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Biomedical subjects

S M Rappaport

Publications and source records attributed to S M Rappaport.

At least 73 records · Page 4Linked to original sources
PubMed1993

A comprehensive evaluation of within- and between-worker components of occupational exposure to chemical agents.

A database of approximately 20,000 chemical exposures has been constructed in close co-operation between the School of Public Health of the University of North Carolina at Chapel Hill and the Department of Air Pollution of the Wageningen Agricultural University. A special feature of this database is that only multiple measurements of exposure from the same workers were included. This enabled estimation of within- and between-worker variance components of occupational exposure to chemical agents throughout industry. Most of the groups were not uniformly exposed as is generally assumed by occupational hygienists. In fact only 42 out of a total of 165 groups (25%), based on job title and factory, had 95% of individual mean exposures within a two-fold range. On the contrary, about 30% of the groups had 95% of individual mean exposures in a range which was greater than 10-fold. Environmental and production factors were shown to have distinct influences on the within-worker (day-to-day) variability, but not on the between-worker variability. Groups working outdoors and those working without local exhaust ventilation showed more day-to-day variability than groups working indoors and those working with local exhaust ventilation. Groups consisting of mobile workers, those working with an intermittent process and those where the source of contamination was either local or mobile also showed great day-to-day variability. In a multivariate regression model, environment (indoors-outdoors) and type of process (continuous-intermittent) explained 41% of the variability in the within-worker component of variance. Another model, in which only type of process (continuous-intermittent) had a significant effect, explained only 13% of the variability in the between-worker component of variance.

Air Pollutants, Occupational↗
PubMed1993

Production of benzoquinone adducts with hemoglobin and bone-marrow proteins following administration of [13C6]benzene to rats.

Adduction of hemoglobin (Hb) and bone-marrow proteins with 1,2- and 1,4-benzoquinone (1,2-BQ and 1,4-BQ) and 4,4'-diphenoquinone was examined following oral administration of [13C6]benzene to F344 rats. Linear production of [13C6]1,4-BQ adducts was observed with both Hb and bone-marrow proteins over the entire range of dosages of 0-400 mg/kg. The slopes of the regressions were 3.4 x 10(-4) (r2 = 0.997) and 1.6 x 10(-3) (r3 = 0.926) nmol/g protein/mg/kg respectively, for Hb and bone-marrow proteins. Production of [13C6]1,2-BQ adducts of Hb and bone-marrow proteins also increased with benzene dosage. Although the shapes of the relationships between 1,2-BQ adducts and dosage were nonlinear, the levels were approximately 10 times greater than those associated with 1,4-BQ, suggesting a significantly greater benzene-specific dose of 1,2-BQ. Adducts of 4,4'-diphenoquinone were not detected. High background levels of [12C6]adducts of 1,2-BQ and 1,4-BQ were found in Hb and bone-marrow proteins as might be expected from the many dietary sources of the phenolic precursors of the benzoquinones, i.e. phenol, catechol and hydroquinone. Background levels of the 1,2-BQ and 1,4-BQ adducts were 27.3 and 11.5 nmol/g in Hb and 44.6 and 25.6 nmol/g in the bone-marrow proteins respectively. Interestingly, the production of benzene-specific adducts represented only a small fraction (< 4%) of the background levels of the same adducts. If the genotoxicity of benzene is, indeed, related to the in vivo production of BQ isomers, our results suggest that very large exposures to benzene would be needed to produce detectable increases in adduct levels and the associated risks of leukemia.

Animals↗
PubMed1993

Measurement of adducts of benzoquinone with hemoglobin and albumin.

Benzoquinones (BQ) are genotoxic species that stem from metabolism of phenolic compounds. We have developed a method for measuring adducts of 1,2- and 1,4-benzoquinone (1,2-BQ and 1,4-BQ) with cysteine residues of hemoglobin (Hb) and albumin (Alb). The method employs a reductive catalyst (Raney nickel) to selectively cleave sulfur-bound adducts so that they may be extracted with an organic solvent, derivatized with heptafluorobutyrylimidazole and measured by GC-ECD or GC-MS. Reactions of 1,4-BQ (0-300 microM) with whole blood of both F344 rats and humans resulted in linear formation of adducts with Hb and Alb. Adducts of 1,2-BQ with human Alb were formed by activation of catechol (0-300 microM) in situ with horseradish peroxidase. The mean half lives in vitro of 1,4-BQ in blood from humans and rats were 3.5 and 0.68 h, respectively. Second-order rate constants for reaction of 1,4-BQ with Hb and Alb in whole blood were estimated to be 18 and 76 l/mol/h for humans and 180 and 74 l/mol/h for rats respectively. Interestingly, the following high background levels of 1,2-BQ and 1,4-BQ adducts were observed in the proteins: 1,2-BQ-human Hb = 1.5 nmol/g, rat Hb = 25.1 nmol/g; human Alb = 8.0 nmol/g; 1,4-BQ-human Hb = 27.2 nmol/g, rat Hb = 11.5 nmol/g; human Alb = 20.5 nmol/g. These large background levels of BQ adducts suggest that significant exposure to BQ precursors occurs from dietary and/or endogenous sources. Given current evidence regarding the genotoxicity of BQ, such exposures and their health consequences should be investigated.

Animals↗
PubMed1993

Use of the glycophorin A human mutation assay to study workers exposed to styrene.

The glycophorin A (GPA) assay is a human mutation assay that is potentially useful for large epidemiological studies. The assay is rapid and requires a minimal amount of blood, which can be stored before analysis. The data presented here were collected from workers exposed to styrene in a boat manufacturing plant. This study was the first to apply the GPA assay to an occupationally exposed population. Subjects with a mean styrene exposure of 30 ppm had a higher frequency of GPA N phi variant cells than subjects with mean exposure of 1 ppm, but the subjects differed in respect to smoking and age distribution. Results indicate that the original 1-W-1 version of the assay may not be suitable for studies of small numbers of exposed subjects due to variability and artifacts. The newer BR6 version, however, has much lower variability and shows promise for use in the occupational setting.

Evaluation Studies as Topic↗
PubMed1991

Implications of OSHA's reliance on TLVs in developing the air contaminants standard.

This paper evaluates the decision by the Occupational Safety and Health Administration (OSHA) to base its Air Contaminants Standard on the threshold limit values (TLVs) of the American Conference of Governmental Industrial Hygienists. Contrary to the claim made by OSHA in promulgating the standard, the TLV list was not the sole available basis for a generic standard covering toxic air contaminants. The National Institute for Occupational Safety and Health (NIOSH) presented data indicating that the TLVs were insufficiently protective for 98 substances. NIOSH Recommended Exposure Limits (RELs) were available for 59 of these substances. The ratio of PEL to REL ranged up to 1,000, with a median of 2.5 and a mean of 71.4. OSHA excluded 42 substances from the standard altogether despite the availability of NIOSH RELs, solely because no TLV had been established.

Air Pollutants, Occupational↗
PubMed1991

A measure of goodness-of-fit for the lognormal model applied to occupational exposures.

The lognormal distribution is often applied to occupational exposures, yet the assumption of lognormality is rarely verified. This lack of rigor in evaluating the appropriateness of the lognormal model has resulted, in part, from the difficulty of applying formal goodness-of-fit tests. When evaluation of model fit has been attempted, occupational hygienists have relied upon probability plotting of exposures rather than upon formal statistical methods. The goal of this work was to develop for the occupational hygienist a simple quantitative evaluation to supplement the probability plot. A measure of goodness-of-fit to the lognormal model based on the ratio of two estimators of the mean of the distribution, the simple or direct estimate of the mean and the maximum likelihood estimate of the mean of a lognormal distribution, is described. This new measure, the ratio metric, is a simple extension of calculations made routinely by many occupational hygienists. Results from using the ratio metric were compared to probability plotting and to two traditional measures of goodness-of-fit, the Lilliefors test and the W test, for two occupational exposure data sets. The results of the ratio and W tests are comparable for a variety of occupational exposure data, but the Lilliefors test is overly conservative and does not detect several cases of gross deviations from lognormality. The ratio metric is an effective alternative to the Lilliefors test and is easier to perform than the W test for the range of data usually encountered by occupational hygienists. Occupational hygienists are encouraged to use the ratio metric in conjunction with the probability plot in evaluating the lognormal assumption.

Air Pollutants, Occupational↗
PubMed1991

Assessment of long-term exposures to toxic substances in air.

Because airborne exposure varies greatly over time and between individual workers, occupational hygienists should adopt sampling strategies which recognize the inherent statistical nature of assessing exposure. This analysis indicates that the traditional practice of testing 'compliance' with occupational exposure limits (OELs) should be discarded. Rather, it is argued that acceptable exposure should be defined with reference to the exposure distribution. Regarding the many statistical issues which come into play, it is concluded that hygienists should continue to apply the log-normal model for summarizing and testing data. However, sampling designs should move away from methods which are biased (e.g. sampling only the worst case) and which rely upon job title and observation as the primary means of assigning workers into groups. Since exposure data often lack independence (e.g. owing to the autocorrelation of serial measurements) and there exist large differences in exposure between workers in the same job group, random sampling designs should be adopted. It is also shown that the relationship between the mean of a log-normal distribution and exposures in the right tail allows one to evaluate simultaneously the mean exposure and the maximum frequency with which exposures exceed the OEL. Investigation of the biological concepts relies heavily upon a conceptual model which depicts the exposure-response continuum as a sequence of time series related to exposure, burden, damage and risk. Analysis of the linkages between these processes identifies two kinetic conditions which are necessary if variability of exposure is to affect appreciably the individual's risk of chronic disease. First, the variation of exposure from interval to interval must be efficiently translated into burden and damage (no damping), and second, during periods of intense exposure the relationship between burden and damage must be non-linear (curving upwards). On the basis of current knowledge it appears that relatively few chronic toxicants satisfy both these conditions. Even for those substances which cause damage only when a threshold is exceeded, a statistical argument suggests that the maximum risk can still be related to the mean exposure received over time. It is concluded that the risk of chronic disease generally depends upon the mean exposure received by the individual worker over time. Thus, the sampling strategy must allow the distribution of individual mean exposures to be characterized across the population at risk. It follows from this paradigm for assessing exposures that relatively little effort should be devoted to the evaluation of short-term 'peak' exposures since such transients are unlikely to exert undue influence on long-term effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Air Pollutants, Occupational↗
PubMed1991

A field method for measuring solvent vapors in exhaled air--application to styrene exposure.

A method is described for measuring solvent vapors in mixed-exhaled air. The subject exhales through a carbon-containing tube connected to a Wright respirometer. Adsorbed vapors are subsequently eluted by carbon disulfide and analyzed by gas chromatography. Twenty-minute exposures to styrene and the corresponding concentrations of styrene in the breath and venous blood were repeatedly measured for two subjects. Regression analyses indicated that the breath measurements were highly correlated with both the exposures and the blood concentrations of styrene. In another study, styrene was measured simultaneously in the mixed-exhaled air by this technique and in the end-exhaled air by a portable gas chromatograph. The mixed-exhaled air obtained with this method contained about half alveolar air. Analysis of the components of the variance obtained from all the data indicated that the error in measurement by this method was about one-fourth of the total variance.

Adult↗
PubMed1990

Use of a surface-acoustic-wave sensor to characterize the reaction of styrene vapor with a square-planar organoplatinum complex.

A coated surface-acoustic-wave (SAW) sensor is used to probe the reaction of styrene vapor with the square-planar platinum-ethylene pi-complex, trans-PtCl2(ethylene)(pyridine). A dual-SAW delay-line oscillator configuration is employed: one oscillator is coated with a solvent-cast film of the solid platinum-ethylene complex dispersed in a poly(isobutylene) matrix, and the second oscillator is coated only with polymer. Absorbed styrene vapor displaces ethylene to form the stable styrene-substituted complex, trans-PtCl2(styrene)(pyridine), causing a decrease in the oscillator frequency from the increase of mass on the surface of the sensor. For short-term exposures, there is a linear relationship between the logarithm of the rate of frequency change and the logarithm of the styrene vapor concentration, consistent with a power-law kinetic model for the heterogeneous trapping reaction. Deviation from this relationship above 300 ppm at 25 degrees C is attributed to the onset of multilayer adsorption of styrene at the surface of the trapping reagent. The sensor response exhibits an Arrhenius temperature dependence permitting estimation of the thermal activation energy for the olefin-substitution reaction. Calculated detection limits of 3 and 0.6 ppm of styrene vapor are achieved for operation at 25 and 40 degrees C, respectively.

Chemical Phenomena↗
PubMed1990

Selective real-time measurement of styrene vapor using a surface-acoustic-wave sensor with a regenerable organoplatinum coating.

The performance of a coated surface-acoustic-wave (SAW) sensor for monitoring styrene vapor is investigated. The effects of several organic co-contaminants and atmospheric humidity are described, and regeneration of the sensor coating is demonstrated. The dual-SAW delay-line oscillator employs a reagent coating of trans-PtCl2(ethylene)(pyridine) to trap styrene via ethylene substitution. The rate of change of the sensor frequency is used to provide real-time measurement of styrene vapor concentrations. No effect on the response to styrene is observed upon simultaneous exposure to each of several olefin and non-olefin solvent vapors used with styrene in industrial processes. Butadiene, however, presents a reversible negative interference by successfully competing with styrene for reaction with the trapping agent. The response to styrene exhibits a moderate positive humidity dependence. Following prolonged exposure, the original complex can be regenerated in situ by exposure to ethylene gas, permitting repeated use of the sensor. An emphasis is placed on the application of the sensor to workplace air monitoring.

Chemical Phenomena↗
PubMed1990

But they are not thresholds: a critical analysis of the documentation of Threshold Limit Values.

Threshold Limit Values (TLVs) represent conditions under which the TLV Committee of the American Conference of Governmental Industrial Hygienists (ACGIH) believes that nearly all workers may be repeatedly exposed without adverse effect. A detailed research was made of the references in the 1976 Documentation to data on "industrial experience" and "experimental human studies." The references, sorted for those including both the incidence of adverse effects and the corresponding exposure, yielded 158 paired sets of data. Upon analysis it was found that, where the exposure was at or below the TLV, only a minority of studies showed no adverse effects (11 instances) and the remainder indicated that up to 100% of those exposed had been affected (8 instances of 100%). Although, the TLVs were poorly correlated with the incidence of adverse effects, a surprisingly strong correlation was found between the TLVs and the exposures reported in the corresponding studies cited in the Documentation. Upon repeating the search of references to human experience, at or below the TLVs, listed in the more recent, 1986 edition of the Documentation, a very similar picture has emerged from the 72 sets of clear data which were found. Again, only a minority of studies showed no adverse effects and TLVs were poorly correlated with the incidence of adverse effect and well correlated with the measured exposure. Finally, a careful analysis revealed that authors' conclusions in the references (cited in the 1976 Documentation) regarding exposure-response relationships at or below the TLVs were generally found to be at odds with the conclusions of the TLV Committee. These findings suggest that those TLVs which are justified on the basis of "industrial experience" are not based purely upon health considerations. Rather, those TLVs appear to reflect the levels of exposure which were perceived at the time to be achievable in industry. Thus, ACGIH TLVs may represent guides of levels which have been achieved, but they are certainly not thresholds.

Air Pollutants, Occupational↗
PubMed1990

Analysis of OSHA's short-term-exposure limit for benzene.

A review of the data cited by OSHA in its final standard for exposure to benzene provides no clear scientific basis for a short-term-exposure limit (STEL). While leukemia and bone marrow toxicity were related to cumulative exposures of benzene received by workers, no evidence was presented that the rate of exposure at a given cumulative exposure contributed to the effects. Likewise, animal experiments suggested that exposures of several hours duration at a given level of benzene induced more bone-marrow toxicity when administered 3 rather than 5 days/week but did not indicate that the rate of exposure over shorter time scales played any role. The toxicokinetics of benzene in humans were also studied to determine whether nonlinear dose-rate effects would be likely to result from peak exposures associated with an exposure dose of 8 ppm-hr, which is allowed under the permissible exposure limit. This led to three conclusions. First, the concentration of benzene in the bone marrow should be sufficiently damped that the impact of a peak exposure should be minimal. Second, the peak concentration of benzene in the liver should be within the capacity of the cytochrome P450 system to maintain first-order metabolism. And finally, the maximum blood concentration of metabolites should be well below levels which have been shown to induce toxic effects in vitro. Taken together, the toxicokinetic relationships and the absence of clear experimental dose-rate effects suggest that the current STEL for benzene is unwarranted, assuming that 8-hr average exposures are kept below 1 ppm. While the argument can be made, on the basis of health considerations, that the existing 8-hr limit for benzene is too high, the rate of exposure during short periods appears to be irrelevant. Thus, we recommend that health professionals focus upon long-term exposures to benzene received by large numbers of workers rather than devote scarce resources to evaluate transient air levels.

Animals↗
PubMed1990

Analysis of styrene oxide-globin adducts based upon reaction with Raney nickel.

A new method has been developed for determination of styrene oxide-globin adducts. The technique takes advantage of the reaction between alkylated globin and Raney nickel, which cleaves the carbon-sulfur bond in the styrene oxide-cysteine adduct to form 1-phenylethanol (1-PE) and 2-phenylethanol (2-PE). These alcohols are then reacted with pentafluorobenzoyl chloride and analyzed by GC-ECD. The method appears useful for biological monitoring of individuals exposed to styrene and, potentially, to other chemicals or their electrophilic metabolites which can react with cysteine residues in available proteins. The detection limit of the method, which is 0.04 nmol adducts/sample, indicates that it should be possible to detect adducts in the blood of people who are occupationally exposed to at least 18 mg/m3 of styrene. Analysis of globin from human whole blood which had been modified with [14C]styrene oxide indicated that 6% of the total globin adducts were detected. The method was applied to human and rat blood which had been treated with styrene oxide in vitro and to blood from rats given a single i.p. dose of styrene in vivo. Results from these experiments indicate that 77 times more adducts were detected at a given dose from rat globin than from human globin and that only 0.015% of the styrene dose was bioavailable as styrene oxide in the blood of rats. The reaction with Raney nickel is conducted at 5 degrees C to minimize unfavorable side reactions, such as degradation of 1- and 2-PE and conversion of styrene glycol to 1- and 2-PE. The optimal amount of Raney nickel was found to be 5-6 g/g globin. Since the recovery of 1-PE was not reproducible, only 2-PE is used for quantitation.

Animals↗
PubMed1990

Sister chromatid exchanges induced in peripheral lymphocytes of workers exposed to low concentrations of styrene.

This study employed a longitudinal sampling design to obtain measurements of exposure and exhaled air from all members of a cohort several times over the course of one year. Styrene in exhaled air correlated well with styrene in breathing zone air. Both smoking and exposure to styrene appear to have contributed significantly and separately to increased SCEs. Early results imply that SCEs were somewhat more highly correlated with styrene in exhaled air than in breathing zone air.

Adult↗
PubMed1988

Detection of styrene oxide-DNA adducts by 32P-postlabeling.

In vitro reaction of DNA with styrene-7,8-oxide (styrene oxide) produced five adducts, as determined by 32P-postlabeling. When styrene oxide was reacted in vitro with deoxyribonucleotides, five adducts were observed from 2'-deoxyguanosine-3'-monophosphate, two from 2'-deoxyadenosine-3'-monophosphate, none from 2'-deoxythymidine-3-monophosphate or 2'-deoxycytidine-3'-monophosphate. Chromatographic comparison of the adducts formed in DNA with those formed with the deoxyribonucleotides suggests that deoxyguanosine is the primary site of DNA modification. Treatment of 9L cells with 1 mM styrene oxide resulted in the formation of several DNA adducts as detected by the postlabeling procedure. Our results indicate that 32P-postlabeling can be used to investigate DNA adducts formed by styrene oxide.

DNA↗