Stephen M. Rappaport

Hematotoxicity in Workers Exposed to Low Levels of Benzene

Benzene is known to have toxic effects on the blood and bone marrow, but its impact at levels below the U.S. occupational standard of 1 part per million (ppm) remains uncertain. In a study of 250 workers exposed to benzene, white blood cell and platelet counts were significantly lower than in 140 controls, even for exposure below 1 ppm in air. Progenitor cell colony formation significantly declined with increasing benzene exposure and was more sensitive to the effects of benzene than was the number of mature blood cells. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, influenced susceptibility to benzene hematotoxicity. Thus, hematotoxicity from exposure to benzene occurred at air levels of 1 ppm or less and may be particularly evident among genetically susceptible subpopulations.

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.

Application of mixed models to assess exposures monitored by construction workers during hot processes

Particulate exposures were assessed among construction workers engaged in hot processes in four jobs (boilermakers, ironworkers, pipefitters and welder-fitters) at nine sites in the U.S. After being trained by occupational hygienists, the workers obtained shift-long personal samples at each site for total particulates (TP). Selected samples were also assayed for manganese (Mn), nickel (Ni), and chromium (Cr). Workers provided information about process- and task-related covariates that were present on the days of monitoring. Data were investigated with mixed-model regression analyses that designated the jobs and covariates as fixed effects and the worker and error terms as random effects. Results indicated that the within-worker variance components, but not the between-worker variance components, could be pooled among jobs. Mean air levels for a given agent varied by roughly six to 100 fold among the jobs, with boilermakers and ironworkers experiencing much higher levels of TP and Mn than pipefitters and welder-fitters. Limited data also suggested that welder-fitters were exposed to greater levels of Ni and Cr than pipefitters. Sufficient sample sizes were available to evaluate the effects of covariates upon exposures to TP and Mn. As expected, processes involving more than 50% hot work led to substantially higher levels of TP and Mn than those involving shorter durations of hot work. Local-exhaust or mechanical ventilation reduced exposure to TP (but not Mn) by as much as 44%, and shielded or manual arc welding increased exposure to Mn (but not TP) by about 80%. Parameters estimated with these mixed models were used to calculate probabilities that workers were exposed at levels above U.S. occupational exposure limits (OELs). Regarding TP and Mn, these calculations suggested that 26-95% of exposures to boilermakers and pipefitters and 2-13% of exposures to pipefitters and welder-fitters exceeded the current Threshold Limit Values. Among welder-fitters, limited data also pointed to probabilities of 2-50% for exceeding particular OELs for Ni and Cr. Using the significance of the estimated random-worker effects as a gauge for the uniformity of exposure within a job, administrative or engineering changes appear appropriate for reducing exposures to boilermakers and ironworkers, while individual personal environments should be investigated for pipefitters and welder-fitters.

Simultaneous determination of urinary 1- and 2-naphthols, 3- and 9-phenanthrols, and 1-pyrenol in coke oven workers

A method was developed for simultaneous quantification of urinary 1- and 2-naphthols, 3- and 9-phenanthrols and 1-pyrenol using gas chromatography with mass spectrometry (GC-MS). This method was applied to urine samples from coke oven workers (n =28) and controls (n =22) from Northern China. Geometric mean levels of urinary 1-naphthol (58.8 μg l−1), 2-naphthol (34.1 μg l−1), 3-phenanthrol (7.35 μg l−1), 9-phenanthrol (1.28 μg l−1) and 1-pyrenol (25.4 μg l−1) were significantly higher among coke oven workers than controls. All the substances tested were highest among top-of-oven workers, who had 15-fold higher 1-naphthol, eight-fold higher 2-naphthol and 20-fold higher 1-pyrenol levels compared with controls. Using multiple linear regression models, 72.5% of the variation in 1- and 2-naphthol and 82.8% of the variation in 1-pyrenol were explained by the concentration of naphthalene or pyrene in the urine, the work category and the smoking intensity. Cigarette consumption significantly contributed to levels of urinary 1-pyrenol and naphthols, particularly 2-naphthol. A negative relationship between work category and the ratio of naphthols/1-pyrenol was observed among smokers. Our results suggest that urinary naphthols and phenanthrols reflect polycyclic aromatic hydrocarbon (PAH) exposure as well as the widely used 1-pyrenol, and that interactions between cigarette smoking and PAH exposure result in different patterns of metabolism for individual PAHs.

A COMPREHENSIVE EVALUATION OF THE POTENTIAL HEALTH RISKS ASSOCIATED WITH OCCUPATIONAL AND ENVIRONMENTAL EXPOSURE TO STYRENE

HEALTH RISKS ASSOCIATED WITH OCCUPATIONAL AND ENVIRONMENTAL EXPOSURE TO STYRENE Joshua T. Cohen Harvard Center for Risk Analysis, Harvard School of Public Health, Boston, Massachusetts, USA Gary Carlson School of Health Sciences, Purdue University, West Lafayette, Indiana, USA Gail Charnley Health Risk Strategies, Washington, DC, USA David Coggon MRC Environmental Epidemiology Unit, University of Southampton, Southampton, United Kingdom Elizabeth Delzell Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama John D. Graham Harvard Center for Risk Analysis, Harvard School of Public Health, Boston, Massachusetts, USA Helmut Greim GSF-Institute of Toxicology, Neuerberg, Germany

Comprehensive evaluation of long-term trends in occupational exposure: Part 1. Description of the database.

OBJECTIVES: To conduct a comprehensive evaluation of long term changes in occupational exposure among a broad cross section of industries worldwide. METHODS: A review of the scientific literature identified studies that reported historical changes in exposure. About 700 sets of data from 119 published and several unpublished sources were compiled. Data were published over a 30 year period in 25 journals that spanned a range of disciplines. For each data set, the average exposure level was compiled for each period and details on the contaminant, the industry and location, changes in the threshold limit value (TLV), as well as the type of sampling method were recorded. Spearman rank correlation coefficients were used to identify monotonic changes in exposure over time and simple linear regression analyses were used to characterise trends in exposure. RESULTS: About 78% of the natural log transformed data showed linear trends towards lower exposure levels whereas 22% indicated increasing trends. (The Spearman rank correlation analyses produced a similar breakdown between exposures monotonically increasing or decreasing over time.) Although the rates of reduction for the data showing downward trends ranged from -1% to -62% per year, most exposures declined at rates between -4% and -14% per year (the interquartile range), with a median value of -8% per year. Exposures seemed to increase at rates that were slightly lower than those of exposures which have declined over time. Data sets that showed downward (versus upward) trends were influenced by several factors including type and carcinogenicity of the contaminant, type of monitoring, historical changes in the threshold limit values (TLVs), and period of sampling. CONCLUSIONS: This review supports the notion that occupational exposures are generally lower today than they were years or decades ago. However, such trends seem to have been affected by factors related to the contaminant, as well as to the period and type of sampling.

Determination of polycyclic aromatic hydrocarbons in urine of coke oven workers by headspace solid phase microextraction and gas chromatography–mass spectrometry

Polycyclic aromatic hydrocarbons (PAHs) represent a complex mixture of toxic compounds that are ubiquitous in the environment. We investigated the utility of head space-solid phase microextraction (HS-SPME) to measure the following surrogate PAHs in urine: naphthalene (NAP), phenanthrene (PHE), pyrene (PYR), and benzo(a)pyrene (BAP), representing classes of 2-, 3-, 4- and 5-ring compounds, respectively. We then applied the method to urine from 28 coke oven workers (median levels (microg/l) were: NAP=3.65, PHE=1.51, PYR=0.003, BAP not detected) and 22 controls (median (microg/l) NAP=0.859, PHE=0.062, PYR=0.001, BAP not detected). Urinary levels of NAP, PHE, and PYR were all associated with exposure category (controls, side- and bottom-workers, and top-workers) but not with smoking status. Strong correlations were observed between urinary levels of NAP, PHE, and PYR in coke-oven workers. Our results indicate that unmetabolized 2-, 3- and 4-ring PAHs can be measured in urine by HS-SPME. Such measurements can be used to investigate the uptake and metabolism of complex PAH mixtures in humans.

A lognormal distribution-based exposure assessment method for unbalanced data

We present a generalization of existing statistical methodology for assessing occupational exposures while explicitly accounting for between- and within-worker sources of variability. The approach relies upon an intuitively reasonable model for shift-long exposures, and requires repeated exposure measurements on at least some members of a random sample of workers from a job group. We make the methodology more readily applicable by providing the necessary details for its use when the exposure data are unbalanced (that is, when there are varying numbers of measurements per worker). The hypothesis testing strategy focuses on the probability that an arbitrary worker in a job group experiences a long-term mean exposure above the occupational exposure limit (OEL). We also provide a statistical approach to aid in the determination of an appropriate intervention strategy in the event that exposure levels are deemed unacceptable for a group of workers. We discuss important practical considerations associated with the methodology, and we provide several examples using unbalanced sets of shift-long exposure data-taken on workers in various sectors of the nickel-producing industry. We conclude that the statistical methods discussed afford sizable practical advantages, while maintaining similar overall performance to that of existing methods appropriate for balanced data only.

Comprehensive evaluation of long-term trends in occupational exposure: Part 2. Predictive models for declining exposures

OBJECTIVES: To explore the effects of various factors related to the industry, the contaminant, and the period and type of sampling on long term declining trends in occupational exposure. METHODS: Linear regression analyses were used to assess the relation between reductions in exposure and geographical location, industrial sector, type of contaminant, type of monitoring, carcinogenic classification, calendar period, duration of sampling, and number of reductions in the threshold limit value during the sampling period. Both univariable and multivariable models were applied. RESULTS: Based on univariable analyses, the findings suggest that exposures declined more rapidly in manufacturing than in mining, more rapidly for aerosol contaminants than for vapours, and more rapidly when biological, rather than airborne, monitoring was conducted. Exposures collected more recently (first year of sampling in 1972 or later) fell more rapidly than exposures first evaluated during earlier periods. Irrespective of when the data were collected, the results also suggest that the longer the duration of sampling the slower the rate of decline. Taken together, we found that characteristics related to the contaminant, the industry, the sampling period, and the type of sampling explained a substantial proportion of the variability for exposures evaluated before 1972 (R2 = 0.78) and for sites evaluated both before and after 1972 (R2 = 0.91), but explained essentially no variation for data gathered exclusively after 1972 (R2 = 0.04). CONCLUSIONS: By identifying factors that have affected the rates of reduction in a consistent fashion, the results should guide investigators in estimating historical levels when studies assessing exposure-response relations are carried out.

Measurement of hemoglobin and albumin adducts of naphthalene-1,2-oxide, 1,2-naphthoquinone and 1,4-naphthoquinone after administration of naphthalene to F344 rats

Naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) are the major metabolites of naphthalene that are thought to be responsible for the cytotoxicity and genotoxicity of this chemical. We measured cysteinyl adducts of these metabolites in hemoglobin (Hb) and albumin (Alb) from F344 rats dosed with 100-800 mg naphthalene per kg body weight. The method employs cleavage and derivatization of these adducts by trifluoroacetic anhydride and methanesulfonic acid followed by gas chromatography-mass spectrometry in negative ion chemical ionization mode. Cysteinyl adducts of both proteins with NPO, and 1,2- and 1,4-NPQ (designated NPO-Hb and -Alb, 1,2-NPQ-Hb and -Alb, and 1,4-NPQ-Hb and -Alb, respectively) were produced in a dose-dependent manner. Of the two structural isomers resulting from NPO, levels of NPO1 adducts were greater than those of NPO2 adducts in both Hb and Alb, indicating that aromatic substitution is favored in vivo at positions 1 over 2. Of the quinone adducts, 1,2-NPQ-Hb and -Alb were produced in greater quantities than 1,4-NPQ-Hb and -Alb, indicating either that the formation of 1,2-NPQ from NPO is favored or that more than one pathway leads to the formation of 1,2-NPQ. The shapes of the dose-response curves were generally nonlinear at doses above 200 mg naphthalene per kg body weight. However, the nature of nonlinearity differed, showing evidence of supralinearity for NPO-Hb, NPQ-Hb and NPQ-Alb and of sublinearity for NPO-Alb. Low background levels of 1,2-NPQ-Hb and -Alb and 1,4-NPQ-Hb and -Alb were detected in control animals without known exposure to naphthalene. However, the corresponding NPO-Hb and -Alb adducts were not detected in control animals.