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Biomedical subjects

S M Rappaport

Publications and source records attributed to S M Rappaport.

At least 55 records · Page 3Linked to original sources
PubMed1996

An investigation of multiple biomarkers among workers exposed to styrene and styrene-7,8-oxide.

Investigations of cancer and cytogenetic damage among reinforced-plastics workers have produced contradictory results. In all studies, the focus has been on styrene rather than the carcinogen, styrene-7,8-oxide (SO), traces of which are generated during the manufacturing process. Because styrene is present at very high levels and is metabolized almost exclusively through SO, coexposures to SO have been discounted. This study investigated the relative contributions of airborne styrene and SO and of smoking toward several SO-specific biomarkers (DNA and albumin adducts) and sister chromatid exchanges in the blood of 48 reinforced-plastics workers. Among individual subjects, albumin and DNA adducts as well as sister chromatid exchanges were significantly correlated with styrene exposure. However, among the 20 subjects with measurements to both styrene and SO, albumin adducts were significantly correlated with exposure to SO but not to styrene. Finally, among the 10 job groups, surprisingly strong correlations (0.709 < or = r < or = 0.966) were found between all SO biomarkers and exposure to SO but not to styrene. Calculations suggest that SO was about 2000 times more effective than styrene in producing SO biomarkers. After accounting for the disparate exposures to the two chemicals, a typical worker received 71% of the systemic dose of SO via inhalation; nonetheless, 5 of the 20 subjects received the majority of the SO dose from styrene. Cigarette smoking increased levels of SO-albumin and SO-DNA adducts, suggesting that SO was a constituent of tobacco smoke. We conclude that inhalation of SO should be considered in any interventions to reduce health risks.

Adult↗
PubMed1996

Analysis of hemoglobin adducts of benzene oxide by gas chromatography-mass spectrometry.

A method is reported for measuring cysteinyl adducts of the benzene metabolite benzene oxide (BO) with hemoglobin (Hb) in blood from humans or rodents exposed to benzene. After reacting the purified, dried protein with trifluoroacetic anhydride and methanesulfonic acid, the resulting phenyltrifluorothioacetate is extracted, washed, and detected by GC-MS in the negative-ion chemical ionization mode. The analysis of Hb adducts of BO from rats dosed with 50-400 mg/kg [13C6]benzene via this method resulted in values which were generally consistent, though slightly lower, than those obtained using an established method. However, while 3 weeks were required to process the samples by the former method, only 2 days were needed with the new procedure. This new method should, therefore, prove to be reliable and convenient for the rapid quantitation of cysteine-bound Hb adducts of BO.

Animals↗
PubMed1996

An investigation of systematic changes in occupational exposure.

Nonstationary behavior in occupational exposure was examined among a number of job groups from different industries. A change in the mean level of exposure between two survey periods was evaluated by applying mixed-effects models. Overall, differences between surveys were observed in slightly more than one-third of the industries analyzed and in about one-quarter of the total number of comparisons performed. Exposures in the majority of cases decreased in the later survey. Further analyses examined the impact of nonstationary exposures on the estimation of the between- and within-worker components of variance. When changes in the mean exposure level were detected, point estimates of the variance components generated under the mixed model were compared with those estimates obtained under the one-way random-effects model, which assumes that the mean exposure level remains constant over time. The results indicate that the magnitude of the bias in the variance component estimates can be substantial when the misspecified model is applied. It is concluded that, in the absence of changes known to affect exposure, data collected within a year are likely to result in relatively valid inferences about mean and variance parameters using models that assume stationarity; for periods extending beyond a year, systematic changes in exposure are more likely to occur. Thus, exposure assessment strategies should be designed so that sufficient data are collected among groups of workers to investigate systematic changes and to ensure that appropriate statistical models are applied. In this way, occupational hygienists will be able to make reliable inferences about the underlying distribution of exposures pertinent to each occupational group.

Analysis of Variance↗
PubMed1996

Relation between pulmonary clearance and particle burden: a Michaelis-Menten-like kinetic model.

OBJECTIVES: To test the validity of a Michaelis-Menten-like kinetic model of pulmonary clearance of insoluble dusts. METHODS: Data were investigated from studies of pulmonary clearance in F344 rats exposed to antimony trioxide (Sb2O3), photocopy test toner, polyvinyl chloride powder (PVC), and diesel exhaust particles. The Michaelis-Menten-like model was used to develop a relation in which the pulmonary clearance half time was a linear function of lung burden. After combining all data, linear regression techniques were applied to investigate the underlying relations. With the estimated intercepts and slopes, the Michaelis-Menten-like kinetic parameters kmax (maximal clearance rate) and m1/2 (a characteristic lung burden at which kmax is reduced by 50%) were derived for the four dusts. RESULTS: The experimental data fit the linear regression very well (R2 = 0.989), suggesting that pulmonary clearance for the four dusts followed Michaelis-Menten-like kinetics. Values of the intercept terms were not significantly different among the four dusts (P = 0.294), indicating that the intrinsic clearance rates of F344 rats were the same among the four experiments. The intrinsic clearance half time was estimated to be 77.8 days, leading to an estimated kmax of 0.0089 day-1. However, the slopes of the linear relations were significantly different among the four dusts (P < 0.001). Values of m1/2 were ranked in the order of: Sb2O3 (0.69 mg) < photocopy test toner (0.97 mg) < diesel exhaust (2.49 mg) congruent to PVC (2.90 mg). CONCLUSION: This study suggests that the Michaelis-Menten-like kinetic model reasonably describes the kinetic behavior of pulmonary clearance in F344 rats. The parameters m1/2 can be used to differentiate the potency of a particular dust for impairing pulmonary clearance.

Air Pollutants↗
PubMed1996

Comparison of average estimated metabolic rates for styrene in previously exposed and unexposed groups with pharmacokinetic modelling.

OBJECTIVE: To understand whether previous styrene exposure increases the human liver's ability to convert styrene into styrene oxide. METHODS: The hypothesis was tested that the average linear metabolic rate constant kappa was the same in both exposed and unexposed groups, when the exposed group comprised people with a history of styrene exposure and the unexposed group had no exposure. In an experimental chamber, these two groups of subjects were exposed to a concentration of 80 ppm styrene for two hours. A three compartment pharmacokinetic model was used to define kappa. Based on large sample theory, the comparison of estimated mean values of kappa in the exposed and unexposed groups was shown to be equivalent to a comparison of the estimated mean values of the hepatic clearance X in the two groups. A method was developed to estimate X for each subject in both groups from the subject's height, weight, and estimated asymptotic styrene decay constant alpha. Here, alpha was estimated individually from observed blood concentrations over time when sufficient time had elapsed after the controlled exposure. RESULTS: The proposed methodology of comparing the estimated mean values of kappa in exposed and unexposed groups reduced the number of specific physiological variables involved to three, all of which were estimable from data based on simple direct measurements. In contrast, other methods based on pharmacokinetic models usually involved many variables that were non-estimable on an individual basis. Consequently, statistical comparisons were impossible. These methods were applied to analyse previously published data on the time course of styrene concentrations in arterial blood of subjects in both exposed and unexposed groups. A Wilcoxon non-parametric rank sum test with the individually estimated X values was used, and no significant difference in the means of X in the two groups was found. CONCLUSION: The linear metabolic rate constant kappa for humans is probably not altered by previous exposure to styrene. This result is in agreement with some experimental studies on animals. However, in the data analysis, it was noted that the number of subjects in each group was small (6-7) and that the styrene concentration data did not exactly reflect true behaviour of asymptotic decay. Further studies are still needed to draw more definitive conclusions.

Adipose Tissue↗
PubMed1996

The use of protein adducts to investigate the disposition of reactive metabolites of benzene.

Benzene is metabolized to a number of electrophilic species that are capable of binding to both DNA and proteins. We used adducts of hemoglobin (Hb) and bone marrow proteins to study the disposition of three benzene and metabolites (benzene oxide [BO], 1,2-benzoquinone [1,2-BQ], and 1,4-benzoquinone [1,4-BQ]) in F344 rats and B6C3F1 mice following a single oral dosage of [13C6]benzene and/or [14C]benzene. Our assays focused upon cysteine adducts that accounted for 38 to 45% of protein binding to Hb and 63 to 81% of protein binding to bone marrow. Although both mice and rats showed dose-related increases in Hb and bone marrow protein adducts of BO and of the two benzoquinones, large intertissue and interspecies differences were noted, suggesting different preferences in metabolic pathways. The highest levels of adducts in mice were of 1,4-BQ (10-27% of all cysteine adducts), while in rats, BO adducts predominated in Hb (73% of all cysteine adducts) and 1,2-BQ adducts predominated in the bone marrow (14% of all cysteine adducts). High background levels of 1,2-BQ and 1,4-BQ adducts were also detected in both species, indicating that the toxic effects of quinone metabolites may only be important at high levels of benzene exposure.

Animals↗
PubMed1996

Determination of albumin and hemoglobin adducts in workers exposed to styrene and styrene oxide.

Hemoglobin and albumin adducts of the carcinogen styrene-7,8-oxide (SO) were measured in 48 workers exposed to both styrene and SO in a boat manufacturing plant. Personal exposures to both substances were measured repeatedly over the course of 1 year (styrene:0.9-235 mg/m3 with a mean of 64.3 mg/m3 for 48 subjects; S0: 13.4-525 mu g/m3 with a mean of 159 mu g/m3 for 20 subjects). Cysteine and carboxylic acid adducts of SO with hemoglobin and albumin were assayed on one or more occasions for each subject. The proteins were subjected to base hydrolysis to release styrene glycol, representing carboxylic acid-bound SO, and were then treated with Raney nickel to release 1-phenylethanol and 2-phenylethanol, representing cysteine-bound SO. These three analytes were extracted, derivatized, and analyzed by gas chromatography-mass spectrometry. No evidence was found of any exposure-related increase in hemoglobin adducts. In contrast, albumin adducts were found to increase with exposures to either styrene or SO, the latter apparently being more important. This suggests that exposure to low levels of SO in the air may be important among workers in the reinforced plastics industry. Significant levels of SO adducts of albumin and hemoglobin were also detected in proteins obtained from persons without occupational exposure to styrene or to SO. This finding opens the possibility that SO is either a dietary or an environmental contaminant or is produced endogenously.

Air Pollutants, Occupational↗
PubMed1995

Retention of styrene following controlled exposure to constant and fluctuating air concentrations.

An experiment was designed to determine whether the respiratory retention of styrene vapor, as estimated from measurements of end-exhaled air, was the same during periods of both constant and fluctuating exposure. Six human subjects were exposed to styrene inside a experimental chamber. A computer-controlled system was used to generate time-varying air concentrations of styrene over 4-5h in both multistep sequences of constant exposure (four subjects exposed to 15-99 ppm of styrene in 100-min steps) and fluctuating patterns representative of occupational exposures (two subjects exposed to mean concentrations of styrene of 50 ppm). In the latter case, lognormally distributed exposures, which fit one of two first-order autoregressive models, were generated at intervals of 2.5 min. It was found that the concentration of styrene in end-exhaled air was reduced by about half if the subject inhaled one to three breaths of clean air prior to sampling. This suggests that significant amounts of styrene were desorbed from the lining of the lungs during the initial exhalation. The retention of styrene vapor during constant exposures was 0.935 and was independent of the level. During each of the two sets of fluctuating exposure the retention of styrene was also constant and was independent of both the variance and autocorrelation coefficient. However, the retention of styrene during the fluctuating exposure (estimates ranged from 0.957 to 0.973) was significantly higher than that observed during the constant exposures.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

An exposure-assessments strategy accounting for within- and between-worker sources of variability.

A strategy is presented for comparing exposures to an occupational exposure limit (OEL) and for suggesting appropriate interventions when exposures are unacceptable. The major departure from previous approaches is the explicit recognition that exposures vary both within and between workers in a given occupational group. The primary goal is to determine whether the probability of overexposure is acceptably small (a value of 0.10 or less is recommended), with overexposure being defined as the likelihood that a randomly selected worker's true mean exposure exceeds the OEL. The exposure-assessment protocol contains five levels. It is suggested that at least two shift-long measurements be randomly collected from each of 10 workers for preliminary analysis. If the logged exposure data appear to be appropriate for testing (Level 1), the probability of overexposure is compared to the pre-determined value via a rigorous test of statistical significance (Level 2). Based upon published data, this test is likely to classify exposures as acceptable with 20 measurements when the group mean exposure is less than one-fifth of the OEL. However, if exposure is found to be unacceptable, re-sampling can be considered to increase the power of the test (Level 3). Otherwise, it is necessary to reduce exposures and then to re-apply the protocol. If it appears that all persons in the group have essentially the same predicted mean exposures (Level 4), then engineering or administrative controls are recommended. If, on the other hand, substantial differences appear to exist amongst these predicted mean values, regrouping and/or modifications of tasks and work practices should be considered (Level 5). Application of the protocol is illustrated with samples of data from four groups of workers exposed to inorganic nickel in the nickel-producing industry.

Analysis of Variance↗
PubMed1995

Biological monitoring and standard setting in the USA: a critical appraisal.

Occupational exposure limits (OELs) issued in the US by the Occupational Safety and Health Administration (OSHA) require measurements of toxic substances in air rather than in biological samples. Most of OSHA's limits were adopted from the 1968 list of the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLVs). Although there are no formal requirements to monitor exposures to these substances, it is implicit in the standards that air sampling will be performed. Of the 13 OELs which OSHA has set de novo, 2 (i.e., those for lead and cadmium) require biomonitoring after air sampling has identified the heavily exposed workers. OSHA appears to value biomonitoring in some circumstances but has apparently not found a consistent rationale for using biomarkers to set and enforce its standards. This paper discusses 2 valuable features of biomarkers which should be exploited by OSHA to further its regulatory agenda. The first relates to controversies associated with dose rate which have come into play in setting short-term exposure limits (STELs) when acute effects do not provide the necessary justification. OSHA has not provided evidence that its STELs are needed to reduce the risks of disease (as in the cases of benzene and ethylene oxide). By investigating the exposure-biomarker relationship, it is possible to determine whether the rate of exposure has any influence on the uptake and elimination of toxic substances and, therefore, whether STELs is needed. This is illustrated with data from 2 studies on styrene exposure. The second feature concerns biomonitoring as the primary means of exposure assessment in situations where the biomarker is accumulated over months or years (as in the cases of lead and cadmium). Using data from the lead-battery industry, it is shown that 'correct' compliance decisions are more likely to arise from evaluation of blood lead measurements than from traditional air monitoring.

Chemistry, Clinical↗
PubMed1995

The relationship between environmental monitoring and biological markers in exposure assessment.

The poor quality of traditional assessments of exposure has encouraged epidemiologists to explore biological monitoring in studies of chronic diseases. Yet, despite theoretical advantages, biomarkers have not been widely used in such applications. This article compares the general utility of a biomarker with that of the measurement of exposure per se. Points are illustrated with a longitudinal study of boat workers in which levels of styrene in the breathing zone and in exhaled air were compared to sister chromatid exchanges (SCEs) in peripheral lymphocytes. First, the linear relationship is explored between personal exposure and the levels of a biomarker in the cohort. A good fit to the straight-line relationship reflected by a correlation coefficient which is close to 1, such as observed with styrene in exhaled air (r2 = 0.83), suggests linear kinetics, that the appropriate route of exposure was measured by personal monitoring, small interindividual differences, adequate sample sizes, and a specific biomarker. However, a small correlation coefficient, as observed between SCEs and styrene exposure (r2 = 0.11), indicates that either kinetics were nonlinear or that more complex issues were involved with one or more of these factors. Second, environmental and biologic measurements are compared for use as independent variables in establishing a straight-line relationship between exposure and the health effect. If the ratio of the within-person to the between-person components of variance of the independent variable is large, then significant attenuation results when estimating the slope of the line.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMed1994

Comparison of protein adducts of benzene oxide and benzoquinone in the blood and bone marrow of rats and mice exposed to [14C/13C6]benzene.

Protein binding of hemoglobin (Hb) and bone marrow was used to compare in vivo reactions of 3 electrophilic metabolites of benzene, i.e., benzene oxide and 1,2- and 1,4-benzoquinone (1, 2-BQ and 1, 4-BQ), in F344 rats and B6C3F1 mice. Following a single p.o. administration of a mixture of [14C]- and [13C6]benzene between 50 and 400 mg/kg body weight, cysteine adducts of benzene oxide, 1,2-BQ, and 1,4-BQ were assayed, and the proportions of cysteine-bound adducts to total protein binding were estimated. Although dose-related production of each adduct was seen, large differences were observed between species and tissues. With rat Hb, benzene oxide adducts represented 27% of the total Hb binding and 73% of the cysteinyl binding, whereas quinone adducts represented relatively small proportions. However, with mouse Hb, the 1,4-BQ adducts accounted for 5.5% of the total Hb binding and 12.2% of the cysteinyl binding, while 1,2-BQ and benzene oxide each accounted for less than 3% of the total. In the bone marrow of both rats and mice, BQ adducts were more abundant than those of benzene oxide. However, adducts of 1,2-BQ predominated in rat marrow (9% of binding), whereas adducts of 1,4-BQ were more abundant in the mouse (21% of binding). The average blood concentrations of 1,4-BQ were estimated from the adduct levels and reaction-rate constants to be 2-5-fold higher in the mouse than in the rat. This work suggests that BQ binding is favored over that of benzene oxide in the bone marrow; however, high background levels of BQ adducts, observed with Hb and bone marrow proteins, suggest that any toxic effects of the quinones should only arise from high exposures to benzene.

Animals↗
PubMed1994

An investigation of the dependence of exposure variability on the interval between measurements.

Investigations have suggested that owing to the effects of autocorrelation and/or non-stationary behaviour exposure variability increases with the number of days between measurements. This study confirmed such increasing variability with the interval between observations in a collection of occupational data sets after controlling for factors likely to contribute to variability and for sample size. Consecutive shift-long exposure measurements for 53 workers from five different data sets in 123 time series were analysed. When the data were combined a clear increasing trend in the variance was observed with interval, but a breakdown by data set revealed that this trend was present in only two of the five data sets. The effect was further isolated in 30% of the workers who contributed data and in 29% of the total number of time series analysed. Amongst the data where the trend was evident the combination of autocorrelation and non-stationary behavior explained the increase in 64% of the time series. Significant autocorrelation was detected for a small group of workers in only one of the data sets and for a minority of cases amongst workers who contributed more than one time series to the analysis. Thus, autocorrelation of shift-long exposures does not appear to be pervasive and is unlikely to present significant problems when implementing statistically-based sampling strategies. On the other hand, the issue of non-stationarity remains equivocal. Although only a small proportion of time series was found to be non-stationary, the period investigated was short (around 30 days) and it remains to be seen whether the problem is more pronounced over longer time scales.

Analysis of Variance↗
PubMed1993

Threshold limit values, permissible exposure limits, and feasibility: the bases for exposure limits in the United States.

The development of exposure limits in the United States has always relied heavily upon the threshold limit values (TLVs) developed by the American Conference of Governmental Industrial Hygienists (ACGIH). In fact, the TLVs were adopted as official exposure limits by the Occupational Safety and Health Administration (OSHA) in 1972 and 1989. Given the continuing importance of the ACGIH limits, this paper compares the basis of the TLVs with that employed by OSHA de novo in its 12 new permissible exposure limits (PELs). Using benzene as an example, it is shown that OSHA's new PELs have been established following a rigorous assessment of the inherent risks and the feasibility of instituting the limit. The TLVs, on the other hand, have been developed by ad hoc procedures and appear to have traditionally reflected levels thought to be achievable at the time. However, this might be changing. Analysis of the historical reductions of TLVs, for 27 substances on the 1991-1992 list of intended changes, indicates smaller reductions in the past (median reduction of 2.0-2.5-fold between 1946 and 1988) compared to those currently being observed (median reduction of 7.5-fold between 1989 and 1991). Further analysis suggests a more aggressive policy of the ACGIH regarding TLVs for carcinogens but not for substances that produce effects other than cancer. Regardless of whether the basis of the TLVs has changed recently, it would take a relatively long time for the impact of any change to be felt, since the median age of the 1991-1992 TLVs is 16.5 years, and 75% of these limits are more than 10 years old. The implications of OSHA's continued reliance on the TLVs as a means of updating its PELs are discussed, and four alternatives are presented to the ACGIH regarding the future of its activities related to exposure limits. It is concluded that new mechanisms are needed for OSHA to update its PELs in a timely fashion so that the TLVs will not be adopted by default in the future.

Air Pollutants, Occupational↗
PubMed1993

Biological considerations in assessing exposures to genotoxic and carcinogenic agents.

This analysis of the relationship between long-term exposure to carcinogens and the risk of cancer relies upon a model which depicts exposure, burden and genetic damage as time series. It is shown that the dose of the carcinogen and the resulting damage to susceptible tissues can be related to cumulative exposure provided that linear kinetics are maintained and the exposure series remains stationary. Since saturable processes can lead to nonlinear behavior, the role of metabolism is investigated. It is argued that by maintaining the mean burden below 1/8 of the value of KM the contribution of nonlinear kinetics to the dose should be minimal, at least in occupational settings where saturable metabolism is most likely. Under this conjecture an expression is derived for the maximum mean air concentration, designated Xmax, which should maintain linear kinetics. By comparing values of Xmax, estimated for five genotoxic and/or carcinogenic substances (benzene, styrene, tetrachloroethylene, trichloroethylene, and vinyl chloride) with the corresponding U.S. occupational exposure limits, it is shown that saturable metabolism is unlikely to occur in some situations but is likely in others. This suggests that biological monitoring can play an important role in defining dose-response relationships for some, but not all, carcinogenic substances.

Carcinogens, Environmental↗
PubMed1993

Sister-chromatid exchanges in lymphocytes are increased in relation to longitudinally measured occupational exposure to low concentrations of styrene.

A longitudinal investigation of styrene exposure was conducted among 48 workers employed at a reinforced plastic boat manufacturing facility. 8-h time-weighted average (TWA) exposures to styrene and concentrations of styrene in the breath were determined for each individual on 7 randomly chosen days during 1 year. Peripheral blood lymphocytes from each subject were analyzed for sister chromatid exchanges (SCEs) 2 times and micronuclei (MN) 4 times during this period. Individual mean SCEs ranged from 4.7 to 9.5 SCEs per cell with a population mean of 6.4 +/- 0.2 SCEs per cell. SCEs were found to be significantly increased with an overall observed increase of 11.7% related to increasing exposure to styrene (mean air concentration 64.2 mg/m3 +/- 71.5; range 0.88-235 mg/m3) and with cigarette smoking. Examination of the relative contribution of each variable to regression of SCEs showed that smoking contributed about 62% and styrene exposure contributed about 25% of the total variability. Intra-individual lymphocyte MN frequencies did not vary significantly over time nor was a gradient toward increased MN observed with styrene exposure. However, significant inter-individual differences in MN frequencies were observed. Females had significantly higher MN frequencies than did males; MN were also increased with age. This study is highly unusual in that it illustrates the ability to separately quantify the relative contribution of each of two variables--smoking and styrene exposure--to an increase in SCEs in lymphocytes of an exposed human population.

Adult↗
PubMed1993

Variation of exposure between workers in homogeneous exposure groups.

It is generally assumed that workers employed in the same job at a given location are uniformly exposed, i.e., that they have the same long-term mean exposure. This assumption has led to observational schemes for classifying workers into homogeneous exposure groups (HEGs), based on job title, location, and other identifiable features of the work environment. This paper presents results from analysis of 183 HEGs (comprised of 15,495 personal measurements) in which it was possible to determine the between-worker component of variance in exposure. The results indicate that, contrary to popular belief, only about one fifth of the HEGs were uniformly exposed (less than a two-fold difference among 95% of individual mean exposures) while an equal number showed a high degree of variation between workers (more than 15-fold differences among 95% of individuals). Further analyses indicate that the identifiable features of the work environment, which are typically used to establish HEGs, are only marginally related to the between-person variation (accounting for only 13% of this variance component). It is concluded that industrial hygienists should not rely on observational schemes to guarantee that groups of workers are uniformly exposed. Rather, they should adopt methods of statistical sampling and analysis that allow the variance components to be estimated so that decisions regarding the evaluation of hazard and selection of controls will be appropriate.

Analysis of Variance↗