Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers.

Benzene exposure causes acute myeloid leukemia and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to <10 p.p.m. (20%, P=0.0419 and 28%, P=0.0056, respectively) and ≥ 10 p.p.m. (48%, P=0.0045 and 32%, 0.0354) benzene, compared with controls, and significant exposure-response trends were detected (P(trend)=0.0033 and 0.0057). These data show that monosomies 7 and 8 are produced in a dose-dependent manner in the blood progenitor cells of workers exposed to benzene, and may be mechanistically relevant biomarkers of early effect for benzene and other leukemogens.

Assessing variability and comparing short-term biomarkers of styrene exposure using a repeated measurements approach.

The aim of this work is to compare several short-term biomarkers of styrene exposure, namely urinary styrene (StyU), mercapturic acids (M1+M2), mandelic acid (MA), phenylglyoxylic acid (PGA), phenylglycine (PHG), and 4-vinylphenol conjugates (VP), for use as biomarkers of exposure in epidemiologic studies. A repeated measurements protocol (typically 4 measurements per worker over 6 weeks) was applied to measure airborne styrene (StyA) and urinary biomarkers in 10 varnish and 8 fiberglass reinforced plastic workers. Estimated geometric mean personal exposures to StyA were 2.96mg/m(3) in varnish workers and 15.7mg/m(3) in plastic workers. The corresponding levels of StyU, M1+M2, MA, PGA, MA+PGA, PHG and VP were 5.13microg/L, 0.111, 38.2, 22.7, 62.6, 0.978, and 3.97mg/g creatinine in varnish workers and 8.38microg/L, 0.303, 146, 83.4, 232, 2.85 and 3.97mg/g creatinine in plastic workers. Within-worker (sigma(wY)(2)) and between-worker (sigma(bY)(2)) variance components were estimated from the log-transformed data as were the corresponding fold ranges containing 95% of the respective lognormal distributions of daily levels ((w)R(0.95)) and subject-specific mean levels ((b)R(0.95)). Estimates of (w)R(0.95) (range: 4-26) were generally smaller than those of (b)R(0.95) (range: 5-790) for both environmental and biological markers; this indicates that exposures varied much more between workers than within workers in these groups. Since attenuation bias in an estimated exposure-response relationship increases with the variance ratio lambda=sigma(wY)(2)/sigma(bY)(2), we estimated values of lambda for all exposure measures in our study. Values of lambda were typically much less than one (median=0.220) and ranged from 0.089 for M1+M2 in plastic workers to 1.38 for PHG in varnish workers. Since values of lambda were 0.147 and 0.271 for StyA in varnish workers and plastic workers, respectively, compared to 0.178 and 0.210 for MA in the same groups, our results suggest that either air measurements or conventional biomarker measurements (urinary MA) would be comparable surrogates for individual exposures in epidemiologic studies.

Urinary naphthalene and phenanthrene as biomarkers of occupational exposure to polycyclic aromatic hydrocarbons.

OBJECTIVES: The study investigated the utility of unmetabolised naphthalene (Nap) and phenanthrene (Phe) in urine as surrogates for exposures to mixtures of polycyclic aromatic hydrocarbons (PAHs). METHODS: The report included workers exposed to diesel exhausts (low PAH exposure level, n = 39) as well as those exposed to emissions from asphalt (medium PAH exposure level, n = 26) and coke ovens (high PAH exposure level, n = 28). Levels of Nap and Phe were measured in urine from each subject using head space-solid phase microextraction and gas chromatography-mass spectrometry. Published levels of airborne Nap, Phe and other PAHs in the coke-producing and aluminium industries were also investigated. RESULTS: In post-shift urine, the highest estimated geometric mean concentrations of Nap and Phe were observed in coke-oven workers (Nap: 2490 ng/l; Phe: 975 ng/l), followed by asphalt workers (Nap: 71.5 ng/l; Phe: 54.3 ng/l), and by diesel-exposed workers (Nap: 17.7 ng/l; Phe: 3.60 ng/l). After subtracting logged background levels of Nap and Phe from the logged post-shift levels of these PAHs in urine, the resulting values (referred to as ln(adjNap) and ln(adjPhe), respectively) were significantly correlated in each group of workers (0.71 < or = Pearson r < or = 0.89), suggesting a common exposure source in each case. Surprisingly, multiple linear regression analysis of ln(adjNap) on ln(adjPhe) showed no significant effect of the source of exposure (coke ovens, asphalt and diesel exhaust) and further suggested that the ratio of urinary Nap/Phe (in natural scale) decreased with increasing exposure levels. These results were corroborated with published data for airborne Nap and Phe in the coke-producing and aluminium industries. The published air measurements also indicated that Nap and Phe levels were proportional to the levels of all combined PAHs in those industries. CONCLUSION: Levels of Nap and Phe in urine reflect airborne exposures to these compounds and are promising surrogates for occupational exposures to PAH mixtures.

Model of DNA bending by cooperative binding of proteins.

We present a model of nonspecific cooperative binding of proteins to DNA in which the binding of isolated proteins generates local bends but binding of proteins at neighboring sites on DNA straightens the polymer. We solve the statistical mechanical problem and calculate the effective persistence length, site occupancy, and cooperativity. Cooperativity leads to nonmonotonic variation of the persistence length with protein concentration, and to an unusual shape of the binding isotherm. The results are in qualitative agreement with recent single molecule experiments on nucleoid protein HU-DNA complexes.

An integrated approach to biomonitoring exposure to styrene and styrene-(7,8)-oxide using a repeated measurements sampling design.

The aim of this work was to investigate urinary analytes and haemoglobin and albumin adducts as biomarkers of exposure to airborne styrene (Sty) and styrene-(7,8)-oxide (StyOX) and to evaluate the influence of smoking habit and genetic polymorphism of metabolic enzymes GSTM1 and GSTT1 on these biomarkers. We obtained three or four air and urine samples from each exposed worker (eight reinforced plastics workers and 13 varnish workers), one air and urine samples from 22 control workers (automobile mechanics) and one blood sample from all subjects. Median levels of exposure to Sty and StyOX, respectively, were 18.2 mg m(-3) and 133 microg m(-3) for reinforced plastics workers, 3.4 mg m(-3) and 12 microg m(-3) for varnish workers, and <0.3 mg m(-3) and <5 microg m(-3) for controls. Urinary levels of styrene, mandelic acid, phenylglyoxylic acid, phenylglycine (PHG), 4-vinylphenol (VP) and mercapturic acids (M1+M2), as well as cysteinyl adducts of serum albumin (but not those of haemoglobin) were significantly associated with exposure status (controls

Relationships between levels of volatile organic compounds in air and blood from the general population.

The relationships between levels of volatile organic compounds (VOCs) in blood and air have not been well characterized in the general population where exposure concentrations are generally at parts per billion levels. This study investigates relationships between the levels of nine VOCs, namely, benzene, chloroform, 1,4-dichlorobenzene, ethylbenzene, methyl tert-butyl ether (MTBE), tetrachloroethene, toluene, and m-/p- and o-xylene, in blood and air from a stratified random sample of the general US population. We used data collected from 354 participants, including 89 smokers and 265 nonsmokers, aged 20-59 years, who provided samples of blood and air in the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Demographic and physiological characteristics were obtained from self-reported information; smoking status was determined from levels of serum cotinine. Multiple linear regression models were used to investigate the relationships between VOC levels in air and blood, while adjusting for effects of smoking and demographic factors. Although levels of VOCs in blood were positively correlated with the corresponding air levels, the strength of association (R(2)) varied from 0.02 (ethylbenzene) to 0.68 (1,4-DCB). Also the blood-air relationships of benzene, toluene, ethylbenzene, and the xylenes (BTEX) were influenced by smoking, exposure-smoking interactions, and by gender, age, and BMI, whereas those of the other VOCs were not. Interestingly, the particular exposure-smoking interaction for benzene was different from those for toluene, ethylbenzene, and the xylenes. Whereas smokers retained more benzene in their blood at increasing exposure levels, they retained less toluene, ethylbenzene, and xylenes at increasing exposure levels. Investigators should consider interaction effects of exposure levels and smoking when exploring the blood-air relationships of the BTEX compounds in the general population.

Exposure reconstruction for reducing uncertainty in risk assessment: example using MTBE biomarkers and a simple pharmacokinetic model.

Adverse health risks from environmental agents are generally related to average (long-term) exposures. Because a given individual's contact with a pollutant is highly variable and dependent on activity patterns, local sources and exposure pathways, simple 'snapshot' measurements of surrounding environmental media may not accurately assign the exposure level. Furthermore, susceptibility to adverse effects from contaminants is considered highly variable in the population so that even similar environmental exposure levels may result in differential health outcomes in different individuals. The use of biomarker measurements coupled to knowledge of rates of uptake, metabolism and elimination has been suggested as a remedy for reducing this type of uncertainty. To demonstrate the utility of such an approach, we invoke results from a series of controlled human exposure tests and classical first-order rate kinetic calculations to estimate how well spot measurements of methyl tertiary butyl ether and the primary metabolite, tertiary butyl alcohol, can be expected to predict different hypothetical scenarios of previous exposures. We found that blood and breath biomarker measurements give similar results and that the biological damping effect of the metabolite production gives more stable estimates of previous exposure. We also explore the value of a potential urinary biomarker, 2-hydroxyisobutyrate suggested in the literature. We find that individual biomarker measurements are a valuable tool in reconstruction of previous exposures and that a simple pharmacokinetic model can identify the time frames over which an exogenous chemical and the related chemical biomarker are useful. These techniques could be applied to broader ranges of environmental contaminants to assess cumulative exposure risks if ADME (Absorption, Distribution, Metabolization and Excretion) is understood and systemic biomarkers can be measured.

Predictors of occupational exposure to styrene and styrene-7,8-oxide in the reinforced plastics industry.

OBJECTIVE: To identify demographic and work related factors that predict blood levels of styrene and styrene-7,8-oxide (SO) in the fibreglass reinforced plastics (FRP) industry. METHODS: Personal breathing-zone air samples and whole blood samples were collected repeatedly from 328 reinforced plastics workers in the Unuted States between 1996 and 1999. Styrene and its major metabolite SO were measured in these samples. Multivariable linear regression analyses were applied to the subject-specific levels to explain the variation in exposure and biomarker levels. RESULTS: Exposure levels of styrene were approximately 500-fold higher than those of SO. Exposure levels of styrene and SO varied greatly among the types of products manufactured, with an 11-fold range of median air levels among categories for styrene and a 23-fold range for SO. Even after stratification by job title, median exposures of styrene and SO among laminators varied 14- and 31-fold across product categories. Furthermore, the relative proportions of exposures to styrene and SO varied among product categories. Multivariable regression analyses explained 70% and 63% of the variation in air levels of styrene and SO, respectively, and 72% and 34% of the variation in blood levels of styrene and SO, respectively. Overall, air levels of styrene and SO appear to have decreased substantially in this industry over the last 10-20 years in the US and were greatest among workers with the least seniority. CONCLUSIONS: As levels of styrene and SO in air and blood varied among product categories in the FRP industry, use of job title as a surrogate for exposure can introduce unpredictable measurement errors and can confound the relation between exposure and health outcomes in epidemiology studies. Also, inverse relations between the intensity of exposure to styrene and SO and years on the job suggest that younger workers with little seniority are typically exposed to higher levels of styrene and SO than their coworkers.

Variability of albumin adducts of 1,4-benzoquinone, a toxic metabolite of benzene, in human volunteers.

A putative haematotoxic and leukaemogenic metabolite of benzene, 1,4-benzoquinone (1,4-BQ), reacts rapidly with macromolecules. The authors previously characterized levels of the albumin (Alb) adduct (1,4-BQ-Alb) of this reactive species in populations of workers exposed to benzene. Since high levels of 1,4-BQ-Alb were also measured in unexposed workers from those investigations, the current study was initiated to determine potential sources of 1,4-BQ in the general population. A single blood sample was collected from 191 healthy subjects from the Research Triangle area, NC, USA, to determine the baseline 1,4-BQ-Alb levels and contributing sources. The median 1,4-BQ-Alb at baseline was 550?pmol?g(-1) Alb (interquartile range 435-814?pmol?g(-1)). A second blood sample was collected approximately 3 months later from a subgroup of 33 subjects to estimate the within- and between-person variation in 1,4-BQ-Alb. Standardized questionnaires were administered to collect information about demographic, dietary and lifestyle factors. Multiple linear regression models identified several significant contributors to 1,4-BQ-Alb levels, including gender, body mass index (BMI), the gender-BMI interaction, automobile refuelling, smoking status, and consumption of fruit and the artificial sweetener, aspartame. The authors predicted that these background levels of 1,4-BQ-Alb were equivalent to occupational exposures between 1 and 3 parts per million of benzene. Mixed effects linear models indicated that the random variation in adduct levels was about equally divided between and within subjects. The observations indicate that levels of 1,4-BQ-Alb cover a wide range in the general population, and they support the hypotheses that demographic, diet and lifestyle factors are contributing sources.

Air samples versus biomarkers for epidemiology.

BACKGROUND: It has been speculated on theoretical grounds that biomarkers are superior surrogates for chemical exposures to air samples in epidemiology studies. METHODS AND RESULTS: Biomarkers were classified according to their position in the exposure-disease continuum-that is, parent compound, reactive intermediate, stable metabolite, macromolecular adduct, or measure of cellular damage. Because airborne exposures and these different biomarkers are time series that vary within and between persons in a population, they are all prone to measurement error effects when used as surrogates for true chemical exposures. It was shown that the attenuation bias in the estimated slope characterising a log exposure-log disease relation should decrease as the within- to between-person variance ratio of a given set of air or biomarker measurements decreases. To gauge the magnitudes of these variance ratios, a database of 12,077 repeated observations was constructed from 127 datasets, including air and biological measurements from either occupational or environmental settings. The within- and between-person variance components (in log scale, after controlling for fixed effects of time) and the corresponding variance ratios for each set of air and biomarker measurements were estimated. It was shown that estimated variance ratios of biomarkers decreased in the order short term (residence time < or =2 days) > intermediate term (2 days < residence time < or =2 months) > long term biomarkers (residence time >2 months). Overall, biomarkers had smaller variance ratios than air measurements, particularly in environmental settings. This suggests that a typical biomarker would provide a less biasing surrogate for exposure than would a typical air measurement. CONCLUSION: Epidemiologists are encouraged to consider the magnitudes of variance ratios, along with other factors related to practicality and cost, in choosing among candidate surrogate measures of exposure.

On the importance of exposure variability to the doses of volatile organic compounds.

The connection between occupational exposure to volatile organic compounds (VOCs) and the resulting internal doses is complicated by variability in air levels from day to day and by nonlinear kinetics of metabolism. We investigated long-term liver doses of VOCs and their metabolites using a physiologically based toxicokinetic model, to which 10,000 random 8-h exposures were inputted. Three carcinogenic VOCs were studied (i.e., benzene, perchloroethylene, and acrylonitrile); these compounds are all bioactivated in the liver and represent a wide range of an important toxicokinetic parameter Vmax/QL x KM. For each VOC, simulations were performed using mean air concentrations (muX) between 0.0003 and 1 mg/l (which covers both linear and saturated metabolism) and using coefficients of variation of exposure (CVX) between 0.23 and 2.18 (which includes most occupational settings). Two long-term measures of internal dose were examined, i.e., the area under the liver concentration-time curve (AUCL) and the area under the metabolic rate-time curve (AURC). Interestingly, both AUCL and AURC were linear functions of cumulative exposure (CE, mg x h/l air) even when metabolism was saturated and CVX was large. Yet, at a given CE, both AUCL and AURC were affected by CVX, with the magnitude of the effect increasing with Vmax/QL x KM (i.e., perchloroethylene < benzene < acrylonitrile). Nonetheless, the effects of CVX were typically only a few percent and should be of little consequence unless a VOC has large values of Vmax/QL x KM, muX,and CVX. We conclude that CE should be a sufficient predictor of the dose of either the parent chemical (VOC) or its metabolite in the liver, even when metabolism is nonlinear. We also observed that AUCL and AURC were sensitive to changes in values of model parameters in the high-variability scenarios, suggesting that (when CVX is large) the population variability of AUCL and AURC can be quite large at a fixed CE.

Benzene and naphthalene in air and breath as indicators of exposure to jet fuel.

AIMS: To estimate exposures to benzene and naphthalene among military personnel working with jet fuel (JP-8) and to determine whether naphthalene might serve as a surrogate for JP-8 in studies of health effects. METHODS: Benzene and naphthalene were measured in air and breath of 326 personnel in the US Air Force, who had been assigned a priori into low, moderate, and high exposure categories for JP-8. RESULTS: Median air concentrations for persons in the low, moderate, and high exposure categories were 3.1, 7.4, and 252 microg benzene/m3 air, 4.6, 9.0, and 11.4 microg benzene/m3 breath, 1.9, 10.3, and 485 microg naphthalene/m3 air, and 0.73, 0.93, and 1.83 microg naphthalene/m3 breath, respectively. In the moderate and high exposure categories, 5% and 15% of the benzene air concentrations, respectively, were above the 2002 threshold limit value (TLV) of 1.6 mg/m3. Multiple regression analyses of air and breath levels revealed prominent background sources of benzene exposure, including cigarette smoke. However, naphthalene exposure was not unduly influenced by sources other than JP-8. Among heavily exposed workers, dermal contact with JP-8 contributed to air and breath concentrations along with several physical and environmental factors. CONCLUSIONS: Personnel having regular contact with JP-8 are occasionally exposed to benzene at levels above the current TLV. Among heavily exposed workers, uptake of JP-8 components occurs via both inhalation and dermal contact. Naphthalene in air and breath can serve as useful measures of exposure to JP-8 and uptake of fuel components in the body.

Commentary: two seminal contributions of S. A. Roach to the evaluation and control of hazardous substances in air.

S. A. Roach was a pioneer in the assessment and control of hazardous substances in the working environment during the second half of the 20th century. The two papers discussed in this commentary are generally regarded as his most important scientific contributions. The first paper (Roach, 1977) dealt with the determinants of the body burdens of toxic air contaminants. Using simple kinetic models, he showed how levels of toxicants rise and fall in the body according to the patterns of airborne exposures received during relevant time windows. This led to several useful rules of thumb, including the timing of grab samples for 'fast acting' substances, the appropriate duration of air samples relative to the biological half time, how to deal with unusual work schedules, and how to integrate exposure assessment with control. He also offered sage advice regarding the meaning and interpretation of exposure limits, the importance of repeated monitoring, and the extent to which unacceptable levels of exposure might be reduced. In concluding this work, Roach emphasized that the hygienist can fulfill a central role in occupational health simply by intervening to reduce the body burden. The second paper (Roach, 1981) dealt with the design of effective ventilation systems to control worker exposure to toxic airborne contaminants. By developing a series of simple differential equations, Roach evaluated the impact of turbulent diffusion upon industrial ventilation. He emphasized that the stationary contaminant concentration was proportional to the contaminant generation rate and that velocity alone was not a sufficient design criterion to control exposures. Rather, he argued that the equivalent ventilation rate (the ratio of the contaminant generation rate to the steady concentration in the breathing zone) should be the guiding criterion for ventilation design. Throughout both papers, Roach used fundamental principles to tie together exposure assessment and engineering control, and pointed the way to a science for occupational hygiene. The profession can still learn a great deal from these seminal contributions.

Excessive exposure to silica in the US construction industry.

Exposures to respirable dust and silica were investigated among 36 construction sites in the USA. Personal measurements (n = 151) were analyzed from 80 workers in four trades, namely bricklayers, painters (while abrasive blasting), operating engineers and laborers. Painters had the highest exposures (median values for respirable dust and silica: 13.5 and 1.28 mg/m(3), respectively), followed by laborers (2.46 and 0.350 mg/m(3)), bricklayers (2.13 and 3.20 mg/m(3)) and operating engineers (0.720 and 0.075 mg/m(3)). Mixed models were fitted to the log-transformed air levels to estimate the means and within- and between-worker variance components of the distributions in each trade. We refer to the likelihood that a typical worker from a given trade would be exposed, on average, above the occupational exposure limit (OEL) as the probability of overexposure. Given US OELs of 0.05 mg/m(3) for respirable silica and 3 mg/m(3) for respirable dust, we estimated probabilities of overexposure as between 64.5 and 100% for silica and between 8.2 and 89.2% for dust; in no instance could it be inferred with certainty that this probability was <10%. This indicates that silica exposures are grossly unacceptable in the US construction industry. While engineering and administrative interventions are needed to reduce overall air levels, the heterogeneous exposures among members of each trade suggest that controls should focus, in part, upon the individual sites, activities and equipment involved. The effects of current controls and workplace characteristics upon silica exposures were investigated among operating engineers and laborers. Silica exposures were significantly reduced by wet dust suppression (approximately 3-fold for laborers) and use of ventilated cabs (approximately 6-fold for operating engineers) and were significantly increased indoors (about 4-fold for laborers). It is concluded that urgent action is required to reduce silica exposures in the US construction industry.

Physiological modeling of the relative contributions of styrene-7,8-oxide derived from direct inhalation and from styrene metabolism to the systemic dose in humans.

Workers in the reinforced plastics industry are exposed to large quantities of styrene and to small amounts of the carcinogen, styrene-7,8-oxide (SO), in air. Since SO is also the primary metabolite of styrene, we modified a published physiologically based pharmacokinetic (PBPK) model to investigate the relative contributions of inhaled SO and metabolically derived SO to the systemic levels of SO in humans. The model was tested against air and blood measurements of styrene and SO from 252 reinforced plastics workers. Results suggest that the highly efficient first-pass hydrolysis of SO via epoxide hydrolase in the liver greatly reduces the systemic availability of SO formed in situ from styrene. In contrast, airborne SO, absorbed via inhalation, is distributed to the systemic circulation, thereby avoiding such privileged-access metabolism. The best fit to the model was obtained when the relative systemic availability (the ratio of metabolic SO to absorbed SO per unit exposure) equaled 2.75 x 10(-4), indicating that absorbed SO contributed 3640 times more SO to the blood than an equivalent amount of inhaled styrene. Since the ratio of airborne styrene to SO rarely exceeds 1500 in the reinforced plastics industry, this indicates that inhalation of SO presents a greater hazard of cytogenetic damage than inhalation of styrene. We conclude that future studies should assess exposures to airborne SO as well as styrene.

Comparison of self-assessment and expert assessment of occupational exposure to chemicals.

OBJECTIVES: Occupational assessments of chemical exposure are often inadequate because of difficulties in obtaining sufficient numbers of measurements by trained professionals (experts). The objective of this study was to determine whether workers can provide unbiased data via self-assessments of exposure facilitated by the use of simple passive monitors for personal sampling. METHODS: Untrained workers obtained personal measurements of their exposures to gaseous contaminants (terpenes in sawmills and styrene in reinforced plastics factories) with passive monitors and written instructions. To study the validity of the self-assessments, an occupational hygienist performed exposure measurements on the same occupational groups after the workers had obtained two or more measurements independently. The potential bias of the self-assessments was evaluated by comparing the self-assessments with the expert assessments in mixed-effects statistical models. RESULTS: A total of 153 terpene (97 self and 56 expert) and 216 styrene (159 self and 57 expert) measurements were obtained from four sawmills and six reinforced plastics factories, respectively. No significant differences in the geometric mean exposures were observed between the self-assessments and the expert assessments in 3 of 4 sawmills and 5 of 6 reinforced plastics factories (P > 0.10). The potential bias of the self-assessments of exposure ranged from less than 0.1% to 102% and was less than 17% in 9 of the 10 groups investigated. CONCLUSIONS: The results indicate that untrained, unsupervised workers are able to collect consistently unbiased exposure data by employing currently available passive monitors.

Simultaneous assessment of occupational exposures from multiple worker groups.

The methods developed by Rappaport et al. [Ann. Occup. Hyg. 39 (1995) 469] and Lyles et al. [J. Agri. Bio. Environ. Stat. 2 (1997a) 64; Ann. Occup. Hyg. 41 (1997b) 63]) for assessing workplace exposures on a group-by-group basis are extended to allow for the simultaneous assessment of data from multiple worker groups within the same industry. These extended methods allow models to be fit simultaneously to data on all groups in a study, even when some of the groups might not contribute adequate information to be modeled separately. We assume that the exposures are log-normally distributed, and that they can be adequately modeled by a mixed effects regression model with parameters for exposure levels and for between- and within-worker variance components. Simultaneously analyzing data from multiple groups is only advantageous when at least one of these variance components can be assumed to be homogeneous across the groups. Here, we advocate testing an assumption of homogeneous within-worker variance components, sigma(2)(w,h), using a likelihood ratio test to choose between a full model (distinct sigma(2)(w,h) for each group) and a reduced model (common sigma(2)(w) across groups). We then develop a procedure, which is conditional on the results of the likelihood ratio test, for testing whether or not each group of workers is overexposed to the contaminant of interest. This modeling and testing procedure was applied to 39 different data sets, each containing data for multiple groups, from a wide variety of industries. For these data, the testing procedure generally resulted in the same conclusion regarding overexposure under both models, even in those data sets where the within-worker variance components appeared to be quite heterogeneous. We also conducted a small simulation study to estimate the significance level of the proposed testing procedure, and found that the significance levels tended to be adequately close to the specified nominal level when a likelihood ratio test with significance level of at least 0.01 was used as a preliminary test. Additionally, we make specific recommendations for designing studies and suggest a method for determining whether engineering and administrative controls or individual-level interventions would be of most benefit to an overexposed group of workers.

A mixture model for occupational exposure mean testing with a limit of detection.

Information from detectable exposure measurements randomly sampled from a left-truncated log-normal distribution may be used to evaluate the distribution of nondetectable values that fall below an analytic limit of detection. If the proportion of nondetects is larger than expected under log normality, alternative models to account for these unobserved data should be considered. We discuss one such model that incorporates a mixture of true zero exposures and a log-normal distribution with possible left censoring, previously considered in a different context by Moulton and Halsey (1995, Biometrics 51, 1570-1578). A particular relationship is demonstrated between maximum likelihood parameter estimates based on this mixture model and those assuming either left-truncated or left-censored data. These results emphasize the need for caution when choosing a model to fit data involving nondetectable values. A one-sided likelihood ratio test for comparing mean exposure under the mixture model to an occupational exposure limit is then developed and evaluated via simulations. An example demonstrates the potential impact of specifying an incorrect model for the nondetectable values.