr. The main treatment-related developmental toxicity noted in litters at term consisted of increased lethality (EBIS, TPTH) and decreased fetal weight (EBIS and CAC). Treatment-related anomalies were seen in litters treated with 2,4-D and TOX (supernumerary ribs) and with EBIS and STY (enlarged renal pelvis). No significant developmental effects were produced with DIQ, or 2,4,5-Tr. This study indicates that overt maternal toxicity as defined by weight loss or mortality is not always associated with the same defined syndrome of adverse developmental effects in the rat.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed1990

An exploratory analysis of the occupational correlates of large pigmented nevi at Lawrence Livermore National Laboratory.

To examine the association between exposure to occupational factors and the presence on the body of large pigmented nevi greater than 5 mm, data were collected from 110 employees of Lawrence Livermore National Laboratory employed between 1969 and 1980. In this exploratory prevalent case-control study analysis, 38 employees reported having at least one large pigmented nevus and 72 reported none. Occupational factors associated with the presence of large pigmented nevi (adjusted for age and the number of sunburns per year under age 21) were being an engineer (prevalence odds ratio [POR] = 3.20, 95% confidence interval [CI] = 1.0,10.6) or an electrical engineer (POR = 2.56, 95% CI = 0.3,20.3), being hired at Lawrence Livermore National Laboratory before 1962 (POR = 3.07, 95% CI = 1.2,7.7), and having one's skin exposed to rare earth metals (POR = 3.78, 95% CI = 0.9,15.1).

Adult↗

PubMed1988

The effect of growth-promoting agents on replication and cell cycle withdrawal in cultures of epidermal keratinocytes.

Epidermal keratinocytes grow in culture to form a stratified squamous epithelium. These cultures contain a replicating as well as a terminally differentiating population and undergo surface desquamation. Epidermal growth factor (EGF) and cholera toxin are usually employed as growth-promoting agents because they reduce the population doubling time; that is, the period required to increase the total cell number twofold. There are three ways in which this reduction in population doubling time could be achieved: (a) the time for one cell cycle or the cell cycle length may be shortened; (b) the number of cells that withdraw from the cell cycle and terminally differentiate may be reduced; or (c) the number of cells that desquamate into the medium over a set period of time may be reduced. We have explored these possibilities in growing cultures of epidermal keratinocytes using a newly developed double-label assay. This assay gives a measure of both cell length and cell cycle withdrawal. Results show that the growth enhancement induced by EGF and cholera toxin can be attributed primarily to a reduction in cell cycle withdrawal and, to a lesser degree, to a reduction in cell cycle length. EGF and cholera toxin have no significant effect on the rate of desquamation. A linear correlation was noted between cell cycle lengths and withdrawal, suggesting an interconnection between the rate of cell renewal and the likelihood of undergoing terminal differentiation.

Cell Cycle↗

PubMed1987

Cell-cycle withdrawal in cultured keratinocytes.

Cell-cycle withdrawal is the irreversible arrest of replication that occurs in keratinocytes early in terminal differentiation. According to the epidermal proliferation unit (EPU) model of renewal, withdrawal takes place in a subset of cells that have completed a final cycle of amplification replication. Using a recently developed double-labelling assay, we followed cell-cycle withdrawal in growing cultures of epidermal keratinocytes and correlated these results with population-growth kinetics. The levels of withdrawal measured were much too high to be consistent with the population-growth kinetics. These unexpectedly high levels could be explained by postulating that withdrawal takes place in a specific subset of cells, as described by the EPU model. Other possible explanations were entertained but, for various reasons, were considered unlikely. To learn whether withdrawal occurred in basal or suprabasal cells, confluent cultures were pulse labeled with 3H-thymidine, and the position of the labeled cells was monitored by autoradiography during the period of cold chase. The results indicated that, in cultured keratinocytes, withdrawal takes place while the cells are still in the basal compartment.

Bromodeoxyuridine↗

PubMed1986

Heterogeneity in the replicating population of cultured human epidermal keratinocytes.

We studied the replication of keratinocytes in stratified squamous epithelia. Other studies have revealed functional and morphological heterogeneity in the replicating population of such cells. To examine possible kinetic heterogeneity, we determined the cell-cycle lengths of replicating cells in cultures of human epidermal keratinocytes. A double-label assay was developed, which measures the time between two successive cycles of DNA synthesis. The first cycle of DNA synthesis was marked by pulse labeling cultures for a brief period with 14C-thymidine (dThd), and the second cycle was detected by labeling at a later time with bromodeoxyuridine (BrdUrd). The time taken for the 14C-labeled DNA to become doubly labeled with BrdUrd was shown to correspond to the length of the cell cycle. In subconfluent cultures in which the cell number increased at an exponential rate, the average cell-cycle time was 21.5 h. In confluent cultures in which desquamation was balanced by cell renewal, the average cell cycle was 31.5 h. However, in confluent cultures, three populations of replicating cells were evident, these having cycle times of 22, 33, and 40 h. In subconfluent cultures, there was no clear evidence for cell-cycle heterogeneity of the replicating cells, although the most rapidly cycling cells in these cultures had a cycle time (16 h) considerably less than the most rapidly cycling cells in the confluent cultures (21 h). It is possible that the rapidly cycling cells seen in the subconfluent cultures were stem cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Cycle↗

PubMedDate not supplied

Human sperm morphometry and smoking, caffeine, and alcohol consumption.

The purpose of this study is to determine whether sperm nuclear size, shape, and chromatin texture parameters are associated with lifestyle exposures including smoking, caffeine, and alcohol consumption. Eighty-six healthy male volunteers (ages 18-35), recruited through newspaper advertisements, provided a semen, blood, and urine sample and completed a questionnaire concerning demographic and lifestyle exposures. Sperm nuclear size, shape, and chromatin texture parameters were measured using computerized image analysis. Results indicated no associations between the sperm nuclear morphometric parameters and age, smoking, or alcohol consumption. There was weak evidence for an association with caffeine intake. In conclusion, the lifestyle factors smoking, caffeine intake, and alcohol consumption do not appear to significantly affect sperm nuclear size, shape, or chromatin texture in this study population.

Adult↗